CN118525017A - Quinoline compounds as KRAS inhibitors - Google Patents

Abstract

Disclosed herein are compounds of formula I, methods of using the compounds to inhibit KRAS activity, and pharmaceutical compositions comprising such compounds. The compounds are useful for treating, preventing or ameliorating diseases or disorders associated with KRAS activity, such as cancer.

Description

Translated fromChinese

作为KRAS抑制剂的喹啉化合物Quinoline compounds as KRAS inhibitors

相关申请Related Applications

本申请要求于2021年10月14日申请的美国临时申请第63/255,610号、2021年11月15日申请的美国临时申请第63/279,464号、2022年4月20日申请的美国临时申请第63/363,270号和2022年7月15日申请的美国临时申请第63/368,563号的优先权，所述申请的全部内容特此以全文引用的方式并入。This application claims priority to U.S. Provisional Application No. 63/255,610 filed on October 14, 2021, U.S. Provisional Application No. 63/279,464 filed on November 15, 2021, U.S. Provisional Application No. 63/363,270 filed on April 20, 2022, and U.S. Provisional Application No. 63/368,563 filed on July 15, 2022, the entire contents of which are hereby incorporated by reference in their entirety.

技术领域Technical Field

本公开提供化合物以及其组合物和使用方法。所述化合物调节KRAS活性并且可用于治疗各种疾病，包括癌症。The present disclosure provides compounds, compositions and methods of use thereof. The compounds modulate KRAS activity and can be used to treat various diseases, including cancer.

背景技术Background Art

Ras蛋白质是通过生长因子和各种细胞外刺激活化的小GTP酶家族的一部分。Ras家族调节负责细胞生长、迁移、存活和分化的细胞内信号传导路径。RAS蛋白质在细胞膜处的活化引起关键效应子的结合以及在细胞内起始包括RAF和PI3K激酶路径的细胞内信号传导路径的级联。RAS中的体细胞突变可能导致不可控的细胞生长和恶性转化，而RAS蛋白质的活化在正常细胞中受到严格调节(Simanshu,D.等人，Cell 170.1(2017):17-33)。Ras protein is part of a family of small GTPases activated by growth factors and various extracellular stimuli. The Ras family regulates the intracellular signal transduction pathways responsible for cell growth, migration, survival and differentiation. The activation of RAS protein at the cell membrane causes the binding of key effectors and initiates a cascade of intracellular signal transduction pathways including RAF and PI3K kinase pathways in the cell. Somatic mutations in RAS may lead to uncontrollable cell growth and malignant transformation, while the activation of RAS protein is strictly regulated in normal cells (Simanshu, D. et al., Cell 170.1 (2017): 17-33).

Ras家族由三个成员构成：KRAS、NRAS和HRAS。RAS突变型癌症占人类癌症的约25％。KRAS为最常突变的同工型，占所有RAS突变的85％，而NRAS和HRAS被发现分别在所有Ras突变型癌症的12％和3％中突变(Simanshu,D.等人Cell 170.1(2017):17-33)。KRAS突变在前三种最致命的癌症类型中普遍存在：胰腺癌(97％)、结肠直肠癌(44％)和肺癌(30％)(Cox,A.D.等人，Nat Rev Drug Discov(2014)13:828-51)。大部分RAS突变出现在氨基酸残基12、13和61处。特异性突变的频率在RAS基因同工型之间变化，并且虽然G12和Q61突变分别在KRAS和NRAS中占主导，但G12、G13和Q61突变在HRAS中仍最常见。此外，RAS同工型中的突变谱在癌症类型之间有所不同。例如，KRAS G12D突变在胰腺癌(51％)中占主导，其次是结肠直肠腺癌(45％)和肺癌(17％)，而KRAS G12V突变与胰腺癌(30％)相关，其次是结肠直肠腺癌(27％)和肺腺癌(23％)(Cox,A.D.等人Nat Rev Drug Discov(2014)13:828-51)。相比之下，KRAS G12C突变主要存在于非小细胞肺癌(NSCLC)中，所述非小细胞肺癌包含11％至16％的肺腺癌和2％至5％的胰腺癌和结肠直肠腺癌(Cox,A.D.等人，Nat.Rev.Drug Discov.(2014)13:828-51)。跨数百个癌细胞系的基因组研究已证明，含有KRAS突变的癌细胞高度依赖于用于细胞生长和存活的KRAS功能(McDonald,R等人Cell 170(2017):577-592)。突变KRAS作为致癌驱动因子的作用进一步由广泛体内实验证据支持，所述实验证据表明突变KRAS为早期肿瘤发作和动物模型维持所需(Cox,A.D.等人，Nat RevDrug Discov(2014)13:828-51)。The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS mutant cancers account for about 25% of human cancers. KRAS is the most commonly mutated isoform, accounting for 85% of all RAS mutations, while NRAS and HRAS are found to be mutated in 12% and 3% of all Ras mutant cancers, respectively (Simanshu, D. et al. Cell 170.1 (2017): 17-33). KRAS mutations are prevalent in the top three most lethal cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (Cox, A.D. et al., Nat Rev Drug Discov (2014) 13: 828-51). Most RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations varies between RAS gene isoforms, and although G12 and Q61 mutations are dominant in KRAS and NRAS, respectively, G12, G13, and Q61 mutations are still most common in HRAS. In addition, the mutation spectrum in RAS isoforms varies between cancer types. For example, KRAS G12D mutations are dominant in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%), while KRAS G12V mutations are associated with pancreatic cancer (30%), followed by colorectal adenocarcinoma (27%) and lung adenocarcinoma (23%) (Cox, A.D. et al. Nat Rev Drug Discov (2014) 13: 828-51). In contrast, KRAS G12C mutations are predominantly found in non-small cell lung cancer (NSCLC), which comprises 11% to 16% of lung adenocarcinomas and 2% to 5% of pancreatic and colorectal adenocarcinomas (Cox, A.D. et al., Nat. Rev. Drug Discov. (2014) 13: 828-51). Genomic studies across hundreds of cancer cell lines have demonstrated that cancer cells containing KRAS mutations are highly dependent on KRAS function for cell growth and survival (McDonald, R et al. Cell 170 (2017): 577-592). The role of mutant KRAS as an oncogenic driver is further supported by extensive in vivo experimental evidence that mutant KRAS is required for early tumor onset and maintenance in animal models (Cox, A.D. et al., Nat Rev Drug Discov (2014) 13: 828-51).

综合来说，这些研究结果表明KRAS突变在人类癌症中起关键作用；靶向突变KRAS的抑制剂的开发因此可适用于临床治疗特征在于KRAS突变的疾病。Taken together, these findings suggest that KRAS mutations play a critical role in human cancer; the development of inhibitors targeting mutant KRAS may therefore be applicable to the clinical treatment of diseases characterized by KRAS mutations.

发明内容Summary of the invention

本公开尤其提供式I化合物：The present disclosure provides, inter alia, compounds of formula I:

或其药学上可接受的盐，其中构成变量在本文中进行定义。or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

本公开进一步提供一种药物组合物，其包含本公开的化合物，或其药学上可接受的盐，和至少一种药学上可接受的载剂或赋形剂。The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

本公开进一步提供抑制KRAS活性的方法，其包括向个体施用本公开的化合物或其药学上可接受的盐。本公开还提供本文所描述的化合物的用途，其是用以制造用于疗法的药剂。本公开还提供用于疗法中的本文所描述的化合物。The present disclosure further provides a method of inhibiting KRAS activity, comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to an individual. The present disclosure also provides the use of the compound described herein, which is used to manufacture a medicament for therapy. The present disclosure also provides a compound described herein for use in therapy.

本公开进一步提供治疗患者的疾病或病症的方法，其包括向所述患者施用治疗有效量的本公开化合物或其药学上可接受的盐。The present disclosure further provides methods of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

具体实施方式DETAILED DESCRIPTION

化合物Compound

在一方面中，本文提供一种具有式(I)的化合物：In one aspect, provided herein is a compound having formula (I):

或其药学上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein:

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至9元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至9元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 9-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5-membered to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 and C(O)NR^c6 R^d6 ; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 9-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene are each optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;

其限制条件为式I化合物不为The proviso is that the compound of formula I is not

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

在式I或其药学上可接受的盐的一个实施方案中，In one embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 , and C(O)NR^c6 R^d6 ; wherein each of the C_1-3 alkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;

其限制条件为式I化合物不为The proviso is that the compound of formula I is not

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

在式I或其药学上可接受的盐的一个实施方案中，In one embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹选自H、C_1-3烷基和C_1-3卤烷基；R¹ is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基任选地被1或2个独立地选自R^g的取代基取代；^R2 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, halo, D, CN and^ORa2 ; wherein the_C1-3 alkyl is optionally substituted by 1 or 2 substituents independently selected from^Rg ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、C(O)NR^c3R^d3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN, C(O)^{NRc3Rd3andNRc3C} (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from^R30 ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基和卤基；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl and halo;

R⁶选自H、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_3-6环烷基、4元至8元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, CN, OR^a6 , and C(O)NR^c6 R^d6 ; wherein the C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、卤基和CN；R⁷ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo and CN;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、CN、卤基、C_1-3烷基和C_1-3卤烷基。Each^Rg is independently selected from D, CN, halo,_C1-3 alkyl and_C1-3 haloalkyl.

在式I或其药学上可接受的盐的另一个实施方案中，In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and -CH₂ CH₂ CN;

Cy¹选自C_3-10环烷基、C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_3-10环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein each of the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from^R30 ;

R⁵选自H和卤基；^R5 is selected from H and halogen;

R⁶选自H、C_1-3卤烷基、4元至8元杂环烷基和5元至6元杂芳基；其中所述4元至8元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, C_1-3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a10 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN、OR^a31和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a31 and NR^c31 R^d31 ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和CN；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and CN;

各R^a10独立地选自H和C_1-3烷基；Each R^a10 is independently selected from H and C_1-3 alkyl;

各R^a30、R^c30和R^d30独立地选自H和C_1-3烷基；Each of R^a30 , R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31、R^c31和R^d31独立地选自H和C_1-3烷基；Each of R^a31 , R^c31 and R^d31 is independently selected from H and C_1-3 alkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的又一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H和卤基；^R5 is selected from H and halogen;

R⁶选自C_1-3烷基和5元至9元杂环烷基；其中所述C_1-3烷基和5元至9元杂环烷基任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl and 5- to 9-membered heterocycloalkyl; wherein the C_1-3 alkyl and 5- to 9-membered heterocycloalkyl are optionally substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基、卤基、OH和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halo, OH and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent independently selected from R³¹ ;

各R³¹独立地选自OH、O(C_1-3烷基)和N(C_1-3烷基)₂；Each R³¹ is independently selected from OH, O(C_1-3 alkyl) and N(C_1-3 alkyl)₂ ;

各R⁶⁰独立地选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halogen, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；以及Each of R^c30 and R^d30 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的再一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H和卤基；^R5 is selected from H and halogen;

R⁶选自C_1-3烷基和6元至9元稠合杂环烷基；其中所述C_1-3烷基和6元至9元融合杂环烷基任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl and 6- to 9-membered fused heterocycloalkyl; wherein the C_1-3 alkyl and 6- to 9-membered fused heterocycloalkyl are optionally substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基、卤基、OH和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halo, OH and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent independently selected from R³¹ ;

各R³¹独立地选自OH、O(C_1-3烷基)和N(C_1-3烷基)₂；Each R³¹ is independently selected from OH, O(C_1-3 alkyl) and N(C_1-3 alkyl)₂ ;

各R⁶⁰独立地选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halogen, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；以及Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的又一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H和卤基；^R5 is selected from H and halogen;

R⁶选自4元至8元杂环烷基；其中所述4元至8元杂环烷基任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from 4- to 8-membered heterocycloalkyl; wherein the 4- to 8-membered heterocycloalkyl is optionally substituted by 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基、卤基、D和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halo, D and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent independently selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halogen, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31独立地选自H和C_1-3烷基；以及Each R^a31 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的再一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基；其中所述甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, methyl, phenyl, 1,2,4-triazolyl, pyrazolyl and pyridinyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazolyl and pyridinyl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H和氯；^R5 is selected from H and chlorine;

R⁶选自吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基；其中所述吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-2烷基；其中所述C_1-2烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-2 alkyl; wherein the C_1-2 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为氟；^R7 is fluorine;

Cy²为Cy² is

各R¹⁰独立地选自甲基、氟和氯；each R¹⁰ is independently selected from methyl, fluoro and chloro;

各R³⁰独立地选自甲基、氟、D和C(O)NR^c30R^d30；其中所述甲基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from methyl, fluorine, D and C(O)NR^c30 R^d30 ; wherein the methyl is optionally substituted with 1 substituent independently selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自甲基、氟、3-氧代吗啉基、2-氧代吡嗪-1(2H)-基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述3-氧代吗啉基和2-氧代吡嗪-1(2H)-基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from methyl, fluoro, 3-oxomorpholinyl, 2-oxopyrazine-1(2H)-yl, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the 3-oxomorpholinyl and 2-oxopyrazine-1(2H)-yl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自甲基和氟；Each R⁶¹ is independently selected from methyl and fluoro;

各R^c30和R^d30独立地选自H和甲基；Each R^c30 and R^d30 is independently selected from H and methyl;

各R^a31独立地选自H和甲基；以及each R^a31 is independently selected from H and methyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-2烷基、C₁卤烷基、环丙基、四氢呋喃基和噻唑基；其中所述C_1-2烷基、环丙基、四氢呋喃基和噻唑基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-2 alkyl,_C1 haloalkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl; wherein the_C1-2 alkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成任选地被1或2个独立地选自R⁶¹的取代基取代的氮杂环丁烷基。Or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form an azetidinyl group optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的另一个实施方案中，In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为C_6-10芳基或6元至10元杂芳基；其中C_6-10芳基和6元至10元杂芳基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is C_6-10 aryl or 6- to 10-membered heteroaryl; wherein C_6-10 aryl and 6- to 10-membered heteroaryl are optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、苯基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, C_1-3 alkyl, phenyl, 5- to 6-membered heteroaryl, and OR^f3 ; wherein the C_1-3 alkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R³⁰ ;

R⁵选自H和卤基；^R5 is selected from H and halogen;

R⁶选自H、吡啶基、吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基；其中所述吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, pyridyl, pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-2烷基；其中所述C_1-2烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-2 alkyl; wherein the C_1-2 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自甲基和卤基；Each R¹⁰ is independently selected from methyl and halo;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, CN, OR^a30 , C(O) R^b30 , C(O) NR^c30 R^d30 , C(O) OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自甲基、卤基、3-氧代吗啉基、2-氧代吡嗪-1(2H)-基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述3-氧代吗啉基和2-氧代吡嗪-1(2H)-基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from methyl, halogen, 3-oxomorpholinyl, 2-oxopyrazine-1(2H)-yl, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the 3-oxomorpholinyl and 2-oxopyrazine-1(2H)-yl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自甲基和卤基；Each R⁶¹ is independently selected from methyl and halo;

R^f3为R^f3-a；^Rf3 is^Rf3 -a;

各R^c30和R^d30独立地选自H和甲基；Each R^c30 and R^d30 is independently selected from H and methyl;

各R^a31独立地选自H和甲基；以及each R^a31 is independently selected from H and methyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-2烷基、C₁卤烷基、环丙基、四氢呋喃基和噻唑基；其中所述C_1-2烷基、环丙基、四氢呋喃基和噻唑基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-2 alkyl,_C1 haloalkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl; wherein the_C1-2 alkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成任选地被1或2个独立地选自R⁶¹的取代基取代的氮杂环丁烷基。Or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form an azetidinyl group optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .

在另一方面中，本文提供一种式I化合物：In another aspect, provided herein is a compound of Formula I:

或其药学上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein:

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 , and C(O)NR^c6 R^d6 ; wherein each of the C_1-3 alkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60、NR^c60R^d60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 , NR^c60 R^d60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;

其限制条件为式I化合物不为The proviso is that the compound of formula I is not

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

在式I或其药学上可接受的盐的一个实施方案中，In one embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、C(O)NR^c3R^d3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN, C(O)^{NRc3Rd3andNRc3C} (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或^R is selected from H,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4- to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5- to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORa6 , and C(O)^NRc6Rd6 ; wherein each of the_C3-6 cycloalkyl, 4- to 8-membered^{heterocycloalkyl} , phenyl, 5- to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4- to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, and 5- to 6-membered heteroaryl-_C1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60、NR^c60R^d60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 , NR^c60 R^d60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基。Each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino and di(_C1-3 alkyl)amino.

在式I或其药学上可接受的盐的另一个实施方案中，In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and -CH₂ CH₂ CN;

Cy¹选自C_3-10环烷基、C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_3-10环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自H、C_1-3卤烷基、4元至8元杂环烷基和5元至6元杂芳基；其中所述4元至8元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, C_1-3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and OR^a10 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN、OR^a31和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a31 and NR^c31 R^d31 ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60和NR^c60R^d60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halogen, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和CN；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and CN;

各R^a10独立地选自H和C_1-3烷基；Each R^a10 is independently selected from H and C_1-3 alkyl;

各R^a30、R^c30和R^d30独立地选自H和C_1-3烷基；Each of R^a30 , R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31、R^c31和R^d31独立地选自H和C_1-3烷基；以及each of R^a31 , R^c31 and R^d31 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^a60 , R^b60 , R^c60 and R^d60 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl and C_3-6 cycloalkyl; wherein the C_1-3 alkyl and C_3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的又一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl group is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自5元至6元杂芳基；其中所述5元至6元杂芳基任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或^R6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基、卤基和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halogen and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自4元至6元杂环烷基、5元至6元杂芳基、C(O)R^b60、C(O)NR^c60R^d60和C(O)OR^a60；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R^b60 , C(O)NR^c60 R^d60 and C(O)OR^a60 ; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31独立地选自H和C_1-3烷基；以及Each R^a31 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^a60 , R^b60 , R^c60 and R^d60 is independently selected from H, C_1-3 alkyl and C_3-6 cycloalkyl; wherein the C_1-3 alkyl and C_3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的另一个实施方案中，In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自C_1-3烷基和5元至6元杂芳基；其中所述5元至6元杂芳基任选地被1或2个独立地选自R³⁰的取代基取代；R³ is selected from C_1-3 alkyl and 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from R³⁰ ;

R⁵为H；^R5 is H;

R⁶选自4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或^R6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶为C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基、卤基和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halogen and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自4元至6元杂环烷基、5元至6元杂芳基、C(O)R^b60、C(O)NR^c60R^d60和C(O)OR^a60；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R^b60 , C(O)NR^c60 R^d60 and C(O)OR^a60 ; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31独立地选自H和C_1-3烷基；以及Each R^a31 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^a60 , R^b60 , R^c60 and R^d60 is independently selected from H, C_1-3 alkyl and C_3-6 cycloalkyl; wherein the C_1-3 alkyl and C_3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的又一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;

Cy¹为苯基或萘基；其中所述苯基和萘基各自任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl or naphthyl; wherein the phenyl and naphthyl are each optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;

R³选自H和5元至6元杂芳基；其中所述5元至6元杂芳基任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from H and 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或^R6 is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;

各R³⁰独立地选自C_1-3烷基和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent selected from R³¹ ;

各R³¹为OR^a31；each R³¹ is OR^a31 ;

各R⁶⁰独立地选自4元至6元杂环烷基、5元至6元杂芳基、C(O)R^b60、C(O)NR^c60R^d60和C(O)OR^a60；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R^b60 , C(O)NR^c60 R^d60 and C(O)OR^a60 ; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;

各R^c30和R^d30独立地选自H和C_1-3烷基；Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;

各R^a31独立地选自H和C_1-3烷基；以及Each R^a31 is independently selected from H and C_1-3 alkyl; and

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^a60 , R^b60 , R^c60 and R^d60 is independently selected from H, C_1-3 alkyl and C_3-6 cycloalkyl; wherein the C_1-3 alkyl and C_3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一方面中，本文提供一种具有式I的化合物：In one aspect, provided herein is a compound having Formula I:

或其药学上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein:

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5-membered to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 and C(O)NR^c6 R^d6 ; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene are each optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60、NR^c60R^d60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 , NR^c60 R^d60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;

其限制条件为式I化合物不为The proviso is that the compound of formula I is not

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

在式I或其药学上可接受的盐的一个实施方案中，In one embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5-membered to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 and C(O)NR^c6 R^d6 ; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene are each optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

R³³选自C_2-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_2-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_2-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60、NR^c60R^d60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 , NR^c60 R^d60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^a2选自H、C_1-3烷基和C_1-3卤烷基；R^a2 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基。Each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino and di(_C1-3 alkyl)amino.

在式I或其药学上可接受的盐的另一个实施方案中，In another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;

R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;

Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5-membered to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 and C(O)NR^c6 R^d6 ; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene are each optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;

Cy²选自Cy² is selected from

其中n为0、1或2；Where n is 0, 1 or 2;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;

各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60、NR^c60R^d60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 , NR^c60 R^d60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;

R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;

R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60和R^b60独立地选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 and^Rb60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

各R^c60和R^d60独立地选自H、C_2-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_2-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R^c60 and R^d60 is independently selected from H, C_2-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein the C_2-3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基。Each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino and di(_C1-3 alkyl)amino.

在式I或其药学上可接受的盐的又一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹选自H、C_1-3烷基、C_1-3卤烷基和D；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl and D;

R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基任选地被1或2个独立地选自R^g的取代基取代；^R2 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, halo, D, CN and^ORa2 ; wherein the_C1-3 alkyl is optionally substituted by 1 or 2 substituents independently selected from^Rg ;

Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1、2或3个独立地选自N、O和S的成环杂原子；其中所述6元至10元杂芳基的所述形成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atom of the 6- to 10-membered heteroaryl is optionally substituted with oxo to form a carbonyl; and wherein the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^f3和NR^c3R^j3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN,^ORf3 and^NRc3Rj3 ; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1^, 2 or 3 substituents independently selected from^R30 ;

R⁵选自H、C_1-3烷基、C_1-3卤烷基和D；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl and D;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D和CN；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D and CN; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷选自H、C_1-3烷基、C_1-3卤烷基、卤基、D和CN；R⁷ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN;

Cy²选自Cy² is selected from

其中n为0或1；Where n is 0 or 1;

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10和NR^c10R^d10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 and NR^c10 R^d10 ;

各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN；each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 and NR^c31 R^d31 ;

R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_2-3烷基、4元杂环烷基、6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein the C_2-3 alkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)NR^c60R^d60和NR^c60R^d60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)NR^c60 R^d60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN;

R^a2选自H、C_1-3烷基和C_1-3卤烷基；R^a2 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^c3选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R^c3 is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;

R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;

各R^a10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;

各R^a30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and

各R^g独立地选自D、CN、卤基、C_1-3烷基和C_1-3卤烷基。Each^Rg is independently selected from D, CN, halo,_C1-3 alkyl and_C1-3 haloalkyl.

在式I或其药学上可接受的盐的再一个实施方案中，In yet another embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹为H；^R1 is H;

R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和-CH₂CH₂CN；R² is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and -CH₂ CH₂ CN;

Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1或2个独立地选自N、O和S的成环杂原子；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O and S; and wherein the C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ ;

R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, and^ORf3 ; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D和CN；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D and CN; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²选自Cy² is selected from

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a10 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 and NR^c31 R^d31 ;

R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein each of the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a60、C(O)NR^c60R^d60和NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a60 , C(O)NR^c60 R^d60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN;

R^f3选自C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl; wherein the 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

各R^a10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自C_1-3烷基和_1-3卤烷基；R^b20 is selected from C_1-3 alkyl and_1-3 haloalkyl;

各R^a30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^a31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^a60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基和4元至6元杂环烷基；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of^Ra60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl and 4- to 6-membered heterocycloalkyl; wherein the_C1-3 alkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在式I或其药学上可接受的盐的一个实施方案中，In one embodiment of Formula I or a pharmaceutically acceptable salt thereof,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹为H；^R1 is H;

R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and -CH₂ CH₂ CN;

Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ ;

R³选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl and^ORf3 ; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自H、C_1-3烷基、C_1-3卤烷基和5元至6元杂芳基；其中所述C_1-3烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²选自Cy² is selected from

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and OR^a10 ;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and NR^c31 R^d31 ;

R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基和CN；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo and CN; wherein each of the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和C(O)NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and C(O)NR^c60 R^d60 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl and halo;

R^f3为C_1-3卤烷基；或R^f3 is C_1-3 haloalkyl; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

各R^a10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

R^b20选自C_1-3烷基和C_1-3卤烷基；R^b20 is selected from C_1-3 alkyl and C_1-3 haloalkyl;

各R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;

各R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and

各R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基和4元至6元杂环烷基；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^c60 and R^d60 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 4- to 6-membered heterocycloalkyl; wherein the C_1-3 alkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元或5元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4- or 5-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，In one embodiment,

Y为N或CR⁶；Y is N or CR⁶ ;

R¹为H；^R1 is H;

R²选自C_1-3烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, halo, CN and -CH₂ CH₂ CN;

Cy¹为苯基、萘基、吲哚基、苯并噻吩基和异喹啉基，其皆任选地被1、2或3个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl, naphthyl, indolyl, benzothienyl and isoquinolinyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ ;

R³选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl and^ORf3 ; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 ;

R⁵为H；^R5 is H;

R⁶选自H、C_1-3烷基和5元至6元杂芳基；其中所述C_1-3烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from H, C_1-3 alkyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ;

R⁷为卤基；^R7 is halogen;

Cy²选自Cy² is selected from

各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OH；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and OH;

各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和N(C_1-3烷基)₂；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and N(C_1-3 alkyl)₂ ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R³¹ ;

各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和N(C_1-3烷基)₂；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and N(C_1-3 alkyl)₂ ;

R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基和CN；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo and CN; wherein each of the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R³¹ ;

各R⁶⁰独立地选自4元至6元杂环烷基和C(O)NR^c60R^d60；其中4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each R⁶⁰ is independently selected from 4- to 6-membered heterocycloalkyl and C(O)NR^c60 R^d60 ; wherein each 4- to 6-membered heterocycloalkyl is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;

各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl and halo;

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;

R^b20为C_1-3烷基；以及R^b20 is C_1-3 alkyl; and

各R^c60和R^d60独立地选自H和C_1-3烷基；Each R^c60 and R^d60 is independently selected from H and C_1-3 alkyl;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元或5元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered or 5-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在又一个实施方案中，式I化合物为式Ia化合物：In yet another embodiment, the compound of formula I is a compound of formula Ia:

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在又一个实施方案中，式I化合物为式Ib化合物：In yet another embodiment, the compound of formula I is a compound of formula Ib:

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在一个实施方案中，Y为N。在另一个实施方案中，Y为CR⁶。In one embodiment, Y is N. In another embodiment, Y is CR⁶ .

在另一个实施方案中，R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1。在另一个实施方案中，R¹选自H、C_1-3烷基、C_1-3卤烷基和D。在一个实施方案中，R¹为H。在一个实施方案中，R¹选自H、C_1-3烷基和C_1-3卤烷基。In another embodiment, R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN, and OR^a1 . In another embodiment, R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, and D. In one embodiment, R¹ is H. In one embodiment, R¹ is selected from H, C_1-3 alkyl, and C_1-3 haloalkyl.

在另一个实施方案中，R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基任选地被1或2个独立地选自R^g的取代基取代。在又一个实施方案中，R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和-CH₂CH₂CN。在另一个实施方案中，R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN。在实施方案中，R²为-CH₂CH₂CN。In another embodiment, R² is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, and OR^a2 ; wherein the C_1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from R^g . In yet another embodiment, R² is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, and -CH₂ CH₂ CN. In another embodiment, R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, and -CH₂ CH₂ CN. In an embodiment, R² is -CH₂ CH₂ CN.

在一个实施方案中，Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代。In one embodiment,^Cy1 is selected from_C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl,_C6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; wherein the_C3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl,_C6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from^R10 .

在一个实施方案中，Cy¹选自C_3-10环烷基、C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_3-10环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1或2个独立地选自R¹⁰的取代基取代。In one embodiment,^Cy1 is selected from_C3-10 cycloalkyl,_C6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the_C3-10 cycloalkyl,_C6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R10 .

在再另一个实施方案中，Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基各自具有至少一个成环碳原子和1、2或3个独立地选自N、O和S的成环杂原子；其中所述6元至10元杂芳基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代。In yet another embodiment, Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein each of the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl are optionally substituted with oxo to form a carbonyl; and wherein each of the C_6-10 aryl and 6- to 10-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ .

在又一个实施方案中，Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代。In yet another embodiment, Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ .

在一个实施方案中，Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代。在另一个实施方案中，Cy¹为2,3-二氯苯基。In one embodiment, Cy¹ is phenyl; wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from R^10. In another embodiment, Cy¹ is 2,3-dichlorophenyl.

在另一个实施方案中，Cy¹为苯基、萘基、吲哚、苯并噻吩和异喹啉，其皆任选地被1、2或3个独立地选自R¹⁰的取代基取代。In another embodiment, Cy¹ is phenyl, naphthyl, indole, benzothiophene and isoquinoline, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ .

在一个实施方案中，Cy¹为任选地被1、2或3个独立地选自R¹⁰的取代基取代的苯基。在另一个实施方案中，Cy¹为任选地被1、2或3个独立地选自R¹⁰的取代基取代的萘基。在另一个实施方案中，Cy¹为任选地被1、2或3个独立地选自R¹⁰的取代基取代的吲哚基。在又一个实施方案中，Cy¹为任选地被1、2或3个独立地选自R¹⁰的取代基取代的苯并噻吩基。在一个实施方案中，Cy¹为任选地被1、2或3个独立地选自R¹⁰的取代基取代的异喹啉基。In one embodiment, Cy¹ is phenyl optionally substituted by 1, 2 or 3 substituents independently selected from R^10. In another embodiment, Cy¹ is naphthyl optionally substituted by 1, 2 or 3 substituents independently selected from R^10. In another embodiment, Cy¹ is indolyl optionally substituted by 1, 2 or 3 substituents independently selected from R^10. In yet another embodiment, Cy¹ is benzothienyl optionally substituted by 1, 2 or 3 substituents independently selected from R^10. In one embodiment, Cy¹ is isoquinolinyl optionally substituted by 1, 2 or 3 substituents independently selected from R¹⁰ .

在再一个实施方案中，R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^f3和NR^c3R^j3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。In yet another embodiment,^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN,^ORf3 and^NRc3Rj3 ; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or³ substituents independently selected from^R30 .

在一个实施方案中，R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代。In one embodiment,^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN and^ORf3 ; wherein said_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 .

在另一个实施方案中，R³选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代。In another embodiment, R³ is selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl and OR^f3 ; wherein said C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R³⁰ .

在一个实施方案中，R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、C(O)NR^c3R^d3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。In one embodiment,^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN, C(O)^{NRc3Rd3andNRc3C} (O)^Rb3 ; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1, 2 or 3 substituents independently selected from^R30 .

在另一个实施方案中，R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。In another embodiment,^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from^R30 .

在一个实施方案中，R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代。在另一个实施方案中，R³选自H、C_1-3烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。在又一个实施方案中，R³选自H、甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基；其中所述甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。In one embodiment,^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl; wherein each of the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R30 . In another embodiment,^R3 is selected from H,_C1-3 alkyl, phenyl, and 5-membered to 6-membered heteroaryl; wherein each of the_C1-3 alkyl, phenyl, and 5-membered to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from^R30 . In yet another embodiment,^R3 is selected from H, methyl, phenyl, 1,2,4-triazolyl, pyrazolyl, and pyridinyl; wherein each of the methyl, phenyl, 1,2,4-triazolyl, pyrazolyl, and pyridinyl is optionally substituted with 1, 2, or 3 substituents independently selected from^R30 .

在一个实施方案中，R³为5元至6元杂芳基；其中所述5元至6元杂芳基任选地被1或2个独立地选自R³⁰的取代基取代。在一个实施方案中，R³为6元杂芳基；其中所述6元杂芳基任选地被1或2个独立地选自R³⁰的取代基取代。In one embodiment,^R3 is 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R30 . In one embodiment,^R3 is 6-membered heteroaryl; wherein the 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R30 .

在另一个实施方案中，R³为C_1-3烷基。在又一个实施方案中，R³为甲基。In another embodiment, R³ is C_1-3 alkyl. In yet another embodiment, R³ is methyl.

在又一个实施方案中，R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5。在再一个实施方案中，R⁵选自H、C_1-3烷基、C_1-3卤烷基和D。在一个实施方案中，R⁵选自H、C_1-3烷基、C_1-3卤烷基和卤基。在另一个实施方案中，R⁵选自H和卤基。在又一个实施方案中，R⁵选自H和氯。在一个实施方案中，R⁵为H。在另一个实施方案中，R⁵为氯。In yet another embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN, and^OR . In yet another embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, and D. In one embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, and halo. In another embodiment,^R is selected from H and halo. In yet another embodiment,^R is selected from H and chloro. In one embodiment,^R is H. In another embodiment,^R is chloro.

在另一个实施方案中，R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代。In another embodiment,^R6 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN,^ORa6 and C(O)^NRc6Rd6 ; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl,^phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 .

在又一个实施方案中，R⁶选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D和CN；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代。In yet another embodiment, R is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D and CN; wherein each of the_C1-3 alkyl,⁴ -membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl is optionally substituted with 1 or 2 substituents independently selected from^R60 .

在又一个实施方案中，R⁶选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D和CN；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代。In yet another embodiment, R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D and CN; wherein said C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ .

在另一个实施方案中，R⁶选自H、C_1-3烷基、C_1-3卤烷基和5元至6元杂芳基；其中所述C_1-3烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代。In another embodiment, R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 5- to 6-membered heteroaryl; wherein said C_1-3 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ .

在一个实施方案中，R⁶选自H、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_3-6环烷基、4元至8元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或In one embodiment,^R6 is selected from H,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 8-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN,^ORa6 and C(O)^NRc6Rd6 ; wherein said_C3-6 cycloalkyl, 4-membered to 8-membered heterocycloalkyl, phenyl and 5-membered^to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶为C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代。R⁶ is a C_1-3 alkyl group; wherein the C_1-3 alkyl group is substituted by 1 or 2 substituents independently selected from R⁶⁰ .

在一个实施方案中，R⁶选自H、C_1-3卤烷基、4元至8元杂环烷基和5元至6元杂芳基；其中所述4元至8元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或In one embodiment,^R6 is selected from H,_C1-3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代。R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ .

在一个实施方案中，R⁶选自4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或In one embodiment, R⁶ is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; or

R⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代。R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ .

在一个实施方案中，R⁶选自吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基；其中所述吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基任选地被1或2个独立地选自R⁶⁰的取代基取代；或In one embodiment,^R6 is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein said pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally substituted with 1 or 2 substituents independently selected from^R60 ; or

R⁶为C_1-2烷基；其中所述C_1-2烷基被1或2个独立地选自R⁶⁰的取代基取代。R⁶ is a C_1-2 alkyl group; wherein the C_1-2 alkyl group is substituted by 1 or 2 substituents independently selected from R⁶⁰ .

在一个实施方案中，R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7。在另一个实施方案中，R⁷选自H、C_1-3烷基、C_1-3卤烷基、卤基、D和CN。在另一个实施方案中，R⁷选自H、C_1-3烷基、C_1-3卤烷基、卤基和CN。在又一个实施方案中，R⁷为卤基。在一个实施方案中，R⁷为F。In one embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a7 . In another embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN. In another embodiment,^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo and CN. In yet another embodiment,^R is halo. In one embodiment,^R is F.

在再一个实施方案中，Cy²选自In yet another embodiment, Cy² is selected from

其中n为0或1。Where n is 0 or 1.

在一个实施方案中，Cy²选自In one embodiment, Cy² is selected from

其中n为0或1。Where n is 0 or 1.

在另一个实施方案中，Cy²选自In another embodiment, Cy² is selected from

在一个实施方案中，Cy²选自Cy²-a和Cy²-b；其中n为0。在一个实施方案中，Cy²为Cy²-b；其中n为0。在一个实施方案中，Cy²选自Cy²-a；其中n为0。在另一个实施方案中，Cy²为Cy²-a。在又一个实施方案中，Cy²为Cy²-b。In one embodiment, Cy² is selected from Cy² -a and Cy² -b; wherein n is 0. In one embodiment, Cy² is Cy² -b; wherein n is 0. In one embodiment, Cy² is selected from Cy² -a; wherein n is 0. In another embodiment, Cy² is Cy² -a. In yet another embodiment, Cy² is Cy² -b.

在另一个实施方案中，n为0或1。在一个实施方案中，n为0。在另一个实施方案中，n为1。在又一个实施方案中，n为2。In another embodiment, n is 0 or 1. In one embodiment, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2.

在再一个实施方案中，各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10和NR^c10R^d10。在一个实施方案中，各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a10。在另一个实施方案中，各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OR^a10。在一个实施方案中，各R¹⁰独立地选自C_1-3烷基和卤基。在另一个实施方案中，各R¹⁰独立地选自甲基、氟和氯。在一个实施方案中，各R¹⁰为氯。In yet another embodiment, each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 and NR^c10 R^d10 . In one embodiment, each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a10 . In another embodiment, each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and OR^a10 . In one embodiment, each R¹⁰ is independently selected from C_1-3 alkyl and halo. In another embodiment, each R¹⁰ is independently selected from methyl, fluorine and chlorine. In one embodiment, each R¹⁰ is chlorine.

在又一个实施方案中，各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN。In yet another embodiment, each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, and CN.

在再一个实施方案中，各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代。In yet another embodiment, each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ .

在一个实施方案中，各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。In one embodiment, each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ .

在一个实施方案中，各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。在一个实施方案中，各R³⁰独立地选自C_1-3烷基、卤基和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个选自R³¹的取代基取代。In one embodiment, each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein each of the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R^31. In one embodiment, each R³⁰ is independently selected from C_1-3 alkyl, halo and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent selected from R³¹ .

在一个实施方案中，各R³⁰独立地选自C_1-3烷基、卤基、D和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个选自R³¹的取代基取代。在一个实施方案中，各R³⁰独立地选自甲基、氟、D和C(O)NR^c30R^d30；其中所述甲基任选地被1个选自R³¹的取代基取代。In one embodiment, each R³⁰ is independently selected from C_1-3 alkyl, halo, D and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent selected from R^31. In one embodiment, each R³⁰ is independently selected from methyl, fluoro, D and C(O)NR^c30 R^d30 ; wherein the methyl is optionally substituted with 1 substituent selected from R³¹ .

在另一个实施方案中，各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。In another embodiment, each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and NR^c30 R^d30 ; wherein said C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R³¹ .

在一个实施方案中，各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31和NR^c31R^d31。在另一个实施方案中，各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和NR^c31R^d31。在一个实施方案中，各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN、OR^a31和NR^c31R^d31。在一个实施方案中，各R³¹独立地选自OR^a31。In one embodiment, each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 and NR^c31 R^d31 . In another embodiment, each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and NR^c31 R^d31 . In one embodiment, each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a31 and NR^c31 R^d31 . In one embodiment, each R³¹ is independently selected from OR^a31 .

在另一个实施方案中，R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基、D、CN、OR^a30和NR^c30R^d30；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。In another embodiment, R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo, D, CN, OR^a30 and NR^c30 R^d30 ; wherein each of the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R³¹ .

在又一个实施方案中，R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基和CN；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。In yet another embodiment, R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo and CN; wherein each of said C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R³¹ .

在一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、C(O)OR^a60和NR^c60R^d60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。在一个实施方案中，各R⁶⁰独立地选自4元至6元杂环烷基、5元至6元杂芳基、C(O)R^b60、C(O)NR^c60R^d60和C(O)OR^a60；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In one embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , C(O)OR^a60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ . In one embodiment, each R⁶⁰ is independently selected from 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C(O)R^b60 , C(O)NR^c60 R^d60 and C(O)OR^a60 ; wherein the 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在再一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)NR^c60R^d60和NR^c60R^d60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In yet another embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)NR^c60 R^d60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a60、C(O)NR^c60R^d60和NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In one embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a60 , C(O)NR^c60 R^d60 and NR^c60 R^d60 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在另一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和C(O)NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In another embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and C(O)NR^c60 R^d60 ; wherein said C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .

在另一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、C(O)OR^a60和C(O)NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In another embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, C(O)OR^a60 and C(O)NR^c60 R^d60 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In one embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在另一个实施方案中，各R⁶⁰独立地选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。在另一个实施方案中，各R⁶⁰独立地选自甲基、氟、3-氧代吗啉基、2-氧代吡嗪-1(2H)-基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述3-氧代吗啉基和2-氧代吡嗪-1(2H)-基各自任选地被1或2个独立地选自R⁶¹的取代基取代。In another embodiment, each R⁶⁰ is independently selected from C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ . In another embodiment, each R⁶⁰ is independently selected from methyl, fluoro, 3-oxomorpholinyl, 2-oxopyrazin-1(2H)-yl, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the 3-oxomorpholinyl and 2-oxopyrazin-1(2H)-yl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在又一个实施方案中，各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN。在再一个实施方案中，各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基和卤基。在一个实施方案中，各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和CN。在一个实施方案中，各R⁶¹独立地选自C_1-3烷基和卤基。在一个实施方案中，各R⁶¹独立地选自甲基和氟。In yet another embodiment, each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN. In yet another embodiment, each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl and halo. In one embodiment, each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and CN. In one embodiment, each R⁶¹ is independently selected from C_1-3 alkyl and halo. In one embodiment, each R⁶¹ is independently selected from methyl and fluorine.

在一个实施方案中，R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或In one embodiment, R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; or

R^f3选自R^f3 is selected from

其中R^x为H或C_1-2烷基；以及wherein^Rx is H or_C1-2 alkyl; and

R^y为C_1-2烷基。R^y is a C_1-2 alkyl group.

在另一个实施方案中，R^f3选自C_1-3卤烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；或In another embodiment, R^f3 is selected from C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl; wherein the 4-membered to 6-membered heterocycloalkyl and the 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R³⁰ ; or

R^f3选自R^f3-a和R^f3-b；^Rf3 is selected from^Rf3 -a and^Rf3 -b;

其中R^x为H或C_1-2烷基；以及wherein^Rx is H or_C1-2 alkyl; and

R^y为C_1-2烷基。R^y is a C_1-2 alkyl group.

在又一个实施方案中，R^f3为C_1-3卤烷基；或R^f3选自R^f3-a和R^f3-b；其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基。In yet another embodiment,^Rf3 is_C1-3 haloalkyl; or^Rf3 is selected from^Rf3 -a and^Rf3 -b; wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl.

在再一个实施方案中，R^f3为R^f3-a。在一个实施方案中，R^f3为R^f3-b。In yet another embodiment,^Rf3 is^Rf3 -a. In one embodiment,^Rf3 is^Rf3 -b.

在另一个实施方案中，R^x为H。在又一个实施方案中，R^x为C_1-2烷基。In another embodiment,^Rx is H. In yet another embodiment,^Rx is_C1-2 alkyl.

在一个实施方案中，各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基。In one embodiment, each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl.

在一个实施方案中，各R^a30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基。在一个实施方案中，各R^a30、R^c30和R^d30独立地选自H和C_1-3烷基。在另一个实施方案中，各R^c30和R^d30独立地选自H和C_1-3烷基。在又一个实施方案中，各R^c30和R^d30独立地选自H和甲基。In one embodiment, each^Ra30 ,^Rc30 and^Rd30 are independently selected from H,_C1-3 alkyl and_C1-3 haloalkyl. In one embodiment, each^Ra30 ,^Rc30 and^Rd30 are independently selected from H and_{C1-3 alkyl. In another embodiment, each Rc30 and Rd30 are independently selected from H and C1-3}^alkyl._In yet another embodiment, each^Rc30 and^Rd30 are independently selected from H and methyl.

在一个实施方案中，各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基。在另一个实施方案中，各R^a31、R^c31和R^d31独立地选自H和C_1-3烷基。在又一个实施方案中，各R^a31独立地选自H和甲基。In one embodiment, each of^Ra31 ,^Rb31 ,^Rc31 and^Rd31 is independently selected from H,_C1-3 alkyl and_C1-3 haloalkyl. In another embodiment, each of^Ra31 ,^Rc31 and^Rd31 is independently selected from H and_C1-3 alkyl. In yet another embodiment, each of^Ra31 is independently selected from H and methyl.

在一个实施方案中，各R^a60、R^c60和R^d60独立地选自H、C_1-3烷基和C_1-3卤烷基；或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基。In one embodiment, each of^Ra60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl and_C1-3 haloalkyl; or any^Rc60 and^Rd60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl.

在一个实施方案中，各R^c60和R^d60独立地选自H、C_1-3烷基和C_1-3卤烷基；或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基。在又一个实施方案中，各R^c60和R^d60独立地选自H、C_2-3烷基和C_1-3卤烷基；或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元杂环烷基。In one embodiment, each R^c60 and R^d60 are independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl. In another embodiment, each R^c60 and R^d60 are independently selected from H, C_2-3 alkyl and C_1-3 haloalkyl; or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered heterocycloalkyl.

在一个实施方案中，各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；In one embodiment, each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl and_C3-6 cycloalkyl; wherein the_C1-3 alkyl and_C3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基和C_3-6环烷基；其中所述C_1-3烷基和C_3-6环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；In one embodiment, each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl and_C3-6 cycloalkyl; wherein the_C1-3 alkyl and_C3-6 cycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；In one embodiment, each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .

在另一个实施方案中，各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-2烷基、C₁卤烷基、环丙基、四氢呋喃基和噻唑基；其中所述C_1-2烷基、环丙基、四氢呋喃基和噻唑基各自任选地被1或2个独立地选自R⁶¹的取代基取代；In another embodiment, each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-2 alkyl,_C1 haloalkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl; wherein said_C1-2 alkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;

或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成任选地被1或2个独立地选自R⁶¹的取代基取代的氮杂环丁烷基。Or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form an azetidinyl group optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .

在一个实施方案中，式I化合物或其药学上可接受的盐经氘化。In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is deuterated.

在另一个实施方案中，式I化合物不为3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。In another embodiment, the compound of Formula I is not 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.

在一些实施方案中：In some embodiments:

Y为CR⁶；Y is CR⁶ ;

R¹为H；^R1 is H;

R²为C_1-3烷基，其被CN取代；^R2 is_C1-3 alkyl, which is substituted by CN;

Cy¹为被1或2个独立地选自R¹⁰的取代基取代的苯基，其中各R¹⁰独立地为卤基；Cy¹ is phenyl substituted by 1 or 2 substituents independently selected from R¹⁰ , wherein each R¹⁰ is independently halogen;

R³选自-CH₃、-CH(CH₃)-OH和经-C(CH₃)₂OH取代的6元杂芳基；R³ is selected from -CH₃ , -CH(CH₃ )-OH and a 6-membered heteroaryl substituted with -C(CH₃ )₂ OH;

R⁵为H；^R5 is H;

R⁶选自-6元杂环烷基-C(O)R^b60、-CH(CH₃)-R⁶⁰和-CH(CH₃)-NHC(O)R^b60；R⁶ is selected from -6-membered heterocycloalkyl-C(O)R^b60 , -CH(CH₃ )-R⁶⁰ and -CH(CH₃ )-NHC(O)R^b60 ;

R⁷为卤基；^R7 is halogen;

Cy²为Cy² is

R⁶⁰为6元杂环烷基；R⁶⁰ is a 6-membered heterocycloalkyl group;

R^b60为C_3-4环烷基，其被R⁶¹取代；以及R^b60 is a C_3-4 cycloalkyl group substituted by R⁶¹ ; and

R⁶¹为卤基。^R61 is a halogen group.

在另一个实施方案中，R²为CH₂CH₂CN。In another embodiment,^R2 is_CH2CH2CN.

在另一个实施方案中，R¹⁰为Cl。In another embodiment, R¹⁰ is Cl.

在另一个实施方案中，Cy¹为2,3-二氯苯基。In another embodiment, Cy¹ is 2,3-dichlorophenyl.

在另一个实施方案中，R³为-CH₃。在另一个实施方案中，R³为-CH(CH₃)-OH。在另一个实施方案中，R³为被-C(CH₃)₂OH取代的6元杂芳基。在另一个实施方案中，R³为被-C(CH₃)₂OH取代的吡啶。In another embodiment, R³ is -CH_3. In another embodiment, R³ is -CH(CH₃ )-OH. In another embodiment, R³ is 6-membered heteroaryl substituted with -C(CH₃ )₂ OH. In another embodiment, R³ is pyridine substituted with -C(CH₃ )₂ OH.

在另一个实施方案中，R⁶为-CH(CH₃)-R⁶⁰。在另一个实施方案中，R⁶为-CH(CH₃)-NHC(O)R^b60。在另一个实施方案中，R⁶为6元杂环烷基-C(O)R^b60。在另一个实施方案中，R⁶为-CH(CH₃)-R⁶⁰，其中R⁶⁰为在另一个实施方案中，R⁶为--CH(CH₃)-NHC(O)R^b60，其中R^b60为1-氟环烷基。在另一个实施方案中，R⁶为在另一个实施方案中，R⁶为其中R^b60为1-氟环烷基。In another embodiment, R⁶ is -CH(CH₃ )-R⁶⁰ . In another embodiment, R⁶ is -CH(CH₃ )-NHC(O)R^b60 . In another embodiment, R⁶ is 6-membered heterocycloalkyl-C(O)R^b60 . In another embodiment, R⁶ is -CH(CH₃ )-R⁶⁰ , wherein R⁶⁰ is In another embodiment, R⁶ is --CH(CH₃ )-NHC(O)R^b60 , wherein R^b60 is 1-fluorocycloalkyl. In another embodiment, R⁶ is In another embodiment,^R6 is wherein R^b60 is 1-fluorocycloalkyl.

在另一个实施方案中，R⁷为F。In another embodiment,^R7 is F.

在另一个实施方案中，式I化合物选自：In another embodiment, the compound of formula I is selected from:

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(6-氟-5-甲基-1H-吲哚-3-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮；3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈；1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-4-((3-氟-1-甲基氮杂环丁烷-3-基)甲氧基)-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪基-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-2-(1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7,8-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(6,7-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈；1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物选自：In another embodiment, the compound of formula I is selected from:

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(6-氟-5-甲基-1H-吲哚-3-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮；3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈；1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-4-((3-氟-1-甲基氮杂环丁烷-3-基)甲氧基)-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪基-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7,8-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(6,7-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈；1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物选自：In another embodiment, the compound of formula I is selected from:

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(6-氟-5-甲基-1H-吲哚-3-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮；3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈；1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪基-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-(2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-(2-氮杂双环[2.1.1]己烷-5-基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-2-(1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-(2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7,8-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(6,7-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈；1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;

8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在又一个实施方案中，式I化合物选自：In yet another embodiment, the compound of formula I is selected from:

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基吡咯烷-1-甲酰胺；以及(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; and

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物选自：In another embodiment, the compound of formula I is selected from:

(1S,3R,5S)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯；(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-氟苯基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

8-(2-((R)-1-乙酰基吡咯烷-2-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-(2-甲基吡啶-4-基)-1H-吡咯并[3,2-c]喹啉-7-基)-1,2,3,4-四氢萘-1-甲腈；8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile;

5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺；5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪基-2-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(5-氟-6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸乙酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid ethyl ester;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d3)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪基-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺；5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(5-甲基吡嗪基-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

(1R,3R,5R)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯；(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在又一个实施方案中，式I化合物选自：In yet another embodiment, the compound of formula I is selected from:

5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺；5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪基-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物选自：In another embodiment, the compound of formula I is selected from:

(2R,4S)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-4-氟吡咯烷-1-甲酸甲酯；(2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester;

(2R,5R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-5-甲基吡咯烷-1-甲酸甲酯；(2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylic acid methyl ester;

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-3-氯-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

4-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-2-氟-N-甲基苯甲酰胺；4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide;

((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)氨基甲酸甲酯；Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-2,2-二氟乙酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-2,2-二氟乙酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide;

(2S)-N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)四氢呋喃-2-甲酰胺；(2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)环丙烷磺酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)噻唑-4-甲酰胺；以及N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide; and

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-N-甲基环丙烷甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物选自In another embodiment, the compound of formula I is selected from

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-甲基环丙烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丙烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丁烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-2-(1-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)乙基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)嘧啶-4-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)哒嗪-3-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide;

N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-3,3-二氟氮杂环丁烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide;

3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-((1-甲基-1H-吡唑-4-基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;

5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-4-基)-N,N-二甲基吡啶甲酰胺；以及5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide; and

(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(4-((二甲基氨基)甲基)-2,3-二氟苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

在另一个实施方案中，式I化合物为药学上可接受的盐。In another embodiment, the compound of Formula I is a pharmaceutically acceptable salt.

在另一方面中，本文提供一种药物组合物，其包含式I化合物或其药学上可接受的盐和药学上可接受的载剂。In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

进一步应了解，出于清楚起见而描述于单独实施方案的上下文中的本发明的某些特征也可以组合形式提供于单个实施方案中(同时实施方案意图以如同多种相关形式书写的形式并入)。相反，为简洁起见而描述于单个实施方案的上下文中的本发明的各种特征也可分别或以任何适合的子组合形式提供。因此，预期描述为式I化合物的实施方案的特征可以任何适合的组合形式组合。It will be further appreciated that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment (with the embodiments intended to be incorporated as if written in multiple related forms). Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. Thus, it is contemplated that the features of the embodiments described as compounds of Formula I may be combined in any suitable combination.

在本说明书中的各种位置处，化合物的某些特征以群组或范围形式公开。具体而言，期望此公开内容包括此类群组和范围的成员的每一个别子组合。例如，术语“C_1-6烷基”具体地预期独立地公开(但不限于)甲基、乙基、C₃烷基、C₄烷基、C₅烷基和C₆烷基。At various locations in this specification, certain features of compounds are disclosed in groups or ranges. Specifically, it is expected that this disclosure includes each individual subcombination of members of such groups and ranges. For example, the term "C_1-6 alkyl" specifically intends to independently disclose (but not be limited to) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

其中n为整数的术语“n元”通常描述部分中成环原子的数目，其中成环原子的数目为n。例如，哌啶基为6元杂环烷基环的实例，吡唑基为5元杂芳环的实例，吡啶基为6元杂芳环的实例，并且1,2,3,4-四氢-萘为10元环烷基的实例。The term "n-membered," where n is an integer, generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaromatic ring, pyridinyl is an example of a 6-membered heteroaromatic ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

在本说明书中的多处，可描述定义二价连接基团的变量。特别地，期望各连接取代基包括连接取代基的前向和后向形式。例如，-NR(CR'R")_n-包括-NR(CR'R")_n-和-(CR'R")_nNR-，并且预期独立地公开每一种形式。当结构需要连接基团时，针对所述基团所列的马库什变量(Markush variables)应理解为连接基团。例如，如果结构需要连接基团并且所述变量的马库什基团定义列出“烷基”或“芳基”，则应理解，“烷基”或“芳基”分别表示亚烷基连接基团或亚芳基连接基团。At various places in this specification, variables defining a divalent linking group may be described. In particular, it is expected that each linking substituent includes both forward and backward forms of the linking substituent. For example, -NR(CR'R")_n - includes -NR(CR'R")_n - and -(CR'R")_n NR-, and each form is expected to be disclosed independently. When a structure requires a linking group, the Markush variables listed for that group are to be understood as linking groups. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it is to be understood that "alkyl" or "aryl" refers to an alkylene linking group or an arylene linking group, respectively.

术语“取代”意指原子或原子基团作为连接至另一基团的“取代基”在形式上替代氢。除非另外指示，否则术语“取代”是指任何程度的取代，例如单取代、二取代、三取代、四取代或五取代，其中准许此类取代。独立地选择取代基，并且取代可位于可以化学方式接近的任何位置。应了解，给定原子处的取代受价数限制。应理解，给定原子处的取代产生化学上稳定的分子。短语“任选地被取代”意指未取代或取代。术语“取代”意指氢原子被去除并且被取代基替代。单个二价取代基(例如氧代)可替代两个氢原子。The term "substituted" means that an atom or a group of atoms formally replaces hydrogen as a "substituent" connected to another group. Unless otherwise indicated, the term "substituted" refers to any degree of substitution, such as monosubstitution, disubstitution, trisubstitution, tetrasubstitution or pentasubstitution, wherein such substitution is permitted. The substituent is selected independently, and the substitution may be located at any position that can be chemically approached. It should be understood that the substitution at a given atom is limited by the valence number. It should be understood that the substitution at a given atom produces a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (such as oxo) can replace two hydrogen atoms.

术语“C_n-m”表示包括端点的范围，其中n和m为整数并且表示碳原子数目。实例包括C_1-4、C_1-6和类似者。The term "C_nm " denotes an inclusive range, where n and m are integers and denote the number of carbon atoms. Examples include C_1-4 , C_1-6 and the like.

单独或与其他术语组合使用的术语“烷基”是指可为直链或支链的饱和烃基。术语“C_n-m烷基”是指具有n至m个碳原子的烷基。烷基在形式上对应于一个C-H键由烷基与化合物的其余部分的连接点替代的烷烃。在一些实施方案中，烷基含有1至6个碳原子、1至4个碳原子、1至3个碳原子或1至2个碳原子。烷基部分的实例包括(但不限于)化学基团，诸如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基；高碳数同系物，诸如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丙基和类似基团。The term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight or branched. The term "C_nm alkyl" refers to an alkyl group having n to m carbon atoms. Alkyl formally corresponds to an alkane in which a C—H bond is replaced by the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; high carbon number homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and similar groups.

单独或与其他术语组合使用的术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上对应于两个C-H键由亚烷基与化合物的其余部分的连接点替代的烷烃。术语“C_n-m亚烷基”是指具有n至m个碳原子的亚烷基。亚烷基的实例包括(但不限于)乙-1,2-二基、乙-1,1-二基、丙-1,3-二基、丙-1,2-二基、丙-1,1-二基、丁-1,4-二基、丁-1,3-二基、丁-1,2-二基、2-甲基-丙-1,3-二基和类似基团。The term "alkylene", used alone or in combination with other terms, refers to a divalent alkyl linking group. Alkylene formally corresponds to an alkane in which two C—H bonds are replaced by the connection points of the alkylene group to the rest of the compound. The term "C_nm alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, second-1,2-diyl, second-1,1-diyl, third-1,3-diyl, third-1,2-diyl, third-1,1-diyl, fourth-1,4-diyl, fourth-1,3-diyl, fourth-1,2-diyl, 2-methyl-third-1,3-diyl and similar groups.

单独或与其他术语组合使用的术语“烷氧基”是指具有式-O-烷基的基团，其中所述烷基如上文所定义。术语“C_n-m烷氧基”是指其中烷基具有n至m个碳的烷氧基。实例烷氧基包括甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)、叔丁氧基和类似基团。在一些实施方案中，烷基具有1至6个、1至4个或1至3个碳原子。术语“C_n-m二烷氧基”是指具有式-O-(C_n-m烷基)-O-的连接基团，其中烷基具有n至m个碳原子。实例二烷氧基包括-OCH₂CH₂O-和OCH₂CH₂CH₂O-。在一些实施方案中，C_n-m二烷氧基的两个O原子可连接至同一B原子以形成5元或6元杂环烷基。The term "alkoxy" used alone or in combination with other terms refers to a group having the formula -O-alkyl, wherein the alkyl is as defined above. The term "C_nm alkoxy" refers to an alkoxy group in which the alkyl has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and similar groups. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term "C_nm dialkoxy" refers to a linking group having the formula -O-(C_nm alkyl)-O-, wherein the alkyl has n to m carbon atoms. Example dialkoxy groups include -OCH₂ CH₂ O- and OCH₂ CH₂ CH₂ O-. In some embodiments, the two O atoms of the C_nm dialkoxy group may be connected to the same B atom to form a 5-membered or 6-membered heterocycloalkyl group.

单独或与其他术语组合使用的术语“氨基”是指具有式-NH₂的基团，其中氢原子可经本文所述的取代基取代。例如，“烷氨基”可指-NH(烷基)和-N(烷基)₂。The term "amino," used alone or in combination with other terms, refers to a group having the formula_-NH2 , wherein the hydrogen atom may be substituted with a substituent as described herein. For example, "alkylamino" may refer to -NH(alkyl) and -N(alkyl)₂ .

单独或与其他术语组合使用的术语“卤基”或“卤素”是指氟、氯、溴和碘。在一些实施方案中，“卤基”是指选自F、Cl或Br的卤素原子。在一些实施方案中，卤基为F。The term "halo" or "halogen" used alone or in combination with other terms refers to fluorine, chlorine, bromine and iodine. In some embodiments, "halo" refers to a halogen atom selected from F, Cl or Br. In some embodiments, halo is F.

如本文所用的术语“卤烷基”是指其中一个或多个氢原子已由卤素原子替代的烷基。术语“C_n-m卤烷基”是指具有n至m个碳原子和至少一个至多{2(n-m)+1}个卤素原子的C_n-m烷基，其可相同或不同。在一些实施方案中，卤素原子为氟原子。在一些实施方案中，卤烷基具有1至6个或1至4个碳原子。实例卤烷基包括CF₃、C₂F₅、CHF₂、CH₂F、CCl₃、CHCl₂、C₂Cl₅和类似基团。在一些实施方案中，卤烷基为氟烷基。As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom. The term "C_nm haloalkyl" refers to a C_nm alkyl group having n to m carbon atoms and at least one up to {2(nm)+1} halogen atoms, which may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃ , C₂ F₅ , CHF₂ , CH₂ F, CCl₃ , CHCl₂ , C₂ Cl₅ and similar groups. In some embodiments, the haloalkyl group is a fluoroalkyl group.

单独或与其他术语组合使用的术语“卤烷氧基”是指具有式-O-卤烷基的基团，其中卤烷基如上文所定义。术语“C_n-m卤烷氧基”是指其中卤烷基具有n至m个碳的卤烷氧基。实例卤烷氧基包括三氟甲氧基和类似基团。在一些实施方案中，卤烷氧基具有1至6个、1至4个或1至3个碳原子。The term "haloalkoxy" used alone or in combination with other terms refers to a group with the formula -O-haloalkyl, wherein the haloalkyl is as defined above. The term "C_nm haloalkoxy" refers to a haloalkoxy group wherein the haloalkyl has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and similar groups. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

术语“氧代”或“氧基”是指作为二价取代基的氧原子，其在连接至碳时形成羰基，或连接至杂原子而形成亚砜或砜基团或N-氧化物基团。在一些实施方案中，杂环基可任选地被1或2个氧代(＝O)取代基取代。The term "oxo" or "oxy" refers to an oxygen atom as a divalent substituent, which forms a carbonyl when attached to carbon, or forms a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom. In some embodiments, the heterocyclyl group may be optionally substituted with 1 or 2 oxo (=O) substituents.

关于成环N原子的术语“被氧化”是指成环N-氧化物。The term "oxidized" with respect to a ring-forming N atom refers to a ring-forming N-oxide.

关于成环S原子的术语“被氧化”是指成环磺酰基或成环亚磺酰基。The term "oxidized" with respect to a ring-forming S atom refers to a ring-forming sulfonyl group or a ring-forming sulfinyl group.

术语“芳族基”是指具有一个或多个多元不饱和环的碳环或杂环，所述一个或多个多元不饱和环具有芳族特性(即具有(4n+2)个离域π(pi)电子，其中n为整数)。The term "aromatic group" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings having aromatic character (ie, having (4n+2) delocalized π (pi) electrons, where n is an integer).

单独或与其他术语组合使用的术语“芳基”是指芳族烃基，其可为单环或多环(例如具有2个稠合环)。术语“C_n-m芳基”是指具有n至m个环碳原子的芳基。芳基包括例如苯基、萘基和类似基团。在一些实施方案中，芳基具有6至约10个碳原子。在一些实施方案中，芳基具有6个碳原子。在一些实施方案中，芳基具有10个碳原子。在一些实施方案中，芳基为苯基。在一些实施方案中，芳基为萘基。The term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C_nm aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, and similar groups. In some embodiments, aryl groups have 6 to about 10 carbon atoms. In some embodiments, aryl groups have 6 carbon atoms. In some embodiments, aryl groups have 10 carbon atoms. In some embodiments, aryl groups are phenyl groups. In some embodiments, aryl groups are naphthyl groups.

单独或与其他术语组合使用的术语“杂芳基”或“杂芳族”是指具有至少一个选自硫、氧和氮的杂原子环成员的单环或多环芳族杂环。在一些实施方案中，杂芳基环具有1、2、3或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中，杂芳基部分中的任何成环N可为N-氧化物。在一些实施方案中，杂芳基具有5至14个环原子，其包括碳原子和1、2、3或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中，杂芳基具有5至10个环原子，其包括碳原子和1、2、3或4个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中，杂芳基具有5至6个环原子和1或2个独立地选自氮、硫和氧的杂原子环成员。在一些实施方案中，杂芳基为五元或六元杂芳基环。在其他实施方案中，杂芳基为八元、九元或十元稠合双环杂芳基环。实例杂芳基包括(但不限于)吡啶基(pyridinyl/pyridyl)、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、唑基、噁唑基、异噁唑基、噻唑基、咪唑基、呋喃基、噻吩基、喹啉基、异喹啉基、萘啶基(包括1,2-萘啶、1,3-萘啶、1,4-萘啶、1,5-萘啶、1,6-萘啶、1,7-萘啶、1,8-萘啶、2,3-萘啶和2,6-萘啶)、吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、苯并异噁唑基、咪唑并[1,2-b]噻唑基、嘌呤基和类似基团。在一些实施方案中，杂芳基为吡啶酮(例如2-吡啶酮)。The term "heteroaryl" or "heteroaromatic" used alone or in combination with other terms refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms, which include carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5 to 10 ring atoms, which include carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, heteroaryl is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl includes, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thienyl, quinolyl, isoquinolyl, naphthyridinyl (including 1,2-naphthyridine, 1,3-naphthyridine, 1,4-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,3-naphthyridine, and 2,6-naphthyridine), indolyl, isoindolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, heteroaryl is pyridone (e.g., 2-pyridone).

五元杂芳基环为具有五个环原子的杂芳基，其中一个或多个(例如1、2或3个)环原子独立地选自N、O和S。例示性五元环杂芳基包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、异噻唑基、异噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基和1,3,4-噁二唑基。A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl ring groups include thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

六元杂芳基环为具有六个环原子的杂芳基，其中一个或多个(例如1、2或3个)环原子独立地选自N、O和S。例示性六元环杂芳基为吡啶基、吡嗪基、嘧啶基、三嗪基、异吲哚基和哒嗪基。A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (eg, 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryl groups are pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

单独或与其他术语组合使用的术语“环烷基”是指非芳族烃环系统(单环、双环或多环)，包括环化的烷基和烯基。术语“C_n-m环烷基”是指具有n至m个环成员碳原子的环烷基。环烷基可包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。环烷基可具有3、4、5、6或7个成环碳(C_3-7)。在一些实施方案中，环烷基具有3至6个环成员、3至5个环成员或3至4个环成员。在一些实施方案中，环烷基为单环环烷基。在一些实施方案中，环烷基为单环或双环环烷基。在一些实施方案中，环烷基为C_3-6单环环烷基。环烷基的成环碳原子可任选地氧化以形成氧代或硫离子基。环烷基还包括环亚烷基。在一些实施方案中，环烷基为环丙基、环丁基、环戊基或环己基。环烷基的定义中还包括具有一个或多个与环烷基环稠合(即，具有共用的一键)的芳族环的部分，例如环戊烷、环己烷和类似者的苯并或噻吩基衍生物。含有稠合芳族环的环烷基可经由任何成环原子(包括稠合芳族环的成环原子)连接。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、降冰片基、降蒎基(norpinyl)、降蒈基(norcarnyl)、双环[1.1.1]戊基、双环[2.1.1]己基以及其类似基团。在一些实施方案中，环烷基为环丙基、环丁基、环戊基或环己基。在一些实施方案中，环烷基为四氢萘基(例如1,2,3,4-四氢萘基)。The term "cycloalkyl" used alone or in combination with other terms refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl. The term "C_nm cycloalkyl" refers to a cycloalkyl with n to m ring member carbon atoms. Cycloalkyl may include monocyclic or polycyclic (e.g., with 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl may have 3, 4, 5, 6 or 7 ring carbons (C_3-7 ). In some embodiments, cycloalkyl has 3 to 6 ring members, 3 to 5 ring members or 3 to 4 ring members. In some embodiments, cycloalkyl is a monocyclic cycloalkyl. In some embodiments, cycloalkyl is a monocyclic or bicyclic cycloalkyl. In some embodiments, cycloalkyl is a C_3-6 monocyclic cycloalkyl. The ring carbon atoms of cycloalkyl may be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylidene. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The definition of cycloalkyl also includes a part having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a shared key), such as benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. The cycloalkyl containing the fused aromatic ring can be connected via any ring-forming atom (including the ring-forming atom of the fused aromatic ring). The example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl and its similar groups. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, cycloalkyl is tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphthyl).

单独或与其他术语组合使用的术语“杂环烷基”是指非芳族环或环系统，其可任选地含有一个或多个作为环结构的部分的亚烯基，其具有至少一个独立地选自氮、硫、氧和磷的杂原子环成员，并且其具有4至10个环成员、4至7个环成员或4至6个环成员。术语“杂环烷基”内包括4元、5元、6元和7元单环杂环烷基。杂环烷基可包括单环或双环(例如，具有两个稠合或桥接环)环系统或螺环环系统。在一些实施方案中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可任选地被氧化以形成氧代或硫离子基或其他氧化键(例如，C(O)、S(O)、C(S)或S(O)₂、N-氧化物等)，或氮原子可经季铵化。杂环烷基可经由成环碳原子或成环杂原子连接。在一些实施方案中，杂环烷基含有0至3个双键。在一些实施方案中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与杂环烷基环具有共同键)的芳族环的部分，例如哌啶、吗啉、氮杂卓等的苯并或噻吩基衍生物。含有稠合芳族环的杂环烷基可经由包括稠合芳族环的成环原子的任何成环原子连接。杂环烷基的实例包括2,5-二氮杂双环[2.2.1]庚烯基；吡咯烷基；六氢吡咯并[3,4-b]吡咯-1(2H)-基；1,6-二氢吡啶基；吗啉基；氮杂环丁烷基；哌嗪基；以及4,7-二氮螺[2.5]辛-7-基。The term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4 to 10 ring members, 4 to 7 ring members or 4 to 6 ring members. The term "heterocycloalkyl" includes 4-, 5-, 6- and 7-membered monocyclic heterocycloalkyls. Heterocycloalkyls may include monocyclic or bicyclic (e.g., having two fused or bridged rings) ring systems or spirocyclic ring systems. In some embodiments, heterocycloalkyls are monocyclic groups with 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyls may be optionally oxidized to form oxo or sulfide ion groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O)₂ , N-oxides, etc.), or nitrogen atoms may be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion of an aromatic ring having one or more fused to a heterocycloalkyl ring (i.e., having a common bond with a heterocycloalkyl ring), such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atom including the ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl include 2,5-diazabicyclo [2.2.1] heptenyl; pyrrolidinyl; hexahydropyrrolo [3,4-b] pyrrole -1 (2H) -yl; 1,6-dihydropyridyl; morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro [2.5] octane -7-yl.

在某些地方，定义或实施方案是指特定环(例如，氮杂环丁烷环、吡啶环等)。除非另外指示，否则这些环可连接至任何环成员，其限制条件为不超出原子的价数。例如，氮杂环丁烷环可在环的任何位置处连接，而氮杂环丁烷-3-基环在3-位置处连接。In some places, definition or embodiment refers to a specific ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings may be connected to any ring member, with the restriction that the valence of the atom is not exceeded. For example, an azetidine ring may be connected at any position of the ring, while an azetidine-3-yl ring is connected at the 3-position.

本文所述的化合物可为不对称的(例如具有一个或多个立体中心)。除非另外指明，否则意指所有立体异构体，诸如对映异构体和非对映异构体。含有经不对称取代的碳原子的本发明的化合物可以光学活性或外消旋形式分离。本领域中已知如何自光学非活性起始物质制备光学活性形式的方法，诸如拆分外消旋混合物或立体选择性合成。烯烃、C＝N双键和类似者的许多几何异构体也可存在于本文所描述的化合物中，并且所有此类稳定异构体均涵盖于本发明中。已描述本发明化合物的顺式和反式几何异构体并且其可以异构体混合物形式或以分离的异构体形式分离。The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods of preparing optically active forms from optically inactive starting materials, such as resolving racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of alkenes, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are encompassed in the present invention. Cis and trans geometric isomers of the compounds of the present invention have been described and can be separated in the form of isomeric mixtures or in the form of separated isomers.

化合物的外消旋混合物的拆分可通过本领域中已知的许多方法中的任一者来进行。一种方法包括使用手性拆分酸进行分步再结晶，所述手性拆分酸为光学活性成盐有机酸。用于分步再结晶方法的适合拆分剂为例如光学活性酸，诸如酒石酸的D和L形式、二乙酰基酒石酸、二苯甲酰基酒石酸、杏仁酸、苹果酸、乳酸或各种光学活性樟脑磺酸(诸如β-樟脑磺酸)。适用于分步结晶方法的其他拆分剂包括α-甲基苯甲胺(例如S和R形式或非对映异构纯形式)、2-苯甘氨醇、降麻黄碱(norephedrine)、麻黄碱(ephedrine)、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷和其类似物的立体异构纯形式。The resolution of the racemic mixture of compound can be carried out by any one of many methods known in the art. One method includes using chiral resolution acid to carry out fractional recrystallization, and the chiral resolution acid is an optically active salified organic acid. Suitable resolution agents for fractional recrystallization method are, for example, optically active acids, such as tartaric acid D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids (such as β-camphorsulfonic acid). Other resolution agents suitable for fractional crystallization method include α-methylbenzylamine (such as S and R forms or diastereoisomeric pure forms), 2-phenylglycinol, norephedrine (norephedrine), ephedrine (ephedrine), N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the stereoisomeric pure forms of its analogs.

外消旋混合物的拆分也可通过装填有光学活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的柱洗脱来进行。适合的洗脱溶剂组合物可通过本领域的技术人员来确定。The resolution of the racemic mixture can also be carried out by eluting with a column filled with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

在一些实施方案中，本发明化合物具有(R)-构型。在其他实施方案中，所述化合物具有(S)-构型。在具有超过一个手性中心的化合物中，除非另外指示，否则化合物中的各手性中心可独立地为(R)或(S)。In some embodiments, the compounds of the invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, unless otherwise indicated, each chiral center in the compound may independently be (R) or (S).

本发明的化合物还包括互变异构形式。互变异构形式由单键与相邻双键的交换以及伴随的质子迁移而产生。互变异构形式包括处于具有相同经验式和总电荷的异构质子化状态的质子转移互变异构体。实例质子转移互变异构体包括酮-烯醇对、酰胺-亚胺酸对、内酰胺-内酰亚胺对、烯胺-亚胺对和其中质子可占据杂环系统的两个或更多个位置的环形形式，例如1H-咪唑和3H-咪唑、1H-1,2,4-三唑、2H-1,2,4-三唑和4H-1,2,4-三唑、1H-异吲哚和2H-异吲哚以及1H-吡唑和2H-吡唑。互变异构形式可处于平衡状态或通过适当取代而在空间上锁定为一种形式。Compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers in isomeric protonation states with the same empirical formula and total charge. Example proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms in which protons can occupy two or more positions of heterocyclic systems, such as 1H-imidazoles and 3H-imidazoles, 1H-1,2,4-triazoles, 2H-1,2,4-triazoles and 4H-1,2,4-triazoles, 1H-isoindoles and 2H-isoindoles and 1H-pyrazoles and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

本发明的化合物还可包括中间体或最终化合物中出现的原子的所有同位素。同位素包括具有相同原子数但质量数不同的那些原子。例如，氢的同位素包括氚和氘。本发明的化合物的一个或多个组成原子可经天然或非天然丰度的原子同位素替代或取代。在一些实施方案中，化合物包括至少一个氘原子。例如，本公开的化合物中的一个或多个氢原子可经氘替代或取代。在一些实施方案中，化合物包括两个或更多个氘原子。在一些实施方案中，化合物包括1、2、3、4、5、6、7、8、9、10、11或12个氘原子。使有机化合物中包括同位素和合成方法是本领域中已知的(Alan F.Thomas的Deuterium Labeling in Organic Chemistry(New York,N.Y.,Appleton-Century-Crofts,1971；Jens Atzrodt、Volker Derdau、Thorsten Fey和Jochen Zimmermann的The Renaissance of H/D Exchange,Angew.Chem.网路版2007,7744-7765；James R.Hanson的The Organic Chemistry of IsotopicLabelling，Royal Society of Chemistry,2011)。同位素标记的化合物可用于各种研究中，诸如NMR光谱法、代谢实验和/或测定。The compounds of the present invention may also include all isotopes of atoms that appear in the intermediate or final compound. Isotopes include those atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be substituted or replaced by atomic isotopes of natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be substituted or replaced by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Including isotopes in organic compounds and synthetic methods are known in the art (Alan F. Thomas, Deuterium Labeling in Organic Chemistry (New York, N.Y., Appleton-Century-Crofts, 1971); Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, The Renaissance of H/D Exchange, Angew. Chem. Web Edition 2007, 7744-7765; James R. Hanson, The Organic Chemistry of Isotopic Labelling, Royal Society of Chemistry, 2011). Isotopically labeled compounds are useful in various studies, such as NMR spectroscopy, metabolic experiments and/or assays.

经诸如氘的较重同位素取代可获得由更大代谢稳定性产生的某些治疗优势，例如增加的体内半衰期或降低的剂量需求，并且因此在一些情况下可为优选的。(A.Kerekes等人,J.Med.Chem.2011,54,201-210；R.Xu等人,J.Label Compd.Radiopharm.2015,58,308-312)。Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312).

如本文中所用，术语“化合物”意图包括所描绘结构的所有立体异构体、几何异构体、互变异构体和同位素。术语还意指以任何方式制备，例如以合成方式、经由生物过程(例如，代谢或酶转化)或其组合制备的本发明的化合物。As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the depicted structure. The term also means a compound of the invention prepared in any manner, such as synthetically, via a biological process (e.g., metabolic or enzymatic conversion) or a combination thereof.

所有化合物及其药学上可接受的盐均可与诸如水和溶剂(例如水合物和溶剂化物)的其他物质一起存在或可经分离。当处于固态时，本文所述的化合物及其盐可以各种形式存在，并且可例如采取包括水合物在内的溶剂化物的形式。化合物可呈任何固态形式，诸如多晶型物或溶剂化物，因此除非另外明确指示，否则本说明书中对化合物及其盐的提及应理解为涵盖化合物的任何固态形式。All compounds and their pharmaceutically acceptable salts may exist together with other substances such as water and solvents (e.g., hydrates and solvates) or may be separated. When in the solid state, the compounds described herein and their salts may exist in various forms and may, for example, take the form of solvates including hydrates. The compound may be in any solid state form, such as a polymorph or solvate, so unless otherwise expressly indicated, reference to the compound and its salt in this specification should be understood to cover any solid state form of the compound.

在一些实施方案中，本发明的化合物或其盐是基本上分离的。“基本上分离”意指所述化合物至少部分或基本上与其形成或检测所在的环境分离。部分分离可包括例如富含本发明的化合物的组合物。基本分离可包括含有按本发明的化合物的重量计的至少约50％、至少约60％、至少约70％、至少约80％、至少约90％、至少约95％、至少约97％或至少约99％的组合物或其盐。In some embodiments, the compounds of the present invention or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the present invention. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the weight of the compound of the present invention, or its salt.

短语“药学上可接受”在本文中用于指在合理医学判断范围内，适用于与人类和动物的组织接触而无过度毒性、刺激、过敏反应或其他问题或并发症、与合理益处/风险比相称的那些化合物、材料、组合物和/或剂型。The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

如本文所用，表述“环境温度”和“室温”为本领域中所理解的，并且通常指温度，例如反应温度，其约为在其中进行反应的室温，例如约20℃至约30℃的温度。As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to temperatures, such as reaction temperatures, which are about room temperature in which the reaction is conducted, such as temperatures of about 20°C to about 30°C.

本发明还包括本文中所描述的化合物的药学上可接受的盐。术语“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物通过将现有酸或碱部分转化为其盐形式而经修饰。药学上可接受的盐的实例包括(但不限于)碱性残基(诸如胺)的无机或有机酸盐；酸性残基(诸如羧酸)的碱盐或有机盐；以及其类似者。本发明的药学上可接受的盐包括例如由无毒性无机酸或有机酸形成的母体化合物的无毒性盐。本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。一般而言，此类盐可通过使这些化合物的游离酸或碱形式与化学计算量的适当碱或酸于水或有机溶剂或两者的混合物中反应而制备；一般而言，非水性介质如醚、乙酸乙酯、醇(例如，甲醇、乙醇、异丙醇或丁醇)或乙腈(MeCN)为优选的。适合的盐的清单发现于Remington's PharmaceuticalSciences,第17版,(Mack Publishing Company,Easton,1985),第1418页,Berge等人,J.Pharm.Sci.,1977,66(1),1-19中，并且发现于Stahl等人,Handbook of PharmaceuticalSalts:Properties,Selection,and Use,(Wiley,2002)中。在一些实施方案中，本文所描述的化合物包括N-氧化物形式。The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed by non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th edition, (Mack Publishing Company, Easton, 1985), page 1418, Berge et al., J. Pharm. Sci., 1977, 66 (1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

合成synthesis

本发明的化合物(包括其盐)可使用已知有机合成技术制备，并且可根据诸多可能合成途径(诸如下文流程中的那些途径)中的任一者合成。The compounds of the present invention, including salts thereof, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below.

用于制备本发明化合物的反应可在熟习有机合成技术者容易选择的适合溶剂中进行。在反应进行的温度(例如范围可为溶剂冷冻温度至溶剂沸腾温度的温度)下，适合溶剂可基本上与起始物质(反应物)、中间体或产物不反应。指定反应可在一种溶剂或超过一种溶剂的混合物中进行。取决于特定反应步骤，适用于特定反应步骤的溶剂可通过本领域的技术人员选择。The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by a person skilled in the art of organic synthesis. At the temperature at which the reaction is carried out (e.g., a temperature ranging from the solvent freezing temperature to the solvent boiling temperature), a suitable solvent may be substantially unreactive with the starting material (reactant), intermediate or product. A given reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction step, a solvent suitable for a specific reaction step can be selected by a person skilled in the art.

本发明的化合物的制备可涉及各种化学基团的保护和脱保护。本领域的技术人员可容易地判定是否需要保护和脱保护，以及对适当保护基的选择。保护基的化学性描述于例如Kocienski,Protecting Groups,(Thieme,2007)；Robertson,Protecting GroupChemistry,(Oxford University Press,2000)；Smith等人，March's Advanced OrganicChemistry:Reactions,Mechanisms,and Structure,第6版(Wiley,2007)；Peturssion等人，“Protecting Groups in Carbohydrate Chemistry”,J.Chem.Educ.,1997,74(11),1297；以及Wuts等人,Protective Groups in Organic Synthesis，第4版，(Wiley,2006)中。The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine whether protection and deprotection are required, as well as the selection of appropriate protecting groups. The chemistry of protecting groups is described in, for example, Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry", J. Chem. Educ., 1997, 74 (11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th edition, (Wiley, 2006).

反应可根据本领域中已知的任何适合方法来进行监测。例如，产物形成可通过光谱手段(诸如核磁共振光谱法(例如¹H或¹³C)、红外光谱法、分光光度法(例如UV可见)、质谱或通过色谱法(诸如高效液相色谱(HPLC)或薄层色谱(TLC))加以监测。The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g.,¹ H or¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry, or by chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography (TLC)).

以下流程提供关于制备本发明的化合物的一般指导。本领域的技术人员将理解，可使用有机化学的常识修改或优化流程中所展示的制备，以制备各种本发明的化合物。The following schemes provide general guidance for preparing compounds of the present invention. Those skilled in the art will appreciate that the preparations shown in the schemes can be modified or optimized using common knowledge of organic chemistry to prepare a variety of compounds of the present invention.

流程1Process 1

式1-12的化合物可经由流程1中所概述的合成途径制备。用诸如N-氯代二酰亚胺(NCS)的适当试剂使起始物质1-1卤化，得到中间体1-2(Hal为卤化物，诸如F、Cl、Br或I)。中间体1-4可随后通过中间体1-2与2-(乙氧基亚甲基)丙二酸二乙酯(1-3)的缩合来制备，随后通过在适当高沸点溶剂(例如Ph₂O)中加热来环化以得到喹啉酮1-5。用POCl₃处理中间体1-5，得到中间体1-6。用还原剂(诸如DIBAL)还原乙酯，接着用诸如戴斯-马丁高碘烷的适当试剂来氧化醇，得到中间体1-7。使用肼1-8(PG为适当保护基，诸如Boc)的环化反应产生三环加合物1-9。可通过在标准铃木交叉偶合条件下(例如，在钯催化剂和适合的碱的存在下)，或在标准施蒂勒交叉偶合条件下(例如，在钯催化剂的存在下)，或在标准根岸交叉偶合条件下(例如，在钯催化剂的存在下)使1-9与式1-10(其中M为硼酸、硼酸酯或经适当取代的金属[例如，M为B(OR)₂、Sn(烷基)₃或Zn-Hal])的加合物相偶合来制备化合物1-11。去除1-11中的保护基并且随后对所得加合物进行官能化(诸如与酰氯(例如丙烯酰氯)偶合)，得到所需产物1-12。Compounds of formula 1-12 can be prepared via the synthetic routes outlined in Scheme 1. Halogenation of starting material 1-1 with a suitable reagent such as N-chlorodiimide (NCS) provides intermediate 1-2 (Hal is a halide such as F, Cl, Br or I). Intermediate 1-4 can then be prepared by condensation of intermediate 1-2 with diethyl 2-(ethoxymethylene)malonate (1-3), followed by cyclization by heating in a suitable high boiling solvent (e.g.,_Ph2O ) to provide quinolinone 1-5. Treatment of intermediate_1-5 with POCl3 provides intermediate 1-6. Reduction of the ethyl ester with a reducing agent such as DIBAL followed by oxidation of the alcohol with a suitable reagent such as Dess-Martin periodinane provides intermediate 1-7. Cyclization using hydrazine 1-8 (PG is a suitable protecting group such as Boc) produces the tricyclic adduct 1-9. Compound 1-11 can be prepared by coupling 1-9 with an adduct of formula 1-10 (wherein M is a boronic acid, a boronate ester, or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(alkyl) 3 or Zn-Hal]) under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stiller cross-coupling conditions (e.g._, in the presence of a palladium catalyst), or under standard Negishi_cross -coupling conditions (e.g., in the presence of a palladium catalyst). Removal of the protecting groups in 1-11 and subsequent functionalization of the resulting adduct (such as coupling with an acyl chloride (e.g., acryloyl chloride)) affords the desired product 1-12.

流程2Process 2

式2-13的化合物可经由流程2中所概述的合成途径制备。用诸如N-氯代二酰亚胺(NCS)的适当试剂使起始物质2-1卤化，得到中间体2-2(Hal为卤化物，诸如F、Cl、Br或I)。可通过用诸如2,2-二甲基-1,3-二噁烷-4,6-二酮(2-3)的试剂处理2-2来制备化合物2-4。中间体2-4可惊醒环化反应(在热条件下在聚磷酸中)以传递化合物2-5，所述化合物可用适当试剂(例如POCl₃)处理以得到化合物2-6。中间体2-6可用适当试剂(诸如含LDA的THF，接着DMF)处理以产生化合物2-7。可进行中间体2-7与胺2-8的缩合(PG为适当保护基，诸如Boc)以产生化合物2-9。2-10中的R³基团可随后经由适合转化(诸如S_NAr反应或偶合反应)安装。中间体2-10可首先进行保护基PG的脱保护，接着对所得胺进行官能化(诸如与酰氯(例如丙烯酰氯)偶合)，接着得到化合物2-11。可通过在标准铃木交叉偶合条件下(例如，在钯催化剂和适合的碱的存在下)，或在标准施蒂勒交叉偶合条件下(例如，在钯催化剂的存在下)，或在标准根岸交叉偶合条件下(例如，在钯催化剂的存在下)使2-11与式2-12(其中M为硼酸、硼酸酯或经适当取代的金属[例如，M为B(OR)₂、Sn(烷基)₃或Zn-Hal])的加合物之间发生交叉偶合反应来制备所需产物2-13。上文所描述的化学反应的次序可按需要重新配置以适合不同类似物的制备。Compounds of formula 2-13 can be prepared via the synthetic pathways outlined in Scheme 2. Starting material 2-1 is halogenated with an appropriate reagent such as N-chlorodiimide (NCS) to give intermediate 2-2 (Hal is a halide such as F, Cl, Br or I). Compound 2-4 can be prepared by treating 2-2 with a reagent such as 2,2-dimethyl-1,3-dioxane-4,6-dione (2-3). Intermediate 2-4 can undergo a cyclization reaction (under thermal conditions in polyphosphoric acid) to deliver compound 2-5, which can be treated with an appropriate reagent (e.g., POCl₃ ) to give compound 2-6. Intermediate 2-6 can be treated with an appropriate reagent (such as LDA in THF followed by DMF) to produce compound 2-7. Condensation of intermediate 2-7 with amine 2-8 (PG is a suitable protecting group such as Boc) can be carried out to produce compound 2-9. The^R3 group in 2-10 can then be installed via a suitable transformation such as an S_N Ar reaction or a coupling reaction. Intermediate 2-10 can first be subjected to deprotection of the protecting group PG, followed by functionalization of the resulting amine (such as coupling with an acyl chloride (e.g., acryloyl chloride)), followed by compound 2-11. The desired product 2-13 can be prepared by cross-coupling reaction between 2-11 and an adduct of formula 2-12 (wherein M is a boronic acid, a boronate ester, or a suitably substituted metal [e.g., M is B(OR)2, Sn(alkyl)3, or Zn-Hal]) under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stiller cross-coupling conditions (e.g._, in the presence of a palladium catalyst), or under standard_Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). The order of chemical reactions described above can be rearranged as necessary to accommodate the preparation of different analogs.

流程3Process 3

式3-16的化合物可经由流程3中所概述的合成途径制备。在乙醇中用H₂SO₄酯化市售起始物质3-1。用诸如N-氯代二酰亚胺(NCS)的适当试剂使化合物3-2卤化，得到中间体3-3(Hal为卤化物，诸如F、Cl、Br或I)。可通过用诸如乙基丙二酰氯(3-4)的试剂处理3-3来制备化合物3-5。中间体3-5可进行环化反应(诸如乙醇中的乙醇钠)以传递化合物3-6，其可用适当试剂(例如POCl₃)处理，得到化合物3-7。可进行中间体3-7与胺3-8的缩合(PG为适当保护基，诸如Boc)以产生化合物3-9。用还原剂(诸如DIBAL)还原酯，之后用氧化剂(诸如戴斯-马丁高碘烷)氧化中间体，得到醛3-10。用羟胺盐酸盐和吡啶处理中间体3-10，得到化合物3-11。中间体3-11可进行环化反应(诸如甲磺酰氯、氨基吡啶于DCM中)，以传递化合物3-12。3-13中的R³基团可随后经由适合转化(诸如S_NAr反应或偶合反应)安装。中间体3-13可首先进行保护基PG的脱保护，接着对所得胺进行官能化(诸如与酰氯(例如丙烯酰氯)偶合)，接着得到化合物3-14。可通过在标准铃木交叉偶合条件下(例如，在钯催化剂和适合的碱的存在下)，或在标准施蒂勒交叉偶合条件下(例如，在钯催化剂的存在下)，或在标准根岸交叉偶合条件下(例如，在钯催化剂的存在下)使3-14与式3-15(其中M为硼酸、硼酸酯或经适当取代的金属[例如，M为B(OR)₂、Sn(烷基)₃或Zn-Hal])的加合物之间发生交叉偶合反应来制备所需产物3-16。上文所描述的化学反应的次序可按需要重新配置以适合不同类似物的制备。Compounds of formula 3-16 can be prepared via the synthetic pathways outlined in Scheme 3. Commercially available starting material 3-1_is esterified with_H2SO4 in ethanol. Compound 3-2 is halogenated with a suitable reagent such as N-chlorodiimide (NCS) to give intermediate 3-3 (Hal is a halide such as F, Cl, Br or I). Compound 3-5 can be prepared by treating 3-3 with a reagent such as ethylmalonyl chloride (3-4). Intermediate 3-5 can undergo a cyclization reaction (such as sodium ethoxide in ethanol) to deliver compound 3-6, which can be treated with a suitable reagent (e.g.,_POCl3 ) to give compound 3-7. Condensation of intermediate 3-7 with amine 3-8 (PG is a suitable protecting group such as Boc) can be carried out to produce compound 3-9. Reduction of the ester with a reducing agent such as DIBAL followed by oxidation of the intermediate with an oxidizing agent such as Dess-Martin periodinane gives aldehyde 3-10. Intermediate 3-10 is treated with hydroxylamine hydrochloride and pyridine to give compound 3-11. Intermediate 3-11 can be subjected to a cyclization reaction (such as methanesulfonyl chloride, aminopyridine in DCM) to deliver compound 3-12. The^R3 group in 3-13 can then be installed via a suitable transformation (such as an S_N Ar reaction or a coupling reaction). Intermediate 3-13 can first be subjected to deprotection of the protecting group PG, followed by functionalization of the resulting amine (such as coupling with an acyl chloride (e.g., acryloyl chloride)), followed by compound 3-14. The desired product 3-16 can be prepared by cross-coupling reaction between 3-14 and an adduct of formula 3-15 (wherein M is a boronic acid, a boronate ester, or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(alkyl)₃ or Zn-Hal]) under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stiller cross-coupling conditions (e.g., in the presence of a palladium catalyst), or under_standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst). The order of the chemical reactions described above can be rearranged as desired to accommodate the preparation of different analogs.

流程4Process 4

式4-6的化合物可经由流程4中所概述的合成途径制备。中间体3-10经由适合转化(诸如S_NAr反应或偶合反应)转化为化合物4-1。醛4-1与(甲氧基甲基)三苯基氯化鏻和叔丁醇钾于THF中发生维蒂希反应(Wittig reaction)得到化合物4-2。中间体4-2可进行环化反应(诸如TFA于DCM中)以传递化合物4-3。可通过在标准铃木交叉偶合条件下(例如，在钯催化剂和适合的碱的存在下)，或在标准施蒂勒交叉偶合条件下(例如，在钯催化剂的存在下)，或在标准根岸交叉偶合条件下(例如，在钯催化剂的存在下)使4-3与式4-4(其中M为硼酸、硼酸酯或经适当取代的金属[例如，M为B(OR)₂、Sn(烷基)₃或Zn-Hal])的加合物之间发生交叉偶合反应来制备中间体4-5。化合物4-5可首先进行保护基PG的脱保护，接着对所得胺进行官能化(诸如与酰氯(例如丙烯酰氯)偶合)，接着得到化合物4-6。上文所描述的化学反应的次序可按需要重新配置以适合不同类似物的制备。Compounds of formula 4-6 can be prepared via the synthetic routes outlined in Scheme 4. Intermediate 3-10 is converted to compound 4-1 via a suitable transformation such as an_SN Ar reaction or a coupling reaction. Aldehyde 4-1 undergoes a Wittig reaction with (methoxymethyl)triphenylphosphonium chloride and potassium tert-butoxide in THF to provide compound 4-2. Intermediate 4-2 can undergo a cyclization reaction such as TFA in DCM to deliver compound 4-3. Intermediate 4-5 can be prepared by a cross coupling reaction between 4-3 and an adduct of formula 4-4 (wherein M is a boronic acid, a boronate ester, or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(alkyl) 3 or Zn-Hal]) under standard Suzuki cross coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or under standard Stiller cross coupling conditions (e.g., in the presence of a palladium catalyst), or under_standard Negishi cross coupling conditions (_e.g. , in the presence of a palladium catalyst). Compound 4-5 can first undergo deprotection of the protecting group PG, followed by functionalization of the resulting amine (such as coupling with an acyl chloride (e.g., acryloyl chloride)), and then provide compound 4-6. The order of the chemical reactions described above can be rearranged as needed to accommodate the preparation of different analogs.

流程5Process 5

式5-18的化合物可经由流程5中所概述的合成途径制备。用诸如N-氯-丁二酰亚胺(NCS)的适当试剂使起始物质5-1卤化，得到中间体5-2(Hal为卤化物，诸如F、Cl、Br或I)。可通过用诸如三光气的试剂处理5-2来制备化合物5-3。中间体5-3可随后与酯5-4反应以提供硝基化合物5-5，其可用适当试剂(例如POCl₃)处理，得到化合物5-6。可进行中间体5-6与胺5-7的S_NAr反应(PG为适当保护基，诸如Boc)以产生化合物5-8。5-9中的R³基团可随后经由适合转化(诸如S_NAr反应或偶合反应)安装。保护氨基获得中间体5-10，其可在还原剂(例如Fe于乙酸中)存在下还原，得到5-11。5-11(Hal)的卤素可任选地被由过渡金属介导的偶合或其他适合方法转化成R²以获得5-12。重氮化和使5-12中的氨基还原得到中间体5-13，其在保护基(PG)去除之后得到5-14。5-14中溴的偶合得到5-15，其可经卤化以得到中间体5-16。薗头偶合得到5-17，其在环化之后脱保护，得到式5-18的化合物。Compounds of formula 5-18 can be prepared via the synthetic pathways outlined in Scheme 5. Starting material 5-1 is halogenated with a suitable reagent such as N-chloro-succinimide (NCS) to give intermediate 5-2 (Hal is a halide such as F, Cl, Br or I). Compound 5-3 can be prepared by treating 5-2 with a reagent such as triphosgene. Intermediate 5-3 can then react with ester 5-4 to provide nitro compound 5-5, which can be treated with a suitable reagent (e.g.,_POCl3 ) to give compound 5-6._SN Ar reaction of intermediate 5-6 with amine 5-7 (PG is a suitable protecting group such as Boc) can be carried out to produce compound 5-8. The^R3 group in 5-9 can then be installed via a suitable transformation such as a_SN Ar reaction or a coupling reaction. Protection of the amino group affords intermediate 5-10, which can be reduced in the presence of a reducing agent (e.g., Fe in acetic acid) to afford 5-11. The halogen of 5-11 (Hal) can optionally be converted to^R2 by transition metal-mediated coupling or other suitable methods to afford 5-12. Diazotization and reduction of the amino group in 5-12 affords intermediate 5-13, which after removal of the protecting group (PG) affords 5-14. Coupling of the bromine in 5-14 affords 5-15, which can be halogenated to afford intermediate 5-16. Sonogashira coupling affords 5-17, which after cyclization is deprotected to afford compounds of formula 5-18.

流程6Process 6

式6-6的化合物可经由流程6中所概述的合成途径制备。使5-16与经M(B、Sn、Si、Zn)取代的乙烯基醚6-1偶合得到中间体6-2，其在酸性条件(例如TFA)下处理后产生6-3。卤化6-3得到6-4，其可经由偶合或其他适合的转换转化为衍生物6-5。接着使6-5脱保护，得到式6-6的化合物。Compounds of formula 6-6 can be prepared via the synthetic route outlined in Scheme 6. Coupling 5-16 with M (B, Sn, Si, Zn) substituted vinyl ether 6-1 affords intermediate 6-2, which upon treatment under acidic conditions (e.g., TFA) yields 6-3. Halogenation of 6-3 affords 6-4, which can be converted to derivative 6-5 via coupling or other suitable transformations. Deprotection of 6-5 then affords compounds of formula 6-6.

KRAS蛋白KRAS protein

Ras家族由三个成员构成：KRAS、NRAS和HRAS。RAS突变型癌症占人类癌症的约25％。KRAS为人类癌症中最常突变的同工型：所有RAS突变中的85％在KRAS中，12％在NRAS中，并且3％在HRAS中(Simanshu,D等人Cell 170.1(2017):17-33)。KRAS突变在前三种最致命的癌症类型中普遍存在：胰腺癌(97％)、结肠直肠癌(44％)和肺癌(30％)(Cox,A.D.等人Nat Rev Drug Discov(2014)13:828-51)。大部分RAS突变出现在氨基酸残基/密码子12、13和61处；密码子12突变在KRAS中最常见。特定突变的频率在RAS基因之间变化，并且G12D突变在KRAS中最占主导，而Q61R和G12R突变在NRAS和HRAS中最常见。此外，RAS同工型中的突变谱在癌症类型之间有所不同。例如，KRAS G12D突变在胰腺癌(51％)中占主导，其次是结肠直肠腺癌(45％)和肺癌(17％)(Cox,A.D.等人Nat Rev Drug Discov(2014)13:828-51)。相比之下，KRAS G12C突变分别在非小细胞肺癌(NSCLC)，包含11-16％的肺腺癌(近一半突变KRAS为G12C)，以及2-5％的胰腺和结肠直肠腺癌中占主导(Cox,A.D.等人Nat.Rev.DrugDiscov.(2014)13:828-51)。使用shRNA阻断跨数百个癌细胞系的数千个基因，基因组研究已证明，展现KRAS突变的癌细胞高度依赖于KRAS功能来实现细胞生长(McDonald,R.等人Cell 170(2017):577-592)。综合来说，这些研究结果表明，KRAS突变在人类癌症中起关键作用；因此，开发靶向突变KRAS的抑制剂可用于临床治疗以KRAS突变为特征的疾病。The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS mutant cancers account for about 25% of human cancers. KRAS is the most commonly mutated isoform in human cancers: 85% of all RAS mutations are in KRAS, 12% in NRAS, and 3% in HRAS (Simanshu, D et al. Cell 170.1 (2017): 17-33). KRAS mutations are prevalent in the top three most lethal cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (Cox, A.D. et al. Nat Rev Drug Discov (2014) 13: 828-51). Most RAS mutations occur at amino acid residues/codons 12, 13, and 61; codon 12 mutations are most common in KRAS. The frequency of specific mutations varies between RAS genes, and G12D mutations are most dominant in KRAS, while Q61R and G12R mutations are most common in NRAS and HRAS. In addition, the mutation spectrum in RAS isoforms varies between cancer types. For example, KRAS G12D mutations are dominant in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%) (Cox, A.D. et al. Nat Rev Drug Discov (2014) 13: 828-51). In contrast, KRAS G12C mutations are dominant in non-small cell lung cancer (NSCLC), lung adenocarcinomas containing 11-16% (nearly half of the mutant KRAS is G12C), and pancreatic and colorectal adenocarcinomas of 2-5%, respectively (Cox, A.D. et al. Nat. Rev. Drug Discov. (2014) 13: 828-51). Using shRNA to block thousands of genes across hundreds of cancer cell lines, genomic studies have demonstrated that cancer cells displaying KRAS mutations are highly dependent on KRAS function for cell growth (McDonald, R. et al. Cell 170 (2017): 577-592). Taken together, these findings suggest that KRAS mutations play a key role in human cancer; therefore, the development of inhibitors targeting mutant KRAS could be used to clinically treat diseases characterized by KRAS mutations.

使用方法How to use

涉及具有G12C、G12V和G12D突变的KRAS的癌症类型包括但不限于：癌瘤(例如胰腺癌、结肠直肠癌、肺癌、膀胱癌、胃癌、食道癌、乳腺癌、头颈癌、宫颈癌、皮肤癌、甲状腺癌)；造血性恶性病(例如骨髓增生性赘瘤(MPN)、骨髓发育不良综合征(MDS)、慢性和幼年型粒单核细胞白血病(CMML和JMML)、急性骨髓性白血病(AML)、急性淋巴细胞性白血病(ALL)和多发性骨髓瘤(MM))；以及其他赘瘤(例如神经胶质母细胞瘤和肉瘤)。另外，在抗EGFR疗法的获得性耐药中发现KRAS突变(Knickelbein,K.等人Genes&Cancer,(2015):4-12)。KRAS突变在免疫和发炎性病症中发现(Fernandez-Medarde,A.等人Genes&Cancer,(2011):344-358)，诸如由KRAS或NRAS的体细胞突变引起的Ras相关淋巴增生性病症(RALD)或幼年型粒单核细胞白血病(JMML)。Cancer types involving KRAS with G12C, G12V, and G12D mutations include, but are not limited to: carcinomas (e.g., pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, thyroid cancer); hematopoietic malignancies (e.g., myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), chronic and juvenile myelomonocytic leukemias (CMML and JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and multiple myeloma (MM)); and other neoplasms (e.g., glioblastoma and sarcoma). In addition, KRAS mutations have been found in acquired resistance to anti-EGFR therapy (Knickelbein, K. et al. Genes & Cancer, (2015): 4-12). KRAS mutations are found in immune and inflammatory disorders (Fernandez-Medarde, A. et al. Genes & Cancer, (2011): 344-358), such as Ras-associated lymphoproliferative disorder (RALD) or juvenile myelomonocytic leukemia (JMML), which are caused by somatic mutations of KRAS or NRAS.

本公开的化合物可抑制KRAS蛋白的活性。例如，本公开的化合物可用于通过向细胞、个体或患者施用抑制量的一种或多种本公开的化合物来抑制细胞或需要抑制酶的个体或患者中KRAS的活性。The compounds of the present disclosure can inhibit the activity of the KRAS protein. For example, the compounds of the present disclosure can be used to inhibit the activity of KRAS in cells or individuals or patients in need of enzyme inhibition by administering an inhibitory amount of one or more compounds of the present disclosure to the cells, individuals or patients.

作为KRAS抑制剂，本公开的化合物可用于治疗与KRAS的异常表达或活性相关的各种疾病。抑制KRAS的化合物将可用于提供一种在肿瘤中预防生长或诱导细胞凋亡或通过抑制血管生成的手段。因此，预期本公开的化合物将证明可用于治疗或预防增生性病症，诸如癌症。特别地，具有受体酪氨酸激酶的活化突变体或受体酪氨酸激酶上调的肿瘤可对抑制剂特别敏感。As KRAS inhibitors, the compounds of the present disclosure can be used to treat various diseases associated with abnormal expression or activity of KRAS. Compounds that inhibit KRAS will be useful for providing a means of preventing growth or inducing apoptosis in tumors or by inhibiting angiogenesis. Therefore, it is expected that the compounds of the present disclosure will prove useful for treating or preventing proliferative disorders, such as cancer. In particular, tumors with activated mutants of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

在一方面中，本文提供一种抑制KRAS活性的方法，所述方法包括使本公开的化合物与KRAS接触。在一个实施方案中，接触包括向患者施用化合物。In one aspect, provided herein is a method of inhibiting KRAS activity, the method comprising contacting a compound of the present disclosure with KRAS. In one embodiment, contacting comprises administering the compound to a patient.

在一方面中，本文提供一种抑制具有G12C突变的KRAS蛋白的方法，所述方法包括使本公开的化合物与KRAS接触。In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12C mutation, the method comprising contacting a compound of the present disclosure with KRAS.

在一方面中，本文提供一种抑制具有G12D突变的KRAS蛋白的方法，所述方法包括使本公开的化合物与KRAS接触。In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12D mutation, the method comprising contacting a compound of the present disclosure with KRAS.

在一方面中，本文提供一种抑制具有G12V突变的KRAS蛋白的方法，所述方法包括使本公开的化合物与KRAS接触。In one aspect, provided herein is a method of inhibiting a KRAS protein having a G12V mutation, the method comprising contacting a compound of the present disclosure with KRAS.

在另一方面中，本文提供一种治疗与抑制KRAS相互作用相关的疾病或病症的方法，所述方法包括向有需要患者施用治疗有效量的本文所公开的任一式的化合物或其药学上可接受的盐。In another aspect, provided herein is a method of treating a disease or condition associated with inhibition of KRAS interaction, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt thereof.

在一个实施方案中，疾病或病症为免疫或发炎病症。在另一个实施方案中，免疫或发炎病症是由KRAS体细胞突变引起的Ras相关淋巴增生性病症和幼年型粒单核细胞白血病。In one embodiment, the disease or disorder is an immune or inflammatory disorder. In another embodiment, the immune or inflammatory disorder is Ras-associated lymphoproliferative disorder and juvenile myelomonocytic leukemia caused by somatic mutations in KRAS.

在又一方面中，本文提供一种治疗与抑制具有G12D突变的KRAS蛋白相关的疾病或病症的方法，所述方法包括向有需要患者施用治疗有效量的本文所公开的任一式的化合物或其药学上可接受的盐。In yet another aspect, provided herein is a method for treating a disease or condition associated with inhibiting a KRAS protein having a G12D mutation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any formula disclosed herein or a pharmaceutically acceptable salt thereof.

在另一方面中，本文提供一种治疗与抑制带有G12V突变的KRAS蛋白相关的疾病或病症的方法，所述方法包括向有需要患者施用治疗有效量的本文所公开的任一式的化合物或其药学上可接受的盐。In another aspect, provided herein is a method for treating a disease or condition associated with the inhibition of a KRAS protein with a G12V mutation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any formula disclosed herein or a pharmaceutically acceptable salt thereof.

在另一方面中，本文还提供一种治疗有需要患者的癌症的方法，其包括向所述患者施用治疗有效量的本文所公开的化合物。In another aspect, also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein.

在再一方面中，本文还提供一种治疗有需要患者的癌症的方法，其包括向所述患者施用治疗有效量的本文所公开的化合物，其中所述癌症的特征在于与具有G12D突变的KRAS蛋白相互作用。In yet another aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, wherein the cancer is characterized by interaction with a KRAS protein having a G12D mutation.

在另一方面中，本文还提供一种治疗有需要患者的癌症的方法，其包括向所述患者施用治疗有效量的本文所公开的化合物，其中所述癌症的特征在于与具有G12V突变的KRAS蛋白相互作用。In another aspect, also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, wherein the cancer is characterized by interaction with a KRAS protein having a G12V mutation.

在又一方面中，本文提供一种治疗患者的癌症的方法，所述方法包括向所述患者施用治疗有效量的本文所公开的任一化合物或其药学上可接受的盐。In yet another aspect, provided herein is a method of treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof.

在一个实施方案中，所述癌症选自癌瘤、血液癌、肉瘤和神经胶质母细胞瘤。在另一个实施方案中，所述血液癌选自骨髓增生性赘瘤、骨髓发育不良综合征、慢性和幼年型粒单核细胞白血病、急性骨髓白血病、急性淋巴细胞性白血病和多发性骨髓瘤。在又一个实施方案中，所述癌瘤选自胰腺、结肠直肠、肺、膀胱、胃、食道、乳房、头颈部、宫颈、皮肤和甲状腺。In one embodiment, the cancer is selected from carcinoma, blood cancer, sarcoma and glioblastoma. In another embodiment, the blood cancer is selected from myeloproliferative neoplasms, myelodysplastic syndrome, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia and multiple myeloma. In yet another embodiment, the carcinoma is selected from pancreas, colorectal, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin and thyroid.

在一方面中，本文提供一种治疗有需要患者的与抑制KRAS相互作用或其突变体相关的疾病或病症的方法，所述方法包括以下步骤：向所述患者施用本文所公开的化合物或其药学上可接受的盐，或包含本文所公开的化合物或其药学上可接受的盐的组合物，与如本文所描述的另一疗法或治疗剂组合。In one aspect, provided herein is a method of treating a disease or condition associated with inhibition of KRAS interaction or a mutant thereof in a patient in need thereof, the method comprising the steps of administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with another therapy or therapeutic agent as described herein.

在一个实施方案中，癌症选自血液癌、肉瘤、肺癌、胃肠道癌、泌尿生殖道癌、肝癌、骨癌、神经系统癌症、妇科癌症和皮肤癌。In one embodiment, the cancer is selected from the group consisting of hematological cancer, sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

在另一个实施方案中，肺癌选自非小细胞肺癌(NSCLC)、小细胞肺癌、支气管癌瘤、鳞状细胞支气管癌瘤、未分化小细胞支气管癌瘤、未分化大细胞支气管癌瘤、腺癌瘤、支气管癌瘤、肺泡癌瘤、细支气管癌瘤、支气管腺瘤、软骨瘤性错构瘤、间皮瘤、小细胞和非小细胞癌瘤、支气管腺瘤和胸膜肺母细胞瘤。In another embodiment, the lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma, squamous cell bronchogenic carcinoma, undifferentiated small cell bronchogenic carcinoma, undifferentiated large cell bronchogenic carcinoma, adenocarcinoma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, small cell and non-small cell carcinoma, bronchogenic adenoma and pleuropulmonary blastoma.

在又一个实施方案中，肺癌为非小细胞肺癌(NSCLC)。在再一个实施方案中，肺癌为腺癌。In yet another embodiment, the lung cancer is non-small cell lung cancer (NSCLC).In yet another embodiment, the lung cancer is adenocarcinoma.

在一个实施方案中，胃肠道癌选自食道鳞状细胞癌、食道腺癌、食道平滑肌肉瘤、食道淋巴瘤、胃癌瘤、胃淋巴瘤、胃平滑肌肉瘤、外分泌胰腺癌、胰管腺癌、胰腺胰岛素瘤、胰腺升糖素瘤、胰腺胃泌素瘤、胰腺类癌瘤、胰腺VIP瘤、小肠腺癌、小肠淋巴瘤、小肠类癌瘤、卡波西氏肉瘤(Kaposi's sarcoma)、小肠平滑肌瘤、小肠血管瘤、小肠脂肪瘤、小肠神经纤维瘤、小肠纤维瘤、大肠腺癌、大肠管状腺瘤、大肠绒毛状腺瘤、大肠错构瘤、大肠平滑肌瘤、结肠直肠癌、胆囊癌和肛门癌。In one embodiment, the gastrointestinal cancer is selected from the group consisting of esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric carcinoma, gastric lymphoma, gastric leiomyosarcoma, exocrine pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic insulinoma, pancreatic glucagonoma, pancreatic gastrinoma, pancreatic carcinoid tumor, pancreatic VIP tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal villous adenoma, large intestinal hamartoma, large intestinal leiomyoma, colorectal cancer, gallbladder cancer, and anal cancer.

在一个实施方案中，胃肠道癌为结肠直肠癌。In one embodiment, the gastrointestinal cancer is colorectal cancer.

在另一个实施方案中，癌症为癌瘤。在又一个实施方案中，癌瘤选自胰腺癌瘤、结肠直肠癌瘤、肺癌瘤、膀胱癌瘤、胃癌瘤、食道癌瘤、乳腺癌瘤、头颈癌瘤、宫颈癌、皮肤癌瘤和甲状腺癌瘤。In another embodiment, the cancer is a carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic carcinoma, colorectal carcinoma, lung carcinoma, bladder carcinoma, stomach carcinoma, esophageal carcinoma, breast carcinoma, head and neck carcinoma, cervical cancer, skin carcinoma and thyroid carcinoma.

在再一个实施方案中，癌症为造血系统恶性肿瘤。在一个实施方案中，造血系统恶性肿瘤选自多发性骨髓瘤、急性骨髓性白血病和骨髓增生性赘瘤。In yet another embodiment, the cancer is a hematopoietic malignancy. In one embodiment, the hematopoietic malignancy is selected from multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasms.

在另一个实施方案中，癌症为赘瘤。在又一个实施方案中，赘瘤为神经胶质母细胞瘤或肉瘤。In another embodiment, the cancer is a neoplasm. In yet another embodiment, the neoplasm is a glioblastoma or a sarcoma.

在某些实施方案中，本公开提供一种治疗有需要患者的KRAS介导的病症的方法，其包括以下步骤：向所述患者施用根据本公开的化合物或其药学上可接受的组合物。In certain embodiments, the present disclosure provides a method of treating a KRAS-mediated disorder in a patient in need thereof, comprising the step of administering to the patient a compound according to the present disclosure or a pharmaceutically acceptable composition thereof.

在一些实施方案中，可使用本公开化合物治疗的疾病和适应症包括但不限于血液癌、肉瘤、肺癌、胃肠道癌、泌尿生殖道癌、肝癌、骨癌、神经系统癌、妇科癌和皮肤癌。In some embodiments, diseases and indications that may be treated using the disclosed compounds include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

例示性血液癌包括淋巴瘤和白血病，诸如急性淋巴母细胞白血病(ALL)、急性骨髓性白血病(AML)、急性前髓细胞性白血病(APL)、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤、非霍奇金氏淋巴瘤(包括复发性或难治性NHL和复发性滤泡性淋巴瘤)、霍奇金氏淋巴瘤、骨髓增生性疾病(例如原发性骨髓纤维化(PMF)、真性红细胞增多症(PV)、自发性血小板增多症(ET)、8p11骨髓增生性综合征、骨髓发育不良综合征(MDS)、T细胞急性淋巴母细胞淋巴瘤(T-ALL)、多发性骨髓瘤、皮肤T细胞淋巴瘤、成人T细胞白血病、华式巨球蛋白血症(Waldenstrom'sMacroglubulinemia)、毛状细胞淋巴瘤、边缘区淋巴瘤、慢性骨髓性淋巴瘤和伯基特氏淋巴瘤(Burkitt's lymphoma)。Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF) , polycythemia vera (PV), essential thrombocythemia (ET), 8p11 myeloproliferative syndrome, myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, marginal zone lymphoma, chronic myeloid lymphoma and Burkitt's lymphoma.

例示性肉瘤包括软骨肉瘤、尤文氏肉瘤(Ewing's sarcoma)、骨肉瘤、横纹肌肉瘤、血管肉瘤、纤维肉瘤、脂肉瘤、粘液瘤、横纹肌瘤、横纹肌肉瘤、纤维瘤、脂肪瘤、错构瘤、淋巴肉瘤、平滑肌肉瘤和畸胎瘤。Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

例示性肺癌包括非小细胞肺癌(NSCLC)、小细胞肺癌、支气管癌瘤(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌瘤)、肺泡癌瘤(细支气管癌瘤)、支气管腺瘤、软骨错构瘤、间皮瘤、小细胞和非小细胞癌瘤、支气管腺瘤和胸膜肺母细胞瘤。Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, chondroitinoma, mesothelioma, small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

例示性胃肠道癌包括食道癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌瘤、淋巴瘤、平滑肌肉瘤)、胰腺癌(外分泌胰腺癌、导管腺癌、胰岛素瘤、升糖素瘤、胃泌素瘤、类癌瘤、VIP瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)、结肠直肠癌、胆囊癌和肛门癌。Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (exocrine pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer, and anal cancer.

例示性泌尿生殖道癌包括肾癌(腺癌、威姆氏肿瘤(Wilm'stumor)[肾胚细胞瘤]、肾细胞癌瘤)、膀胱和尿道癌(鳞状细胞癌瘤、移行细胞癌瘤、腺癌瘤)、前列腺癌(腺癌瘤、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎性癌瘤、畸胎上皮癌瘤、绒膜癌瘤、肉瘤、间质细胞癌瘤、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤)和尿道上皮癌瘤。Exemplary genitourinary tract cancers include renal cancer (adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratothelial carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma), and urothelial carcinoma.

例示性肝癌包括肝癌(肝细胞癌瘤)、胆管癌瘤、肝母细胞瘤、血管肉瘤、肝细胞腺瘤和血管瘤。Exemplary liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

例示性骨癌包括例如骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液性纤维瘤、骨样骨瘤和巨细胞肿瘤。Exemplary bone cancers include, e.g., osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

例示性神经系统癌包括颅骨癌(骨瘤、血管瘤、肉芽肿、黄瘤、畸形性骨炎)、脑膜癌(脊膜瘤、脊膜肉瘤、神经胶瘤病)、脑癌(星形细胞瘤、神经管胚细胞瘤(meduoblastoma)、神经胶质瘤、室管膜瘤、胚细胞瘤(松果体瘤)、神经胶质母细胞瘤、多形性神经胶质母细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤、神经外胚层肿瘤)和脊髓癌(神经纤维瘤、脊膜瘤、神经胶质瘤、肉瘤)、神经母细胞瘤、莱尔米特-杜多斯病(Lhermitte-Duclos disease)和松果体肿瘤。Exemplary cancers of the nervous system include cancers of the skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancers (meningiomas, meningeal sarcomas, gliomatosis), brain cancers (astrocytomas, meduoblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas, glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors, neuroectodermal tumors), and spinal cord cancers (neurofibromas, meningiomas, gliomas, sarcomas), neuroblastomas, Lhermitte-Duclos disease, and pineal tumors.

例示性妇科癌包括乳腺癌(导管癌瘤、小叶癌瘤、乳房肉瘤、三阴性乳腺癌、HER2阳性乳腺癌、发炎性乳腺癌、乳头状癌瘤)、子宫癌(子宫内膜癌瘤)、宫颈癌(宫颈癌瘤、肿瘤前宫颈发育不良)、卵巢癌(卵巢癌瘤(浆液性囊腺癌瘤、粘液性囊腺癌瘤、未分类癌瘤)、颗粒性膜细胞瘤、塞特利氏-莱迪希氏(Sertoli-Leydig)细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌瘤、上皮内癌瘤、腺癌瘤、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌瘤、鳞状细胞癌瘤、葡萄样肉瘤(胚胎性横纹肌肉瘤)和输卵管癌(癌瘤)。Exemplary gynecological cancers include breast cancer (ductal carcinoma, lobular carcinoma, breast sarcoma, triple negative breast cancer, HER2 positive breast cancer, inflammatory breast cancer, papillary carcinoma), uterine cancer (endometrial carcinoma), cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) and fallopian tube cancer (carcinoma).

例示性皮肤癌包括黑色素瘤、基底细胞癌瘤、鳞状细胞癌瘤、卡波西氏肉瘤、梅克尔细胞皮肤癌(Merkel cell skin cancer)、发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤和瘢痕瘤。Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid.

例示性头颈癌包括神经胶质母细胞瘤、黑色素瘤、横纹肌肉瘤、淋巴肉瘤、骨肉瘤、鳞状细胞癌瘤、腺癌瘤、口腔癌、喉癌、鼻咽癌、鼻癌和副鼻癌、甲状腺癌和副甲状腺癌、眼部肿瘤、嘴口肿瘤以及鳞状头颈癌。Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, thyroid cancer and parathyroid cancer, eye tumors, mouth tumors, and squamous head and neck cancer.

本公开的化合物还可用于抑制肿瘤转移。The compounds of the present disclosure may also be used to inhibit tumor metastasis.

除致癌赘瘤之外，本公开化合物可用于治疗骨胳和软骨细胞病症，其包括但不限于软骨发育不全(achrondroplasia)、季肋发育不全(hypochondroplasia)、侏儒症、致死性发育不良(TD)(临床形式TD I和TD II)、阿佩尔氏综合征(Apert syndrome)、克鲁宗综合征(Crouzon syndrome)、杰克逊-魏斯综合征(Jackson-Weiss syndrome)、比尔-斯蒂文森螺旋皮肤综合征(Beare-Stevenson cutis gyrate syndrome)、普菲弗综合征(Pfeiffersyndrome)和颅缝封闭过早综合征(craniosynostosis syndrome)。在一些实施方案中，本公开提供一种治疗患有骨胳和软骨细胞病症的患者的方法。In addition to oncogenic neoplasms, the disclosed compounds can be used to treat bone and cartilage cell disorders, including but not limited to achrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndrome. In some embodiments, the present disclosure provides a method of treating a patient suffering from a bone and cartilage cell disorder.

在一些实施方案中，本文所描述的化合物可用于治疗阿尔茨海默病(Alzheimer'sdisease)、HIV或肺结核。In some embodiments, the compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

如本文所使用，术语“8p11骨髓增生性综合征”意指与嗜酸性粒细胞增多症和FGFR1异常相关的骨髓/淋巴赘瘤。As used herein, the term "8p11 myeloproliferative syndrome" refers to a myeloid/lymphoid neoplasm associated with hypereosinophilia and FGFR1 abnormalities.

如本文所使用，术语“细胞”意指体外、离体或体内的细胞。在一些实施方案中，离体细胞可为自诸如哺乳动物的有机体切除的组织样本的一部分。在一些实施方案中，体外细胞可为细胞培养物中的细胞。在一些实施方案中，体内细胞为存活于诸如哺乳动物的有机体中的细胞。As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be a portion of a tissue sample removed from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism such as a mammal.

如本文所使用，术语“接触”是指在体外系统或体内系统中将指定部分聚集在一起。例如，使KRAS与本文所描述的化合物“接触”包括向具有KRAS的个体或患者，诸如人类，施用本文所描述的化合物，以及例如将本文所描述的化合物引入含有细胞或经纯化的制剂的样本中，所述细胞或经纯化的制剂含有KRAS。As used herein, the term "contacting" refers to bringing together specified moieties in an in vitro system or an in vivo system. For example, "contacting" KRAS with a compound described herein includes administering a compound described herein to an individual or patient, such as a human, having KRAS, and, for example, introducing a compound described herein into a sample containing cells or a purified preparation containing KRAS.

如本文所使用，可互换地使用的术语“个体”、“受试者”或“患者”是指任何动物，包括哺乳动物，优选为小鼠、大鼠、其他啮齿动物、兔、犬、猫、猪、牛、绵羊、马或灵长类动物，并且最优选为人类。As used herein, the terms "individual," "subject," or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

如本文所使用，短语“治疗有效量”是指在组织、系统、动物、个体或人类中引发由研究人员、兽医、医生或其他临床医师所寻求的生物或医学反应的活性化合物或药剂的量，诸如本文所公开的任何固体形式或其盐的量。在任何个别情况下的适当“有效”量可使用本领域的技术人员已知的技术测定。As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or agent, such as any solid form disclosed herein or a salt thereof, that elicits a biological or medical response in a tissue, system, animal, individual or human being that is sought by a researcher, veterinarian, medical doctor or other clinician. The appropriate "effective" amount in any individual case can be determined using techniques known to those skilled in the art.

短语“药学上可接受”在本文中用于指在合理医学判断范围内，适用于与人类和动物的组织接触而无过度毒性、刺激、过敏反应、免疫原性或其他问题或并发症、与合理益处/风险比相称的那些化合物、物质、组合物和/或剂型。The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

如本文所使用，短语“药学上可接受的载剂或赋形剂”是指药学上可接受的材料、组合物或媒介物，诸如液体或固体填充剂、稀释剂、溶剂或囊封材料。赋形剂或载剂一般为安全、无毒的并且既不是生物学上不合需要的，也不是在其他方面不合需要的，并且包括可接受用于兽医学用途以及人类药物用途的赋形剂或载剂。在一个实施方案中，各组分为如本文中所定义的“药学上可接受的”。参见例如Remington:The Science and Practice ofPharmacy,第21版；Lippincott Williams&Wilkins:Philadelphia,Pa,2005；Handbook ofPharmaceutical Excipients,第6版；Rowe等人编；The Pharmaceutical Press and theAmerican Pharmaceutical Association:2009；Handbook of PharmaceuticalAdditives,第3版；Ash和Ash编；Gower Publishing Company:2007；PharmaceuticalPreformulation and Formulation,第2版；Gibson编；CRC Press LLC:Boca Raton,Fla.,2009。As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, solvent or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically undesirable nor otherwise undesirable, and include excipients or carriers acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, Fla., 2009.

如本文所使用，术语“治疗(treating/treatment)”是指抑制疾病；例如抑制正在经历或呈现疾病、疾患或病症的病变或症状的个体的疾病、疾患或病症(即阻止病变和/或症状的进一步发展)，或改善疾病；例如改善正在经历或呈现疾病、疾患或病症的病变或症状的个体的疾病、疾患或病症(即逆转病变和/或症状)，诸如降低疾病的严重程度。As used herein, the terms "treating" or "treatment" refer to inhibiting a disease; e.g., inhibiting a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms), or ameliorating a disease; e.g., ameliorating a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, disorder or condition (i.e., reversing the pathology and/or symptoms), such as reducing the severity of the disease.

如本文所使用，术语“预防(prevent/preventing/prevention)”包含预防至少一种与所预防的疾患、疾病或病症相关或由其引起的症状。As used herein, the terms "prevent," "preventing," and "prevention" encompass preventing at least one symptom associated with or caused by the disorder, disease, or condition being prevented.

应理解，为了清楚起见而在单独实施方案的上下文中描述的本发明的某些特征也可在单个实施方案中以组合方式提供(在意图将实施方案组合，如同以多重依赖性方式书写时)。相反，为了简洁起见而在单个实施方案的上下文中描述的本发明的各种特征也可分别或以任何适合的子组合形式提供。It will be appreciated that certain features of the invention, which are, for the sake of clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (where the embodiments are intended to be combined, as if written in a multiple dependency manner). Conversely, various features of the invention, which are, for the sake of brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

组合疗法Combination therapy

I.癌症疗法I. Cancer Therapy

癌细胞生长和存活可受多个信号传导路径的功能障碍影响。因此，组合不同的酶/蛋白/受体抑制剂为有用的，所述抑制剂在其调节活性的目标方面表现出不同的偏好，以治疗此类疾患。靶向超过一种信号传导路径(或超过一种参与指定信号传导路径的生物分子)可降低细胞群体中产生耐药性的可能性，和/或降低治疗的毒性。Cancer cell growth and survival can be affected by dysfunction of multiple signaling pathways. Therefore, it is useful to combine different enzyme/protein/receptor inhibitors that show different preferences in the targets of their modulated activity to treat such disorders. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance in a cell population, and/or reduce the toxicity of the treatment.

一种或多种其他药物剂，诸如化学治疗剂、消炎剂、类固醇、免疫抑制剂、免疫肿瘤剂、代谢酶抑制剂、趋化因子受体抑制剂和磷酸酶抑制剂，以及靶向疗法，诸如Bcr-Abl、Flt-3、EGFR、HER2、JAK、c-MET、VEGFR、PDGFR、c-Kit、IGF-1R、RAF、FAK和CDK4/6激酶抑制剂，诸如WO 2006/056399中描述的那些，可与本公开的化合物组合使用以治疗CDK2相关的疾病、病症或疾患。诸如治疗抗体的其他药剂可与本公开的化合物组合使用以治疗CDK2相关的疾病、病症或疾患。一种或多种其他药物剂可同时或依次向患者施用。One or more other pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immuno-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors and phosphatase inhibitors, and targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK and CDK4/6 kinase inhibitors, such as those described in WO 2006/056399, can be used in combination with the compounds of the present disclosure to treat diseases, disorders or conditions associated with CDK2. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure to treat diseases, disorders or conditions associated with CDK2. One or more other pharmaceutical agents can be administered to the patient simultaneously or sequentially.

在一些实施方案中，CDK2抑制剂与BCL2抑制剂或CDK4/6抑制剂组合施用或使用。In some embodiments, a CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4/6 inhibitor.

如本文所公开的化合物可与一种或多种其他酶/蛋白/受体抑制剂疗法组合使用以用于治疗疾病，诸如癌症和本文所描述的其他疾病或病症。可用组合疗法治疗的疾病和适应症的实例包括如本文所描述的疾病和适应症。癌症的实例包括实体肿瘤和非实体肿瘤，诸如液体肿瘤、血癌。感染的实例包括病毒感染、细菌感染、真菌感染或寄生虫感染。例如，本公开的化合物可与一种或多种以下激酶的抑制剂组合以用于治疗癌症：Akt1、Akt2、Akt3、BCL2、CDK4/6、TGF-βR、PKA、PKG、PKC、CaM激酶、磷酸酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IDH2、IGF-1R、IR-R、PDGFαR、PDGFβR、PI3K(α、β、γ、δ和多重或选择性的)、CSF1R、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、PARP、Ron、Sea、TRKA、TRKB、TRKC、TAM激酶(Axl、Mer、Tyro3)、FLT3、VEGFR/Flt2、Flt4、EphA1、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK和B-Raf。在一些实施方案中，本公开的化合物可与一种或多种以下抑制剂组合以用于治疗癌症或感染。可与本公开的化合物组合用于治疗癌症和感染的抑制剂的非限制性实例包括FGFR抑制剂(FGFR1、FGFR2、FGFR3或FGFR4，例如培米加替尼(pemigatinib)(INCB54828)、INCB62079)、EGFR抑制剂(也称为ErB-1或HER-1；例如埃罗替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、奥希替尼(orsimertinib)、西妥昔单抗(cetuximab)、耐昔妥珠单抗(necitumumab)或帕尼单抗(panitumumab))、VEGFR抑制剂或路径阻断剂(例如贝伐单抗(bevacizumab)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、阿西替尼(axitinib)、瑞戈非尼(regorafenib)、普纳替尼(ponatinib)、卡博替尼(cabozantinib)、凡德他尼(vandetanib)、雷莫芦单抗(ramucirumab)、乐伐替尼(lenvatinib)、阿柏西普(ziv-aflibercept))、PARP抑制剂(例如，奥拉帕尼(olaparib)、卢卡帕尼(rucaparib)、维利帕尼(veliparib)或尼拉帕尼(niraparib))、JAK抑制剂(JAK1和/或JAK2；例如鲁索替尼(ruxolitinib)或巴瑞替尼(baricitinib)；或JAK1；例如伊他替尼(itacitinib)(INCB39110)、INCB052793或INCB054707)、IDO抑制剂(例如艾卡哚司他(epacadostat)、NLG919或BMS-986205、MK7162)、LSD1抑制剂(例如GSK2979552、INCB59872和INCB60003)、TDO抑制剂、PI3K-δ抑制剂(例如帕萨利西布(parsaclisib)(INCB50465)或INCB50797)、PI3K-γ抑制剂诸如PI3K-γ选择性抑制剂、Pim抑制剂(例如INCB53914)、CSF1R抑制剂、TAM受体酪氨酸激酶(Tyro-3、Axl和Mer；例如INCB081776)、腺苷受体拮抗剂(例如A2a/A2b受体拮抗剂)、HPK1抑制剂、趋化因子受体抑制剂(例如CCR2或CCR5抑制剂)、SHP1/2磷酸酶抑制剂、组蛋白脱乙酰基酶抑制剂(HDAC)诸如HDAC8抑制剂、血管生成抑制剂、白介素受体抑制剂、溴和额外末端家族成员抑制剂(例如溴结构域抑制剂或BET抑制剂诸如INCB54329和INCB57643)、c-MET抑制剂(例如卡马替尼(capmatinib))、抗CD19抗体(例如他法西他单抗(tafasitamab))、ALK2抑制剂(例如INCB00928)；或其组合。Compounds as disclosed herein can be used in combination with one or more other enzyme/protein/receptor inhibitor therapies for the treatment of diseases, such as cancer and other diseases or conditions described herein. Examples of diseases and indications that can be treated with combination therapy include diseases and indications as described herein. Examples of cancer include solid tumors and non-solid tumors, such as liquid tumors, blood cancers. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-βR, PKA, PKG, PKC, CaM kinases, phosphatase kinases, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (α, β, γ, δ and multiple or selective), CSF1R, KIT, FLK-II , KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infection. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infection include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1; such as erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (such as bevacizumab, pazopanib), pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and/or JAK2; e.g., ruxolitinib), litinib) or baricitinib; or JAK1; for example itacitinib (INCB39110), INCB052793 or INCB054707), IDO inhibitors (for example epacadostat, NLG919 or BMS-986205, MK7162), LSD1 inhibitors (for example GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-δ inhibitors (for example parsaclisib (INCB50465) or INCB50797), PI3K-γ inhibitors such as PI3K-γ selective inhibitors, Pim inhibitors (for example INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl and Mer; e.g., INCB081776), adenosine receptor antagonists (e.g., A2a/A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1/2 phosphatase inhibitors, histone deacetylase inhibitors (HDAC) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromodomain and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928); or a combination thereof.

在一些实施方案中，本文所描述的化合物或盐与PI3Kδ抑制剂一起施用。在一些实施方案中，本文所描述的化合物或盐与JAK抑制剂一起施用。在一些实施方案中，本文所描述的化合物或盐与JAK1或JAK2抑制剂(例如巴瑞替尼或鲁索替尼)一起施用。在一些实施方案中，本文所描述的化合物或盐与JAK1抑制剂一起施用。在一些实施方案中，本文所描述的化合物或盐与JAK1抑制剂一起施用，所述抑制剂相对于JAK2具有选择性。In some embodiments, the compounds or salts described herein are administered with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK1 inhibitor, which is selective for JAK2.

组合疗法中使用的例示性抗体包括但不限于曲妥珠单抗(trastuzumab)(例如抗HER2)、雷尼株单抗(ranibizumab)(例如抗VEGF-A)、贝伐单抗(AVASTIN^TM，例如抗VEGF)、帕尼单抗(例如抗EGFR)、西妥昔单抗(例如抗EGFR)、美罗华(rituxan)(例如抗CD20)和针对c-MET的抗体。Exemplary antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN^™ , e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and antibodies against c-MET.

一种或多种以下药剂可与本公开的化合物组合使用并且作为非限制性清单呈现：细胞生长抑制剂、顺铂(cisplatin)、小红莓(doxorubicin)、泰素帝(taxotere)、紫杉醇(taxol)、依托泊苷(etoposide)、伊立替康(irinotecan)、坎普托沙(camptosar)、拓朴替康(topotecan)、太平洋紫杉醇(paclitaxel)、多西他赛(docetaxel)、埃博霉素(epothilones)、他莫昔芬(tamoxifen)、5-氟尿嘧啶、甲氨蝶呤、替莫唑胺(temozolomide)、环磷酰胺、SCH 66336、R115777、L778,123、BMS 214662、IRESSA^TM(吉非替尼(gefitinib))、TARCEVA^TM(埃罗替尼(erlotinib))、EGFR抗体、内含子、ara-C、阿霉素(adriamycin)、环磷酰胺、吉西他滨(gemcitabine)、尿嘧啶芥、氮芥、异环磷酰胺、美法仑(melphalan)、苯丁酸氮芥、哌泊溴烷、三亚乙基三聚氰胺、三亚乙基硫代磷胺、白消安(busulfan)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、链脲菌素(streptozocin)、达卡巴嗪(dacarbazine)、氟尿苷、阿糖胞苷、6-巯基嘌呤、6-硫代鸟嘌呤、氟达拉宾磷酸盐、奥沙利铂(oxaliplatin)、甲酰四氢叶酸(leucovirin)、ELOXATIN^TM(奥沙利铂)、喷司他丁(pentostatine)、长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、博莱霉素(bleomycin)、放线菌素(dactinomycin)、道诺霉素(daunorubicin)、小红莓、表柔比星(epirubicin)、艾达霉素(idarubicin)、光神霉素(mithramycin)、脱氧助间型霉素(deoxycoformycin)、丝裂霉素-C、L-天冬酰胺酶、替尼泊苷(teniposide)17.α.-炔雌醇、己烯雌酚、睪固酮、泼尼松(Prednisone)、氟羟甲基睪酮(Fluoxymesterone)、屈他雄酮丙酸酯(Dromostanolone propionate)、睾内酯酮(testolactone)、甲地孕酮乙酸酯(megestrolacetate)、甲基泼尼松龙(methylprednisolone)、甲基睪固酮(methyltestosterone)、泼尼松龙(prednisolone)、曲安西龙(triamcinolone)、氯烯雌醚(chlorotrianisene)、羟孕酮(hydroxyprogesterone)、氨鲁米特(aminoglutethimide)、雌莫司汀(estramustine)、甲羟孕酮乙酸酯(medroxyprogesteroneacetate)、亮丙瑞林(leuprolide)、氟他胺(flutamide)、托瑞米芬(toremifene)、戈舍瑞林(goserelin)、卡铂(carboplatin)、羟基尿素(hydroxyurea)、安吖啶(amsacrine)、甲基苄肼(procarbazine)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、左旋咪唑(levamisole)、诺维本(navelbene)、阿那曲唑(anastrazole)、来曲唑(letrazole)、卡培他滨(capecitabine)、瑞洛萨芬(reloxafine)、着洛萨芬(droloxafine)、六甲蜜胺(hexamethylmelamine)、阿瓦斯汀(avastin)、HERCEPTIN^TM(曲妥珠单抗)、BEXXAR^TM(托西莫单抗(tositumomab))、VELCADE^TM(硼替佐米(bortezomib))、ZEVALIN^TM(替伊莫单抗(ibritumomab tiuxetan))、TRISENOX^TM(三氧化二砷)、XELODA^TM(卡培他滨)、长春瑞滨(vinorelbine)、卟吩姆(porfimer)、ERBITUX^TM(西妥昔单抗)、噻替派(thiotepa)、六甲蜜胺(altretamine)、美法仑、曲妥珠单抗、来曲唑(lerozole)、氟维司群(fulvestrant)、依西美坦(exemestane)、异环磷酰胺、利妥昔单抗(rituximab)、C225(西妥昔单抗(cetuximab))、坎帕斯(Campath)(阿仑单抗(alemtuzumab))、氯法拉滨(clofarabine)、克拉屈滨(cladribine)、艾菲地可宁(aphidicolon)、美罗华、舒尼替尼(sunitinib)、达沙替尼(dasatinib)、替扎他滨(tezacitabine)、Sml1、氟达拉宾(fludarabine)、喷司他丁(pentostatin)、三安平(triapine)、地多西(didox)、曲美多斯(trimidox)、艾美多(amidox)、3-AP和MDL-101,731。One or more of the following agents may be used in combination with the compounds of the present disclosure and are presented as a non-limiting list: cytostatics, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA^™ (gefitinib), TARCEVA^™ (erlotinib), EGFR antibody, intron, ara-C, adriamycin, cyclophosphamide, gemcitabine, uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene melamine, triethylene thiophosphamide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN^TM (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, cranberries, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17.α.-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide de), toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTIN^™ (trastuzumab), BEXXAR^™ (tositumomab), VELCADE^™ (bortezomib), ZEVALIN^™ (ibritumomab tiuxetan), TRISENOX^™ (arsenic trioxide), XELODA^™ (capecitabine), vinorelbine, porfimer, ERBITUX^™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladrol cladribine, aphidicolon, rituximab, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

本公开的化合物可进一步与其他治疗癌症的方法组合使用，例如通过化学疗法、辐射疗法、肿瘤靶向疗法、辅助疗法、免疫疗法或手术。免疫疗法的实例包括细胞因子治疗(例如干扰素、GM-CSF、G-CSF、IL-2)、CRS-207免疫疗法、癌症疫苗、单克隆抗体、双特异性或多特异性抗体、抗体药物结合物、过继T细胞转移、铎受体激动剂、RIG-I激动剂、溶瘤病毒疗法和免疫调节小分子，包括沙立度胺(thalidomide)或JAK1/2抑制剂、PI3Kδ抑制剂和其类似物。化合物可与一种或多种抗癌药，诸如化学治疗剂组合施用。化学治疗剂的实例包括以下中的任一者：阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿仑单抗、亚利崔托寜(alitretinoin)、异嘌呤醇(allopurinol)、六甲蜜胺、阿那曲唑(anastrozole)、三氧化二砷、天冬酰胺酶、阿扎胞苷(azacitidine)、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、巴瑞替尼、博莱霉素、硼替佐米、白消安静脉注射、口服白消安、卡鲁睾酮(calusterone)、卡培他滨、卡铂、卡莫司汀、西妥昔单抗、苯丁酸氮芥、顺铂、克拉屈滨、氯法拉滨、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素、达肝素钠、达沙替尼、道诺霉素、地西他滨、地尼白介素(denileukin)、地尼白介素(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他赛、小红莓、屈他雄酮丙酸酯、托西珠单抗(eculizumab)、表柔比星、埃罗替尼、雌莫司汀、磷酸依托泊苷、依托泊苷、依西美坦(exemestane)、柠檬酸芬太尼(fentanylcitrate)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟达拉宾(fludarabine)、氟尿嘧啶、氟维司群、吉非替尼、吉西他滨、吉妥单抗奥佐米星(gemtuzumab ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸组胺瑞林(histrelin acetate)、替伊莫单抗、艾达霉素(idarubicin)、异环磷酰胺、甲磺酸伊马替尼(imatinib mesylate)、干扰素α2a、伊立替康、拉帕替尼(lapatinib)二甲苯磺酸盐、来那度胺(lenalidomide)、来曲唑、甲酰四氢叶酸、乙酸亮甲瑞林、左旋咪唑、洛莫司汀(lomustine)、氮芥、乙酸甲地孕酮(megestrolacetate)、美法仑、巯基嘌呤、甲胺喋呤、甲氧沙林(methoxsalen)、丝裂霉素C、米托坦、米托蒽醌、苯丙酸诺龙(nandrolone phenpropionate)、奈拉滨(nelarabine)、诺非妥莫单抗(nofetumomab)、奥沙利铂、太平洋紫杉醇、帕米膦酸盐、帕尼单抗、培门冬酶(pegaspargase)、派非格司亭(pegfilgrastim)、培美曲塞二钠(pemetrexed disodium)、喷司他丁、哌泊溴烷、普卡霉素、甲基苄肼、奎纳克林(quinacrine)、拉布立酶(rasburicase)、利妥昔单抗、鲁索替尼、索拉非尼(sorafenib)、链脲菌素(streptozocin)、舒尼替尼、马来酸舒尼替尼、他莫昔芬、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睾内酯酮、沙利度胺(thalidomide)、硫鸟嘌呤、噻替派、拓朴替康、托瑞米芬、托西莫单抗、曲妥珠单抗、视黄酸(tretinoin)、尿嘧啶芥、伐柔比星(valrubicin)、长春碱、长春新碱、长春瑞滨、伏立诺他(vorinostat)和唑来膦酸盐(zoledronate)。The compounds disclosed herein can be further used in combination with other methods for treating cancer, for example, by chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody drug conjugates, adoptive T cell transfer, Duo receptor agonists, RIG-I agonists, oncolytic virus therapy and immunomodulatory small molecules, including thalidomide or JAK1/2 inhibitors, PI3Kδ inhibitors and analogs thereof. The compound can be administered in combination with one or more anticancer drugs, such as chemotherapeutic agents. Examples of chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bexarotene), baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, actinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, cranberry, drostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, nitrogen mustard, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium disodium), pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

化学治疗剂的额外实例包括蛋白酶体抑制剂(例如硼替佐米)、沙立度胺、雷利米得(revlimid)和DNA损伤剂，诸如美法仑、多柔比星、环磷酰胺、长春新碱、依托泊苷、卡莫司汀和其类似物。Additional examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and analogs thereof.

例示性类固醇包括皮质类固醇，诸如地塞米松(dexamethasone)或泼尼松。Exemplary steroids include corticosteroids, such as dexamethasone or prednisone.

例示性Bcr-Abl抑制剂包括甲磺酸伊马替尼(GLEEVAC^TM)、尼罗替尼、达沙替尼、伯舒替尼(bosutinib)和普纳替尼，和药学上可接受的盐。适合的Bcr-Abl抑制剂的其他实例包括美国专利第5,521,184号、WO 04/005281和美国序列号60/578,491中所公开的属和物种的化合物及其药学上可接受的盐。Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC^™ ), nilotinib, dasatinib, bosutinib and ponatinib, and pharmaceutically acceptable salts. Other examples of suitable Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281 and U.S. Serial No. 60/578,491 and pharmaceutically acceptable salts thereof.

适合的Flt-3抑制剂的实例包括米哚妥林(midostaurin)、来他替尼(lestaurtinib)、立尼法尼(linifanib)、舒尼替尼、舒尼替尼、顺丁烯二酸酯、索拉非尼(sorafenib)、奎扎替尼(quizartinib)、克拉尼布(crenolanib)、帕瑞替尼(pacritinib)、坦度替尼(tandutinib)、PLX3397和ASP2215及其药学上可接受的盐。适合的Flt-3抑制剂的其他实例包括如WO 03/037347、WO 03/099771和WO 04/046120中所公开的化合物及其药学上可接受的盐。Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleic acid esters, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215 and pharmaceutically acceptable salts thereof. Other examples of suitable Flt-3 inhibitors include compounds disclosed in WO 03/037347, WO 03/099771 and WO 04/046120 and pharmaceutically acceptable salts thereof.

适合的RAF抑制剂的实例包括达拉非尼(dabrafenib)、索拉非尼(sorafenib)和维罗非尼(vemurafenib)及其药学上可接受的盐。适合的RAF抑制剂的其他实例包括如WO 00/09495和WO 05/028444中所公开的化合物及其药学上可接受的盐。Examples of suitable RAF inhibitors include dabrafenib, sorafenib and vemurafenib and pharmaceutically acceptable salts thereof. Other examples of suitable RAF inhibitors include compounds disclosed in WO 00/09495 and WO 05/028444 and pharmaceutically acceptable salts thereof.

适合的FAK抑制剂的实例包括VS-4718、VS-5095、VS-6062、VS-6063、BI853520和GSK2256098及其药学上可接受的盐。适合的FAK抑制剂的其他实例包括如WO 04/080980、WO04/056786、WO 03/024967、WO 01/064655、WO 00/053595和WO 01/014402中所公开的化合物及其药学上可接受的盐。Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520 and GSK2256098 and pharmaceutically acceptable salts thereof. Other examples of suitable FAK inhibitors include compounds disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595 and WO 01/014402 and pharmaceutically acceptable salts thereof.

适合的CDK4/6抑制剂的实例包括帕柏西利(palbociclib)、利波西利(ribociclib)、曲拉西利(trilaciclib)、乐罗西利(lerociclib)和阿贝西利(abemaciclib)及其药学上可接受的盐。适合的CDK4/6抑制剂的其他实例包括如WO 09/085185、WO 12/129344、WO 11/101409、WO 03/062236、WO 10/075074和WO 12/061156中所公开的化合物及其药学上可接受的盐。Examples of suitable CDK4/6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib and abemaciclib and pharmaceutically acceptable salts thereof. Other examples of suitable CDK4/6 inhibitors include compounds disclosed in WO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074 and WO 12/061156 and pharmaceutically acceptable salts thereof.

在一些实施方案中，本公开的化合物可与一种或多种其他激酶抑制剂(包括伊马替尼(imatinib))组合使用，特别是用于治疗对伊马替尼或其他激酶抑制剂具有抗性的患者。In some embodiments, the compounds of the present disclosure may be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients who are resistant to imatinib or other kinase inhibitors.

在一些实施方案中，本公开的化合物可在癌症治疗中与化学治疗剂组合使用，并且相较于对单独化学治疗剂的反应可改良治疗反应，而不加重其毒性效应。在一些实施方案中，本公开的化合物可与本文所提供的化学治疗剂组合使用。例如，用于治疗多发性骨髓瘤的额外药剂可包括但不限于美法仑、美法仑加泼尼松[MP]、多柔比星、地塞米松和Velcade(硼替佐米)。用于治疗多发性骨髓瘤的其他额外药剂包括Bcr-Abl、Flt-3、RAF和FAK激酶抑制剂。在一些实施方案中，药剂为烷化剂、蛋白酶体抑制剂、皮质类固醇或免疫调节剂。烷化剂的实例包括环磷酰胺(CY)、美法仑(MEL)和苯达莫司汀。在一些实施方案中，蛋白酶体抑制剂为卡非佐米(carfilzomib)。在一些实施方案中，皮质类固醇为地塞米松(DEX)。在一些实施方案中，免疫调节剂是来那度胺(LEN)或泊利度胺(pomalidomide)(POM)。累加或协同效应为将本公开的CDK2抑制剂与额外药剂组合的所需结果。In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents in cancer treatment, and the therapeutic response can be improved compared to the response to a single chemotherapeutic agent without aggravating its toxic effects. In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents provided herein. For example, additional agents for treating multiple myeloma may include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Other additional agents for treating multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).An additive or synergistic effect is a desired result of combining a CDK2 inhibitor of the present disclosure with an additional agent.

所述药剂可以单一或连续剂型与本公开的化合物组合，或所述药剂可以单独剂型同时或依次施用。The agents may be combined with the compounds of the present disclosure in single or sequential dosage forms, or the agents may be administered simultaneously or sequentially in separate dosage forms.

本公开的化合物可与一种或多种其他抑制剂或一种或多种疗法组合使用以用于治疗感染。感染的实例包括病毒感染、细菌感染、真菌感染或寄生虫感染。The compounds of the present disclosure may be used in combination with one or more other inhibitors or one or more therapies for the treatment of infection. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections.

在一些实施方案中，皮质类固醇诸如地塞米松与本公开的化合物组合向患者施用，其中地塞米松是间歇施用而非连续施用。In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, wherein the dexamethasone is administered intermittently rather than continuously.

式(I)或如本文所述的任一式的化合物、权利要求书中的任一者中所列举和本文所描述的化合物或其盐可与另一种免疫原性剂组合，诸如癌细胞、纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)、细胞和经编码免疫刺激细胞因子的基因转染的细胞。可使用的肿瘤疫苗的非限制性实例包括黑色素瘤抗原的肽，诸如gp100、MAGE抗原、Trp-2、MARTI和/或酪胺酸酶的肽，或经转染以表达细胞因子GM-CSF的肿瘤细胞。The compound of formula (I) or any of the formulas as described herein, the compound listed in any of the claims and described herein, or a salt thereof can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

式(I)或如本文所描述的任一式的化合物、权利要求书中的任一者中所列举和本文所描述的化合物或其盐可与疫苗接种方案组合使用以用于治疗癌症。在一些实施方案中，肿瘤细胞经转导以表达GM-CSF。在一些实施方案中，肿瘤疫苗包括人类癌症中所涉及的病毒的蛋白，所述病毒诸如人乳头状瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西氏疱疹肉瘤病毒(KHSV)。在一些实施方案中，本公开的化合物可与肿瘤特异性抗原，诸如自肿瘤组织本身分离的热休克蛋白组合使用。在一些实施方案中，式(I)或如本文所描述的任一式的化合物、权利要求书中的任一者中所列举和本文所描述的化合物或其盐可与树突状细胞免疫接种组合以活化强效抗肿瘤反应。Compounds of formula (I) or any of the formulas as described herein, compounds listed in any of the claims and described herein, or salts thereof, can be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins of viruses involved in human cancers, such as human papilloma virus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from tumor tissue itself. In some embodiments, compounds of formula (I) or any of the formulas as described herein, compounds listed in any of the claims and described herein, or salts thereof, can be combined with dendritic cell immunization to activate a potent anti-tumor response.

本公开的化合物可与将表达Feα或Feγ受体的效应细胞靶向至肿瘤细胞的双特异性巨环肽组合使用。本公开的化合物也可与活化宿主免疫反应性的巨环肽组合。The compounds of the present disclosure may be used in combination with bispecific macrocyclic peptides that target effector cells expressing Feα or Feγ receptors to tumor cells. The compounds of the present disclosure may also be combined with macrocyclic peptides that activate host immune responsiveness.

在一些其他实施方案中，本公开的化合物与其他治疗剂的组合可在骨髓移植或干细胞移植之前、期间和/或之后向患者施用。本公开的化合物可与骨髓移植组合以用于治疗多种造血来源肿瘤。In some other embodiments, the compounds of the present disclosure in combination with other therapeutic agents may be administered to a patient before, during, and/or after a bone marrow transplant or stem cell transplant. The compounds of the present disclosure may be combined with a bone marrow transplant for the treatment of a variety of hematopoietic tumors.

式(I)或如本文所描述的任一式的化合物、权利要求书中的任一者中所列举和本文所描述的化合物或其盐可与疫苗组合使用，以刺激针对病原体、毒素和自抗原的免疫反应。此治疗方法可特别适用的病原体的实例包括当前无有效疫苗的病原体或常规疫苗不完全有效的病原体。这些包括但不限于HIV、肝炎(A、B和C)、流感、疱疹、贾第虫属(Giardia)、疟疾、利什曼原虫(Leishmania)、金黄色葡萄球菌(Staphylococcus aureus)、铜绿假单胞菌(Pseudomonas Aeruginosa)。Formula (I) or any of the compounds described herein, any of the compounds listed in the claims and described herein or their salts can be used in combination with vaccines to stimulate immune responses against pathogens, toxins and self-antigens. Examples of pathogens to which this treatment method can be particularly applicable include pathogens for which there is currently no effective vaccine or pathogens for which conventional vaccines are not completely effective. These include but are not limited to HIV, hepatitis (A, B and C), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa.

引起可通过本公开的方法治疗的感染的病毒包括但不限于人乳头瘤病毒、流感病毒、甲型、乙型、丙型或丁型肝炎病毒、腺病毒、痘病毒、单纯疱疹病毒、人巨细胞病毒、严重急性呼吸道综合征病毒、埃博拉病毒、麻疹病毒、疱疹病毒(例如VZV、HSV-1、HAV6、HSV-II和CMV埃-巴二氏病毒)、黄病毒属(flaviviruses)、埃可病毒(echovirus)、鼻病毒(rhinovirus)、科沙奇病毒(coxsackie virus)、冠状病毒(cornovirus)、呼吸道合胞病毒(respiratory syncytial virus)、腮腺炎病毒(mumps virus)、轮状病毒(rotavirus)、麻疹病毒(measles virus)、德国麻疹病毒(rubella virus)、小病毒(parvovirus)、痘疮病毒(vaccinia virus)、HTLV病毒、登革热病毒(dengue virus)、乳头瘤病毒(papillomavirus)、软疣病毒(molluscum virus)、脊髓灰白质炎病毒(poliovirus)、狂犬病病毒、JC病毒和虫媒脑炎病毒(arboviral encephalitis virus)。Viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza virus, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes viruses (e.g., VZV, HSV-1, HAV6, HSV-II, and CMV Epstein-Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, virus), poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

引起可通过本公开的方法治疗的感染的病原菌包含但不限于衣原体(chlamydia)、立克次体细菌(rickettsial bacteria)、分枝杆菌(mycobacteria)、葡萄球菌(staphylococci)、链球菌(streptococci)、肺炎球菌(pneumonococci)、脑膜炎球菌(meningococci)和淋球菌(conococci)、克雷伯氏菌(klebsiella)、变形杆菌(proteus)、沙雷氏菌(serratia)、假单胞菌(pseudomonas)、军团菌(legionella)、白喉(diphtheria)、沙门氏菌(salmonella)、杆菌(bacilli)、霍乱(cholera)、破伤风(tetanus)、肉毒中毒(botulism)、炭疽病(anthrax)、瘟疫(plague)、钩端螺旋体病(leptospirosis)和莱姆病(Lyme's disease)细菌。Pathogenic bacteria that cause infections that may be treated by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.

引起可通过本公开的方法治疗的感染的病原性真菌包括但不限于念珠菌属(Candida)(白色念珠菌(albicans)、克鲁斯氏念珠菌(krusei)、光滑念珠菌(glabrata)、热带念珠菌(tropicalis)等)、新型隐球菌(Cryptococcus neoformans)、曲霉菌属(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉菌目(Mucorales)属(白霉菌属(mucor)、犁头霉属(absidia)、根霉属(rhizophus))、申克氏胞丝菌(Sporothrixschenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasma capsulatum)。Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

引起可通过本公开的方法治疗的感染的病原性寄生虫包括但不限于溶组织内阿米巴(Entamoeba histolytica)、大肠纤毛虫(Balantidiumcoli)、福氏耐格里阿米巴原虫(Naegleriafowleri)、棘阿米巴虫属(Acanthamoeba sp.)、蓝氏贾第鞭毛虫(Giardialambia)、隐胞子虫属(Cryptosporidium sp.)、肺炎肺囊虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、微小巴倍虫(Babesia microti)、布氏锥虫(Trypanosomabrucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishmania donovani)、刚地弓形虫(Toxoplasma gondi)和巴西日圆线虫(Nippostrongylus brasiliensis)。Pathogenic parasites causing infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lamblia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

当向患者施用超过一种药物剂时，其可同时、单独、依次或以组合形式施用(例如对于超过两种剂)。When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for more than two agents).

安全且有效地施用大部分这些化学治疗剂的方法为本领域的技术人员已知的。另外，其施用描述于标准文献中。例如，多种化学治疗剂的施用描述于“Physicians'DeskReference”(PDR，例如1996版,Medical Economics Company,Montvale,NJ)中，其公开内容如同阐述一般以全文引用的方式并入本文中。Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of a variety of chemotherapeutic agents is described in "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety as if set forth.

II.免疫检查点疗法II. Immune Checkpoint Therapy

本公开的化合物可与一种或多种免疫检查点抑制剂组合使用以用于治疗诸如癌症或感染的疾病。例示性免疫检查点抑制剂包括针对诸如以下的免疫检查点分子的抑制剂：CBL-B、CD20、CD28、CD40、CD70、CD122、CD96、CD73、CD47、CDK2、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、HPK1、CD137(也称为4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、TLR(TLR7/8)、TIGIT、CD112R、VISTA、PD-1、PD-L1和PD-L2。在一些实施方案中，免疫检查点分子选自CD27、CD28、CD40、ICOS、OX40、GITR和CD137的刺激性检查点分子。在一些实施方案中，免疫检查点分子选自A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3、TIGIT和VISTA的抑制性检查点分子。在一些实施方案中，本文所提供的化合物可与一种或多种选自KIR抑制剂、TIGIT抑制剂、LAIR1抑制剂、CD160抑制剂、2B4抑制剂和TGFRβ抑制剂的药剂组合使用。The compounds disclosed herein can be used in combination with one or more immune checkpoint inhibitors for treating diseases such as cancer or infection. Exemplary immune checkpoint inhibitors include inhibitors for immune checkpoint molecules such as: CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, HPK1, CD137 (also referred to as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7/8), TIGIT, CD112R, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, immune checkpoint molecules are selected from the stimulatory checkpoint molecules of CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is selected from the inhibitory checkpoint molecules of A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

在一些实施方案中，本文所提供的化合物可与免疫检查点分子(例如OX40、CD27、GITR和CD137(也称为4-1BB))的一种或多种激动剂组合使用。In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

在一些实施方案中，免疫检查点分子的抑制剂为抗PD1抗体、抗PD-L1抗体或抗CTLA-4抗体。In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

在一些实施方案中，免疫检查点分子的抑制剂为PD-1或PD-L1的抑制剂，例如抗PD-1或抗PD-L1单克隆抗体。在一些实施方案中，抗PD-1或抗PD-L1抗体为纳武利尤单抗(nivolumab)、帕博利珠单抗(pembrolizumab)、阿替利珠单抗(atezolizumab)、度伐利尤单抗(durvalumab)、阿维鲁单抗(avelumab)、西米普利单抗(cemiplimab)、阿替利珠单抗、阿维鲁单抗、替雷利珠单抗(tislelizumab)、斯巴达珠单抗(spartalizumab)(PDR001)、西利单抗(cetrelimab)(JNJ-63723283)、特瑞普利单抗(toripalimab)(JS001)、卡瑞利珠单抗(camrelizumab)(SHR-1210)、信迪利单抗(sintilimab)(IBI308)、AB122(GLS-010)、AMP-224、AMP-514/MEDI-0680、BMS936559、JTX-4014、BGB-108、SHR-1210、MEDI4736、FAZ053、BCD-100、KN035、CS1001、BAT1306、LZM009、AK105、HLX10、SHR-1316、CBT-502(TQB2450)、A167(KL-A167)、STI-A101(ZKAB001)、CK-301、BGB-A333、MSB-2311、HLX20、TSR-042或LY3300054。在一些实施方案中，PD-1或PD-L1的抑制剂为美国专利第7,488,802号、第7,943,743号、第8,008,449号、第8,168,757号、第8,217,149号或第10,308,644号；美国公开第2017/0145025号、第2017/0174671、第2017/0174679号、第2017/0320875号、第2017/0342060号、第2017/0362253号、第2018/0016260号、第2018/0057486号、第2018/0177784号、第2018/0177870号、第2018/0179179号、第2018/0179201号、第2018/0179202号、第2018/0273519号、第2019/0040082号、第2019/0062345号、第2019/0071439号、第2019/0127467号、第2019/0144439号、第2019/0202824号、第2019/0225601号、第2019/0300524号或第2019/0345170号；或PCT公开第WO 03042402号、第WO 2008156712号、第WO 2010089411号、第WO 2010036959号、第WO 2011066342号、第WO 2011159877号、第WO 2011082400号或第WO 2011161699号中所公开的抑制剂，其各自以全文引用的方式并入本文中。在一些实施方案中，PD-L1抑制剂为INCB086550。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (S HR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514/MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, the inhibitor of PD-1 or PD-L1 is U.S. Pat. Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Publication Nos. 2017/0145025, 2017/0174671, 2017/0174679, 2017/0320875, 2017/0342060, 2017/0362253, 2018/0016260, 2018/0057486, 2018 or PCT Publication No. WO 2018/0177784, 2018/0177870, 2018/0179179, 2018/0179201, 2018/0179202, 2018/0273519, 2019/0040082, 2019/0062345, 2019/0071439, 2019/0127467, 2019/0144439, 2019/0202824, 2019/0225601, 2019/0300524, or 2019/0345170; or PCT Publication No. WO In some embodiments, the PD-L1 inhibitor is INCB086550.

在一些实施方案中，PD-L1抑制剂选自表A中的化合物或其药学上可接受的盐。In some embodiments, the PD-L1 inhibitor is selected from the compounds in Table A or a pharmaceutically acceptable salt thereof.

表ATable A

在一些实施方案中，抗体为抗PD-1抗体，例如抗PD-1单克隆抗体。在一些实施方案中，抗PD-1抗体为纳武利尤单抗(nivolumab)、帕博利珠单抗、西米普利单抗、斯巴达珠单抗、卡瑞利珠单抗、西利单抗、特瑞普利单抗、信迪利单抗、AB122、AMP-224、JTX-4014、BGB-108、BCD-100、BAT1306、LZM009、AK105、HLX10或TSR-042。在一些实施方案中，抗PD-1抗体为纳武利尤单抗、帕博利珠单抗、西米普利单抗、斯巴达珠单抗、卡瑞利珠单抗、西利单抗、特瑞普利单抗或信迪利单抗。在一些实施方案中，抗PD-1抗体为帕博利珠单抗。在一些实施方案中，抗PD-1抗体为纳武利尤单抗。在一些实施方案中，抗PD-1抗体为西米普利单抗。在一些实施方案中，抗PD-1抗体为斯巴达珠单抗。在一些实施方案中，抗PD-1抗体为卡瑞利珠单抗。在一些实施方案中，抗PD-1抗体为西利单抗。在一些实施方案中，抗PD-1抗体为特瑞普利单抗。在一些实施方案中，抗PD-1抗体为信迪利单抗。在一些实施方案中，抗PD-1抗体为AB122。在一些实施方案中，抗PD-1抗体为AMP-224。在一些实施方案中，抗PD-1抗体为JTX-4014。在一些实施方案中，抗PD-1抗体为BGB-108。在一些实施方案中，抗PD-1抗体为BCD-100。在一些实施方案中，抗PD-1抗体为BAT1306。在一些实施方案中，抗PD-1抗体为LZM009。在一些实施方案中，抗PD-1抗体为AK105。在一些实施方案中，抗PD-1抗体为HLX10。在一些实施方案中，抗PD-1抗体为TSR-042。在一些实施方案中，抗PD-1单克隆抗体为纳武利尤单抗或帕博利珠单抗。在一些实施方案中，抗PD-1单克隆抗体为MGA012(INCMGA0012；瑞替凡利单抗(retifanlimab))。在一些实施方案中，抗PD1抗体为SHR-1210。其他抗癌剂包括抗体治疗剂，诸如4-1BB(例如乌瑞芦单抗(urelumab)、乌托米单抗(utomilumab)。在一些实施方案中，免疫检查点分子的抑制剂为PD-L1的抑制剂，例如抗PD-L1单克隆抗体。在一些实施方案中，抗PD-L1单克隆抗体为阿替利珠单抗、阿维鲁单抗、度伐利尤单抗、替雷利珠单抗、BMS-935559、MEDI4736、阿替利珠单抗(MPDL3280A；也称为RG7446)、阿维鲁单抗(MSB0010718C)、FAZ053、KN035、CS1001、SHR-1316、CBT-502、A167、STI-A101、CK-301、BGB-A333、MSB-2311、HLX20或LY3300054。在一些实施方案中，抗PD-L1抗体为阿替利珠单抗、阿维鲁单抗、度伐利尤单抗或替雷利珠单抗。在一些实施方案中，抗PD-L1抗体为阿替利珠单抗。在一些实施方案中，抗PD-L1抗体为阿维鲁单抗。在一些实施方案中，抗PD-L1抗体为度伐利尤单抗。在一些实施方案中，抗PD-L1抗体为替雷利珠单抗。在一些实施方案中，抗PD-L1抗体为BMS-935559。在一些实施方案中，抗PD-L1抗体为MEDI4736。在一些实施方案中，抗PD-L1抗体为FAZ053。在一些实施方案中，抗PD-L1抗体为KN035。在一些实施方案中，抗PD-L1抗体为CS1001。在一些实施方案中，抗PD-L1抗体为SHR-1316。在一些实施方案中，抗PD-L1抗体为CBT-502。在一些实施方案中，抗PD-L1抗体为A167。在一些实施方案中，抗PD-L1抗体为STI-A101。在一些实施方案中，抗PD-L1抗体为CK-301。在一些实施方案中，抗PD-L1抗体为BGB-A333。在一些实施方案中，抗PD-L1抗体为MSB-2311。在一些实施方案中，抗PD-L1抗体为HLX20。在一些实施方案中，抗PD-L1抗体为LY3300054。In some embodiments, the antibody is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiprilimab, spartalizumab, carrelizumab, cilizumab, toripalimab, sindilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10 or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiprilimab, spartalizumab, carrelizumab, cilizumab, toripalimab or sindilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is carrelizumab. In some embodiments, the anti-PD-1 antibody is silizumab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (INCMGA0012; retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agents include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (MPDL3280A; also known as RG7446), avelumab ( MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In one In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

在一些实施方案中，免疫检查点分子的抑制剂是结合至PD-L1或其药学上可接受的盐的小分子。在一些实施方案中，免疫检查点分子的抑制剂是结合至并且内化PD-L1或其药学上可接受的盐的小分子。在一些实施方案中，免疫检查点分子的抑制剂选自US 2018/0179201、US2018/0179197、US2018/0179179、US 2018/0179202、US2018/0177784、US2018/0177870、US序列号16/369,654(申请于2019年3月29日)和美国序列号62/688,164的化合物或其药学上可接受的盐，其各者以全文引用的方式并入本文中。In some embodiments, the inhibitor of immune checkpoint molecules is a small molecule that is bound to PD-L1 or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of immune checkpoint molecules is a small molecule that is bound to and internalizes PD-L1 or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of immune checkpoint molecules is selected from US 2018/0179201, US2018/0179197, US2018/0179179, US 2018/0179202, US2018/0177784, US2018/0177870, US Serial No. 16/369,654 (applied for on March 29, 2019) and U.S. Serial No. 62/688,164 compounds or their pharmaceutically acceptable salts, each of which is incorporated herein by reference in its entirety.

在一些实施方案中，免疫检查点分子的抑制剂为KIR、TIGIT、LAIR1、CD160、2B4和TGFRβ的抑制剂。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRβ.

在一些实施方案中，抑制剂为MCLA-145。In some embodiments, the inhibitor is MCLA-145.

在一些实施方案中，免疫检查点分子的抑制剂为CTLA-4的抑制剂，例如抗CTLA-4抗体。在一些实施方案中，抗CTLA-4抗体为伊匹单抗(ipilimumab)、曲美木单抗(tremelimumab)、AGEN1884或CP-675,206。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884 or CP-675,206.

在一些实施方案中，免疫检查点分子的抑制剂为LAG3的抑制剂，例如抗LAG3抗体。在一些实施方案中，抗LAG3抗体为BMS-986016、LAG525、INCAGN2385或艾法莫德(eftilagimod)α(IMP321)。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimod α (IMP321).

在一些实施方案中，免疫检查点分子的抑制剂为CD73的抑制剂。在一些实施方案中，CD73的抑制剂为奥来鲁单抗(oleclumab)。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

在一些实施方案中，免疫检查点分子的抑制剂为TIGIT的抑制剂。在一些实施方案中，TIGIT的抑制剂为OMP-31M32。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

在一些实施方案中，免疫检查点分子的抑制剂为VISTA的抑制剂。在一些实施方案中，VISTA的抑制剂为JNJ-61610588或CA-170。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

在一些实施方案中，免疫检查点分子的抑制剂为B7-H3的抑制剂。在一些实施方案中，B7-H3的抑制剂为依诺妥珠单抗(enoblituzumab)、MGD009或8H9。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009 or 8H9.

在一些实施方案中，免疫检查点分子的抑制剂为KIR的抑制剂。在一些实施方案中，KIR的抑制剂为利瑞鲁单抗(lirilumab)或IPH4102。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

在一些实施方案中，免疫检查点分子的抑制剂为A2aR的抑制剂。在一些实施方案中，A2aR的抑制剂为CPI-444。In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

在一些实施方案中，免疫检查点分子的抑制剂为TGF-β的抑制剂。在一些实施方案中，TGF-β的抑制剂为曲贝德生(trabedersen)、吉布替尼(galusertinib)或M7824。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TGF-β. In some embodiments, the inhibitor of TGF-β is trabedersen, galusertinib or M7824.

在一些实施方案中，免疫检查点分子的抑制剂为PI3K-γ的抑制剂。在一些实施方案中，PI3K-γ的抑制剂为IPI-549。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PI3K-γ. In some embodiments, the inhibitor of PI3K-γ is IPI-549.

在一些实施方案中，免疫检查点分子的抑制剂为CD47的抑制剂。在一些实施方案中，CD47的抑制剂为Hu5F9-G4或TTI-621。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

在一些实施方案中，免疫检查点分子的抑制剂为CD73的抑制剂。在一些实施方案中，CD73的抑制剂为MEDI9447。In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

在一些实施方案中，免疫检查点分子的抑制剂为CD70的抑制剂。在一些实施方案中，CD70的抑制剂为库妥珠单抗(cusatuzumab)或BMS-936561。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

在一些实施方案中，免疫检查点分子的抑制剂为TIM3的抑制剂，例如抗TIM3抗体。在一些实施方案中，抗TIM3抗体为INCAGN2390、MBG453或TSR-022。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453 or TSR-022.

在一些实施方案中，免疫检查点分子的抑制剂为CD20的抑制剂，例如抗CD20抗体。在一些实施方案中，抗CD20抗体为阿托珠单抗(obinutuzumab)或利妥昔单抗。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

在一些实施方案中，免疫检查点分子的激动剂为OX40、CD27、CD28、GITR、ICOS、CD40、TLR7/8和CD137(也称为4-1BB)的激动剂。In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (also known as 4-1BB).

在一些实施方案中，CD137的激动剂为乌瑞芦单抗。在一些实施方案中，CD137的激动剂为乌托米单抗。In some embodiments, the agonist of CD137 is urerulumab. In some embodiments, the agonist of CD137 is umetropumab.

在一些实施方案中，免疫检查点分子的抑制剂为GITR的抑制剂。在一些实施方案中，GITR的激动剂为TRX518、MK-4166、INCAGN1876、MK-1248、AMG228、BMS-986156、GWN323、MEDI1873或MEDI6469。在一些实施方案中，免疫检查点分子的激动剂为OX40的激动剂，例如OX40激动剂抗体或OX40L融合蛋白。在一些实施方案中，抗OX40抗体为INCAGN01949、MEDI0562(他利昔珠单抗(tavolimab))、MOXR-0916、PF-04518600、GSK3174998、BMS-986178或9B12。在一些实施方案中，OX40L融合蛋白为MEDI6383。In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873 or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178 or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

在一些实施方案中，免疫检查点分子的激动剂为CD40的激动剂。在一些实施方案中，CD40的激动剂为CP-870893、ADC-1013、CDX-1140、SEA-CD40、RO7009789、JNJ-64457107、APX-005M或Chi Lob 7/4。In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M or Chi Lob 7/4.

在一些实施方案中，免疫检查点分子的激动剂为ICOS的激动剂。在一些实施方案中，ICOS的激动剂为GSK-3359609、JTX-2011或MEDI-570。In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011 or MEDI-570.

在一些实施方案中，免疫检查点分子的激动剂为CD28的激动剂。在一些实施方案中，CD28的激动剂为治疗珠单抗(theralizumab)。In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is theralizumab.

在一些实施方案中，免疫检查点分子的激动剂为CD27的激动剂。在一些实施方案中，CD27的激动剂为瓦利鲁单抗(varlilumab)。In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

在一些实施方案中，免疫检查点分子的激动剂为TLR7/8的激动剂。在一些实施方案中，TLR7/8的激动剂为MEDI9197。In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7/8. In some embodiments, the agonist of TLR7/8 is MEDI9197.

本公开的化合物可与双特异性抗体组合使用。在一些实施方案中，双特异性抗体中的一个结构域靶向PD-1、PD-L1、CTLA-4、GITR、OX40、TIM3、LAG3、CD137、ICOS、CD3或TGFβ受体。在一些实施方案中，双特异性抗体结合至PD-1和PD-L1。在一些实施方案中，结合至PD-1和PD-L1的双特异性抗体为MCLA-136。在一些实施方案中，双特异性抗体结合至PD-L1和CTLA-4。在一些实施方案中，结合至PD-L1和CTLA-4的双特异性抗体为AK104。The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one domain in the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

在一些实施方案中，本公开的化合物可与一种或多种新陈代谢酶抑制剂组合使用。在一些实施方案中，新陈代谢酶抑制剂为IDO1、TDO或精氨酸酶的抑制剂。IDO1抑制剂的实例包括艾卡哚司他、NLG919、BMS-986205、PF-06840003、IOM2983、RG-70099和LY338196。精氨酸酶抑制剂的抑制剂包括INCB1158。In some embodiments, the compounds of the present disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO or arginase. Examples of IDO1 inhibitors include icadolstat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. Inhibitors of arginase inhibitors include INCB1158.

如通篇所提供，其他化合物、抑制剂、药剂等可与本公开化合物以单一或连续剂型组合，或其可作为单独剂型同时或依次施用。As provided throughout, other compounds, inhibitors, agents, etc. can be combined with the compounds of the present disclosure in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

制剂、剂型和施用Preparation, dosage form and administration

本公开化合物当用作药物时可以药物组合物形式施用。因此，本公开提供一种组合物，其包含式I化合物、如权利要求书的任一项中所列举和本文中所描述的化合物或其药学上可接受的盐或其实施方案中的任一者；以及至少一种药学上可接受的载剂或赋形剂。这些组合物可以药物技术中熟知的方式制备，并且可通过各种途径施用，其取决于指示局部治疗或全身治疗和待治疗的区域。施用可经局部(包括经皮、表皮、经眼和至粘膜，包括鼻内、阴道和直肠递送)、肺(例如吸入或吹入粉末或气溶胶，包括通过雾化器；气管内或鼻内)、经口或非经肠。非经肠施用包括静脉内、动脉内、皮下、腹膜内、肌内或注射或输注；或颅内，例如鞘内或心室内施用。非经肠施用可呈单次推注给药形式，或可为例如连续灌注泵浦。用于局部施用的药物组合物和制剂可包括经皮贴片、软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体以及散剂。常规药物载剂、水溶液、粉末或油性基剂、增稠剂及其类似物可为必需或合乎需要的。The disclosed compounds can be administered in the form of pharmaceutical compositions when used as drugs. Therefore, the present disclosure provides a composition comprising a compound of formula I, a compound listed in any one of the claims and described herein, or any one of its pharmaceutically acceptable salts or its embodiments; and at least one pharmaceutically acceptable carrier or excipient. These compositions can be prepared in a manner well known in pharmaceutical technology, and can be administered by various routes, depending on the area indicated for local treatment or systemic treatment and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and to mucosa, including intranasal, vaginal and rectal delivery), pulmonary (e.g., inhalation or blowing of powder or aerosol, including through a nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus administration, or can be, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous solutions, powders or oily bases, thickeners and the like may be necessary or desirable.

本发明还包括药物组合物，其含有本公开的化合物或其药学上可接受的盐作为活性成分与一种或多种药学上可接受的载剂或赋形剂的组合。在一些实施方案中，组合物适合于局部施用。制备本发明的组合物时，通常将活性成分与赋形剂混合，通过赋形剂稀释或封闭于呈例如胶囊、药囊、纸或其他容器形式的此类载体中。当赋形剂充当稀释剂时，其可为固体、半固体或液体材料，其充当活性成分的媒介物、载剂或介质。因此，组合物可呈以下形式：片剂、丸剂、散剂、口含剂、药囊、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气溶胶(呈固体形式或于液体介质中)、含有例如高达10重量％活性化合物的软膏、软和硬明胶胶囊、栓剂、无菌可注射溶液和无菌封装散剂。The present invention also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. When preparing the composition of the present invention, the active ingredient is usually mixed with an excipient, diluted by the excipient or enclosed in such a carrier in the form of, for example, a capsule, a sachet, paper or other container. When the excipient acts as a diluent, it can be a solid, semisolid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

在制备制剂时，在与其他成分组合之前，可将活性化合物研磨以提供适当粒度。如果活性化合物基本上不可溶，则可将其研磨至小于200目的粒度。如果活性化合物基本上水可溶，则粒度可通过研磨调节，以在制剂中提供基本上均一的分布，例如约40目。When preparing a formulation, the active compound may be ground to provide an appropriate particle size prior to combining with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

可使用诸如湿式研磨的已知研磨步骤来研磨本发明的化合物，以获得适合于片剂成形和其他制剂类型的粒度。可通过本领域中已知的方法制备本发明的化合物的细微粉碎(纳米颗粒)制剂，参见例如WO 2002/000196。The compounds of the invention may be ground using known grinding procedures such as wet grinding to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) formulations of the compounds of the invention may be prepared by methods known in the art, see for example WO 2002/000196.

适合的赋形剂的一些实例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、黄蓍、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂可另外包括：润滑剂，诸如滑石、硬脂酸镁和矿物油；润湿剂；乳化剂和悬浮剂；防腐剂，诸如羟基苯甲酸甲酯和羟基苯甲酸丙酯；甜味剂；以及调味剂。本发明的组合物可经配制以便在通过采用本领域中已知的程序施用患者之后提供活性成分的快速、持续或延迟释放。Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by procedures known in the art.

在一些实施方案中，药物组合物包含硅化微晶纤维素(SMCC)和本文中所描述的至少一种化合物或其药学上可接受的盐。在一些实施方案中，硅化微晶纤维素包含以w/w计约98％微晶纤维素和约2％二氧化硅。In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide on a w/w basis.

在一些实施方案中，组合物为持续释放组合物，其包含至少一种本文中所描述的化合物或其药学上可接受的盐和至少一种药学上可接受的载剂或赋形剂。在一些实施方案中，组合物包含至少一种本文所描述的化合物或其药学上可接受的盐和至少一种选自以下的组分：微晶纤维素、单水合乳糖、羟丙基甲基纤维素和聚氧化乙烯。在一些实施方案中，组合物包含至少一种本文所描述的化合物或其药学上可接受的盐和微晶纤维素、单水合乳糖以及羟丙基甲基纤维素。在一些实施方案中，组合物包含至少一种本文所描述的化合物或其药学上可接受的盐和微晶纤维素、单水合乳糖以及聚氧化乙烯。在一些实施方案中，组合物进一步包含硬脂酸镁或二氧化硅。在一些实施方案中，微晶纤维素为Avicel PH102^TM。在一些实施方案中，单水合乳糖为Fast-flo 316^TM。在一些实施方案中，羟丙基甲基纤维素为羟丙基甲基纤维素2208K4M(例如Methocel K4 M Premier^TM)和/或羟丙基甲基纤维素2208K100LV(例如Methocel K00LV^TM)。在一些实施方案中，聚氧化乙烯为聚氧化乙烯WSR1105(例如Polyox WSR 1105^TM)。In some embodiments, the composition is a sustained release composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from the following: microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, microcrystalline cellulose is Avicel PH102^TM . In some embodiments, lactose monohydrate is Fast-flo 316^TM . In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208K4M (eg, Methocel K4 M Premier^™ ) and/or hydroxypropyl methylcellulose 2208K100LV (eg, Methocel K00LV^™ ). In some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (eg, Polyox WSR 1105^™ ).

在一些实施方案中，使用湿式造粒法来生产组合物。在一些实施方案中，使用干式造粒法来生产组合物。In some embodiments, a wet granulation method is used to produce the composition. In some embodiments, a dry granulation method is used to produce the composition.

组合物可以单位剂型配制，各剂量含有约5至约1,000mg(1g)，更通常约100mg至约500mg活性成分。在一些实施方案中，各剂量含有约10mg活性成分。在一些实施方案中，各剂量含有约50mg活性成分。在一些实施方案中，各剂量含有约25mg活性成分。术语“单位剂型”是指适合以单位剂量形式用于人类受试者和其他哺乳动物的物理上不连续的单元，各单元含有经计算以产生所需治疗作用的预定量的活性材料，其与适合的药物赋形剂结合。The composition can be formulated in unit dosage form, each dose containing about 5 to about 1,000 mg (1 g), more typically about 100 mg to about 500 mg of active ingredient. In some embodiments, each dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable for use in unit dosage form for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, combined with a suitable pharmaceutical excipient.

用于配制药物组合物的组分为高纯度并且基本上不含可能有害的污染物(例如，至少为国家食品级，通常至少为分析级，并且更通常至少为药物级)。尤其对于人类消耗而言，所述组合物优选地根据如美国食品药物管理局的可适用规定中所定义的良好制造规范标准制造或配制。例如，适合的制剂可为无菌的和/或基本上等张的和/或完全符合美国食品药物管理局的所有良好制造规范规定。The components used to prepare the pharmaceutical composition are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, typically at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably manufactured or formulated according to good manufacturing practice standards as defined in applicable regulations of the U.S. Food and Drug Administration. For example, a suitable formulation may be sterile and/or substantially isotonic and/or fully comply with all good manufacturing practice regulations of the U.S. Food and Drug Administration.

活性化合物可以在宽剂量范围内有效，并且通常以治疗有效量施用。然而，应理解，化合物的实际施用量通常将由医师根据相关情况确定，包括待治疗的疾患、所选施用途径、所施用的实际化合物、个别患者的年龄、体重和反应、患者症状的严重程度和其类似情况。The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it should be understood that the actual amount of compound administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

本发明的化合物的治疗剂量可根据例如治疗的特定用途、化合物的施用方式、患者的健康和状况，以及处方医师的判断而变化。药物组合物中的本发明的化合物的比例或浓度可视多种因素而变化，包括剂量、化学特征(例如疏水性)和施用途径。例如，本发明的化合物可以含有约0.1至约10％w/v的化合物的生理缓冲水溶液形式提供以用于非经肠施用。一些典型剂量范围为每天每公斤体重约1μg至约1g。在一些实施方案中，剂量范围为每天每公斤体重约0.01mg至约100mg。剂量很可能取决于诸如以下各者的变量：疾病或病症的类型和发展程度、特定患者的总体健康状况、所选化合物的相对生物功效、赋形剂的配方和其施用途径。有效剂量可自来源于体外或动物模型测试系统的剂量反应曲线外推得到。The therapeutic dose of the compound of the present invention may vary according to, for example, the specific use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compound of the present invention may be provided in the form of a physiologically buffered aqueous solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dosage range is from about 0.01 mg to about 100 mg per kilogram of body weight per day. The dosage is likely to depend on variables such as the following: the type and degree of development of the disease or condition, the overall health of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

为了制备固体组合物诸如片剂，将主要活性成分与药物赋形剂混合以形成含有本发明的化合物的均匀混合物的固体预配制组合物。当将这些预配制组合物称为均匀组合物时，活性成分通常均匀分散在整个组合物中，以使得所述组合物可易于再分为同等有效的单位剂型，诸如片剂、丸剂和胶囊。随后，此固体预制剂再分为含有例如约0.1至约1000mg本发明的活性成分的上文所描述的类型的单位剂型。In order to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of the compound of the present invention. When these preformulated compositions are referred to as homogeneous compositions, the active ingredient is generally evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. Subsequently, this solid preformulation is subdivided into unit dosage forms of the type described above containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.

本发明的片剂或丸剂可经包覆或另外经混配以提供具有延长作用的优势的剂型。例如，片剂或丸剂可包含内部剂量和外部剂量组分，后者呈包覆前者的包膜形式。两种组分可由肠溶层隔开，所述肠溶层用以防止在胃中崩解并且允许内部组分完整进入十二指肠或释放延迟。各种材料可用于此类肠溶性层或包衣，此类材料包括多种聚合酸和聚合酸与诸如虫胶、鲸蜡醇和乙酸纤维素的此类材料的混合物。The tablet or pill of the present invention can be coated or additionally compounded to provide a dosage form with the advantage of prolonged action. For example, the tablet or pill can include an inner dose and an outer dose component, the latter being in the form of a film coating the former. The two components can be separated by an enteric layer, which is used to prevent disintegration in the stomach and allow the inner component to enter the duodenum intact or release delayed. Various materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

可结合本发明的化合物和组合物以经口或通过注射施用的液体形式包括水溶液、适当调味的糖浆、水性或油性悬浮液、和具有可食用油(诸如棉籽油、芝麻油、椰子油或花生油)的调味乳液、以及酏剂及类似药物媒介物。Liquid forms in which the compounds and compositions of the present invention may be administered orally or by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

用于吸入或吹入的组合物包括药学上可接受的水性或有机溶剂或其混合物中的溶液和悬浮液，和散剂。液体或固体组合物可含有如上文所描述的适合的药学上可接受的赋形剂。在一些实施方案中，通过经口或经鼻呼吸道途径施用组合物以用于局部或全身性作用。组合物可通过使用惰性气体而雾化。雾化溶液可直接自雾化装置吸入或可将雾化装置附接至面罩、围罩或间歇性正压呼吸机。溶液、悬浮液或粉末组合物可自以适当方式递送制剂的装置经口或经鼻施用。Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route for local or systemic effect. The composition can be atomized by using an inert gas. The atomized solution can be inhaled directly from the atomizing device or the atomizing device can be attached to a mask, a hood or an intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

局部制剂可含有一种或多种常规载剂。在一些实施方案中，软膏可含有水和一种或多种选自以下的疏水性载剂：例如液体石蜡、聚氧乙烯烷基醚、丙二醇、白凡士林和其类似者。乳膏的载剂组合物可基于水与甘油和一种或多种其他组分，例如单硬脂酸甘油酯、PEG-单硬脂酸甘油酯和鲸蜡硬脂醇的组合。凝胶可使用异丙醇和水，适当地与其他组分(诸如甘油、羟基乙基纤维素和其类似者)组合来配制。在一些实施方案中，局部制剂含有至少约0.1wt％、至少约0.25wt％、至少约0.5wt％、至少约1wt％、至少约2wt％或至少约5wt％的本发明的化合物。局部制剂可适当地封装于例如100g的管中，其任选地伴随有治疗所选适应症，例如牛皮癣或其他皮肤病状的说明书。The topical preparation may contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from the following: for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline and the like. The carrier composition of the cream may be based on water and glycerol and one or more other components, such as a combination of glyceryl monostearate, PEG-glyceryl monostearate and cetearyl alcohol. Gels may be prepared using isopropyl alcohol and water, appropriately in combination with other components such as glycerol, hydroxyethylcellulose and the like. In some embodiments, the topical preparation contains at least about 0.1wt%, at least about 0.25wt%, at least about 0.5wt%, at least about 1wt%, at least about 2wt% or at least about 5wt% of the compound of the present invention. The topical preparation may be suitably packaged in, for example, a 100g tube, which is optionally accompanied by instructions for treating selected indications, such as psoriasis or other skin conditions.

向患者施用的化合物或组合物的量将视所施用的物质、施用目的(诸如预防或治疗)、患者状态、施用方式和其类似者而变化。在治疗性应用中，可向已患有疾病的患者以足以治愈或至少部分地遏制疾病和其并发症的症状的量施用组合物。治疗有效剂量将取决于所治疗的疾病病状，以及由主治临床医师根据诸如疾病的严重程度、患者的年龄、体重和一般状况和其类似者的因素进行判断。The amount of the compound or composition administered to the patient will vary depending on the substance being administered, the purpose of the administration (such as prevention or treatment), the patient's state, the mode of administration, and the like. In therapeutic applications, the composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The therapeutically effective dose will depend on the disease condition being treated, as well as being judged by the attending clinician based on factors such as the severity of the disease, the patient's age, weight and general condition, and the like.

向患者施用的组合物可呈上文所描述的药物组合物形式。这些组合物可通过常规灭菌技术灭菌，或可经无菌过滤。水溶液可封装以按原样使用或冻干，经冻干的制剂在施用之前与无菌水性载剂组合。化合物制剂的pH通常在3与11之间、更优选5至9并且最优选7至8。应理解，使用某些前述赋形剂、载剂或稳定剂将导致药物盐形成。The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be aseptically filtered. The aqueous solution may be packaged to be used as is or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is generally between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

本发明的化合物的治疗剂量可根据例如治疗的特定用途、化合物的施用方式、患者的健康和状况，以及处方医师的判断而变化。药物组合物中的本发明的化合物的比例或浓度可视多种因素而变化，包括剂量、化学特征(例如疏水性)和施用途径。例如，本发明的化合物可以含有约0.1至约10％w/v的化合物的生理缓冲水溶液形式提供以用于非经肠施用。一些典型剂量范围为每天每公斤体重约1μg至约1g。在一些实施方案中，剂量范围为每天每公斤体重约0.01mg至约100mg。剂量很可能取决于诸如以下各者的变量：疾病或病症的类型和发展程度、特定患者的总体健康状况、所选化合物的相对生物功效、赋形剂的配方和其施用途径。有效剂量可自来源于体外或动物模型测试系统的剂量反应曲线外推得到。The therapeutic dose of the compound of the present invention may vary according to, for example, the specific use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compound of the present invention may be provided in the form of a physiologically buffered aqueous solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dosage range is from about 0.01 mg to about 100 mg per kilogram of body weight per day. The dosage is likely to depend on variables such as the following: the type and degree of development of the disease or condition, the overall health of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

标记的化合物和测定方法Labeled compounds and assays

本发明的另一方面涉及本公开的标记的化合物(经放射性标记、经荧光标记等)，其将不仅可用于成像技术，而且可用于体外和体内测定，以便对包括人类的组织样品中的KRAS蛋白进行定位和定量，和通过标记的化合物的抑制结合来鉴别KRAS配体。本公开的化合物的原子中的一或多者的取代还可用于产生分化的ADME(吸附、分布、代谢和分泌)。因此，本发明包括含有此类标记或取代的化合物的KRAS结合测定。Another aspect of the invention relates to labeled compounds of the present disclosure (radiolabeled, fluorescently labeled, etc.), which will be useful not only for imaging techniques, but also for in vitro and in vivo assays to localize and quantify KRAS proteins in tissue samples, including humans, and to identify KRAS ligands by inhibiting binding of labeled compounds. Substitution of one or more of the atoms of the compounds of the present disclosure may also be used to generate differentiated ADMEs (adsorption, distribution, metabolism, and secretion). Thus, the present invention includes KRAS binding assays containing such labeled or substituted compounds.

本公开进一步包括经同位素标记的本公开的化合物。“经同位素”或“经放射性标记”化合物为其中一个或多个原子由具有与通常在自然界中发现(即，天然存在)的原子质量或质量数不同的原子质量或质量数的原子替代或取代的本公开的化合物。可并入本公开的化合物中的适合的放射性核种包括但不限于²H(氘也写为D)、³H(氚也写为T)、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I和¹³¹I。例如，本公开化合物中的一个或多个氢原子可经氘原子替代(例如，式I的C_1-6烷基的一个或多个氢原子可任选地被氘原子取代，诸如-CD₃取代为-CH₃)。在一些实施方案中，式I中的烷基可经全氘化。The present disclosure further includes compounds of the present disclosure that are isotopically labeled. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into compounds of the present disclosure include, but are not limited to,² H (deuterium is also written as D),³ H (tritium is also written as T),¹¹ C,¹³ C,¹⁴ C,¹³ N,¹⁵ N, 15 O,¹⁷ O,¹⁸ O,¹⁸ F,³⁵ S,³⁶ Cl,⁸² Br,⁷⁵ Br,⁷⁶ Br,⁷⁷ Br,¹²³ I,¹²⁴ I,¹²⁵ I, and^131I. For example, one or more hydrogen atoms in the disclosed compounds may be replaced with deuterium atoms (e.g., one or more hydrogen atoms of the C_1-6 alkyl group of Formula I may be optionally replaced with deuterium atoms, such as -CD₃ replaced with -CH₃ ). In some embodiments, the alkyl group in Formula I may be perdeuterated.

本文中所呈现的化合物的一个或多个组分原子可经天然或非天然丰度的原子同位素替代或取代。在一些实施方案中，化合物包括至少一个氘原子。在一些实施方案中，化合物包括两个或更多个氘原子。在一些实施方案中，化合物包括1至2个、1至3个、1至4个、1至5个或1至6个氘原子。在一些实施方案中，化合物中的所有氢原子可经氘原子替代或取代。One or more component atoms of the compounds presented herein may be substituted or replaced by atomic isotopes of natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be substituted or replaced by deuterium atoms.

使有机化合物中包括同位素和合成方法是本领域中已知的(Alan F.Thomas的Deuterium Labeling in Organic Chemistry(New York,N.Y.,Appleton-Century-Crofts,1971；Jens Atzrodt,Volker Derdau,Thorsten Fey和Jochen Zimmermann的TheRenaissance of H/DExchange,Angew.Chem.Int.Ed.2007,7744-7765；James R.Hanson的The Organic Chemistry of Isotopic Labelling，Royal Society of Chemistry,2011)。经同位素标记的化合物可用于各种研究中，诸如NMR光谱法、代谢实验和/或测定。Including isotopes in organic compounds and synthetic methods are known in the art (Alan F. Thomas, Deuterium Labeling in Organic Chemistry (New York, N.Y., Appleton-Century-Crofts, 1971); Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, The Renaissance of H/D Exchange, Angew. Chem. Int. Ed. 2007, 7744-7765; James R. Hanson, The Organic Chemistry of Isotopic Labelling, Royal Society of Chemistry, 2011). Isotopically labeled compounds are useful in various studies, such as NMR spectroscopy, metabolic experiments and/or assays.

经诸如氘的较重同位素取代可获得由更大代谢稳定性产生的某些治疗优势，例如延长的体内半衰期或降低的剂量需求，并且因此在某些情况下可为优选的。(参见例如A.Kerekes等人,J.Med.Chem.2011,54,201-210；R.Xu等人,J.LabelCompd.Radiopharm.2015,58,308-312)。特别地，一个或多个代谢位点处的取代可获得一种或多种治疗优势。Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as extended in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. (See, for example, A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

并入本发明的经放射性标记的化合物中的放射性核种将取决于经放射性标记的化合物的特定应用。例如，对于体外腺苷受体标记和竞争测定，并入³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I或³⁵S的化合物可为适用的。对于放射性成像应用，¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶Br或⁷⁷Br可为适用的。The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro adenosine receptor labeling and competition assays, compounds incorporating³ H,¹⁴ C,⁸² Br,¹²⁵ I,¹³¹ I, or³⁵ S may be useful. For radioactive imaging applications,¹¹ C,¹⁸ F,¹²⁵ I,¹²³ I,¹²⁴ I,¹³¹ I,⁷⁵ Br,⁷⁶ Br, or⁷⁷ Br may be useful.

应了解，“放射性标记”或“标记的化合物”是并入至少一种放射性核种的化合物。在一些实施方案中，放射性核种选自³H、¹⁴C、¹²⁵I、³⁵S和⁸²Br。It is understood that a "radiolabeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from³ H,¹⁴ C,¹²⁵ I,³⁵ S, and⁸² Br.

本公开可进一步包括将放射性同位素并入至本公开化合物中和合成方法。将放射性同位素并入至有机化合物中和合成方法在本领域中已熟知，并且一般本领域的技术人员将易于认识到可用于本公开化合物的方法。The present disclosure may further include the incorporation of radioisotopes into the disclosed compounds and synthetic methods. The incorporation of radioisotopes into organic compounds and synthetic methods are well known in the art, and one of ordinary skill in the art will readily recognize methods that can be used for the disclosed compounds.

标记的本发明的化合物可用于筛选测定以鉴别和/或评估化合物。例如，经由追踪标记，可通过监测当与KRAS接触时其浓度变化来评估标记的新合成或经鉴别的化合物(即测试化合物)结合KRAS蛋白的能力。例如，可评估测试化合物(标记的化合物)减少已知结合至KRAS蛋白的另一化合物(即标准化合物)的结合的能力。因此，测试化合物与标准化合物竞争结合至KRAS蛋白的能力与其结合亲和力直接相关。相反，在一些其他筛选测定中，标准化合物经标记而测试化合物未经标记。因此，监测标记的标准化合物的浓度以评估标准化合物与测试化合物之间的竞争，并且由此确定测试化合物的相对结合亲和力。The labeled compounds of the present invention can be used in screening assays to identify and/or evaluate compounds. For example, via tracking labels, the ability of a newly synthesized or identified compound (i.e., a test compound) to bind to a KRAS protein can be evaluated by monitoring changes in its concentration when in contact with KRAS. For example, the ability of a test compound (labeled compound) to reduce the binding of another compound (i.e., a standard compound) known to bind to a KRAS protein can be evaluated. Therefore, the ability of a test compound to compete with a standard compound for binding to a KRAS protein is directly related to its binding affinity. In contrast, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thereby determined.

试剂盒Reagent test kit

本公开还包括可用于例如治疗或预防与KRAS活性相关的诸如癌症或感染的疾病或病症的药物试剂盒，其包括含有药物组合物的一个或多个容器，所述药物组合物包含治疗有效量的式I化合物或其实施方案中的任一者。此类试剂盒可进一步包括各种常规药物试剂盒组分中的一或多者，诸如具有一种或多种药学上可接受的载剂的容器、另外的容器等，如对于本领域的技术人员而言将为显而易见的。试剂盒中还可包括呈插页或呈标签形式的说明书，其指示待施用组分的量、施用指南和/或用于混合组分的指南。The present disclosure also includes a pharmaceutical kit that can be used, for example, to treat or prevent a disease or condition associated with KRAS activity, such as cancer or infection, comprising one or more containers containing a pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or any one of its embodiments. Such a kit may further include one or more of various conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. The kit may also include instructions in the form of an insert or a label indicating the amount of the component to be administered, instructions for administration, and/or instructions for mixing the components.

本发明将借助于特定实施例更详细地加以描述。以下实施例出于说明的目的而提供，并且不意图以任何方式限制本发明。本领域的技术人员将容易认识到可经改变或修改以产生基本上相同结果的各种非关键参数。已发现所述实施例的化合物会根据至少一种本文所描述的测定来抑制KRAS的活性。The present invention will be described in more detail with the aid of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce substantially the same results. The compounds of the examples have been found to inhibit the activity of KRAS according to at least one of the assays described herein.

实施例Example

下文提供本发明的化合物的实验程序。一些所制备化合物的制备型LCMS纯化在Waters质量定向分馏系统上进行。用于操作这些系统的基础设备设定、方案和控制软件已详细描述于文献中。参见例如“Two-Pump At Column Dilution Configuration forPreparative LC-MS”,K.Blom,J.Combi.Chem.,4,295(2002)；“Optimizing PreparativeLC-MS Configurations and Methods for Parallel Synthesis Purification”,K.Blom,R.Sparks,J.Doughty,G.Everlof,T.Haque,A.Combs,J.Combi.Chem.,5,670(2003)；以及“Preparative LC-MS Purification:Improved Compound Specific MethodOptimization”,K.Blom,B.Glass,R.Sparks,A.Combs,J.Combi.Chem.,6,874-883(2004)。所分离的化合物通常进行分析型液相色谱质谱分析(LCMS)以进行纯度检查。The experimental procedures for the compounds of the present invention are provided below. Preparative LCMS purification of some of the prepared compounds was performed on a Waters mass directional fractionation system. The basic equipment settings, protocols and control software used to operate these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds are usually subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity examination.

所分离的化合物通常在以下条件下进行分析型液相色谱质谱分析(LCMS)以进行纯度检查：仪器：Agilent 1100系列，LC/MSD，柱：Waters Sunfire^TM C₁₈ 5μm粒度，2.1×5.0mm，缓冲液：流动相A：0.025％TFA水溶液和流动相B：乙腈；梯度为在3分钟内2％至80％B，流速为2.0毫升/分钟。The isolated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) under the following conditions for purity check: Instrument: Agilent 1100 series, LC/MSD, Column: Waters Sunfire^™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffer: Mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient from 2% to 80% B in 3 minutes, flow rate 2.0 mL/min.

一些所制备化合物也通过带有MS检测器的反相高效液相色谱(RP-HPLC)或快速色谱(硅胶)以制备规模分离，如实施例中所指示。典型的制备型反相高效液相色谱(RP-HPLC)柱条件如下：Some of the prepared compounds were also separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel), as indicated in the Examples. Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions were as follows:

pH＝2纯化：Waters Sunfire^TM C₁₈ 5μm粒度，19×100mm柱，用流动相A：0.1％TFA(三氟乙酸)水溶液和流动相B：乙腈洗脱；流速为30毫升/分钟，使用如文献中所描的化合物特定方法优化方案使各化合物的分离梯度优化[参见“Preparative LCMS Purification:Improved Compound Specific Method Optimization”,K.Blom,B.Glass,R.Sparks,A.Combs,J.Comb.Chem.,6,874-883(2004)]。通常，用于30×100mm柱的流速为60毫升/分钟。pH = 2 purification: Waters Sunfire^™ C₁₈ 5 μm particle size, 19×100 mm column, eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; flow rate is 30 ml/min, and the separation gradient of each compound is optimized using the compound specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate for a 30×100 mm column is 60 ml/min.

pH＝10纯化：Waters XBridge C₁₈ 5μm粒度，19×100mm柱，用流动相A：0.15％NH₄OH水溶液和流动相B：乙腈洗脱；流速为30毫升/分钟，使用如文献中所描述的化合物特定方法优化方案使各化合物的分离梯度优化[参见“Preparative LCMS Purification:Improved Compound Specific Method Optimization”,K.Blom,B.Glass,R.Sparks,A.Combs,J.Comb.Chem.,6,874-883(2004)]。通常，用于30×100mm柱的流速为60毫升/分钟。pH = 10 purification: Waters XBridge C₁₈ 5 μm particle size, 19×100 mm column, eluted with mobile phase A: 0.15% NH₄ OH in water and mobile phase B: acetonitrile; flow rate was 30 ml/min, and the separation gradient of each compound was optimized using the compound specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate for a 30×100 mm column was 60 ml/min.

可在本文中使用以下缩写：AcOH(乙酸)；Ac₂O(乙酸酐)；aq.(水溶液)；atm.(大气压)；Boc(叔丁氧基羰基)；BOP((苯并三唑-1-基氧基)三(二甲氨基)六氟磷酸鏻)；br(宽峰)；Cbz(羧基苯甲基)；calc.(计算值)；d(二重峰)；dd(双重二重峰)；DBU(1,8-二氮杂二环[5.4.0]十一-7-烯)；DCM(二氯甲烷)；DIAD(叠氮二甲酸N,N'-二异丙酯)；DIEA(N,N-二异丙基乙胺)；DIPEA(N,N-二异丙基乙胺)；DIBAL(二异丁基氢化铝)；DMF(N,N-二甲基甲酰胺)；Et(乙基)；EtOAc(乙酸乙酯)；FCC(快速柱色谱)；g(克)；h(小时)；HATU(N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)脲六氟磷酸盐)；HCl(盐酸)；HPLC(高效液相色谱)；Hz(赫兹)；J(偶合常数)；LCMS(液相色谱-质谱)；LDA(二异丙氨基锂)；m(多重峰)；M(摩尔)；mCPBA(3-氯过氧苯甲酸)；MS(质谱)；Me(甲基)；MeCN(乙腈)；MeOH(甲醇)；mg(毫克)；min.(分钟)；mL(毫升)；mmol(毫摩尔)；N(当量)；NCS(N-氯丁二酰亚胺)；NEt₃(三乙胺)；nM(纳摩尔)；NMP(N-甲基吡咯烷酮)；NMR(核磁共振光谱)；OTf(三氟甲烷磺酸盐)；Ph(苯基)；pM(皮摩尔)；PPT(沉淀)；RP-HPLC(反相高效液相色谱)；r.t.(室温)；s(单峰)；t(三重峰或叔)；TBS(叔丁基二甲基甲硅烷基)；tert(叔)；tt(三重三重峰)；TFA(三氟乙酸)；THF(四氢呋喃)；μg(微克)；μL(微升)；μM(微摩尔)；wt％(重量百分比)。盐水为饱和氯化钠水溶液。真空为在真空下。The following abbreviations may be used herein: AcOH (acetic acid); Ac₂ O (acetic anhydride); aq. (aqueous solution); atm. (atmospheric pressure); Boc (tert-butoxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublet); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N'-diisopropylazidecarboxylate); DIEA (N,N-diisopropylethylamine); DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminum hydride); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); FCC (flash column chromatography); g (gram); h (hour); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); m (multiplet); M (mole); mCPBA (3-chloroperbenzoic acid); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min. (minute); mL (milliliter); mmol (millimole); N (equivalent); NCS (N-chlorosuccinimide); NEt₃ (triethylamine); nM (nanomolar); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); PPT (precipitate); RP-HPLC (reverse phase high performance liquid chromatography); rt (room temperature); s (singlet); t (triplet or tert); TBS (tert-butyldimethylsilyl); tert (tert-butyldimethylsilyl); tt (triplet triplet); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram); μL (microliter); μM (micromolar); wt% (weight percent). Brine is saturated sodium chloride aqueous solution. Vacuum is under vacuum.

中间体1. 7-溴-2,4-二氯-8-氟-6-碘-3-硝基喹啉Intermediate 1. 7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline

步骤1. 2-氨基-4-溴-3-氟-5-碘苯甲酸Step 1. 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acid

将1-碘吡咯烷-2,5-二酮(21.15g，94mmol)添加至2-氨基-4-溴-3-氟苯甲酸(20g，85mmol)在DMF(200ml)中的溶液中，并且随后在80℃搅拌反应物3h。用冰水冷却混合物，并且随后添加水(500mL)，过滤沉淀物并且用水洗涤，干燥，得到呈固体的所需产物。LC-MS计算值C₇H₅BrFINO₂⁺(M+H)⁺:m/z＝359.9,361.9；实验值359.9,361.9.1-Iodopyrrolidine-2,5-dione (21.15 g, 94 mmol) was added to a solution of 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 85 mmol) in DMF (200 ml), and the reaction was then stirred at 80° C. for 3 h. The mixture was cooled with ice water, and then water (500 mL) was added, the precipitate was filtered and washed with water, and dried to give the desired product as a solid. LC-MS calculated for C₇ H₅ BrFINO₂⁺ (M+H)⁺ : m/z=359.9, 361.9; Found 359.9, 361.9.

步骤2. 7-溴-8-氟-6-碘-2H-苯并[d][1,3]噁嗪-2,4(1H)-二酮Step 2. 7-Bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

将三光气(9.07g，30.6mmol)添加至2-氨基-4-溴-3-氟-5-碘苯甲酸(22g，61.1mmol)于二噁烷(200ml)中的溶液中并且随后在80℃搅拌反应物2h。用冰水冷却反应混合物并且接着过滤。用乙酸乙酯洗涤固体，得到呈固体的所需产物。LC-MS计算值C₈H₃BrFINO₃⁺(M+H)⁺:m/z＝385.8,387.8；实验值385.8,387.8。Triphosgene (9.07 g, 30.6 mmol) was added to a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (22 g, 61.1 mmol) in dioxane (200 ml) and then the reaction was stirred at 80°C for 2 h. The reaction mixture was cooled with ice water and then filtered. The solid was washed with ethyl acetate to give the desired product as a solid. LC-MS calculated for C₈ H₃ BrFINO₃⁺ (M+H)⁺ : m/z = 385.8, 387.8; Found 385.8, 387.8.

步骤3. 7-溴-8-氟-6-碘-3-硝基喹啉-2,4-二醇Step 3. 7-Bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol

在室温下将DIPEA(25.5ml，146mmol)添加至2-硝基乙酸乙酯(16.33ml，146mmol)和7-溴-8-氟-6-甲基-2H-苯并[d][1,3]噁嗪-2,4(1H)-二酮(20g，73.0mmol)于甲苯(200ml)中的溶液中，并且在95℃搅拌反应物3h。冷却反应物并且随后过滤，随后用少量己烷洗涤，得到所需产物。LC-MS计算值C₉H₄BrFIN₂O₄⁺(M+H)⁺:m/z＝428.8,430.8；实验值428.8,430.8。DIPEA (25.5 ml, 146 mmol) was added to a solution of ethyl 2-nitroacetate (16.33 ml, 146 mmol) and 7-bromo-8-fluoro-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (20 g, 73.0 mmol) in toluene (200 ml) at room temperature, and the reaction was stirred at 95° C. for 3 h. The reaction was cooled and then filtered, followed by washing with a small amount of hexane to give the desired product. LC-MS calculated for C₉ H₄ BrFIN₂ O₄⁺ (M+H)⁺ : m/z=428.8, 430.8; Found 428.8, 430.8.

步骤4. 7-溴-2,4-二氯-8-氟-6-碘-3-硝基喹啉Step 4. 7-Bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline

将DIPEA(8.14ml，46.6mmol)添加至7-溴-8-氟-6-碘-3-硝基喹啉-2,4-二醇(10g，23.31mmol)于POCl₃(10.86ml，117mmol)中的混合物中并且随后在100℃搅拌反应物2h。在真空下去除溶剂，并且随后使其与甲苯共沸3次，得到粗物质，将其用闪蒸塔纯化。LC-MS计算值C₉H₂BrCl₂FIN₂O₂⁺(M+H)⁺:m/z＝464.8,466.8；实验值464.8,466.8。DIPEA (8.14 ml, 46.6 mmol) was added to a mixture of 7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol (10 g, 23.31 mmol) in POCl₃ (10.86 ml, 117 mmol) and the reaction was then stirred at 100° C. for 2 h. The solvent was removed under vacuum and then azeotroped with toluene 3 times to give a crude material which was purified with a flash column. LC-MS calculated for C₉ H₂ BrCl₂ FIN₂ O₂⁺ (M+H)⁺ : m/z=464.8, 466.8; Found 464.8, 466.8.

中间体2.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 2. (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

步骤1.(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向7-溴-2,4-二氯-8-氟-6-碘-3-硝基喹啉(25g，53.7mmol，中间体1)和(1R,4R,5S)-5-氨基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(10.6g，53.7mmol)于NMP(200ml)中的溶液中添加休尼格氏碱(14.0ml，81mmol)，并且将反应混合物加热至60℃持续1h。添加冰屑和水(100mL)并且搅拌悬浮液15min。过滤固体，用水冲洗，并且在真空下风干过夜，得到所需产物。To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (25 g, 53.7 mmol, intermediate 1) and (1R, 4R, 5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (10.6 g, 53.7 mmol) in NMP (200 ml) was added Hunig's base (14.0 ml, 81 mmol), and the reaction mixture was heated to 60 ° C for 1 h. Ice chips and water (100 mL) were added and the suspension was stirred for 15 min. The solid was filtered, rinsed with water, and air-dried overnight under vacuum to give the desired product.

将上文所获得的固体悬浮于MeCN(200mL)中并且冷却至0℃。缓慢添加硫代甲醇钠(11.3g，161mmol)在MeOH(30ml)中的溶液并且在此温度下搅拌反应混合物1h。添加冰和水并且过滤固体并风干。用EtOAc萃取滤液并且与固体合并。合并的产物不经纯化即使用。LC-MS计算值C₂₀H₂₂BrFIN₄O₄S⁺(M+H)⁺:m/z＝639.0；实验值639.1。The solid obtained above was suspended in MeCN (200 mL) and cooled to 0°C. A solution of sodium thiomethoxide (11.3 g, 161 mmol) in MeOH (30 ml) was slowly added and the reaction mixture was stirred at this temperature for 1 h. Ice and water were added and the solid was filtered and air-dried. The filtrate was extracted with EtOAc and combined with the solid. The combined product was used without purification. LC-MS calculated for C₂₀ H₂₂ BrFIN₄ O₄ S⁺ (M+H)⁺ : m/z=639.0; found 639.1.

步骤2.(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在室温下向(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(34.3g，53.7mmol)于THF(200ml)中的溶液中依序添加三乙胺(18.7ml，134mmol)、DMAP(0.66g，5.37mmol)和二碳酸-二-叔丁酯(23.4g，107mmol)，并且将反应混合物加热至50℃持续3h。将反应混合物用EtOAc稀释并且用饱和NaHCO₃和盐水洗涤。有机层经MgSO₄干燥，过滤并浓缩。产物不经纯化即使用。LC-MS计算值C₂₁H₂₂BrFIN₄O₆S⁺(M+H-C₄H₈)⁺:m/z＝683.0；实验值683.1。To a solution of (1R,4R,5S)-5-((7-bromo-8-fluoro-6-iodo-2-(methylsulfanyl)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (34.3 g, 53.7 mmol) in THF (200 ml) was added triethylamine (18.7 ml, 134 mmol), DMAP (0.66 g, 5.37 mmol) and di-tert-butyl dicarbonate (23.4 g, 107 mmol) in sequence at room temperature and the reaction mixture was heated to 50 °C for 3 h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO₃ and brine. The organic layer was dried over MgSO₄ , filtered and concentrated. The product was used without purification. LC-MS calculated_{forC21H22BrFIN4O6S}⁺ (_M +_HC4H8 )⁺ : m/_z =_683.0 ; found 683.1.

步骤3.(1R,4R,5S)-5-((3-氨基-7-溴-8-氟-6-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向配备有机械搅拌器的1L烧瓶中装入(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(39.7g，53.7mmol)、MeOH(75ml)、水(75ml)和THF(75ml)。添加铁(15.0g，268mmol)和氯化铵(14.4g，268mmol)，并且在70℃搅拌反应混合物过夜。将反应混合物用EtOAc稀释并且经由硅藻土垫过滤。分离各层，并且将有机层用盐水洗涤，经MgSO₄干燥，过滤，并且浓缩。产物不经纯化即使用。LC-MS计算值C₂₅H₃₂BrFIN₄O₄S⁺(M+H)⁺:m/z＝709.0；实验值709.1。A 1 L flask equipped with a mechanical stirrer was charged with (1R, 4R, 5S) -5- ((7-bromo-8-fluoro-6-iodo-2- (methylthio) -3-nitroquinolin-4-yl) (tert-butoxycarbonyl) amino) -2- azabicyclo [2.1.1] hexane -2- carboxylic acid tert-butyl ester (39.7 g, 53.7 mmol), MeOH (75 ml), water (75 ml) and THF (75 ml). Iron (15.0 g, 268 mmol) and ammonium chloride (14.4 g, 268 mmol) were added, and the reaction mixture was stirred at 70 ° C overnight. The reaction mixture was diluted with EtOAc and filtered through a celite pad. The layers were separated, and the organic layer was washed with brine, dried over MgSO₄ , filtered, and concentrated. The product was used without purification. LC-MS calculated for_{C25H32BrFIN4O4S}⁺ (M+H₎₊^: m/_z =709.0; found 709.1.

步骤4.(1R,4R,5S)-5-((3-氨基-7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-((3-氨基-7-溴-8-氟-6-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(36.7g，51.7mmol)、PdOAc₂(1.16g，5.17mmol)和三邻甲苯膦(3.15g，10.4mmol)溶解于DMF(200ml)中。将丙烯腈(6.78ml，103mmol)和三乙胺(14.3ml，103mmol)一次性添加至反应混合物中。用氮气吹扫顶部空间并且在80℃搅拌反应混合物两小时。将反应混合物冷却至室温并且添加水。过滤所得沉淀物，用水洗涤并风干。Tert-butyl (1R, 4R, 5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (36.7 g, 51.7 mmol), PdOAc₂ (1.16 g, 5.17 mmol) and tri-o-tolylphosphine (3.15 g, 10.4 mmol) were dissolved in DMF (200 ml). Acrylonitrile (6.78 ml, 103 mmol) and triethylamine (14.3 ml, 103 mmol) were added to the reaction mixture in one portion. The headspace was purged with nitrogen and the reaction mixture was stirred at 80° C. for two hours. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was filtered, washed with water and air-dried.

将所得固体溶解于THF(200ml)中并且冷却至0℃。通过LCMS监测逐滴添加超级氢化物(55.8ml，55.8mmol)。完成后，在0℃逐滴添加MeOH和水，随后使反应混合物升温至室温并且搅拌15min。用EtOAc萃取反应混合物并且分离各层。将有机层用盐水洗涤，经MgSO₄干燥，过滤并浓缩。产物不经纯化即使用。LC-MS计算值C₂₈H₃₆BrFN₅O₄S⁺(M+H)⁺:m/z＝636.2；实验值636.3。The resulting solid was dissolved in THF (200 ml) and cooled to 0°C. Superhydride (55.8 ml, 55.8 mmol) was added dropwise by LCMS monitoring. Upon completion, MeOH and water were added dropwise at 0°C, and the reaction mixture was then allowed to warm to room temperature and stirred for 15 min. The reaction mixture was extracted with EtOAc and the layers were separated. The organic layer was washed with brine, dried over MgSO₄ , filtered and concentrated. The product was used without purification. LC-MS calculated for C₂₈ H₃₆ BrFN₅ O₄ S⁺ (M+H)⁺ : m/z=636.2; Found 636.3.

步骤5.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. tert-Butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((3-氨基-7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(32g，50.3mmol)、碘化钾(41.7g，251mmol)和碘化铜(I)(12.45g，65.3mmol)的混合物中添加丙酸(200ml)和水(50mL)，并且将混合物冷却至-10℃。经15分钟缓慢添加t-BuONO(50mL，377mmol)以控制鼓泡。在添加之后，搅拌反应物30分钟。将反应混合物倒入低温硫代硫酸钠溶液中并且接着用乙酸乙酯萃取。将有机层用NH₄OH和饱和NaCl洗涤，经MgSO₄干燥并且浓缩。通过FCC(0至50％EtOAc/己烷)纯化产物，得到呈棕色固体的标题化合物(20g，53％，经5个步骤)。LC-MS计算值C₂₄H₂₆BrFIN₄O₄S⁺(M+H-C₄H₈)⁺:m/z＝691.0；实验值691.1。To a mixture of tert-butyl (1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (32 g, 50.3 mmol), potassium iodide (41.7 g, 251 mmol) and copper (I) iodide (12.45 g, 65.3 mmol) were added propionic acid (200 ml) and water (50 mL) and the mixture was cooled to -10 °C. t-BuONO (50 mL, 377 mmol) was added slowly over 15 minutes to control bubbling. After the addition, the reaction was stirred for 30 minutes. The reaction mixture was poured into a cold sodium thiosulfate solution and then extracted with ethyl acetate. The organic layer was washed with_NH4OH and saturated NaCl, dried over_MgSO4 and concentrated. The product was purified by FCC (0 to 50% EtOAc/hexanes) to give_the title compound as a brown solid₍₂₀ g, 53% over 5 steps).^{LC-MS calcd for C24H26BrFIN4O4S+}_(M +_HC4H8 )⁺ : m/z = 691.0; found 691.1.

中间体3. 5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯Intermediate 3. tert-Butyl 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

步骤1. 3-溴-5,7-二氟-1H-吲哚-1-甲酸叔丁酯Step 1. tert-Butyl 3-bromo-5,7-difluoro-1H-indole-1-carboxylate

在0℃向5,7-二氟-1H-吲哚(300mg，1.96mmol)在DMF(8ml)中的溶液中添加NBS(384mg，2.16mmol)并且在此温度下搅拌反应混合物30min。一旦溴化完成，依序添加三乙胺(410μl，2.94mmol)、Boc-酐(641mg，2.94mmol)和DMAP(24mg，0.2mmol)，并且使反应混合物升温至室温。30min后，将反应物用EtOAc稀释并且用饱和NaHCO₃淬灭。使反应混合物分配于水与EtOAc之间，并且分离各层。将有机层用盐水洗涤，经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至10％己烷/EtOAc)纯化残余物，得到标题化合物(531mg，82％)。LC-MS计算值C₉H₅BrF₂NO₂⁺(M+H-C₄H₈)⁺:m/z＝276.0；实验值276.0。To a solution of 5,7-difluoro-1H-indole (300 mg, 1.96 mmol) in DMF (8 ml) was added NBS (384 mg, 2.16 mmol) at 0 °C and the reaction mixture was stirred at this temperature for 30 min. Once the bromination was complete, triethylamine (410 μl, 2.94 mmol), Boc-anhydride (641 mg, 2.94 mmol) and DMAP (24 mg, 0.2 mmol) were added in sequence and the reaction mixture was allowed to warm to room temperature. After 30 min, the reactant was diluted with EtOAc and quenched with saturated NaHCO_3. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with brine, dried over MgSO₄ , filtered and concentrated. The residue was purified by flash chromatography (0 to 10% hexane/EtOAc) to give the title compound (531 mg, 82%). LC-MS calcd for C₉ H₅ BrF₂ NO₂⁺ (M + HC₄ H₈ )⁺ : m/z = 276.0; found 276.0.

步骤2. 5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯Step 2. tert-Butyl 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

将3-溴-5,7-二氟-1H-吲哚-1-甲酸叔丁酯(531mg，1.60mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(1.21g，4.80mmol)、乙酸钾(471mg，4.80mmol)和PdCl₂(dppf)-CH₂Cl₂加合物(131mg，0.16mmol)于二噁烷(10ml)中的混合物用N₂充气并且加热至95℃过夜。将反应混合物用EtOAc稀释，过滤并浓缩。通过快速色谱(0至10％EtOAc/己烷)纯化残余物。LC-MS计算值C₁₅H₁₇BF₂NO₄⁺(M+H-C₄H₈)⁺:m/z＝324.1；实验值324.2。A mixture of tert-butyl 3-bromo-5,7-difluoro-1H-indole-1-carboxylate (531 mg, 1.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.21 g, 4.80 mmol), potassium acetate (471 mg, 4.80 mmol) and_PdCl2 (dppf)_-CH2Cl2 adduct (131 mg,_0.16 mmol) in dioxane (10 ml) was sparged with_N2 and heated to 95°C overnight. The reaction mixture was diluted with EtOAc, filtered and concentrated. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes). LC-MS calculated_{forC15H17BF2NO4}⁺ (M+_HC4H8 )⁺ : m/_z =_324.1 ; found_324.2 .

中间体4. 6-氟-5-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯Intermediate 4. 6-Fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester

步骤1. 3-溴-6-氟-5-甲基-1H-吲哚-1-甲酸叔丁酯Step 1. tert-Butyl 3-bromo-6-fluoro-5-methyl-1H-indole-1-carboxylate

此化合物通过与针对3-溴-5,7-二氟-1H-吲哚-1-甲酸叔丁酯(中间体3，步骤1)所描述相同的程序,利用6-氟-5-甲基-1H-吲哚代替5,7-二氟-1H-吲哚来制备。LC-MS计算值C₁₄H₁₅BrFNO₂Na⁺(M+Na)⁺:m/z＝350.0；实验值350.0。This compound was prepared by the same procedure as described for tert-butyl 3-bromo-5,7-difluoro-1H-indole-₁ -carboxylate (Intermediate 3, Step 1), using 6-fluoro-5-methyl-1H-indole instead of 5,7-_{difluoro-1H-indole. LC-MS calculated for C14H15BrFNO2Na+}⁽ M+Na)⁺ : m/z=350.0; found 350.0.

步骤2. 6-氟-5-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯Step 2. tert-Butyl 6-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate

在-78℃向3-溴-6-氟-5-甲基-1H-吲哚-1-甲酸叔丁酯(187mg，0.57mmol)于THF(4mL)中的溶液中添加仲丁基锂(1.4M/己烷，0.61ml，0.86mmol)，并且在-78℃搅拌反应混合物15min。随后添加2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(0.29ml，1.43mmol)并且使反应混合物升温至室温。用饱和NH₄Cl淬灭反应物并且用EtOAc萃取。分离各层，并且有机层经MgSO₄干燥，过滤并浓缩。产物不经纯化即使用。LC-MS计算值C₂₀H₂₈BFNO₄⁺(M+H)⁺:m/z＝376.2；实验值376.3。To a solution of tert-butyl 3-bromo-6-fluoro-5-methyl-1H-indole-1-carboxylate (187 mg, 0.57 mmol) in THF (4 mL) was added sec-butyl lithium (1.4 M/hexane, 0.61 ml, 0.86 mmol) at -78 °C and the reaction mixture was stirred at -78 °C for 15 min. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.29 ml, 1.43 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH₄ Cl and extracted with EtOAc. The layers were separated and the organic layer was dried over MgSO₄ , filtered and concentrated. The product was used without purification. LC-MS calculated for C₂₀ H₂₈ BFNO₄⁺ (M+H)⁺ : m/z=376.2; found 376.3.

中间体5.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 5. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在室温下向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(10.0g，13.4mmol，中间体2)在DCM(134ml)中的溶液中添加TFA(134mL)，并且在室温下搅拌反应物2h。随后浓缩反应混合物并且用THF(134ml)溶解。此后，添加Boc₂O(9.32ml，40.1mmol)和TEA(5.59ml，40.1mmol)。在室温下搅拌反应混合物1h。随后浓缩反应物并且通过快速色谱(0至60％EtOAc/己烷)纯化，得到标题化合物(6.5g，75％)。LC-MS计算值C₂₃H₂₆BrFIN₄O₂S⁺(M+H)⁺:m/z＝647.0；实验值647.0。To a solution of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 13.4 mmol, Intermediate 2) in DCM (134 ml) was added TFA (134 mL) at room temperature and the reaction was stirred at room temperature for 2 h. The reaction mixture was then concentrated and dissolved with THF (134 ml). Thereafter, Boc₂ O (9.32 ml, 40.1 mmol) and TEA (5.59 ml, 40.1 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction was then concentrated and purified by flash chromatography (0 to 60% EtOAc/hexanes) to give the title compound (6.5 g, 75%). LC-MS calcd_{forC23H26BrFIN4O2S}⁺ (M+H₎⁺ : m/_z =647.0; found 647.0.

中间体6：(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 6: (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

步骤1：(1R,4R,5S)-5-((3-氨基-7-溴-8-氟-6-甲基-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((3-amino-7-bromo-8-fluoro-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((3-氨基-7-溴-8-氟-6-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(10.0g，14.1mmol)(中间体2，步骤3)、甲基硼酸(4.22g，70.5mmol)、双(三苯膦)氯化钯(II)(1.484g，2.114mmol)和磷酸钾(8.98g，42.3mmol)的混合物中添加1,4-二噁烷(100ml)/水(10ml)，并且抽空反应烧瓶，用氮气回填，接着在80℃搅拌24小时。用水稀释混合物并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过Biotage(0至50％乙酸乙酯/己烷)纯化粗产物，得到所需产物。LC-MS计算值C₂₆H₃₅BrFN₄O₄S(M+H)⁺:m/z＝597.2；实验值597.1。To a mixture of (1R,4R,5S)-tert-butyl 5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 14.1 mmol) (Intermediate 2, Step 3), methylboronic acid (4.22 g, 70.5 mmol), bis(triphenylphosphine)palladium(II) chloride (1.484 g, 2.114 mmol) and potassium phosphate (8.98 g, 42.3 mmol) was added 1,4-dioxane (100 ml)/water (10 ml) and the reaction flask was evacuated, backfilled with nitrogen, then stirred at 80°C for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by_Biotage (0 to 50%_ethyl acetate/hexanes) to give the desired product._LC -MS Calcd for_{C26H35BrFN4O4S} (M+H)⁺ : m/z = 597.2; found 597.1.

步骤2：(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体2，步骤5)和合成中所描述的程序制备。LC-MS计算值C₂₆H₃₃BrFIN₃O₄S(M+H)⁺:m/z＝708.0；实验值708.2。This compound was prepared according to tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2_- carboxylate (Intermediate 2, Step 5) and the procedure described in the synthesis._LC -MS calculated for_{C26H33BrFIN3O4S} (M+H)₊^: m/z=708.0; found 708.2.

中间体7.(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 7. (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体5中所描述的程序，使用(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体6)来制备。LC-MS计算值C₂₁H₂₅BrFIN₃O₂S(M+H)⁺:m/z＝608.0；实验值608.2。This compound was prepared according to the procedure described in Intermediate 5 using tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2_-carboxylate (Intermediate 6)_{. LC-MS calculated for C21H25BrFIN3O2S(} M+H)⁺ : m/z=608.0; found 608.2.

中间体8. 7-溴-2,4-二氯-8-氟-6-碘喹啉-3-甲酸乙酯Intermediate 8. 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinoline-3-carboxylic acid ethyl ester

步骤1:2-氨基-4-溴-3-氟苯甲酸甲酯Step 1: Methyl 2-amino-4-bromo-3-fluorobenzoate

在室温下将硫酸(16.7mL，313mmol)缓慢添加至2-氨基-4-溴-3-氟苯甲酸(36.6g，156mmol)在MeOH(300ml)中的溶液中。将所得混合物加热至80℃过夜。接着将混合物冷却至室温并且用1M NaOH水溶液(150mL)缓慢淬灭。在室温下搅拌混合物30min，接着过滤并且风干，得到标题化合物，其不经进一步纯化即用于下一步骤中。LC-MS计算值C₈H₈BrFNO₂(M+H)⁺:m/z＝247.9,249.9；实验值247.9,249.9.Sulfuric acid (16.7 mL, 313 mmol) was slowly added to a solution of 2-amino-4-bromo-3-fluorobenzoic acid (36.6 g, 156 mmol) in MeOH (300 ml) at room temperature. The resulting mixture was heated to 80°C overnight. The mixture was then cooled to room temperature and slowly quenched with 1 M aqueous NaOH (150 mL). The mixture was stirred at room temperature for 30 min, then filtered and air-dried to give the title compound, which was used in the next step without further purification. LC-MS calculated for C₈ H₈ BrFNO₂ (M+H)⁺ : m/z=247.9, 249.9; Found 247.9, 249.9.

步骤2:2-氨基-4-溴-3-氟-5-碘苯甲酸甲酯Step 2: Methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate

向2-氨基-4-溴-3-氟苯甲酸甲酯(18.0g，72.6mmol)在DMF(363ml)中的溶液中添加NIS(29.4g，131mmol)。在80℃搅拌所得混合物过夜。在冷却至室温之后，添加冰并且搅拌混合物直至所有冰溶解，过滤，用己烷洗涤并风干，得到标题化合物，其不经进一步纯化即用于下一步骤中。LC-MS计算值C₈H₇BrFINO₂(M+H)⁺:m/z＝373.9,375.9；实验值373.9,375.9。To a solution of methyl 2-amino-4-bromo-3-fluorobenzoate (18.0 g, 72.6 mmol) in DMF (363 ml) was added NIS (29.4 g, 131 mmol). The resulting mixture was stirred at 80°C overnight. After cooling to room temperature, ice was added and the mixture was stirred until all ice dissolved, filtered, washed with hexanes and air-dried to give the title compound, which was used in the next step without further purification. LC-MS calculated for C₈ H₇ BrFINO₂ (M+H)⁺ : m/z=373.9, 375.9; found 373.9, 375.9.

步骤3:4-溴-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟-5-碘苯甲酸甲酯Step 3: Methyl 4-bromo-2-(3-ethoxy-3-oxopropionylamino)-3-fluoro-5-iodobenzoate

在空气下在室温下向2-氨基-4-溴-3-氟-5-碘苯甲酸甲酯(10.6g，28.3mmol)和TEA(8.69mL。62.4mmol)在DCM(150mL)中的溶液中逐滴添加3-氯-3-氧代丙酸乙酯(7.26mL，56.7mmol)。将所得混合物在室温下搅拌2h并且用水淬灭。用DCM(×2)萃取所得混合物。合并有机萃取物，干燥并且在减压下浓缩。快速柱色谱(0至100％EtOAc:DCM)得到标题化合物。LC-MS计算值C₁₃H₁₃BrFINO₅(M+H)⁺:m/z＝487.9,489.9；实验值487.9,489.9。To a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid methyl ester (10.6 g, 28.3 mmol) and TEA (8.69 mL. 62.4 mmol) in DCM (150 mL) was added dropwise 3-chloro-3-oxopropanoic acid ethyl ester (7.26 mL, 56.7 mmol) at room temperature under air. The resulting mixture was stirred at room temperature for 2 h and quenched with water. The resulting mixture was extracted with DCM (×2). The organic extracts were combined, dried and concentrated under reduced pressure. Flash column chromatography (0 to 100% EtOAc: DCM) gave the title compound. LC-MS calculated for C₁₃ H₁₃ BrFINO₅ (M+H)⁺ : m/z=487.9,489.9; Found 487.9,489.9.

步骤4:7-溴-8-氟-4-羟基-6-碘-2-氧代-1,2-二氢喹啉-3-甲酸乙酯Step 4: 7-Bromo-8-fluoro-4-hydroxy-6-iodo-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ethyl ester

向4-溴-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟-5-碘苯甲酸甲酯(12.3g，25.2mmol)在MeOH(125mL)中的溶液中添加甲醇钠/MeOH(25％，16.6mL，52.9mmol)，并且在室温下搅拌1h。在真空下去除溶剂，并且粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₁₂H₉BrFINO₄(M+H)⁺:m/z＝455.9,457.9；实验值455.8,457.8。To a solution of methyl 4-bromo-2-(3-ethoxy-3-oxopropionylamino)-3-fluoro-5-iodobenzoate (12.3 g, 25.2 mmol) in MeOH (125 mL) was added sodium methoxide/MeOH (25%, 16.6 mL, 52.9 mmol) and stirred at room temperature for 1 h. The solvent was removed under vacuum and the crude product was used in the next step without further purification. LC-MS calculated for C₁₂ H₉ BrFINO₄ (M+H)⁺ : m/z=455.9, 457.9; found 455.8, 457.8.

步骤5：7-溴-2,4-二氯-8-氟-6-碘喹啉-3-甲酸乙酯Step 5: 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinoline-3-carboxylic acid ethyl ester

将7-溴-8-氟-2,4-二羟基-6-碘喹啉-3-甲酸乙酯(11.0g，24.1mmol)溶解于POCl₃(45.0mL，110mmol)中。在110℃搅拌所得混合物2h。在冷却至室温之后，通过与甲苯共沸(3次)去除POCl₃。快速柱色谱(0至100％DCM:己烷)得到标题化合物。LC-MS计算值C₁₂H₇BrCl₂FINO₂(M+H)⁺:m/z＝491.8,493.8；实验值491.8,493.8。Ethyl 7-bromo-8-fluoro-2,4-dihydroxy-6-iodoquinoline-3-carboxylate (11.0 g, 24.1 mmol) was dissolved in POCl₃ (45.0 mL, 110 mmol). The resulting mixture was stirred at 110° C. for 2 h. After cooling to room temperature, POCl₃ was removed by azeotroping with toluene (3 times). Flash column chromatography (0 to 100% DCM:hexanes) gave the title compound. LC-MS calculated for C₁₂ H₇ BrCl₂ FINO₂ (M+H)⁺ : m/z=491.8, 493.8; Found 491.8, 493.8.

中间体9.(2S,4S)-4-氨基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Intermediate 9. tert-Butyl (2S,4S)-4-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

步骤1：(R)-6-氰基-5-羟基-3-氧代己酸叔丁酯Step 1: (R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate

将2.0M LDA(100ml，200mmol)于无水THF(223ml)中的溶液中冷却至-78℃，持续1h，并且接着在搅拌下经20min逐滴添加乙酸叔丁酯(26.9ml，200mmol)。在-78℃下再维持40分钟后，逐滴添加(R)-4-氰基-3-羟基丁酸乙酯(10.5g，66.8mmol)的溶液。使混合物在-40℃下搅拌4h，并且接着将适量HCl(2M)添加至混合物中，保持pH约6。在此淬灭期间，将混合物的温度维持于-10℃。完成后，将混合物的温度冷却至0℃。用乙酸乙酯(3×100mL)萃取混合物。将合并的有机层用NaHCO₃(100mL)和盐水(100mL)洗涤，经无水Na₂SO₄干燥并蒸发，得到呈黄色油状物的物质(15.0g，99％)。A solution of 2.0M LDA (100ml, 200mmol) in anhydrous THF (223ml) was cooled to -78°C for 1h, and then tert-butyl acetate (26.9ml, 200mmol) was added dropwise under stirring over 20min. After maintaining at -78°C for another 40 minutes, a solution of (R)-ethyl 4-cyano-3-hydroxybutyrate (10.5g, 66.8mmol) was added dropwise. The mixture was stirred at -40°C for 4h, and then an appropriate amount of HCl (2M) was added to the mixture, keeping pH about 6. During this quenching, the temperature of the mixture was maintained at -10°C. After completion, the temperature of the mixture was cooled to 0°C. The mixture was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with NaHCO₃ (100 mL) and brine (100 mL), dried over anhydrous Na₂ SO₄ and evaporated to afford the material as a yellow oil (15.0 g, 99%).

步骤2.(2S,4R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-羟基哌啶-1-甲酸叔丁酯Step 2. tert-Butyl (2S,4R)-2-(2-(tert-Butoxy)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate

用氧化铂(IV)水合物(0.868g，3.30mmol)处理(R)-6-氰基-5-羟基-3氧代己酸叔丁酯(15.0g，66.0mmol)在乙酸(110ml)中的溶液。将帕尔瓶抽成真空并且用H₂回填三次，并在H₂氛围(45psi，再装入4次)下在22℃搅拌3h。经由硅藻土过滤混合物并且用EtOH洗涤滤饼。浓缩滤液，得到具有约9:1顺式:反式非对映异构体比率的产物。将残余物溶解于甲醇(100mL)中，接着添加Boc酸酐(15.3ml，66.0mmol)、碳酸钠(14.0g，132mmol)。在室温下搅拌反应混合物过夜。过滤混合物并且浓缩。经硅胶柱纯化残余物，得到所需产物(11.7g，56％)。LCMS(产物+Na⁺)计算值C₁₆H₂₉NNaO₅(M+Na)⁺:m/z＝338.2；实验值：338.2。A solution of (R)-6-cyano-5-hydroxy-3-oxohexanoic acid tert-butyl ester (15.0 g, 66.0 mmol) in acetic acid (110 ml) was treated with platinum (IV) oxide hydrate (0.868 g, 3.30 mmol). The Parr bottle was evacuated and backfilled three times with_H2 and stirred at 22 ° C for 3 h under_H2 atmosphere (45 psi, reloaded 4 times). The mixture was filtered through diatomaceous earth and the filter cake was washed with EtOH. The filtrate was concentrated to obtain a product with a ratio of about 9:1 cis:trans diastereoisomers. The residue was dissolved in methanol (100 mL), followed by the addition of Boc anhydride (15.3 ml, 66.0 mmol), sodium carbonate (14.0 g, 132 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was purified by silica gel column to obtain the desired product (11.7 g, 56%). LCMS (product + Na⁺ ) calcd for C₁₆ H₂₉ NNaO₅ (M + Na)⁺ : m/z = 338.2; found: 338.2.

步骤3.(2S,4S)-4-叠氮基-2-(2-(叔丁氧基)-2-氧代乙基)哌啶-1-甲酸叔丁酯Step 3. tert-Butyl (2S,4S)-4-azido-2-(2-(tert-butoxy)-2-oxoethyl)piperidine-1-carboxylate

在0℃向(2S,4R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-羟基哌啶-1-甲酸叔丁酯(2.10g，6.66mmol)在DCM(33mL)中的溶液中添加Ms-Cl(0.67mL，8.7mmol)。在搅拌1h之后，用水稀释反应物，并且分离有机层并且经Na₂SO₄干燥，过滤并浓缩。将所得残余物溶解于DMF中并且添加叠氮化钠(1.3g，20mmol)，并且将反应混合物在70℃加热5h。在冷却至室温之后，用EtOAc和水稀释反应物。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。经硅胶柱纯化残余物，得到所需产物(1.9g，84％)。LCMS计算值(产物-Boc)C₁₁H₂₁N₄O₂(M+H)⁺:m/z＝241.2；实验值：241.2。To a solution of tert-butyl (2S,4R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (2.10 g, 6.66 mmol) in DCM (33 mL) was added Ms-Cl (0.67 mL, 8.7 mmol) at 0°_C . After stirring for 1 h, the reaction was diluted with water, and the organic layer was separated and dried over_Na2SO4 , filtered and concentrated. The resulting residue was dissolved in DMF and sodium azide (1.3 g, 20 mmol) was added, and the reaction mixture was heated at 70°C for 5 h. After cooling to room temperature, the reaction was diluted with_EtOAc and water. The organic layer was separated and dried over_Na2SO4 , filtered and concentrated. The residue was purified on a silica gel column to give the desired product (1.9 g, 84%). LCMS calcd (product_-Boc )_C11H21N4O2 (M+H₎⁺ : m/z = 241.2; found: 241.2.

步骤4.(2S,4S)-4-叠氮基-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯Step 4. tert-Butyl (2S,4S)-4-azido-2-(2-hydroxyethyl)piperidine-1-carboxylate

在-78℃向(2S,4S)-4-叠氮基-2-(2-(叔丁氧基)-2-氧代乙基)哌啶-1-甲酸叔丁酯(21.4g，62.9mmol)在DCM(400mL)中的溶液中添加含1.0M DIBAL-H的DCM(113mL，113mmol)。在-78℃搅拌所得混合物2h。在-78℃用甲醇(38.1mL，943mmol)淬灭反应物。在≤10℃下将罗谢尔盐水溶液(由126g(6wt)罗谢尔盐和300mL水制备)添加至溶液中。在15至25℃剧烈搅拌两相混合物≥1h并且分离，得到有机层。分离两相混合物。在15至25℃用NaCl水溶液(×2)洗涤有机层，经Na₂SO₄干燥有机层，过滤并且按原样使用。将残余物溶解于甲醇(300mL)中并且在0℃添加硼氢化钠(1.43g，37.7mmol)。在0℃搅拌反应混合物1h。用水淬灭反应物，在减压下蒸发甲醇。用乙酸乙酯(2×)萃取反应混合物，并且用盐水洗涤有机层，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱(用0至50％乙酸乙酯/己烷的梯度洗脱)纯化粗物质，得到呈无色油状物的所需产物(14.8g，87％)。LCMS计算值(产物-Boc)C₇H₁₅N₄O(M+H)⁺:m/z＝171.1；实验值：171.1。To a solution of tert-butyl (2S,4S)-4-azido-2-(2-(tert-butoxy)-2-oxoethyl)piperidine-1-carboxylate (21.4 g, 62.9 mmol) in DCM (400 mL) was added 1.0 M DIBAL-H in DCM (113 mL, 113 mmol) at -78°C. The resulting mixture was stirred at -78°C for 2 h. The reaction was quenched with methanol (38.1 mL, 943 mmol) at -78°C. An aqueous solution of Rochelle salt (prepared from 126 g (6 wt) of Rochelle salt and 300 mL of water) was added to the solution at ≤10°C. The biphasic mixture was vigorously stirred at 15 to 25°C for ≥1 h and separated to give an organic layer. The biphasic mixture was separated. The organic layer was washed with an aqueous NaCl solution (×2) at 15 to 25°C, dried over Na₂ SO₄ , filtered and used as is. The residue was dissolved in methanol (300 mL) and sodium borohydride (1.43 g, 37.7 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with water and the methanol was evaporated under reduced pressure. The reaction mixture was extracted with ethyl acetate (2×), and the organic layer was washed with brine, dried over Na₂ SO₄ , filtered and concentrated. The crude material was purified by flash chromatography (eluting with a gradient of 0 to 50% ethyl acetate/hexane) to give the desired product (14.8 g, 87%) as a colorless oil. LCMS calculated (product-Boc) C₇ H₁₅ N₄ O (M+H)⁺ : m/z=171.1; Found: 171.1.

步骤5.(2S,4S)-4-叠氮基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 5. tert-Butyl (2S,4S)-4-azido-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

向(2S,4S)-4-叠氮基-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯(4.0g，14.80mmol)在DMF(74.0mL)中的溶液中添加咪唑(1.51g，22.2mmol)和TBS-Cl(2.90g，19.2mmol)。在60℃搅拌所得混合物1h 15min。用EtOAc和水稀释反应混合物。将有机层用水(2×)、盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。经快速色谱(0至20％乙酸乙酯/己烷)纯化残余物，得到呈无色油状物的所需产物(5.3g，93％)。LCMS计算值(产物-Boc)C₁₃H₂₉N₄OSi(M+H)⁺:m/z＝285.2；实验值：285.2。To a solution of tert-butyl (2S,4S)-4-azido-2-(2-hydroxyethyl)piperidine-1-carboxylate (4.0 g, 14.80 mmol) in DMF (74.0 mL) was added imidazole (1.51 g, 22.2 mmol) and TBS-Cl (2.90 g, 19.2 mmol). The resulting mixture was stirred at 60 °C for 1 h 15 min. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with water (2×), brine, dried over Na₂ SO₄ , filtered and concentrated. The residue was purified by flash chromatography (0 to 20% ethyl acetate/hexanes) to give the desired product (5.3 g, 93%) as a colorless oil. LCMS calculated (product-Boc) C₁₃ H₂₉ N₄ OSi (M+H)⁺ : m/z=285.2; found: 285.2.

步骤6.(2S,4S)-4-氨基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 6. tert-Butyl (2S,4S)-4-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

向(2S,4S)-4-叠氮基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-哌啶-1-甲酸叔丁酯(5.30g，13.8mmol)于甲醇(70mL)中的溶液中添加10％钯/碳(1.47g，1.38mmol)。在真空下抽空反应混合物并且用H₂再填充，在室温下搅拌2h。经由硅藻土垫过滤反应混合物并且用甲醇洗涤。浓缩滤液，得到所需产物(4.5g，91％)。LCMS计算值(产物-Boc)C₁₃H₃₁N₂OSi(M+H)⁺:m/z＝259.2；实验值：259.2。To a solution of (2S,4S)-4-azido-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-piperidine-1-carboxylic acid tert-butyl ester (5.30 g, 13.8 mmol) in methanol (70 mL) was added 10% palladium on carbon (1.47 g, 1.38 mmol). The reaction mixture was evacuated under vacuum and refilled with_H2 , stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated to give the desired product (4.5 g, 91%). LCMS calculated (product-_Boc )_{forC13H31N2OSi} (M+H)⁺ : m/z=259.2; found: 259.2.

中间体10. 2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Intermediate 10. 2-(7-Fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

步骤1.三氟甲烷磺酸7-氟萘-1-基酯Step 1. 7-Fluoronaphthalen-1-yl trifluoromethanesulfonate

将7-氟萘-1-醇(1.5g，9.25mmol)溶解于DCM(31mL)中并且用三乙胺(1.6mL，11.6mmol)处理。将溶液冷却至0℃，并且接着经1分钟用三氟甲磺酸酐(1.7ml，10mmol)逐滴处理。在0℃搅拌混合物30分钟，此时用NaHCO₃饱和水溶液淬灭并且用另外的DCM稀释。萃取混合物，经MgSO₄干燥并且不经进一步纯化即用于下一步骤中。产物未通过LCMS电离并且通过以下反应的表征来确认。7-Fluoronaphthalene-1-ol (1.5g, 9.25mmol) is dissolved in DCM (31mL) and treated with triethylamine (1.6mL, 11.6mmol). The solution is cooled to 0°C, and then treated dropwise with trifluoromethanesulfonic anhydride (1.7ml, 10mmol) over 1 minute. The mixture is stirred at 0°C for 30 minutes, quenched with_NaHCO saturated aqueous solution and diluted with other DCM. The extraction mixture is dried_over MgSO and used in the next step without further purification. The product is not ionized by LCMS and is confirmed by the characterization of the following reactions.

步骤2. 2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Step 2. 2-(7-Fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

将三氟甲烷磺酸7-氟萘-1-基酯(2.72g，9.24mmol)溶解于1,4-二噁烷(31mL)中，并且用乙酸钾(1.8g，18mmol)、双(频哪醇基)二硼(2.9g，12mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷复合物(0.75g，0.92mmol)。使溶液升温至80℃并且搅拌。7-Fluoronaphthalen-1-yl trifluoromethanesulfonate (2.72 g, 9.24 mmol) was dissolved in 1,4-dioxane (31 mL) and treated with potassium acetate (1.8 g, 18 mmol), bis(pinacolato)diboron (2.9 g, 12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.75 g, 0.92 mmol). The solution was warmed to 80°C and stirred.

在16小时之后，使反应物冷却至室温，用乙酸乙酯稀释，过滤以去除固体乙酸钾，并且真空浓缩。通过快速柱色谱，用0至50％DCM/己烷纯化粗残余物，得到2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(1.5g，5.6mmol，60％产率)。LC-MS计算值C₁₆H₁₉BFO₂(M+H)⁺:m/z＝273.1；实验值273.1。After 16 hours, the reaction was cooled to room temperature, diluted with ethyl acetate, filtered to remove solid potassium acetate, and concentrated in vacuo. The crude residue was purified by flash column chromatography with 0 to 50% DCM/hexanes to give 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 5.6 mmol, 60% yield). LC-MS calculated for C₁₆ H₁₉ BFO₂ (M+H)⁺ : m/z=273.1; Found 273.1.

中间体11. 2-(2,3-二氯-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Intermediate 11. 2-(2,3-dichloro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

步骤1. 1-溴-2,3-二氯-5-(甲氧基甲氧基)苯Step 1. 1-Bromo-2,3-dichloro-5-(methoxymethoxy)benzene

在0℃向3-溴-4,5-二氯苯酚(3.3g，13.64mmol)于THF(40.9ml)中的溶液中缓慢添加NaH(600mg，15.01mmol)。在室温下搅拌反应混合物15分钟并且冷却至0℃。随后逐滴添加MOM-Cl(0.513ml，6.75mmol)。使反应混合物升温并且在室温下再搅拌30min。通过饱和NH₄Cl溶液淬灭反应混合物，通过EtOAc萃取。合并有机层，经MgSO₄干燥，并且浓缩。所得白色固体直接用于下一步骤。NaH (600mg, 15.01mmol) was slowly added to a solution of 3-bromo-4,5-dichlorophenol (3.3g, 13.64mmol) in THF (40.9ml) at 0°C. The reaction mixture was stirred at room temperature for 15 minutes and cooled to 0°C. MOM-Cl (0.513ml, 6.75mmol) was subsequently added dropwise. The reaction mixture was warmed and stirred for another 30min at room temperature. The reaction mixture was quenched by saturated_NH4Cl solution and extracted by EtOAc. The organic layers were combined, dried over_MgSO4 , and concentrated. The resulting white solid was used directly in the next step.

步骤2. 2-(2,3-二氯-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Step 2. 2-(2,3-Dichloro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

在氮气氛围下在-78℃，向1-溴-2,3-二氯-5-(甲氧基甲氧基)苯(1.0g，3.50mmol)和2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(0.856ml，4.20mmol)于THF(18ml)中的混合物中添加正丁基锂(2.19ml，3.50mmol)。在-78℃下搅拌反应混合物10min并且升温至室温。随后通过NH₄Cl溶液淬灭反应物并且用EtOAc萃取。合并有机层，经MgSO₄干燥，浓缩并且通过快速柱色谱(用梯度0至50％EtOAc/己烷洗脱)纯化，得到无色油状物(0.6g，59％产率)。¹H NMR(400MHz,CDCl₃)δ7.22(d,J＝2.8Hz,1H),7.20(d,J＝2.8Hz,1H),5.14(s,2H),3.46(s,3H),1.37(s,3H)。Under nitrogen atmosphere at -78 ° C, to a mixture of 1-bromo-2,3-dichloro-5-(methoxymethoxy)benzene (1.0 g, 3.50 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.856 ml, 4.20 mmol) in THF (18 ml) was added n-butyl lithium (2.19 ml, 3.50 mmol). The reaction mixture was stirred at -78 ° C for 10 min and warmed to room temperature. The reactant was then quenched by NH₄ Cl solution and extracted with EtOAc. The organic layers were combined, dried over MgSO₄ , concentrated and purified by flash column chromatography (eluted with a gradient of 0 to 50% EtOAc/hexane) to give a colorless oil (0.6 g, 59% yield).¹ H NMR (400MHz, CDCl₃ ) δ7.22 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 5.14 (s, 2H), 3.46 (s, 3H), 1.37 (s, 3H).

中间体12.N,N-二甲基戊-4-炔酰胺Intermediate 12. N,N-dimethylpent-4-ynamide

将4-戊炔酸(5.0g，51.0mmol)于THF(100ml)中的溶液冷却至0℃并且小心地添加乙二酰氯(5.6ml，63.7mmol)。将DMF(0.40ml)在DCM(0.60ml)中的第二溶液添加至以上混合物中并且在0℃搅拌反应物30分钟。去除冰浴并且使混合物升温至室温。2h之后，在减压下去除挥发物并且将残余物溶解于THF(20mL)中。A solution of 4-pentynoic acid (5.0 g, 51.0 mmol) in THF (100 ml) was cooled to 0 °C and oxalyl chloride (5.6 ml, 63.7 mmol) was carefully added. A second solution of DMF (0.40 ml) in DCM (0.60 ml) was added to the above mixture and the reaction was stirred at 0 °C for 30 minutes. The ice bath was removed and the mixture was allowed to warm to room temperature. After 2 h, the volatiles were removed under reduced pressure and the residue was dissolved in THF (20 mL).

在第二反应容器中，将三乙胺(21m，153mmol)和二甲胺(2M/THF，51ml，102mmol)冷却至0℃。在0℃经3分钟逐滴添加来自步骤1的溶液。观测到沉淀物形成。使反应溶液升温至室温并且搅拌1h。完成时，用饱和碳酸氢钠溶液淬灭反应物。使用DCM萃取有机相3×，随后用MgSO₄干燥并且在减压下浓缩，得到所需产物。LC-MS计算值C₇H₁₂NO(M+H)⁺:m/z＝126.1；实验值126.1。In a second reaction vessel, triethylamine (21m, 153mmol) and dimethylamine (2M/THF, 51ml, 102mmol) were cooled to 0°C. The solution from step 1 was added dropwise at 0°C over 3 minutes. Precipitate formation was observed. The reaction solution was allowed to warm to room temperature and stirred for 1h. Upon completion, the reaction was quenched with saturated sodium_bicarbonate solution. The organic phase was extracted 3x with DCM, then dried with_MgSO4 and concentrated under reduced pressure to give the desired product. LC-MS calculated for_C7H12NO (M+H)⁺ : m/z=126.1; Found 126.1.

中间体13. 2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷Intermediate 13. 2-(3-(Methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

向4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇(7.0g，25.9mmol)在DCM(130ml)中的溶液中添加DIPEA(20ml，117mmol)和氯甲基甲醚(7.9ml，104mmol)。在室温下搅拌反应混合物并且通过LC-MS监测进展。再添加MOM-Cl以推动反应完成(约2当量)。用水淬灭反应物并且用DCM萃取。经硫酸钠干燥有机层并且在减压下浓缩。通过快速柱色谱(0至20％乙酸乙酯/己烷)纯化粗产物，得到呈灰白色固体的所需产物。LC-MS计算值C₁₈H₂₄BO₄(M+H)⁺:m/z＝315.2；实验值315.2。To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (7.0 g, 25.9 mmol) in DCM (130 ml) was added DIPEA (20 ml, 117 mmol) and chloromethyl methyl ether (7.9 ml, 104 mmol). The reaction mixture was stirred at room temperature and progress was monitored by LC-MS. MOM-Cl was added again to drive the reaction to completion (about 2 equivalents). The reactant was quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0 to 20% ethyl acetate/hexane) to obtain the desired product as an off-white solid. LC-MS calculated value C₁₈ H₂₄ BO₄ (M+H)⁺ :m/z=315.2; Found value 315.2.

中间体14. 4-(丁-3-炔-2-基)吗啉-3-酮Intermediate 14. 4-(But-3-yn-2-yl)morpholin-3-one

步骤1.N-(丁-3-炔-2-基)-2-(2-氯乙氧基)乙酰胺Step 1. N-(But-3-yn-2-yl)-2-(2-chloroethoxy)acetamide

在0℃向丁-3-炔-2-胺(0.440g，6.37mmol)和三乙胺(1.776ml，12.74mmol)于THF(10mL)中的溶液中添加2-(2-氯乙氧基)乙酰氯(1g，6.37mmol)。使溶液升温至室温并且搅拌1h。用水淬灭反应物，并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且在减压下浓缩。通过快速柱色谱纯化粗产物，得到所需产物。LC-MS计算值C₈H₁₃ClNO₂(M+H)⁺:m/z＝190.1；实验值190.0。To a solution of but-3-yn-2-amine (0.440 g, 6.37 mmol) and triethylamine (1.776 ml, 12.74 mmol) in THF (10 mL) was added 2-(2-chloroethoxy)acetyl chloride (1 g, 6.37 mmol) at 0°C. The solution was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give the desired product. LC-MS calculated for C₈ H₁₃ ClNO₂ (M+H)⁺ : m/z=190.1; found 190.0.

步骤2. 4-(丁-3-炔-2-基)吗啉-3-酮Step 2. 4-(But-3-yn-2-yl)morpholin-3-one

在0℃向N-(丁-3-炔-2-基)-2-(2-氯乙氧基)乙酰胺(450mg，2.373mmol)于THF(5ml)中的溶液中添加氢化钠(114mg，2.85mmol)。使溶液升温至室温并且搅拌18h。用水淬灭反应物，并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且在减压下浓缩。通过快速柱色谱纯化粗产物，得到所需产物。LC-MS计算值C₈H₁₂NO₂(M+H)⁺:m/z＝154.1；实验值154.0。To a solution of N-(but-3-yn-2-yl)-2-(2-chloroethoxy)acetamide (450 mg, 2.373 mmol) in THF (5 ml) was added sodium hydride (114 mg, 2.85 mmol) at 0°C. The solution was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give the desired product. LC-MS calculated for C₈ H₁₂ NO₂ (M+H)⁺ : m/z=154.1; found 154.0.

中间体15. 4-异丙基-1-(丙-2-炔-1-基)哌嗪-2-酮Intermediate 15. 4-isopropyl-1-(prop-2-yn-1-yl)piperazin-2-one

将1-(丙-2-炔-1-基)哌嗪-2-酮盐酸盐(1.32g，7.56mmol)、丙烷-2-酮(4.39g，76mmol)、三乙胺(2.107mL，15.12mmol)、乙酸(0.865ml，15.12mmol)和氰基硼氢化钠(1.425g，22.68mmol)在MeOH(2mL)中的溶液在60℃搅拌6h。用水淬灭反应物，并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且在减压下浓缩。通过快速柱色谱纯化粗产物，得到所需产物。LC-MS计算值C₁₀H₁₇N₂O(M+H)⁺:m/z＝181.1；实验值181.1。A solution of 1-(prop-2-yn-1-yl)piperazin-2-one hydrochloride (1.32 g, 7.56 mmol), propan-2-one (4.39 g, 76 mmol), triethylamine (2.107 mL, 15.12 mmol), acetic acid (0.865 ml, 15.12 mmol) and sodium cyanoborohydride (1.425 g, 22.68 mmol) in MeOH (2 mL) was stirred at 60 °C for 6 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give the desired product. LC-MS calculated for C₁₀ H₁₇ N₂ O (M+H)⁺ : m/z=181.1; found 181.1.

中间体16.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-2-乙氧基-8-氟-3-碘喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 16. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-2-ethoxy-8-fluoro-3-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体2和中间体5中所描述的程序，使用乙醇钠替代硫代甲醇钠来制备。LC-MS计算值C₂₄H₂₈BrFIN₄O₃(M+H)⁺:m/z＝645.0；实验值645.0。This compound was prepared according to the procedures described in Intermediate 2 and Intermediate 5 using sodium ethoxide instead of sodium thiomethoxide. LC-MS calculated for C₂₄ H₂₈ BrFIN₄ O₃ (M+H)⁺ : m/z = 645.0; found 645.0.

中间体17.(R)-2-乙炔基吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯Intermediate 17. (R)-2-(Trimethylsilyl)ethyl 2-ethynylpyrrolidine-1-carboxylate

在室温下搅拌(R)-2-乙炔基吡咯烷-1-甲酸叔丁酯(1.0g，5.12mmol)于4N HCl/二噁烷(10mL)中的溶液2h，随后浓缩。向粗固体中添加THF(17.07ml)、三乙胺(2.141ml，15.36mmol)和1-[2-三甲基甲硅烷基)乙氧基羰基氧基]吡咯烷-2,5-二酮(1.328g，5.12mmol)，并且在室温下搅拌反应混合物5h，接着用水淬灭并且用乙酸乙酯萃取。将有机层用1N HCl、1N NaOH、水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₁₂H₂₂NO₂Si(M+H)⁺:m/z＝240.1；实验值240.1。A solution of (R)-tert-butyl 2-ethynylpyrrolidine-1-carboxylate (1.0 g, 5.12 mmol) in 4N HCl/dioxane (10 mL) was stirred at room temperature for 2 h and then concentrated. THF (17.07 ml), triethylamine (2.141 ml, 15.36 mmol) and 1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (1.328 g, 5.12 mmol) were added to the crude solid, and the reaction mixture was stirred at room temperature for 5 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, 1N NaOH, water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₁₂ H₂₂ NO₂ Si (M+H)⁺ : m/z=240.1; Found 240.1.

中间体18.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 18. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

步骤1.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(2.04g，3.15mmol)和中间体17(1.132g，4.73mmol)的混合物中添加DMF(10.5ml)和三乙胺(1.318ml，9.45mmol)，随后添加双(三苯基膦)二氯钯(II)(0.221g，0.315mmol)和碘化铜(I)(0.600g，3.15mmol)。抽空反应烧瓶，用氮气回填，随后在75℃搅拌2h。用水和少量30％氢氧化铵水溶液淬灭反应混合物，随后用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速色谱(0至40％丙酮/己烷)纯化粗产物。将此物质溶解于DMF(10.5ml)中并且添加碳酸铯(2.054g，6.30mmol)。将反应混合物加热至90℃持续1.5h，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(10至30％丙酮/己烷)纯化粗产物，得到所需产物(1.07g，45％)。LC-MS计算值C₃₅H₄₆BrFN₅O₄SSi⁺(M+H)⁺:m/z＝758.2/760.2；实验值758.0/760.0。To a mixture of intermediate 5 (2.04 g, 3.15 mmol) and intermediate 17 (1.132 g, 4.73 mmol) was added DMF (10.5 ml) and triethylamine (1.318 ml, 9.45 mmol), followed by bis(triphenylphosphine)dichloropalladium(II) (0.221 g, 0.315 mmol) and copper(I) iodide (0.600 g, 3.15 mmol). The reaction flask was evacuated, backfilled with nitrogen, and then stirred at 75 °C for 2 h. The reaction mixture was quenched with water and a small amount of 30% aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 40% acetone/hexane). This material was dissolved in DMF (10.5 ml) and cesium carbonate (2.054 g, 6.30 mmol) was added. The reaction mixture was heated to 90°C for 1.5 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (10 to 30% acetone/hexanes) to give the desired product (1.07 g, 45%). LC-MS calculated for C₃₅ H₄₆ BrFN₅ O₄ SSi⁺ (M+H)⁺ : m/z=758.2/760.2; found 758.0/760.0.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(471mg，0.621mmol)、(2,3-二氯苯基)硼酸(178mg，0.931mmol)、氟化钾(108mg，1.862mmol)和Pd-132(44.0mg，0.062mmol)的混合物中添加1,4-二噁烷(2.4ml)/水(0.6ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌1h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速色谱(0至40％丙酮/己烷)纯化粗产物，得到所需产物(416mg，81％)。LC-MS计算值C₄₁H₄₉Cl₂FN₅O₄SSi⁺(M+H)⁺:m/z＝824.3/826.3；实验值824.2/826.2。To a mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (471 mg, 0.621 mmol), (2,3-dichlorophenyl)boronic acid (178 mg, 0.931 mmol), potassium fluoride (108 mg, 1.862 mmol) and Pd-132 (44.0 mg, 0.062 mmol) was added 1,4-dioxane (2.4 ml)/water (0.6 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C for 1 h. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by flash chromatography (₀ to 40_% acetone/hexanes) to give the desired product (416 mg, 81%)_. LC_- MS calcd for_{C41H49Cl2FN5O4SSi}⁺ (M+H)⁺ : m/z=824.3/826.3; found 824.2/826.2.

中间体19.(R)-4-(丁-3-炔-2-基)吗啉-3-酮Intermediate 19. (R)-4-(But-3-yn-2-yl)morpholin-3-one

此化合物根据中间体14中所描述的程序，使用(R)-丁-3-炔-2-胺盐酸盐代替丁-3-炔-2-胺来制备。LC-MS计算值C₈H₁₂NO₂(M+H)⁺:m/z＝154.1；实验值154.1。This compound was prepared according to the procedure described in Intermediate 14 using (R)-but-3-yn-2-amine hydrochloride instead of but-_{3-yn-2-amine. LC-MS calculated for C8H12NO2(} M+H)⁺ : m/z = 154.1; found 154.1.

中间体20.(R)-1-(丁-3-炔-2-基)吡嗪-2(1H)-酮Intermediate 20. (R)-1-(But-3-yn-2-yl)pyrazin-2(1H)-one

步骤1.甲烷磺酸(S)-丁-3-炔-2-基酯Step 1. (S)-but-3-yn-2-yl methanesulfonate

向冷却至0℃的含有(S)-丁-3-炔-2-醇(3.79g，54.1mmol)的经搅拌DCM溶液(100mL)中缓慢添加N,N-二异丙基乙胺(18.9mL，108mmol)和甲磺酰氯(4.2mL，54.1mmol)。使反应物升温至环境温度。在搅拌1h之后，用水淬灭反应物并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且在减压下浓缩。粗产物直接用于下一步骤。N, N-diisopropylethylamine (18.9 mL, 108 mmol) and methanesulfonyl chloride (4.2 mL, 54.1 mmol) were slowly added to a stirred DCM solution (100 mL) containing (S)-but-3-yn-2-ol (3.79 g, 54.1 mmol) cooled to 0 ° C. The reactants were allowed to warm to ambient temperature. After stirring for 1 h, the reactants were quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was used directly in the next step.

步骤2.(R)-1-(丁-3-炔-2-基)吡嗪-2(1H)-酮Step 2. (R)-1-(But-3-yn-2-yl)pyrazin-2(1H)-one

向含有吡嗪-2(1H)-酮(5.20g，54.1mmol)的经搅拌THF溶液(180mL)中缓慢添加叔丁醇钾(6.1g，54.1mmol)在搅拌0.5h之后，添加含有甲磺酸(S)-丁-3-炔-2-基酯的THF溶液。在60℃搅拌浆液48小时并且接着用水淬灭。用乙酸乙酯萃取混合物。经硫酸钠干燥有机层并且在减压下浓缩。通过快速柱色谱(0至80％乙酸乙酯/己烷)纯化粗产物，得到所需产物。LC-MS计算值C₈H₉N₂O(M+H)⁺:m/z＝149.1；实验值149.1。¹H NMR(500MHz,DMSO-d₆)δ8.04(d,J＝1.2Hz,1H),7.82(dd,J＝4.5,1.2Hz,1H),7.42(d,J＝4.5Hz,1H),5.62(qd,J＝6.9,2.5Hz,1H),3.70(d,J＝2.4Hz,1H),1.52(d,J＝6.9Hz,3H)。To a stirred THF solution (180 mL) containing pyrazin-2(1H)-one (5.20 g, 54.1 mmol) was slowly added potassium tert-butoxide (6.1 g, 54.1 mmol). After stirring for 0.5 h, a THF solution containing (S)-but-3-yn-2-yl methanesulfonate was added. The slurry was stirred at 60° C. for 48 h and then quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0 to 80% ethyl acetate/hexanes) to give the desired product. LC-MS calculated for C₈ H₉ N₂ O (M+H)⁺ : m/z=149.1; found 149.1.¹ H NMR (500MHz, DMSO-d₆ ) δ8.04(d,J＝1.2Hz,1H),7.82(dd,J＝4.5,1.2Hz,1H),7.42(d,J＝4.5Hz,1H),5.62(qd,J＝6.9,2.5Hz,1H),3.70(d,J＝2.4Hz,1H),1.52( d,J＝6.9Hz,3H).

中间体21. 3-氟-N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺Intermediate 21. 3-Fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

步骤1. 5-溴-3-氟-N-甲基吡啶甲酰胺Step 1. 5-Bromo-3-fluoro-N-methylpicolinamide

向5-溴-3-氟吡啶甲酸(0.20g，0.91mmol)在DMF(1.50ml)和DCM(0.30ml)中的溶液中添加N,N-二异丙基乙胺(0.32m,1.82mmol)和HATU(0.52g，1.36mmol)，并且将反应混合物在室温下搅拌15分钟，随后添加甲胺(2M于THF中，0.68ml，1.36mmol)。将反应溶液在室温下搅拌1h，接着用5％LiCl水溶液淬灭并且用乙酸乙酯萃取。将水层再用乙酸乙酯萃取并且将合并的有机物用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至100％乙酸乙酯/己烷洗脱来纯化粗产物。LC-MS计算值C₇H₇BrFN₂O⁺(M+H)⁺:m/z＝233.0/235.0；实验值232.9/234.9。To a solution of 5-bromo-3-fluoropicolinic acid (0.20 g, 0.91 mmol) in DMF (1.50 ml) and DCM (0.30 ml) was added N,N-diisopropylethylamine (0.32 m, 1.82 mmol) and HATU (0.52 g, 1.36 mmol), and the reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of methylamine (2 M in THF, 0.68 ml, 1.36 mmol). The reaction solution was stirred at room temperature for 1 h, then quenched with 5% aqueous LiCl solution and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again and the combined organics were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography, eluting with 0 to 100% ethyl acetate/hexane. LC-MS calculated_{forC7H7BrFN2O}⁺ (M₊ H)⁺ : m/z = 233.0/235.0; found 232.9/234.9.

步骤2. 3-氟-N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺Step 2. 3-Fluoro-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

向5-溴-3-氟-N-甲基吡啶甲酰胺(0.10g，0.43mmol)、双(频哪醇基)二硼(0.16g，0.64mmol)、二氯[1,1'-双(二苯基膦基二茂铁]钯(II)二氯甲烷加合物(0.070g，0.086mmol)和乙酸钾(0.13g，1.29mmol)的混合物中添加二噁烷(3.43ml)。用氮气吹扫反应容器，随后密封并且在100℃搅拌1h。将反应混合物用乙酸乙酯和SiliaMetS硫醇官能化硅胶(Silicycle，PN R51030B，200mg)稀释，随后在室温下搅拌5分钟。经由硅藻土塞过滤浆液。浓缩滤液并且粗产物不经另外纯化即直接使用。LC-MS计算值C₁₃H₁₉BFN₂O₃⁺(M+H)⁺:m/z＝281.1；实验值281.1。To a mixture of 5-bromo-3-fluoro-N-methylpicolinamide (0.10 g, 0.43 mmol), bis(pinacolato)diboron (0.16 g, 0.64 mmol), dichloro[1,1'-bis(diphenylphosphinoferrocene]palladium(II) dichloromethane adduct (0.070 g, 0.086 mmol) and potassium acetate (0.13 g, 1.29 mmol) was added dioxane (3.43 ml). The reaction vessel was purged with nitrogen then sealed and stirred at 100 °C for 1 h. The reaction mixture was diluted with ethyl acetate and SiliaMetS thiol functionalized silica gel (Silicycle, PN R51030B, 200 mg) then stirred at room temperature for 5 minutes. The slurry was filtered through a plug of celite. The filtrate was concentrated and the crude product was used directly without further purification. LC-MS calculated for C₁₃ H₁₉ BFN₂ O₃⁺ (M+H)⁺ :m/z＝281.1; Exp. value 281.1.

中间体22.(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 22. (1R,4R,5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

步骤1.(R)-丁-3-炔-2-基氨基甲酸2-(三甲基甲硅烷基)乙酯Step 1. (R)-2-(Trimethylsilyl)ethylbut-3-yn-2-ylcarbamate

向(R)-丁-3-炔-2-胺盐酸盐(1.0g，9.47mmol)在乙腈(48ml)中的反应混合物中添加三乙胺(2.90ml，20.84mmol)和1-[2-三甲基甲硅烷基)乙氧基羰基氧基]吡咯烷-2,5-二酮(2.457g，9.47mmol)。将反应混合物在室温下搅拌3小时。随后用水淬灭反应物，并且用乙酸乙酯萃取。将合并的有机层用1N NaOH水溶液、1N HCl水溶液、水和盐水洗涤，经MgSO₄干燥并且浓缩。产物不经进一步纯化直接用于下一步骤中。¹H NMR(400MHz,DMSO-d₆)δ7.51(d,J＝8.4Hz,1H),4.38-4.24(m,1H),4.10-4.01(m,2H),3.14-3.10(m,1H),1.28(d,J＝7.0Hz,3H),0.99-0.87(m,2H),0.03(s,9H)。To the reaction mixture of (R)-butyl-3-yn-2-amine hydrochloride (1.0g, 9.47mmol) in acetonitrile (48ml), triethylamine (2.90ml, 20.84mmol) and 1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (2.457g, 9.47mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reactant was then quenched with water and extracted with ethyl acetate. The combined organic layers were washed with 1N NaOH aqueous solution, 1N HCl aqueous solution, water and brine, dried over_MgSO4 and concentrated. The product was used directly in the next step without further purification.¹ H NMR (400MHz, DMSO-d₆ ) δ7.51 (d, J = 8.4Hz, 1H), 4.38-4.24 (m, 1H), 4.10-4.01 (m, 2H), 3.14-3.10 (m, 1H), 1.28 (d, J = 7.0Hz, 3H), 0.99-0.87 (m, 2H), 0.03 (s,9H).

步骤2.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在氮气氛围下在DMF(7.72ml)中将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体5，1.0g，1.545mmol)、(R)-丁-3-炔-2-基氨基甲酸2-(三甲基甲硅烷基)乙酯(0.494g，2.317mmol)、三乙胺(0.646ml，4.63mmol)和碘化铜(I)(0.294g，1.545mmol)的反应混合物在70℃搅拌2小时。冷却至室温后，随后将Cs₂CO₃(1.510g，4.63mmol)添加至反应混合物中。随后在95℃搅拌反应物30分钟。完成后，用水和少量30％氢氧化铵水溶液淬灭混合物，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸镁干燥，浓缩并且通过快速色谱(0至60％EtOAc/己烷)纯化，得到产物(800mg，71％产率)。LCMS计算值C₃₃H₄₄BrFN₅O₄SSi(M+H)⁺:m/z＝732.2；实验值732.2。A reaction mixture of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 1.0 g, 1.545 mmol), 2-(trimethylsilyl)ethyl (R)-but-3-yn-2-ylcarbamate (0.494 g, 2.317 mmol), triethylamine (0.646 ml, 4.63 mmol) and copper(I) iodide (0.294 g, 1.545 mmol) was stirred at 70° C. for 2 hours in DMF (7.72 ml) under nitrogen atmosphere. After cooling to room temperature, Cs₂ CO₃ (1.510 g, 4.63 mmol) was then added to the reaction mixture. The reaction was then stirred at 95°C for 30 minutes. Upon completion, the mixture was quenched with water and a small amount of 30% aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, concentrated and purified by flash chromatography (0 to 60% EtOAc/hexanes) to give the product (800 mg, 71% yield). LCMS calculated for C₃₃ H₄₄ BrFN₅ O₄ SSi (M+H)⁺ : m/z=732.2; Found 732.2.

步骤3.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在氮气氛围下将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(800mg，1.092mmol)、(2,3-二氯苯基)硼酸(1042mg，5.46mmol)、四(三苯基膦)钯(0)(252mg，0.218mmol)和磷酸三钾(1390mg，6.55mmol)在1,4-二噁烷(18.72ml)/水(3.12ml)中的反应混合物在110℃搅拌3小时。此后，将反应物冷却至室温并且向反应混合物中添加更多(2,3-二氯苯基)硼酸(1042mg，5.46mmol)。将反应混合物用氮气回填并且在110℃再搅拌3小时。随后将反应混合物倒入水中，用乙酸乙酯萃取，浓缩并且通过快速色谱(0至60％EtOAc/己烷)纯化，得到呈淡黄色固体的所需产物(700mg，80％产率)。LCMS计算值C₃₉H₄₇Cl₂FN₅O₄SSi(M+H)⁺:m/z＝798.2；实验值798.4。Under nitrogen atmosphere, a reaction mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (800 mg, 1.092 mmol), (2,3-dichlorophenyl)boronic acid (1042 mg, 5.46 mmol), tetrakis(triphenylphosphine)palladium(0) (252 mg, 0.218 mmol) and tripotassium phosphate (1390 mg, 6.55 mmol) in 1,4-dioxane (18.72 ml)/water (3.12 ml) was stirred at 110° C. for 3 hours. After this time, the reaction was cooled to room temperature and more (2,3-dichlorophenyl)boronic acid (1042 mg, 5.46 mmol) was added to the reaction mixture. The reaction mixture was backfilled with nitrogen and stirred at 110°C for another 3 hours. The reaction mixture was then poured into water, extracted with ethyl acetate, concentrated and purified by flash chromatography (0 to 60% EtOAc/hexanes) to give the desired product (700 mg, 80% yield) as a light yellow solid. LCMS calculated for C₃₉ H₄₇ Cl₂ FN₅ O₄ SSi (M+H)⁺ : m/z=798.2; found 798.4.

步骤4.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在氮气氛围下向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(700mg，0.876mmol)、甲基硼酸(262mg，4.38mmol)、四(三苯基膦)钯(0)(304mg，0.263mmol)和3-甲基水杨酸铜(I)(564mg，2.63mmol)的混合物中添加1,4-二噁烷(2.92ml)。在110℃搅拌反应混合物3小时。将反应物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速色谱(0至80％EtOAc/己烷)纯化粗产物，得到呈淡黄色固体的所需产物(480mg，88％产率)。LCMS计算值C₃₉H₄₇Cl₂FN₅O₄Si(M+H)⁺:m/z＝766.3；实验值766.4。To a mixture of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (700 mg, 0.876 mmol), methylboronic acid (262 mg, 4.38 mmol), tetrakis(triphenylphosphine)palladium(0) (304 mg, 0.263 mmol) and 3-methylsalicylatecopper(I) (564 mg, 2.63 mmol) was added 1,4-dioxane (2.92 ml) under nitrogen atmosphere. The reaction mixture was stirred at 110° C. for 3 hours. The reaction was quenched with water and a saturated aqueous solution of ammonium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (₀ to 80% EtOAc/hexanes) to give the desired product (480 mg, 88% yield) as_a light_yellow solid. LCMS_Calcd for_{C39H47Cl2FN5O4Si} (M+H)⁺ : m/z = 766.3; Found 766.4.

步骤5.(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(480mg，0.626mmol)于四氢呋喃(6.26ml)中的溶液中添加TBAF(939μl，0.939mmol)，并且将反应混合物在65℃加热2小时。在冷却至室温之后，将反应物倒入水中并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩并且直接用于下一步骤。LCMS计算值C₃₃H₃₅Cl₂FN₅O₂(M+H)⁺:m/z＝622.2；实验值622.3。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (480 mg, 0.626 mmol) in tetrahydrofuran (6.26 ml) was added TBAF (939 μl, 0.939 mmol) and the reaction mixture was heated at 65 °C for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated and used directly in the next step. LCMS calcd_{forC33H35Cl2FN5O2} (M₊ H⁾⁺_: m/z =_622.2 ; found 622.3.

中间体23.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Intermediate 23. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methylamino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(100mg，0.130mmol，中间体22，步骤4)在DMF(1.304ml)中的溶液中添加NaH(7.82mg，0.196mmol)。10分钟之后，添加碘甲烷(12.23μl，0.196mmol)。在室温下搅拌反应混合物1小时。通过水淬灭反应混合物并且用乙酸乙酯萃取。将合并的有机层用水、盐水洗涤并且经Na₂SO₄干燥，过滤并浓缩。产物不经进一步纯化直接用于下一步骤中。LCMS计算值C₄₀H₄₉Cl₂FN₅O₄Si(M+H)⁺:m/z＝780.3；实验值780.3。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.130 mmol, Intermediate 22, Step 4) in DMF (1.304 ml) was added NaH (7.82 mg, 0.196 mmol) at 0°C. After 10 minutes, iodomethane (12.23 μl, 0.196 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with water,_brine and dried over_Na2S04 , filtered and concentrated. The product_was used directly_in the_next step without further purification._LCMS calcd for_{C40H49Cl2FN5O4Si} (M+H)⁺ : m/z = 780.3; found 780.3.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methylamino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(100mg，0.128mmol)于四氢呋喃(1.281ml)中的溶液中添加TBAF(192μl，0.192mmol)，并且将反应混合物在65℃加热2小时。在冷却至室温之后，将反应物倒入水中并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩并且直接用于下一步骤。LCMS计算值C₃₄H₃₇Cl₂FN₅O₂(M+H)⁺:m/z＝636.2；实验值636.3。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (100 mg, 0.128 mmol) in tetrahydrofuran (1.281 ml) was added TBAF (192 μl, 0.192 mmol) and the reaction mixture was heated at 65 °C for 2 hours. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated and used directly in the next step. LCMS calcd_{for C34H37Cl2FN5O2(} M_+H⁾⁺_: m/z = 636.2; found 636.3.

中间体24. 4-(丁-3-炔-2-基)-2,6-二甲基哒嗪-3(2H)-酮Intermediate 24. 4-(But-3-yn-2-yl)-2,6-dimethylpyridazin-3(2H)-one

步骤1. 4-溴-2,6-二甲基哒嗪-3(2H)-酮Step 1. 4-Bromo-2,6-dimethylpyridazin-3(2H)-one

将4-溴-6-甲基哒嗪-3(2H)-酮(2.0g，10.6mmol)添加至DMF(50ml)的溶液中并且冷却至0℃。分数份添加氢化钠(60％于矿物油中的分散液，0.55g，13.8mmol)。在0℃搅拌反应混合物15分钟。逐滴添加碘甲烷(2M于MTBE中，6.9ml，13.8mmol)并且使反应混合物升温至室温并且搅拌30分钟。使反应混合物冷却至0℃，用饱和NH₄Cl水溶液淬灭，并且用DCM稀释。分离各层，并且用DCM萃取水层。将合并的有机洗脱份经MgSO₄垫过滤，浓缩，并且通过自动快速柱色谱(0至100％乙酸乙酯/己烷)纯化粗残余物，得到所需产物(1.4g，67％)。LC-MS计算值C₆H₈BrN₂O⁺(M+H)⁺:m/z＝203.0；实验值203.0。4-Bromo-6-methylpyridazine-3(2H)-one (2.0 g, 10.6 mmol) was added to a solution of DMF (50 ml) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.55 g, 13.8 mmol) was added in portions. The reaction mixture was stirred at 0°C for 15 minutes. Iodomethane (2M in MTBE, 6.9 ml, 13.8 mmol) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, quenched with saturated_NH4Cl aqueous solution, and diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic eluate was filtered through a pad of_MgSO4 , concentrated, and the crude residue was purified by automatic flash column chromatography (0 to 100% ethyl acetate/hexane) to give the desired product (1.4 g, 67%). LC-MS_calcd for_C6H8BrN2O⁺ (M+H₎⁺ : m/z=203.0; found 203.0.

步骤2. 2-(三丁基锡烷基)丙烯酸苯甲酯Step 2. Benzyl 2-(tributyltinyl)acrylate

向4.84g(30.2mmol)丙炔酸苯甲酯于40ml THF中的0℃溶液中添加0.7g(0.6mmol)Pd(PPh₃)₄，随后逐滴添加9.24g(31.7mmol)氢化三丁基锡。在室温下升温并且搅拌过夜之后，在减压下去除溶剂。经由硅藻土垫过滤残余物，随后用己烷洗涤。真空浓缩滤液并且通过自动快速柱色谱(0至15％乙酸乙酯/己烷)纯化粗产物，得到呈无色油状物的标题化合物(9.5g，70％)。To a 0°C solution of 4.84 g (30.2 mmol) benzyl propiolate in 40 ml THF was added 0.7 g (0.6 mmol) Pd(PPh₃ )₄ followed by dropwise addition of 9.24 g (31.7 mmol) tributyltin hydride. After warming and stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was filtered through a pad of celite followed by washing with hexanes. The filtrate was concentrated in vacuo and the crude product was purified by automated flash column chromatography (0 to 15% ethyl acetate/hexanes) to give the title compound (9.5 g, 70%) as a colorless oil.

步骤3. 2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙烯酸苯甲酯Step 3. Benzyl 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)acrylate

向4-溴-2,6-二甲基哒嗪-3(2H)-酮(来自中间体24，步骤1，1.44g，7.09mmol)于35mL THF中的溶液中添加2-(三丁基锡烷基)丙烯酸苯甲酯(来自中间体24，步骤2，4.16g，9.22mmol)、Pd(PPh₃)₄(1.23g，1.06mmol)和氯化铜(I)(0.77g，7.80mmol)。将反应混合物加热至60℃持续6h，冷却，经由硅藻土垫过滤并浓缩。通过自动快速柱色谱(0至100％乙酸乙酯/DCM)纯化粗残余物，得到标题化合物(1.92g，95％)。LC-MS计算值C₁₆H₁₇N₂O₃⁺(M+H)⁺:m/z＝285.1；实验值285.1。To a solution of 4-bromo-2,6-dimethylpyridazin-3(2H)-one (from Intermediate 24, Step 1, 1.44 g, 7.09 mmol) in 35 mL THF was added benzyl 2-(tributylstannyl)acrylate (from Intermediate 24, Step 2, 4.16 g, 9.22 mmol), Pd(_PPh3 )₄ (1.23 g, 1.06 mmol) and copper(I) chloride (0.77 g, 7.80 mmol). The reaction mixture was heated to 60 °C for 6 h, cooled, filtered^{through a pad of celite and concentrated. The crude residue was purified by automated flash column chromatography (0 to 100% ethyl acetate/DCM) to give the title compound (1.92 g, 95%). LC-MS calculated for Ci6Hi7N2O3+}_(M+H )⁺ : m/z=285.1; found 285.1.

步骤4. 2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙酸Step 4. 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)propanoic acid

在N₂下向含有Pd/C(10wt.％，1.43g，1.35mmol)的小瓶中添加2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙烯酸苯甲酯于20mL 1:1MeOH/乙酸乙酯中的溶液。将悬浮液用H₂充气5分钟并且在1atm H₂下快速搅拌过夜。经硅藻土垫过滤悬浮液，并且在减压下去除溶剂。粗物质不经进一步纯化即用于下一步骤中(1.32g，99％)。LC-MS计算值C₉H₁₃N₂O₃⁺(M+H)⁺:m/z＝197.1；实验值197.1。To a vial containing Pd/C (₁₀ wt.%, 1.43 g, 1.35 mmol) was added a solution of benzyl 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)acrylate in 20 mL 1:1 MeOH/ethyl acetate under N. The suspension was aerated with_H for 5 min and rapidly stirred overnight under₁ atm H. The suspension was filtered through a pad of celite and the solvent_was removed under reduced pressure. The crude material was used in the next step without further purification (_{1.32 g, 99%). LC-MS calculated for C9H13N2O3+(}^M +H)⁺ : m/z=197.1; found 197.1.

步骤5. 2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)-N-甲氧基-N-甲基丙酰胺Step 5. 2-(2,6-Dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)-N-methoxy-N-methylpropionamide

向小瓶中装入2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙酸(1.32g，6.71mmol)、N,O-二甲基羟胺盐酸盐(0.98g，10.1mmol)、DIPEA(2.60g，20.1mmol)和HATU(2.81g，7.38mmol)。在室温下搅拌反应混合物1小时。用水淬灭反应混合物并且用DCM稀释。分离各层并且用DCM萃取水层。合并的有机洗脱份经MgSO₄垫过滤，浓缩，并且经自动快速柱色谱(0至10％MeOH/DCM)纯化，得到所需产物(1.6g，99％)。LC-MS计算值C₁₁H₁₈N₃O₃⁺(M+H)⁺:m/z＝240.1；实验值240.1。A vial was charged with 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)propanoic acid (1.32 g, 6.71 mmol), N,O-dimethylhydroxylamine hydrochloride (0.98 g, 10.1 mmol), DIPEA (2.60 g, 20.1 mmol) and HATU (2.81 g, 7.38 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic fractions were filtered through a pad of MgSO₄ , concentrated, and purified by automated flash column chromatography (0 to 10% MeOH/DCM) to give the desired product (1.6 g, 99%). LC-MS calculated for C₁₁ H₁₈ N₃ O₃⁺ (M+H)⁺ : m/z=240.1; found 240.1.

步骤6. 2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙醛Step 6. 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)propanal

向小瓶中装入2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)-N-甲氧基-N-甲基丙酰胺(1.86g，7.77mmol)和DCM(20ml)。将反应混合物冷却至-78℃并且逐滴添加DIBAL-H(1M于甲苯中，8.55ml，8.55mmol)。在-78℃搅拌反应混合物30分钟。通过在-78℃缓慢添加MeOH(6ml)淬灭反应物，在-78℃搅拌15分钟，随后缓慢升温至室温。添加罗谢尔盐饱和水溶液和DCM，并且快速搅拌两相混合物1小时。分离各层并且用DCM萃取水层。合并的有机洗脱份经MgSO₄垫过滤，浓缩并且不经进一步纯化即用于下一步骤中。LC-MS计算值C₉H₁₃N₂O₂⁺(M+H)⁺:m/z＝181.1；实验值181.1。2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazine-4-yl)-N-methoxy-N-methylpropionamide (1.86 g, 7.77 mmol) and DCM (20 ml) were loaded into a vial. The reaction mixture was cooled to -78 ° C and DIBAL-H (1M in toluene, 8.55 ml, 8.55 mmol) was added dropwise. The reaction mixture was stirred at -78 ° C for 30 minutes. The reactant was quenched by slowly adding MeOH (6 ml) at -78 ° C, stirred at -78 ° C for 15 minutes, and then slowly warmed to room temperature. Rochelle salt saturated aqueous solution and DCM were added, and the two-phase mixture was stirred rapidly for 1 hour. The layers were separated and the aqueous layer was extracted with DCM. The combined organic eluate was filtered through a MgSO₄ pad, concentrated and used in the next step without further purification. LC-MS calculated for C₉ H₁₃ N₂ O₂⁺ (M+H)⁺ : m/z = 181.1; found 181.1.

步骤7. 4-(丁-3-炔-2-基)-2,6-二甲基哒嗪-3(2H)-酮Step 7. 4-(But-3-yn-2-yl)-2,6-dimethylpyridazin-3(2H)-one

向小瓶中装入2-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)丙醛(1.48g，8.2mmol)、MeOH(20ml)和K₂CO₃(2.27g，16.4mmol)。使反应混合物冷却至0℃。逐滴添加(1-重氮-2-氧代丙基)膦酸二甲酯(1.73g，9.02mmol)，并且在0℃搅拌悬浮液1小时。用水淬灭反应物并且用DCM稀释。分离各层，并且用DCM萃取水层。经MgSO₄床过滤经合并的有机洗脱份，浓缩，并且使用自动快速柱色谱(0至100％乙酸乙酯/己烷)纯化，得到所需产物(0.72g，50％)。LC-MS计算值C₁₀H₁₃N₂O⁺(M+H)⁺:m/z＝177.1；实验值177.1。A vial was charged with 2-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)propanal (1.48 g, 8.2 mmol), MeOH (20 ml) and K₂ CO₃ (2.27 g, 16.4 mmol). The reaction mixture was cooled to 0° C. Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.73 g, 9.02 mmol) was added dropwise and the suspension was stirred at 0° C. for 1 hour. The reactants were quenched with water and diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic fractions were filtered through a bed of MgSO₄ , concentrated, and purified using automated flash column chromatography (0 to 100% ethyl acetate/hexane) to give the desired product (0.72 g, 50%). LC-MS calculated for_C10H13N2O⁺ (M₊ H₎⁺ : m/z=177.1; found 177.1.

实施例1. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 1. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(prop-1-yn-1-yl)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(5.0g，6.7mmol，中间体2)、双-(三苯基膦)氯化钯(II)(235mg，0.33mmol)和氟化铯(3.05g，20.0mmol)于NMP(20ml)中的混合物中添加三丁基(丙-1-炔-1-基)锡烷(2.24ml，7.36mmol)，并且将反应混合物加热至105℃持续45min。将反应混合物用EtOAc稀释并且用水(×2)和盐水洗涤。有机层经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至40％EtOAc/己烷)纯化残余物，得到标题化合物(2.4g，54％)。LC-MS计算值C₃₁H₃₇BrFN₄O₄S⁺(M+H)⁺:m/z＝659.2；实验值659.2。To a mixture of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.0 g, 6.7 mmol, Intermediate 2), bis-(triphenylphosphine)palladium(II) chloride (235 mg, 0.33 mmol) and cesium fluoride (3.05 g, 20.0 mmol) in NMP (20 ml) was added tributyl(prop-1-yn-1-yl)stannane (2.24 ml, 7.36 mmol) and the reaction mixture was heated to 105 °C for 45 min. The reaction mixture was diluted with EtOAc and washed with water (×2) and brine. The organic layer was dried over MgSO₄ , filtered and concentrated. The residue_was purified by flash chromatography (0 to 40% EtOAc/hexanes) to give_the title compound (_2.4 g, 54%). LC-MS calcd for_{C31H37BrFN4O4S}⁺ (M+H)⁺ : m/z = 659.2; found 659.2.

步骤2. 3-(4-(((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-6-基)丙腈Step 2. 3-(4-(((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-8-fluoro-2-(methylthio)-3-(prop-1-yn-1-yl)quinolin-6-yl)propanenitrile

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]-己烷-2-甲酸叔丁酯(2.4g，3.6mmol)在DCM(15ml)中的溶液中添加TFA(15ml)，并且将反应混合物在室温下搅拌3h。浓缩反应混合物并且使残余物与MeCN(×3)共沸，随后在高真空下干燥1h。产物不经纯化即使用。LC-MS计算值C₂₁H₂₁BrFN₄S⁺(M+H)⁺:m/z＝459.1；实验值459.1。To a solution of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylsulfanyl)-3-(prop-1-yn-1-yl)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]-hexane-2-carboxylate (2.4 g, 3.6 mmol) in DCM (15 ml) was added TFA (15 ml) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was azeotroped with MeCN (×3) and then dried under high vacuum for 1 h. The product was used without purification. LC-MS calculated for C₂₁ H₂₁ BrFN₄ S⁺ (M+H)⁺ : m/z=459.1; found 459.1.

步骤3.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向含有3-(4-(((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-6-基)丙腈(1.67g，3.64mmol)的反应小瓶中添加1,3-双(2,6-二异丙基苯基-咪唑-2-亚基)氯化金(I)(0.23g，0.36mmol)和六氟锑酸银(1.37g，4.00mmol)。将小瓶抽空并且用氮气回填，并且添加THF(15ml)。将反应混合物加热至70℃持续2h。冷却至室温后，添加三乙胺(1.52ml，10.9mmol)和boc-酐(1.19g，5.45mmol)，并且搅拌反应混合物15分钟。用饱和NaHCO₃淬灭反应物并且用EtOAc稀释。经由硅藻土垫过滤混合物并且分离各层。将有机层用饱和NaHCO₃和盐水洗涤，经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至50％EtOAc/己烷)纯化产物，得到呈黄色固体的标题化合物(1.28g，63％，经3个步骤)。LC-MS计算值C₂₆H₂₉BrFN₄O₂S⁺(M+H)⁺:m/z＝559.1；实验值559.3。To a reaction vial containing 3-(4-(((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-8-fluoro-2-(methylthio)-3-(prop-1-yn-1-yl)quinolin-6-yl)propionitrile (1.67 g, 3.64 mmol) was added 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride (0.23 g, 0.36 mmol) and silver hexafluoroantimonate (1.37 g, 4.00 mmol). The vial was evacuated and backfilled with nitrogen, and THF (15 ml) was added. The reaction mixture was heated to 70° C. for 2 h. After cooling to room temperature, triethylamine (1.52 ml, 10.9 mmol) and boc-anhydride (1.19 g, 5.45 mmol) were added, and the reaction mixture was stirred for 15 minutes. The reaction was quenched with saturated NaHCO₃ and diluted with EtOAc. The mixture was filtered through a celite pad and the layers were separated. The organic layer was washed with saturated NaHCO₃ and brine, dried over MgSO₄ , filtered and concentrated. The product was purified by flash chromatography (0 to 50% EtOAc/hexanes) to give the title compound (1.28 g, 63% over 3 steps) as a yellow solid. LC-MS calculated for C₂₆ H₂₉ BrFN₄ O₂ S⁺ (M+H)⁺ : m/z=559.1; Found 559.3.

步骤4.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(207mg，0.37mmol)在DCM(4ml)中的溶液中添加m-CPBA(207mg，0.93mmol)并且将反应混合物在室温下搅拌1h。完成后，将反应物用DCM稀释，并且用饱和Na₂S₂O_3和饱和NaHCO₃淬灭。在搅拌30min之后，分离各层并且经MgSO₄干燥有机层，过滤并浓缩。产物不经纯化即使用。LC-MS计算值C₂₆H₂₉BrFN₄O₄S⁺(M+H)⁺:m/z＝591.1；实验值591.2。To a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (207 mg, 0.37 mmol) in DCM (4 ml) was added m-CPBA (207 mg, 0.93_mmol ) and the reaction mixture was stirred at room temperature for 1 h. Upon completion, the reaction was diluted with DCM and quenched with saturated_Na2S2O3and saturated_NaHCO3 . After stirring for 30 min, the layers were separated and the organic layer was dried over_MgSO4 , filtered and concentrated. The product was used without purification. LC-MS calcd_{forC26H29BrFN4O4S}⁺ (M₊ H)₊^: m/z=591.1; found 591.2.

步骤5.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(219mg，0.37mmol)、1H-1,2,4-三唑(128mg，1.85mmol)和碳酸铯(362mg，1.11mmol)于NMP(3ml)中的溶液加热至70℃持续1h。将反应混合物分配于水与EtOAc之间并且分离各层。用EtOAc萃取水层，并且将合并的有机层用盐水洗涤，经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至75％EtOAc/己烷)纯化产物，得到标题化合物(120mg，56％，经2个步骤)。LC-MS计算值C₂₇H₂₈BrFN₇O₂⁺(M+H)⁺:m/z＝580.1；实验值580.1。A solution of (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (219 mg, 0.37 mmol), 1H-1,2,4-triazole (128 mg, 1.85 mmol) and cesium carbonate (362 mg, 1.11 mmol) in NMP (3 ml) was heated to 70 °C for 1 h. The reaction mixture was partitioned between water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO₄ , filtered and concentrated. The product was purified by flash chromatography (0 to 75% EtOAc/hexanes) to give the title compound (120 mg, 56% over 2 steps). LC-MS calcd_{forC27H28BrFN7O2}⁺ (M₊ H)₊ : m/z⁼ 580.1; found 580.1.

步骤6. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 6. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向6-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇(10.5mg，34μmol，如WO 2021142252中所描述制备)、Pd(PPh₃)₄(2.0mg，1.7μmol)和碳酸钠(9.1mg，86μmol)的混合物中添加(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(10mg，17μmol)于二噁烷(1ml)中的溶液。添加水(0.3ml)，并且将反应混合物用N₂充气并且加热至100℃持续1h。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₂H₂₆ClFN₇O⁺(M+H)⁺:m/z＝578.2；实验值578.3。To a mixture of 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (10.5 mg, 34 μmol, prepared as described in WO 2021142252), Pd(PPh₃ )₄ (2.0 mg, 1.7 μmol) and sodium carbonate (9.1 mg, 86 μmol) was added a solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10 mg, 17 μmol) in dioxane (1 ml). Water (0.3 ml) was added, and the reaction mixture was aerated with_N2 and heated to 100°C for 1 h. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in 1:1 DCM/TFA (₃ mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2).^{LC-MS calculated for C32H26ClFN7O+}_(M +H)⁺ : m/z=578.2; found 578.3.

实施例2. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 2. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(170μl，1.32mmol)于THF(3ml)中的溶液中添加叔丁醇钾(1M/THF，1.3ml，1.3mmol)，并且搅拌反应混合物5min。随后添加(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(389mg，0.66mmol，实施例1，步骤4)于THF(1mL)中的溶液并且使反应混合物升温至室温。用饱和NH₄Cl淬灭反应混合物并且用EtOAc萃取。分离各层并且将有机层用盐水洗涤，经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至100％EtOAc/己烷，接着0至20％MeOH/DCM)纯化产物，得到标题化合物(244mg，58％)。LC-MS计算值C₃₂H₄₀BrFN₅O₃⁺(M+H)⁺:m/z＝640.2；实验值640.4。To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (170 μl, 1.32 mmol) in THF (3 ml) was added potassium tert-butoxide (1 M/THF, 1.3 ml, 1.3 mmol) at 0°C and the reaction mixture was stirred for 5 min. A solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (389 mg, 0.66 mmol, Example 1, Step 4) in THF (1 mL) was then added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH₄ Cl and extracted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO₄ , filtered and concentrated. The product was purified by flash chromatography (0 to 100% EtOAc/hexanes, then 0 to 20% MeOH/DCM) to give the title compound (244 mg, 58%). LC-MS calculated for C₃₂ H₄₀ BrFN₅ O₃⁺ (M+H)⁺ : m/z = 640.2; found 640.4.

步骤2. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯(26.6mg，0.07mmol)、XPhos Pd G2(1.8mg，2.3μmol)和碳酸钠(12mg，0.1mmol)的混合物中添加(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(15mg，23μmol)于二噁烷(1ml)中的溶液。添加水(0.3ml)，将反应混合物用N₂充气并且加热至100℃持续1h。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。¹H NMR(600MHz,DMSO-d₆)δ12.22(d,J＝2.6Hz,1H),9.96(s,1H),9.52(s,1H),8.23-8.14(m,1H),8.04(s,1H),7.75(d,J＝2.7Hz,1H),7.10(ddd,J＝11.4,9.4,2.2Hz,1H),6.76(s,1H),6.65(s,1H),5.60(dq,J＝9.0,6.2Hz,1H),5.37(d,J＝3.0Hz,1H),4.97(s,1H),3.91-3.75(m,2H),3.64-3.53(m,1H),3.42(s,1H),3.18(dq,J＝12.4,6.6Hz,1H),3.06(d,J＝4.7Hz,3H),2.98(s,1H),2.64(app s,2H),2.53(app s,2H),2.51(app p,J＝1.9Hz,3H),2.30(dq,J＝13.2,8.0,6.5Hz,2H),2.10(dt,J＝13.3,6.8Hz,1H),1.93(ddt,J＝25.4,12.8,7.2Hz,2H),1.60(d,J＝9.1Hz,1H),1.50(d,J＝6.1Hz,3H)。LC-MS计算值C₃₅H₃₆F₃N₆O⁺(M+H)⁺:m/z＝613.3；实验值613.4。To a mixture of tert-butyl 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (26.6 mg, 0.07 mmol), XPhos Pd G2 (1.8 mg, 2.3 μmol) and sodium carbonate (12 mg, 0.1 mmol) was added a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (15 mg, 23 μmol) in dioxane (1 ml). Water (0.3 ml) was added, the reaction mixture was aerated with_N2 and heated to 100°C for 1 h. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in 1:1 DCM/TFA (3 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2).¹ H NMR (600 MHz, DMSO-_d6 ) δ 12.22 (d, J = 2.6 Hz, 1H), 9.96 (s, 1H), 9.52 (s, 1H), 8.23-8.14 (m, 1H), 8.04 (s, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.10 (ddd, J = 11.4, 9.4, 2.2 Hz, 1H), 6.76 (s, 1H), 6.65 (s, 1H), 5.60 (dq, J = 1. ＝9.0,6.2Hz,1H),5.37(d,J＝3.0Hz,1H),4.97(s,1H),3.91-3.75(m,2H),3.64-3.53(m,1H),3.42(s,1H),3.18(dq,J＝12.4,6.6Hz,1H),3.06(d,J＝4.7 Hz,3H),2.98(s,1H),2.64(app s, 2H), 2.53 (app s, 2H), 2.51 (app p, J=1.9 Hz, 3H), 2.30 (dq, J=13.2, 8.0, 6.5 Hz, 2H), 2.10 (dt, J=13.3, 6.8 Hz, 1H), 1.93 (ddt, J=25.4, 12.8, 7.2 Hz, 2H), 1.60 (d, J=9.1 Hz, 1H), 1.50 (d, J=6.1 Hz, 3H). LC-MS calculated for C₃₅ H₃₆ F₃ N₆ O⁺ (M+H)⁺ : m/z=613.3; found 613.4.

实施例3. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(6-氟-5-甲基-1H-吲哚-3-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 3. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例2、步骤2中所描述的程序，利用6-氟-5-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯(中间体4)代替5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯来制备。LC-MS计算值C₃₆H₃₉F₂N₆O⁺(M+H)⁺:m/z＝609.3；实验值609.3。This compound was prepared according to the procedure described in Example 2, Step 2, using 6-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (Intermediate 4) instead of 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester. LC-MS calculated for C₃₆ H₃₉ F₂ N₆ O⁺ (M+H)⁺ : m/z = 609.3; found 609.3.

实施例4. 3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 4. 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-(5-甲氧基-5-氧代戊-1-炔-1-基)-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-(5-methoxy-5-oxopentan-1-yn-1-yl)-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.3g，3.55mmol,中间体5)、戊-4-炔酸甲酯(1.3ml，10.66mmol)、四(三苯基膦)钯(0)(0.4g，0.355mmol)、CuI(0.13g，0.711mmol)和DIPEA(3.1ml，17.76mmol)在DMF(18.0ml)中的反应混合物用N₂充气并且在60℃加热1h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EA萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物(2.0g，89％产率)。LC-MS计算值C₂₉H₃₃BrFN₄O₄S⁺(M+H)⁺:m/z＝631.1；实验值631.3。The reaction mixture of (1R,4R)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.3 g, 3.55 mmol, Intermediate 5), methyl pent-4-ynoate (1.3 ml, 10.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.355 mmol), CuI (0.13 g, 0.711 mmol) and DIPEA (3.1 ml, 17.76 mmol) in DMF (18.0 ml) was sparged with_N2 and heated at 60°C for 1 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EA, washed with brine, concentrated and purified by flash chromatography (0 to 100% EtOAc/hexanes^{) to give the title compound (2.0 g, 89% yield).LC-MS calcd for C29H33BrFN4O4S+}_(M+H )⁺ : m/z=631.1; found 631.3.

步骤2.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-(3-甲氧基-3-氧代丙基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-(3-methoxy-3-oxopropyl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向含有(1R,4R)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-(5-甲氧基-5-氧代戊-1-炔-1-基)-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.0g，3.17mmol)的反应小瓶中添加1,3-双(2,6-二异丙基苯基-咪唑-2-亚基)氯化金(I)(0.39g，0.63mmol)和六氟锑酸银(1.30g，3.8mmol)。将小瓶抽空并且用氮气回填，并且添加THF(30ml)。将反应混合物加热至70℃持续1.5h。冷却至室温后，添加三乙胺(1.5ml，10.8mmol)和boc-酐(1.2g，5.5mmol)，并且搅拌反应混合物15分钟。用饱和NaHCO₃淬灭反应物并且用EtOAc稀释。经由硅藻土垫过滤混合物并且分离各层。将有机层用饱和NaHCO₃和盐水洗涤，经MgSO₄干燥，过滤并浓缩。通过快速色谱(0至10％MeOH/DCM)纯化产物，得到标题化合物(1.8g，90％产率)。LC-MS计算值C₂₉H₃₃BrFN₄O₄S⁺(M+H)⁺:m/z＝631.1；实验值631.3。To a reaction vial containing (1R,4R)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-(5-methoxy-5-oxopent-1-yn-1-yl)-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.0 g, 3.17 mmol) was added 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride (0.39 g, 0.63 mmol) and silver hexafluoroantimonate (1.30 g, 3.8 mmol). The vial was evacuated and backfilled with nitrogen, and THF (30 ml) was added. The reaction mixture was heated to 70° C. for 1.5 h. After cooling to room temperature, triethylamine (1.5 ml, 10.8 mmol) and boc-anhydride (1.2 g, 5.5 mmol) were added, and the reaction mixture was stirred for 15 minutes. The reactant was quenched with saturated NaHCO₃ and diluted with EtOAc. The mixture was filtered through a celite pad and the layers were separated. The organic layer was washed with saturated NaHCO₃ and brine, dried over MgSO₄ , filtered and concentrated. The product was purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound (1.8 g, 90% yield). LC-MS calculated for C₂₉ H₃₃ BrFN₄ O₄ S⁺ (M+H)⁺ :m/z=631.1; Found 631.3.

步骤3.(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-(3-甲氧基-3-氧代丙基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.8g，2.85mmol)于THF/MeOH(1/1，总计30ml)中的溶液中添加LiOH水溶液(2.0M，15mL)。在45℃搅拌反应混合物3h。完成后，则浓缩反应物以去除有机溶剂。随后通过1N HCl溶液酸化残余物水溶液。沉淀出对应的甲酸中间体，过滤并且干燥，得到甲酸中间体。To a solution of (1R, 4R, 5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-(3-methoxy-3-oxopropyl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1.8 g, 2.85 mmol) in THF/MeOH (1/1, 30 ml in total) was added LiOH aqueous solution (2.0 M, 15 mL). The reaction mixture was stirred at 45 °C for 3 h. After completion, the reactant was concentrated to remove the organic solvent. The aqueous residue was then acidified by 1N HCl solution. The corresponding formic acid intermediate was precipitated, filtered and dried to give the formic acid intermediate.

向含有上文获得的甲酸中间体的反应小瓶中添加含三乙胺(0.865g，8.55mmol)、氮杂环丁烷(0.488g，8.55mmol)和PyBOP(2.225g，4.28mmol)的THF(60ml)。将小瓶抽真并且用氮气回填并且加热至60℃持续1h。将反应混合物倒入水中并且用乙酸乙酯萃取。分离有机层，浓缩，得到标题化合物，其不经进一步纯化即直接使用。LC-MS计算值C₃₁H₃₆BrFN₅O₃S⁺(M+H)⁺:m/z＝656.2；实验值656.1。To the reaction vial containing the formic acid intermediate obtained above was added triethylamine (0.865 g, 8.55 mmol), azetidine (0.488 g, 8.55 mmol) and PyBOP (2.225 g, 4.28 mmol) in THF (60 ml). The vial was evacuated and backfilled with nitrogen and heated to 60 °C for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and concentrated to give the title compound, which was used directly without further purification. LC-MS calculated for C₃₁ H₃₆ BrFN₅ O₃ S⁺ (M+H)⁺ : m/z=656.2; found 656.1.

步骤4.(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.3g，2.0mmol)在乙酸乙酯(10ml)中的溶液中添加m-CPBA(0.56g，2.51mmol)，并且将反应混合物在室温下搅拌1h。完成后，用Na₂S₂O₃饱和溶液淬灭反应物。分离有机层，经MgSO₄干燥，过滤并浓缩，得到(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯中间体。To a solution of tert-butyl (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.3 g, 2.0_mmol ) in ethyl acetate (10 ml) was added m-CPBA (0.56 g, 2.51 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with_{saturatedNa2S2O3} solution. The organic layer was separated, dried over_MgSO4 , filtered and concentrated to give tert-butyl (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate intermediate.

在0℃向(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(1.0g，8.0mmol)于THF(80ml)中的溶液中添加叔丁醇钾(8.0ml，8.0mmol)，并且搅拌反应混合物5min。随后添加上文获得的中间体于THF(20mL)中的溶液。使反应混合物升温至室温并且再搅拌1h。用饱和NH₄Cl淬灭反应物并且用EtOAc萃取。合并有机层并且浓缩并且通过快速色谱(0至10％MeOH/DCM)纯化，得到标题化合物(0.88g，60％，经2个步骤)。LC-MS计算值C₃₇H₄₇BrFN₆O₄⁺(M+H)⁺:m/z＝737.3；实验值737.3。To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (1.0 g, 8.0 mmol) in THF (80 ml) was added potassium tert-butoxide (8.0 ml, 8.0 mmol) at 0°C and the reaction mixture was stirred for 5 min. A solution of the intermediate obtained above in THF (20 mL) was then added. The reaction mixture was allowed to warm to room temperature and stirred for another 1 h. The reaction was quenched with saturated NH₄ Cl and extracted with EtOAc. The organic layers were combined and concentrated and purified by flash chromatography (0 to 10% MeOH/DCM) to give the title compound (0.88 g, 60% over 2 steps). LC-MS calculated for C₃₇ H₄₇ BrFN₆ O₄⁺ (M+H)⁺ : m/z=737.3; found 737.3.

步骤5. 3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 5. 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向(2,3-二氯苯基)硼酸(23.3mg，0.12mmol)、Pd(PPh₃)₄(9.4mg，8.1μmol)和碳酸钾(16.9mg，0.12μmol)的混合物中添加(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(30mg，41μmol)于二噁烷(1ml)中的溶液。添加水(0.3ml)，并且将反应混合物用N₂充气并且加热至100℃持续2h。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₈H₄₂Cl₂FN₆O₂⁺(M+H)⁺:m/z＝703.3；实验值703.3。To a mixture of (2,3-dichlorophenyl)boronic acid (23.3 mg, 0.12 mmol), Pd(PPh₃ )₄ (9.4 mg, 8.1 μmol) and potassium carbonate (16.9 mg, 0.12 μmol) was added a solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (30 mg, 41 μmol) in dioxane (1 ml). Water (0.3 ml) was added and the reaction mixture was sparged with N₂ and heated to 100° C. for 2 h. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in₁ :₁ DCM/TFA (3 mL)_for30 min, concentrated, and purified by preparative HPLC (pH 2). LC-MS calcd for_{C38H42Cl2FN6O2}⁺ (M+H)⁺ : m/z = 703.3; found 703.3.

实施例5：3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮Example 5: 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one

步骤1：(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-(甲基硫基)-2-((2-氧代噁唑烷-3-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(7-bromo-6-fluoro-8-methyl-4-(methylthio)-2-((2-oxooxazolidin-3-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例4、步骤1-2中所描述的程序，使用(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体7)和3-(丙-2-炔-1-基)噁唑烷-2-酮来制备。LC-MS计算值C₂₇H₃₁BrFN₄O₄S(M+H)⁺:m/z＝605.1；实验值605.1。This compound was prepared according to the procedure described in Example 4, Step 1-2, using (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 7) and 3-(prop-2-yn-1-yl)oxazolidin-2-one. LC-MS calculated for C₂₇ H₃₁ BrFN₄ O₄ S (M+H)⁺ : m/z=605.1; found 605.1.

步骤2:(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代噁唑烷-3-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxooxazolidin-3-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例4、步骤4中所描述的程序，使用(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-(甲基硫基)-2-((2-氧代噁唑烷-3-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₃H₄₂BrFN₅O₅(M+H)⁺:m/z＝686.2；实验值686.1。This compound was prepared according to the procedure described in Example 4, Step 4, using (1R,4R,5S)-5-(7-bromo-6-fluoro-8-methyl-4-(methylthio)-2-((2-oxooxazolidin-3-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester instead of (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester. LC-MS calculated for C₃₃ H₄₂ BrFN₅ O₅ (M+H)⁺ : m/z = 686.2; found 686.1.

步骤3:3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮Step 3: 3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one

将(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代噁唑烷-3-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(15mg，0.022mmol)、2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(10.30mg，0.033mmol)、XPhos Pd G2(1.719mg，2.185μmol)、碳酸钠(6.95mg，0.066mmol)于二噁烷(1ml)和水(0.2ml)中的混合物用N₂充气并且加热至100℃持续0.5h。在冷却至室温之后，将反应混合物用DCM稀释，经MgSO₄干燥，接着过滤并浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₈H₄₁FN₅O₄(M+H)⁺:m/z＝650.3；实验值650.3Tert-butyl (1R,4R,5S)-5-(7-bromo-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxooxazolidin-3-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (15 mg, 0.022 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.30 mg, 0.033 mmol), XPhos Pd A mixture of G2 (1.719 mg, 2.185 μmol), sodium carbonate (6.95 mg, 0.066 mmol) in dioxane (1 ml) and water (0.2 ml) was aerated with_N2 and heated to 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with DCM, dried over_MgSO4 , then filtered and concentrated. The residue was stirred in 1:1_DCM /TFA (3 mL) for₃₀ min, concentrated, and purified by preparative HPLC (pH 2₎ . LC-MS calculated for_C38H41FN5O4 (M+H)⁺ : m/z=650.3; found 650.3

实施例6:8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Example 6: 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

步骤1:(1R,4R,5S)-5-(7-溴-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-(7-bromo-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例2中所描述的程序，以(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体6)为起始物质来制备。LC-MS计算值C₃₀H₃₉BrFN₄O₃(M+H)⁺:m/z＝601.2；实验值601.1。This compound was prepared according to the procedure described in Example 2 starting from tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 6). LC-MS calculated for C₃₀ H₃₉ BrFN₄ O₃ (M+H)⁺ : m/z=601.2; found 601.1.

步骤2:8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Step 2: 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

将(1R,4R,5S)-5-(7-溴-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(15mg，0.025mmol)、8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1-萘甲腈(10.44mg，0.037mmol)、XPhos Pd G2(1.962mg，2.494μmol)、碳酸钠(7.93mg，0.075mmol)、二噁烷(1ml)和水(0.2ml)的混合物用N₂充气并且加热至100℃持续0.5h。在冷却至室温之后，将反应混合物用DCM稀释，经MgSO₄干燥，接着过滤并浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₆H₃₇FN₅O(M+H)⁺:m/z＝574.3；实验值574.2。A mixture of (1R,4R,5S)-tert-butyl 5-(7-bromo-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (15 mg, 0.025 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (10.44 mg, 0.037 mmol), XPhos Pd G2 (1.962 mg, 2.494 μmol), sodium carbonate (7.93 mg, 0.075 mmol), dioxane (1 ml) and water (0.2 ml) was sparged with_N2 and heated to 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with DCM, dried over MgSO₄ , then filtered and concentrated. The residue was stirred in 1:1 DCM/TFA (3 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2). LC-MS calculated for C₃₆ H₃₇ FN₅ O (M+H)⁺ : m/z=574.3; found 574.2.

实施例7. 1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈Example 7. 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile

步骤1. 7-溴-4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2-氯-8-氟-6-碘喹啉-3-甲酸乙酯Step 1. 7-Bromo-4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2-chloro-8-fluoro-6-iodoquinoline-3-carboxylic acid ethyl ester

向7-溴-2,4-二氯-8-氟-6-碘喹啉-3-甲酸乙酯(中间体8，10.0g，20.3mmol)于THF(100mL)中的溶液中添加(2S,4S)-4-氨基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(中间体9，10.9g，30.4mmol)和DIEA(7.09ml，40.6mmol)。在65℃搅拌所得混合物5h。冷却至室温后，添加乙酸乙酯和水。将有机层用水(2×)和盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱(用0至100％乙酸乙酯/己烷洗脱)纯化残余物，得到所需产物。LC-MS计算值C₃₀H₄₄BrClFIN₃O₅Si(M+H)⁺:m/z＝814.1,816.1；实验值814.0,816.0。To a solution of ethyl 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline-3-carboxylate (Intermediate 8, 10.0 g, 20.3 mmol) in THF (100 mL) was added tert-butyl (2S,4S)-4-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (Intermediate 9, 10.9 g, 30.4 mmol) and DIEA (7.09 ml, 40.6 mmol). The resulting mixture was stirred at 65 °C for 5 h. After cooling to room temperature, ethyl acetate and water were added. The organic layer was washed with water (2x) and_brine , dried over_Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (eluting with 0 to 100% ethyl acetate/hexanes) to give the desired product. LC-MS calculated for C₃₀ H₄₄ BrClFIN₃ O₅ Si (M+H)⁺ : m/z = 814.1, 816.1; found 814.0, 816.0.

步骤2.(2S,4S)-4-((7-溴-2-氯-8-氟-3-(羟基甲基)-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 2. tert-Butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-(hydroxymethyl)-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

在-0℃向7-溴-4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2-氯-8-氟-6-碘喹啉-3-甲酸乙酯(16.2g，19.9mmol)于甲苯(100ml)中的溶液中添加含1.0M DIBAL-H的DCM(60mL，60mmol)。使所得混合物缓慢升温至室温并且再搅拌1h。用甲醇(8.04mL，199mmol)淬灭所得混合物。在室温下向溶液中添加罗谢尔盐水溶液(由88g(6wt)罗谢尔盐和200mL水制备)并且搅拌所得混合物过夜。分离两相混合物。将有机层用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。按原样使用粗物质。LC-MS计算值C₂₈H₄₂BrClFIN₃O₄Si(M+H)⁺:m/z＝772.1,774.1；实验值772.1,774.1。To a solution of ethyl 7-bromo-4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2-chloro-8-fluoro-6-iodoquinoline-3-carboxylate (16.2 g, 19.9 mmol) in toluene (100 ml) was added 1.0 M DIBAL-H in DCM (60 mL, 60 mmol) at -0°C. The resulting mixture was slowly warmed to room temperature and stirred for an additional 1 h. The resulting mixture was quenched with methanol (8.04 mL, 199 mmol). To the solution was added an aqueous solution of Rochelle salt (prepared from 88 g (6 wt) of Rochelle salt and 200 mL of water) at room temperature and the resulting mixture was stirred overnight. The two-phase mixture was separated. The organic layer was washed with_brine , dried over_Na2SO4 , filtered and concentrated. The crude material was used as is. LC-MS calculated for C₂₈ H₄₂ BrClFIN₃ O₄ Si (M+H)⁺ : m/z = 772.1, 774.1; found 772.1, 774.1.

步骤3.(2S,4S)-4-((7-溴-2-氯-8-氟-3-甲酰基-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 3. tert-Butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-formyl-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

向(2S,4S)-4-((7-溴-2-氯-8-氟-3-(羟基甲基)-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(17g，22mmol)在DCM(100mL)中的溶液中缓慢添加DMP(14g，33mmol)在DCM(100mL)中的溶液。将所得反应混合物在室温下搅拌1h，用饱和NaHCO₃淬灭并且用EtOAc萃取。干燥合并的有机萃取物并且在减压下浓缩，得到粗产物，其不经进一步纯化即用于下一步骤中。LC-MS计算值C₂₈H₄₀BrClFIN₃O₄Si(M+H)⁺:m/z＝770.1,772.1；实验值770.0,772.1。To a solution of tert-butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-(hydroxymethyl)-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (17 g, 22 mmol) in DCM (100 mL) was slowly added a solution of DMP (14 g, 33 mmol) in DCM (100 mL). The resulting reaction mixture was stirred at room temperature for 1 h, quenched with saturated NaHCO₃ and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. LC-MS calculated for C₂₈ H₄₀ BrClFIN₃ O₄ Si (M+H)⁺ : m/z=770.1, 772.1; found 770.0, 772.1.

步骤4.(2S,4S)-4-((7-溴-2-氯-8-氟-3-((E)-(羟基亚氨基)甲基)-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 4. tert-Butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-((E)-(hydroxyimino)methyl)-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

向(2S,4S)-4-((7-溴-2-氯-8-氟-3-甲酰基-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(16.0g，20.8mmol)和羟胺盐酸盐(4.33g，62.3mmol)于EtOH(100mL)中的混合物中添加吡啶(10.1mL，125mmol)。在50℃搅拌反应混合物过夜。真空蒸发溶剂。用EtOAc和水稀释残余物，并且分离各层。用EtOAc萃取水层。将合并的有机层用盐水洗涤，经Na₂SO₄干燥并且真空浓缩。通过硅胶柱色谱(0至100％EtOAc:DCM)纯化残余物，得到所需产物。LC-MS计算值C₂₈H₄₁BrClFIN₄O₄Si(M+H)⁺:m/z＝785.1,787.1；实验值785.1,787.0。To a mixture of tert-butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-formyl-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (16.0 g, 20.8 mmol) and hydroxylamine hydrochloride (4.33 g, 62.3 mmol) in EtOH (100 mL) was added pyridine (10.1 mL, 125 mmol). The reaction mixture was stirred at 50 °C overnight. The solvent was evaporated in vacuo. The residue was diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with_brine , dried over_Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc:DCM) to give the desired product. LC-MS calculated for C₂₈ H₄₁ BrClFIN₄ O₄ Si (M+H)⁺ : m/z = 785.1, 787.1; found 785.1, 787.0.

步骤5.(2S,4S)-4-(7-溴-4-氯-6-氟-8-碘-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 5. tert-Butyl (2S,4S)-4-(7-bromo-4-chloro-6-fluoro-8-iodo-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

在0℃向(2S,4S)-4-((7-溴-2-氯-8-氟-3-((E)-(羟基亚氨基)甲基)-6-碘喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(6.7g，8.5mmol)和2-氨基吡啶(1.61g，17.1mmol)在DCM(60mL)中的溶液中添加Ms-Cl(1.33mL，17.1mmol)。使所得混合物缓慢升温至室温并且搅拌过夜。用水稀释反应物。将合并的有机层用盐水洗涤，干燥并且在减压下浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₂₈H₃₉BrClFIN₄O₃Si(M+H)⁺:m/z＝767.1,769.1；实验值767.1,769.1。To a solution of tert-butyl (2S,4S)-4-((7-bromo-2-chloro-8-fluoro-3-((E)-(hydroxyimino)methyl)-6-iodoquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (6.7 g, 8.5 mmol) and 2-aminopyridine (1.61 g, 17.1 mmol) in DCM (60 mL) was added Ms-Cl (1.33 mL, 17.1 mmol) at 0°C. The resulting mixture was slowly warmed to room temperature and stirred overnight. The reactant was diluted with water. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The crude product was used in the next step without further purification. LC-MS calculated for C₂₈ H₃₉ BrClFIN₄ O₃ Si (M+H)⁺ : m/z = 767.1, 769.1; found 767.1, 769.1.

步骤6.(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 6. tert-Butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

将硫代甲醇钠(1.92g，27.3mmol)添加至(2S,4S)-4-(7-溴-4-氯-6-氟-8-碘-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(7.0g，9.1mmol)在MeOH(45.6mL)/DCM(45.6mL)中的混合物中，并且接着在室温下搅拌1h。用饱和NH₄Cl稀释混合物并且用EtOAc萃取。干燥合并的有机层并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₂₉H₄₂BrFIN₄O₃SSi(M+H)⁺:m/z＝779.1,781.1；实验值779.1,781.1。Sodium thiomethoxide (1.92 g, 27.3 mmol) was added to a mixture of tert-butyl (2S,4S)-4-(7-bromo-4-chloro-6-fluoro-8-iodo-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (7.0 g, 9.1 mmol) in MeOH (45.6 mL)/DCM (45.6 mL), and then stirred at room temperature for 1 h. The mixture was diluted with saturated NH₄ Cl and extracted with EtOAc. The combined organic layers were dried and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₂₉ H₄₂ BrFIN₄ O₃ SSi (M+H)⁺ : m/z=779.1, 781.1; found 779.1, 781.1.

步骤7.(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯Step 7. Tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate

向(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(7.5g，9.6mmol)于THF(95mL)中的溶液中添加含1.0M TBAF的THF(11.5mL，11.5mmol)。在60℃搅拌所得混合物1h。在冷却至室温之后，用水和乙酸乙酯稀释反应混合物。分离有机层并且用盐水洗涤，经Na₂SO₄干燥并且浓缩。按原样使用粗物质。LC-MS计算值C₂₃H₂₈BrFIN₄O₃S(M+H)⁺:m/z＝665.0,667.0；实验值664.9,666.9。To a solution of tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylsulfanyl)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (7.5 g, 9.6 mmol) in THF (95 mL) was added 1.0 M TBAF in THF (11.5 mL, 11.5 mmol). The resulting mixture was stirred at 60° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried over Na₂ SO₄ and concentrated. The crude material was used as is. LC-MS calculated for C₂₃ H₂₈ BrFIN₄ O₃ S (M+H)⁺ : m/z=665.0, 667.0; found 664.9, 666.9.

步骤8.(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 8. Tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

向(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯(5.50g，8.27mmol)在DCM(100ml)中的溶液中添加戴斯-马丁高碘烷(5.26g，12.4mmol)在DCM(50mL)中的溶液。将所得混合物搅拌1h。向反应烧瓶中添加饱和NaHCO₃并且搅拌10min。分离有机层并且经Na₂SO₄干燥并且浓缩。将粗物质溶解于THF(100mL)中，向反应烧瓶中添加氢氧化铵(18.6ml，134mmol)，随后加碘(2.14g，8.43mmol)。在室温下搅拌所得混合物1h，用饱和NaS₂O₃溶液淬灭反应溶液。分离有机层。用DCM萃取水层。将合并的有机萃取物用盐水洗涤，经Na₂SO₄干燥并且浓缩。通过快速色谱(0至100％EtOAc:DCM)纯化残余物，得到所需产物。LC-MS计算值C₂₃H₂₅BrFIN₅O₂S(M+H)⁺:m/z＝660.0,662.0；实验值660.0,662.0。To a solution of tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate (5.50 g, 8.27 mmol) in DCM (100 ml) was added a solution of Dess-Martin periodinane (5.26 g, 12.4 mmol) in DCM (50 mL). The resulting mixture was stirred for 1 h. Saturated NaHCO₃ was added to the reaction flask and stirred for 10 min. The organic layer was separated and dried over Na₂ SO₄ and concentrated. The crude material was dissolved in THF (100 mL), and ammonium hydroxide (18.6 ml, 134 mmol) was added to the reaction flask followed by iodine (2.14 g, 8.43 mmol). The resulting mixture was stirred at room temperature for 1 h and the reaction solution was quenched with saturated NaS₂ O₃ solution. The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with_brine , dried over_Na2SO4 and concentrated. The residue was purified by flash chromatography (0 to 100% EtOAc:DCM) to give the desired product. LC-MS Calcd_. for_{C23H25BrFIN5O2S} (M+H)⁺ : m/z = 660.0,_662.0 ; Found_660.0 , 662.0.

步骤9.(2S,4S)-4-(7-溴-6-氟-8-碘-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 9. tert-Butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

在0℃向(2S,4S)-4-(7-溴-6-氟-8-碘-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(130mg，0.197mmol)于EtOAc(2mL)中的溶液中添加m-CPBA(67.9mg，0.295mmol)。使反应混合物缓慢升温至室温并且搅拌1h。通过添加饱和Na₂S₂O₃淬灭反应物，用乙酸乙酯稀释并且用饱和NaHCO₃、盐水洗涤，干燥并且浓缩。将粗物质溶解于THF(2mL)中，并且添加单独制备的LiHMDS(455μL，0.455mmol)、(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(58.8mg，0.455mmol)于THF(2mL)中的溶液(30min搅拌)。在70℃搅拌所得混合物2h。用水稀释反应混合物并且用EtOAc萃取。干燥有机萃取物并且浓缩，并且粗物质直接用于下一步骤中。LC-MS计算值C₂₉H₃₆BrFIN₆O₃(M+H)⁺:m/z＝741.1,743.1；实验值741.3,743.3。To a solution of tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-(methylsulfanyl)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (130 mg, 0.197 mmol) in EtOAc (2 mL) was added m-CPBA (67.9 mg, 0.295 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction was quenched by the addition of saturated_Na2S2O3 , diluted with_ethylacetate and washed with saturated_NaHCO3 , brine, dried and concentrated. The crude material was dissolved in THF (2 mL), and a separately prepared solution of LiHMDS (455 μL, 0.455 mmol), (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (58.8 mg, 0.455 mmol) in THF (2 mL) was added (30 min stirring). The resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried and concentrated, and the crude material was used directly in the next step. LC-MS calculated for C₂₉ H₃₆ BrFIN₆ O₃ (M+H)⁺ : m/z=741.1, 743.1; Found 741.3, 743.3.

步骤10. 2-((2S,4S)-1-乙酰基-4-(7-溴-6-氟-8-碘-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-2-基)乙腈Step 10. 2-((2S,4S)-1-acetyl-4-(7-bromo-6-fluoro-8-iodo-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidin-2-yl)acetonitrile

向(2S,4S)-4-(7-溴-6-氟-8-碘-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(150mg，0.202mmol)于二噁烷(1mL)中的溶液中添加HCl(4M于二噁烷)(0.5mL，2mmol)。在室温下搅拌反应混合物2h并且浓缩。将残余物溶解于DCM(1mL)中并且添加DIEA(720μL，4.13mmol)。将所得混合物冷却至0℃，并且随后逐滴添加乙酰氯(1M于DCM中)(413μL，0.413mmol)。将所得混合物在0℃搅拌20min并且浓缩。快速柱色谱(0至20％MeOH:DCM)得到标题化合物。LC-MS计算值C₂₆H₃₀BrFIN₆O₂(M+H)⁺:m/z＝683.1,685.1；实验值683.3,685.2。To a solution of tert-butyl (2S,4S)-4-(7-bromo-6-fluoro-8-iodo-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (150 mg, 0.202 mmol) in dioxane (1 mL) was added HCl (4M in dioxane) (0.5 mL, 2 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in DCM (1 mL) and DIEA (720 μL, 4.13 mmol) was added. The resulting mixture was cooled to 0 ° C, and then acetyl chloride (1 M in DCM) (413 μL, 0.413 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C for 20 min and concentrated. Flash column chromatography (0 to 20% MeOH:DCM) gave the title compound. LC-MS calculated for C₂₆ H₃₀ BrFIN₆ O₂ (M+H)⁺ : m/z = 683.1, 685.1; found 683.3, 685.2.

步骤11. 1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈Step 11. 1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile

将2-((2S,4S)-1-乙酰基-4-(7-溴-6-氟-8-碘-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-2-基)乙腈(38mg，0.055mmol)、Zn(CN)₂(5.4mg，0.046mmol)、Pd(dppf)Cl₂.DCM(7.5mg，9.2μmol)和乙酸钾(9.0mg，0.092mmol)在DMA(1mL)中的溶液用N₂吹扫大约2min并且接着在100℃搅拌2h。用水淬灭所得混合物并且用EtOAc萃取。干燥有机萃取物并且浓缩。向残余物中添加8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1-萘甲腈(26mg，0.092mmol)、SPhos Pd G4(7.3mg，9.2μmol)、K₃PO₄(29.3mg，0.138mmol)和二噁烷(1mL)/水(0.2mL)。将所得混合物用N₂吹扫大约2min并且在100℃搅拌2h。经由硫基滤筒过滤所得混合物并且使用制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈两个峰的所需产物。A solution of 2-((2S,4S)-1-acetyl-4-(7-bromo-6-fluoro-8-iodo-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidin-2-yl)acetonitrile (38 mg, 0.055 mmol), Zn(CN)₂ (5.4 mg, 0.046 mmol), Pd(dppf)Cl₂ .DCM (7.5 mg, 9.2 μmol) and potassium acetate (9.0 mg, 0.092 mmol) in DMA (1 mL) was purged with N₂ for approximately 2 min and then stirred at 100 °C for 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The organic extracts were dried and concentrated. To the residue was added 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthocarbonitrile (26 mg, 0.092 mmol), SPhos Pd G4 (7.3 mg, 9.2 μmol), K₃ PO₄ (29.3 mg, 0.138 mmol) and dioxane (1 mL)/water (0.2 mL). The resulting mixture was purged with N₂ for approximately 2 min and stirred at 100 ° C. for 2 h. The resulting mixture was filtered through a sulfur-based cartridge and purified using preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired product as two peaks.

非对映异构体1。峰1。LC-MS计算值C₃₈H₃₆FN₈O₂(M+H)⁺:m/z＝655.3；实验值655.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₈ H₃₆ FN₈ O₂ (M+H)⁺ : m/z = 655.3; found 655.3.

非对映异构体2。峰2。LC-MS计算值C₃₈H₃₆FN₈O₂(M+H)⁺:m/z＝655.3；实验值655.3。Diastereomer 2. Peak 2. LC-MS Calcd. for C₃₈ H₃₆ FN₈ O₂ (M+H)⁺ : m/z = 655.3; found 655.3.

实施例8：8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Example 8: 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

步骤1：(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-(甲基硫基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-(7-bromo-6-fluoro-8-methyl-4-(methylthio)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例4、步骤1-2中所描述的程序，使用(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体7)和4-(丙-2-炔-1-基)吗啉-3-酮来制备。LC-MS计算值C₂₈H₃₃BrFN₄O₄S(M+H)⁺:m/z＝619.1；实验值619.1。This compound was prepared according to the procedure described in Example 4, Step 1-2, using tert-butyl (1R,4R,5S)-5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 7) and 4-(prop-2-yn-1-yl)morpholin-3-one. LC-MS calculated for C₂₈ H₃₃ BrFN₄ O₄ S (M+H)⁺ : m/z=619.1; found 619.1.

步骤2:(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-tert-butyl 5-(7-bromo-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例4、步骤4中所描述的程序，使用(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-(甲基硫基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₄H₄₄BrFN₅O₅(M+H)⁺:m/z＝700.3；实验值700.2。This compound was prepared according to the procedure described in Example 4, Step 4 using (1R,4R,5S)-tert-butyl 5-(7-bromo-6-fluoro-8-methyl-4-(methylthio)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate. LC-MS calculated for C₃₄ H₄₄ BrFN₅ O₅ (M+H)⁺ : m/z=700.3; found 700.2.

步骤3：8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Step 3: 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

此化合物根据实施例6、步骤2中所描述的程序，使用(1R,4R,5S)-5-(7-溴-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。获得两种非对映异构体。This compound was prepared according to the procedure described in Example 6, Step 2 using (1R,4R,5S)-5-(7-bromo-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester. Two diastereomers were obtained.

非对映异构体1。峰1。LC-MS计算值C₄₀H₄₂FN₆O₃(M+H)⁺:m/z＝673.3；实验值673.4。Diastereomer 1. Peak 1. LC-MS calculated for C₄₀ H₄₂ FN₆ O₃ (M+H)⁺ : m/z = 673.3; found 673.4.

非对映异构体2。峰2。LC-MS计算值C₄₀H₄₂FN₆O₃(M+H)⁺:m/z＝673.3；实验值673.4。Diastereomer 2. Peak 2. LC-MS Calcd. for C₄₀ H₄₂ FN₆ O₃ (M+H)⁺ : m/z = 673.3; found 673.4.

实施例9:3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 9: 3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(3-(2-氧代吡咯烷-1-基)丙-1-炔-1-基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(3-(2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例4、步骤1中所描述的程序，使用(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体2)作为起始物质和使用1-(丙-2-炔-1-基)吡咯烷-2-酮代替戊-4-炔酸甲酯来制备。LC-MS计算值C₃₅H₄₂BrFN₅O₅S(M+H)⁺:m/z＝742.2,744.2；实验值742.2,744.2。This compound was prepared according to the procedure described in Example 4, Step 1, using (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 2) as starting material and 1-(prop-₂ -yn-1-yl)pyrrolidin-2-one instead of methyl_pent -4-ynoate. LC-MS calculated for_{C35H42BrFN5O5S} (M+H)⁺ : m/z=742.2,_744.2 ; found 742.2, 744.2.

步骤2：3-(4-(((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-8-氟-2-(甲基硫基)-3-(3-(2-氧代吡咯烷-1-基)丙-1-炔-1-基)喹啉-6-基)丙腈Step 2: 3-(4-(((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-8-fluoro-2-(methylthio)-3-(3-(2-oxopyrrolidin-1-yl)prop-1-yn-1-yl)quinolin-6-yl)propanenitrile

此化合物根据实施例1、步骤2中所描述的程序制备。LC-MS计算值C₂₅H₂₆BrFN₅OS(M+H)⁺:m/z＝542.1,544.1；实验值542.1,544.1。This compound was prepared according to the procedure described in Example₁ , Step 2. LC-MS Calcd. for_{C25H26BrFN5OS} (M+H)⁺ : m/z = 542.1, 544.1; Found_. 542.1, 544.1.

步骤3：(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例1、步骤3中所描述的程序制备。LC-MS计算值C₃₀H₃₄BrFN₅O₃S(M+H)⁺:m/z＝642.2,644.2；实验值642.2,644.2。This compound was prepared according to the procedure described in Example 1, Step 3. LC-MS Calcd. for C₃₀ H₃₄ BrFN₅ O₃ S (M+H)⁺ : m/z = 642.2, 644.2; Found. 642.2, 644.2.

步骤4：(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4: (1R,4R,5S)-5-(7-(Benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(200mg，0.311mmol)的样本溶解于1,4-二噁烷(2.5mL)和水(0.6mL)中，并且在室温下搅拌。用K₂CO₃(129mg，0.934mmol)和苯并[b]噻吩-3-基硼酸(139mg，0.778mmol)处理溶液。通过用氮气鼓泡并且音波处理5分钟来使溶液脱气。最后，用Pd XPhos G2(37mg，0.047mmol)处理溶液并且在65℃搅拌。A sample of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (200 mg, 0.311 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.6 mL) and stirred at room temperature. The solution was treated with_K2CO3 (₁₂₉ mg, 0.934 mmol) and benzo[b]thiophen-3-ylboronic acid (139 mg, 0.778 mmol). The solution was degassed by bubbling with nitrogen and sonicating for 5 minutes. Finally, the solution was treated with Pd XPhos G2 (37 mg, 0.047 mmol) and stirred at 65 °C.

90min后，LCMS指示完全转化为产物。将反应物冷却至室温，用NH₄Cl饱和水溶液淬灭并且用EtOAc稀释。分离各层，并且用另外的EtOAc萃取水层。合并的有机层经MgSO₄干燥，过滤并且真空浓缩。After 90 min, LCMS indicated complete conversion to product. The reaction was cooled to room temperature, quenched with saturated aqueous_NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic layers were dried over_MgSO4 , filtered and concentrated in vacuo.

通过快速柱色谱(0至100％EtOAc/己烷)纯化粗物质，得到(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(213mg，0.306mmol，98％产率)。The crude material was purified by flash column chromatography (0 to 100% EtOAc/hexanes) to afford tert-butyl (1R,4R,5S)-5-(7-(benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (213 mg, 0.306 mmol, 98% yield).

LC-MS计算值C₃₈H₃₉FN₅O₃S₂(M+H)⁺:m/z＝696.3；实验值696.3。LC-MS calcd_{forC38H39FN5O3S2} (M+_H)+^: m/z = 696.3; found 696.3.

步骤5：(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基亚磺酰基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5: (1R,4R,5S)-tert-butyl 5-(7-(benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylsulfinyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(100mg，0.144mmol)的样本溶解于DCM(1.4mL)中并且在0℃搅拌。用m-CPBA(35mg，75％w/w，0.15mmol)处理溶液。A sample of (1R,4R,5S)-tert-butyl 5-(7-(benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.144 mmol) was dissolved in DCM (1.4 mL) and stirred at 0° C. The solution was treated with m-CPBA (35 mg, 75% w/w, 0.15 mmol).

45min之后，LCMS显示完全转化为所需产物，其中一些过氧化为相应砜。将反应物用饱和NaHCO₃水溶液淬灭并且用DCM稀释。分离各层，并且用另外的DCM萃取水层。经MgSO₄干燥经合并的有机层，过滤，并且真空浓缩，得到(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基亚磺酰基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(97mg，0.136mmol，95％产率)。The mixture was stirred for_{4 hours} at room temperature for 2 hours.After 45min, LCMS showed that it was completely converted into the desired product, some of which were peroxidized to the corresponding sulfone.The reactant was quenched with saturated_NaHCO3 aqueous solution and diluted with DCM.Separate each layer, and extract the aqueous layer with other DCM.Through MgSO4, the organic layer combined was dried, filtered, and concentrated in vacuo to obtain (1R, 4R, 5S) -5- (7- (benzo [b] thiophene -3- bases) -8- (2- cyanoethyl) -6- fluoro-4- (methylsulfinyl) -2- ((2- oxopyrrolidin -1- bases) methyl) -1H- pyrrolo [3,2-c] quinoline -1- bases) -2- azabicyclo [2.1.1] hexane -2- tert-butyl formate (97mg, 0.136mmol, 95% yield).

LC-MS计算值C₃₈H₃₉FN₅O₄S₂(M+H)⁺:m/z＝712.2；实验值712.3。LC-MS calcd_{forC38H39FN5O4S2} (M+_H)+^: m/z = 712.2; found 712.3.

步骤6：3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 6: 3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

将(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基亚磺酰基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(20mg，0.028mmol)的样本悬浮于甲苯中并且用(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(7mg，0.056mmol)处理。真空浓缩混合物并且再与甲苯共沸两次。随后，用氮气回填烧瓶。将残余物溶解于无水THF(0.3mL)中。最后，逐滴添加叔丁醇钾(73.0μL，0.037mmol)(1M于THF中)，并且在22℃搅拌溶液。A sample of (1R,4R,5S)-tert-butyl 5-(7-(benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylsulfinyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.028 mmol) was suspended in toluene and treated with (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (7 mg, 0.056 mmol). The mixture was concentrated in vacuo and azeotroped twice more with toluene. The flask was then backfilled with nitrogen. The residue was dissolved in anhydrous THF (0.3 mL). Finally, potassium tert-butoxide (73.0 μL, 0.037 mmol) (1 M in THF) was added dropwise, and the solution was stirred at 22 °C.

15分钟之后，LCMS显示反应完成。用NH₄Cl饱和水溶液淬灭反应物并且用DCM稀释。分离各层，并且用另外的DCM萃取水层。合并的有机洗脱份经MgSO₄干燥，过滤并且真空浓缩。After 15 minutes, LCMS showed the reaction was complete. The reaction was quenched with saturated aqueous NH₄ Cl and diluted with DCM. The layers were separated and the aqueous layer was extracted with additional DCM. The combined organic fractions were dried over MgSO₄ , filtered and concentrated in vacuo.

LC-MS计算值C₄₄H₅₀FN₆O₄S(M+H)⁺:m/z＝777.4；实验值777.4。LC^- MS calculated for_C44H50FN6O4S (M+_H)+ : m/z = 777.4; found 777.4.

将粗中间体溶解于DCM(0.5mL)中并且用三氟乙酸(0.5mL)处理。搅拌混合物30分钟，此时LCMS指示完全转化为所需产物。The crude intermediate was dissolved in DCM (0.5 mL) and treated with trifluoroacetic acid (0.5 mL).The mixture was stirred for 30 minutes at which time LCMS indicated complete conversion to the desired product.

真空浓缩溶液，随后通过HPLC(pH＝2方法)纯化，得到呈两种非对映异构体的3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈(峰1：1.4mg，2.1μmol，7％产率；峰2：2.5mg，3.7μmol，13％产率)。The solution was concentrated in vacuo and then purified by HPLC (pH = 2 method) to give 3-(7-(benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile (Peak 1: 1.4 mg, 2.1 μmol, 7% yield; Peak 2: 2.5 mg, 3.7 μmol, 13% yield) as two diastereomers.

非对映异构体1。峰1。LC-MS计算值C₃₉H₄₂FN₆O₂S(M+H)⁺:m/z＝677.3；实验值677.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₉ H₄₂ FN₆ O₂ S (M+H)⁺ : m/z = 677.3; found 677.3.

非对映异构体2。峰2。LC-MS计算值C₃₉H₄₂FN₆O₂S(M+H)⁺:m/z＝677.3；实验值677.4。Diastereomer 2. Peak 2. LC-MS Calcd. for C₃₉ H₄₂ FN₆ O₂ S (M+H)⁺ : m/z = 677.3; found 677.4.

实施例10：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 10: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1:(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例9、步骤4中所描述的程序，使用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(中间体10)代替苯并[b]噻吩-3-基硼酸来制备。LC-MS计算值C₄₀H₄₀F₂N₅O₃S(M+H)⁺:m/z＝708.3；实验值708.3。This compound was prepared according to the procedure described in Example 9, Step 4, using 2-(7-fluoronaphthalen-1-yl)_-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane (Intermediate 10) instead of benzo[b]thiophen_-3 -_ylboronic acid. LC-MS calculated for_{C40H40F2N5O3S} (M+H)⁺ : m/z=708.3; found 708.3.

步骤2:(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基亚磺酰基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylsulfinyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例9、步骤5中所描述的程序，使用(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯作为起始物质来制备。LC-MS计算值C₄₀H₄₀F₂N₅O₄S(M+H)⁺:m/z＝724.3；实验值724.3。This compound was prepared according to the procedure described in Example 9, Step 5, using (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate as starting material. LC-MS calculated for C₄₀ H₄₀ F₂ N₅ O₄ S (M+H)⁺ : m/z=724.3; found 724.3.

步骤3：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 3: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例9、步骤6中所描述的程序，使用(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基亚磺酰基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯作为起始物质和使用(S)-1-(二甲基氨基)丙烷-2-醇代替(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇来制备。以四种非对映异构体形式分离标题化合物。This compound was prepared according to the procedure described in Example 9, Step 6, using tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylsulfinyl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate as starting material and (S)-1-(dimethylamino)propan-2-ol instead of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol. The title compound was isolated as four diastereoisomeric forms.

非对映异构体1。峰1(1.1mg，1.7μmol，6％产率)。LC-MS计算值C₃₉H₄₁F₂N₆O₂(M+H)⁺:m/z＝663.3；实验值663.4。Diastereomer 1. Peak 1 (1.1 mg, 1.7 μmol, 6% yield). LC-MS calculated for C₃₉ H₄₁ F₂ N₆ O₂ (M+H)⁺ : m/z = 663.3; found 663.4.

非对映异构体2。峰2(1.7mg，2.6μmol，9％产率)。LC-MS计算值C₃₉H₄₁F₂N₆O₂(M+H)⁺:m/z＝663.3；实验值663.4。Diastereomer 2. Peak 2 (1.7 mg, 2.6 μmol, 9% yield). LC-MS calculated for C₃₉ H₄₁ F₂ N₆ O₂ (M+H)⁺ : m/z = 663.3; found 663.4.

非对映异构体3。峰3(0.9mg，1.4μmol，5％产率)。LC-MS计算值C₃₉H₄₁F₂N₆O₂(M+H)⁺:m/z＝663.3；实验值663.3。Diastereomer 3. Peak 3 (0.9 mg, 1.4 μmol, 5% yield). LC-MS calculated for C₃₉ H₄₁ F₂ N₆ O₂ (M+H)⁺ : m/z = 663.3; found 663.3.

非对映异构体4。峰4(1.4mg，2.1μmol，8％产率)。LC-MS计算值C₃₉H₄₁F₂N₆O₂(M+H)⁺:m/z＝663.3；实验值663.4。Diastereomer 4. Peak 4 (1.4 mg, 2.1 μmol, 8% yield). LC-MS calculated for C₃₉ H₄₁ F₂ N₆ O₂ (M+H)⁺ : m/z = 663.3; found 663.4.

实施例11：8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Example 11: 8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

向8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1-萘甲腈(84mg，0.30mmol)、Pd(amphos)Cl₂(14mg，0.02mmol)、(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(129mg，0.20mmol)(实施例2，步骤1)和磷酸钾(128mg，0.60mmol)的混合物中添加1,4-二噁烷(0.81ml)和水(0.20ml)。将反应混合物用N₂充气并且加热至100℃持续1h。To a mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthocarbonitrile (84 mg, 0.30 mmol), Pd(amphos)_Cl2 (14 mg, 0.02 mmol), (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (129 mg, 0.20 mmol) (Example 2, Step 1) and potassium phosphate (128 mg, 0.60 mmol) were added 1,4-dioxane (0.81 ml) and water (0.20 ml). The reaction mixture was sparged with_N2 and heated to 100 °C for 1 h.

完成后，用水和EtOAc稀释反应物。分离各层，并且用另外的EtOAc萃取水层。将合并的有机洗脱份用盐水洗涤，经MgSO₄干燥，过滤并且真空浓缩。通过快速柱色谱，用0至30％MeOH/DCM洗脱来分离(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(8-氰基萘-1-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯。通过制备型HPLC(pH 10)进一步纯化，得到呈两个峰的受Boc保护的产物。After completion, the reactant was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic fractions were washed with brine, dried over MgSO₄ , filtered and concentrated in vacuo. (1R, 4R, 5S) -5- (8- (2- cyanoethyl) -7- (8- cyanonaphthalen-1-yl) -6- fluoro-2-methyl -4- ((S) -1- ((S) -1- methylpyrrolidin-2-yl) ethoxy) -1H- pyrrolo [3, 2-c] quinolin-1-yl) -2- azabicyclo [2.1.1] hexane -2- carboxylic acid tert-butyl ester was separated by flash column chromatography with 0 to 30% MeOH / DCM elution. Further purification by preparative HPLC (pH 10) gave a Boc-protected product in two peaks.

非对映异构体1。峰1。LC-MS计算值C₄₃H₄₆FN₆O₃(M+H)⁺:m/z＝713.4；实验值713.4。Diastereomer 1. Peak 1. LC-MS Calcd. for C₄₃ H₄₆ FN₆ O₃ (M+H)⁺ : m/z = 713.4; found 713.4.

非对映异构体2。峰2。LC-MS计算值C₄₃H₄₆FN₆O₃(M+H)⁺:m/z＝713.4；实验值713.4。Diastereomer 2. Peak 2. LC-MS Calcd. for C₄₃ H₄₆ FN₆ O₃ (M+H)⁺ : m/z = 713.4; found 713.4.

在真空浓缩之后，将各峰的残余物分别在2:1DCM/TFA(3mL)中搅拌30min，浓缩并且通过制备型HPLC(pH 2)纯化。以两种非对映异构体形式分离标题化合物。After concentration in vacuo, the residue of each peak was stirred separately in 2:1 DCM/TFA (3 mL) for 30 min, concentrated and purified by preparative HPLC (pH 2).The title compound was isolated in two diastereoisomeric forms.

非对映异构体1。峰1。LC-MS计算值C₃₈H₃₈FN₆O(M+H)⁺:m/z＝613.3；实验值613.6。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₈ H₃₈ FN₆ O (M+H)⁺ : m/z = 613.3; found 613.6.

非对映异构体2。峰2。LC-MS计算值C₃₈H₃₈FN₆O(M+H)⁺:m/z＝613.3；实验值613.6。Diastereomer 2. Peak 2. LC-MS Calcd. for C₃₈ H₃₈ FN₆ O (M+H)⁺ : m/z = 613.3; found 613.6.

实施例12：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 12: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例2、步骤2中所描述的程序，利用2-(2,3-二氯-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(中间体11)代替5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂-硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯来制备。以四种非对映异构体形式分离标题化合物。This compound was prepared according to the procedure described in Example 2, Step 2, using 2-(2,3-dichloro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 11) instead of 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester. The title compound was isolated as four diastereoisomeric forms.

非对映异构体1。峰1。LC-MS计算值C₃₃H₃₅Cl₂FN₅O₂(M+H)⁺:m/z＝622.2,624.2；实验值622.2,624.2。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₃ H₃₅ Cl₂ FN₅ O₂ (M+H)⁺ : m/z = 622.2, 624.2; Found 622.2, 624.2.

非对映异构体2。峰2。LC-MS计算值C₃₃H₃₅Cl₂FN₅O₂(M+H)⁺:m/z＝622.2,624.2；实验值622.2,624.2。Diastereomer 2. Peak 2. LC-MS Calcd. for C₃₃ H₃₅ Cl₂ FN₅ O₂ (M+H)⁺ : m/z = 622.2, 624.2; Found 622.2, 624.2.

非对映异构体3。峰3。LC-MS计算值C₃₃H₃₅Cl₂FN₅O₂(M+H)⁺:m/z＝622.2,624.2；实验值622.2,624.2。Diastereomer 3. Peak 3. LC-MS Calcd. for C₃₃ H₃₅ Cl₂ FN₅ O₂ (M+H)⁺ : m/z = 622.2, 624.2; Found 622.2, 624.2.

非对映异构体4。峰4。LC-MS计算值C₃₃H₃₅Cl₂FN₅O₂(M+H)⁺:m/z＝622.2,624.2；实验值622.2,624.1。Diastereomer 4. Peak 4. LC-MS Calcd. for C₃₃ H₃₅ Cl₂ FN₅ O₂ (M+H)⁺ : m/z = 622.2, 624.2; Found 622.2, 624.1.

实施例13：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-4-((3-氟-1-甲基氮杂环丁烷-3-基)甲氧基)-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺Example 13: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide

步骤1.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-3-(5-(二甲基氨基)-5-氧代戊-1-炔-1-基)-8-氟-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-3-(5-(dimethylamino)-5-oxopentan-1-yn-1-yl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(6.2g，8.33mmol)(中间体2)、N,N-二甲基戊-4-炔酰胺(5.2g，41.7mmol)(中间体12)、双(三苯基膦)氯化钯(II)(1.2g，1.67mmol)、CuI(2.4g，12.5mmol)和TEA(23ml，167mmol)在DMF(42ml)中的反应混合物用N₂充气并且在95℃加热1h。A reaction mixture of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6.2 g, 8.33 mmol) (Intermediate 2), N,N-dimethylpent-4-ynamide (5.2 g, 41.7 mmol) (Intermediate 12), bis(triphenylphosphine)palladium(II) chloride (1.2 g, 1.67 mmol), CuI (2.4 g, 12.5 mmol) and TEA (23 ml, 167 mmol) in DMF (42 ml) was purged with_N2 and heated at 95°C for 1 h.

完成后，将反应物冷却至室温并且倒入5％LiCl于水中的溶液中。将水层用EtOAc萃取，用盐水洗涤，在减压下浓缩并且通过快速柱色谱(0至20％MeOH/DCM)纯化，得到标题化合物(3.7g，60％产率)。LC-MS计算值C₃₅H₄₄BrFN₅O₅S(M+H)⁺:m/z＝744.2,746.2；实验值744.3,746.3。After completion, the reaction was cooled to room temperature and poured into a solution of 5% LiCl in water. The aqueous layer was extracted with EtOAc, washed with brine, concentrated under reduced pressure and purified by flash column chromatography (0 to 20% MeOH/DCM) to give the title compound (3.7 g, 60% yield). LC-MS calculated for C₃₅ H₄₄ BrFN₅ O₅ S (M+H)⁺ : m/z=744.2, 746.2; found 744.3, 746.3.

步骤2. 5-(4-(((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)喹啉-3-基)-N,N-二甲基戊-4-炔酰胺Step 2. 5-(4-(((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-3-yl)-N,N-dimethylpent-4-ynamide

此化合物根据实施例1、步骤2中所描述的程序，用(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-3-(5-(二甲基氨基)-5-氧代戊-1-炔-1-基)-8-氟-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯替代(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]-己烷-2-甲酸叔丁酯作为起始物质来制备。LC-MS计算值C₂₅H₂₈BrFN₅OS(M+H)⁺:m/z＝544.1,546.1；实验值544.1,546.1。This compound was prepared according to the procedure described in Example 1, Step 2, using (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-3-(5-(dimethylamino)-5-oxopent-1-yn-1-yl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate instead of (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(prop-1-yn-1-yl)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate as the starting material. LC-MS calcd for_{C25H28BrFN5OS} (M+H)⁺ : m/z = 544.1_,546.1 ; found 544.1, 546.1.

步骤3.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例1、步骤3中所描述的程序，用5-(4-(((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)喹啉-3-基)-N,N-二甲基戊-4-炔酰胺替代3-(4-(((1R,4R,5R)-2-氮杂双环[2.1.1]己烷-5-基)氨基)-7-溴-8-氟-2-(甲基硫基)-3-(丙-1-炔-1-基)喹啉-6-基)丙腈作为起始物质来制备。LC-MS计算值C₃₀H₃₆BrFN₅O₃S(M+H)⁺:m/z＝644.2,646.2；实验值644.1,646.1。This compound was prepared according to the procedure described in Example 1, Step 3, using 5-(4-(((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-3-yl)-N,N-dimethylpent-4-ynamide instead of 3-(4-(((1R,4R,5R)-2-azabicyclo[2.1.1]hexan-5-yl)amino)-7-bromo-8-fluoro-2-(methylthio)-3-(prop-1-yn-1-yl)quinolin-6-yl)propionitrile as the starting material. LC-MS calculated for C₃₀ H₃₆ BrFN₅ O₃ S (M+H)⁺ : m/z = 644.2, 646.2; found 644.1, 646.1.

步骤4.(1R,4R,5S)-5-(8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3.6g，5.60mmol)、2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(2.6g，8.40mmol)(中间体13)、XPhos Pd G2(220mg，0.28mmol)和碳酸钠(1.78g，16.8mmol)在1,4-二噁烷(31ml)和水(6.2ml)中的混合物用N₂充气并且加热至100℃持续1h。A mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3.6 g, 5.60 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 g, 8.40 mmol) (Intermediate 13), XPhos Pd G2 (220 mg, 0.28 mmol) and sodium carbonate (1.78 g, 16.8 mmol) in 1,4-dioxane (31 ml) and water (6.2 ml) was heated to 40 ℃ and 10 ℃ of reflux.₂ Aerate and heat to 100°C for 1 h.

在冷却至室温之后，用EtOAc和水稀释反应混合物。将有机层用盐水洗涤，在减压下浓缩并且通过快速柱色谱(0至20％MeOH/DCM)纯化，得到标题化合物(2.7g，63％产率)。LC-MS计算值C₄₂H₄₇FN₅O₅S(M+H)⁺:m/z＝752.3；实验值752.2。After cooling to room temperature, the reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, concentrated under reduced pressure and purified by flash column chromatography (0 to 20% MeOH/DCM) to give the title compound (2.7 g, 63% yield). LC-MS calculated for C₄₂ H₄₇ FN₅ O₅ S (M+H)⁺ : m/z=752.3; found 752.2.

步骤5.(1R,4R,5S)-5-(8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例9、步骤5中所描述的程序，用(1R,4R,5S)-5-(8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯替代(1R,4R,5S)-5-(7-(苯并[b]噻吩-3-基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯作为起始物质来制备。LC-MS计算值C₄₂H₄₇FN₅O₆S(M+H)⁺:m/z＝768.3；实验值768.5。This compound was reacted with (1R,4R,5S)-5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane according to the procedure described in Example 9, Step 5. -2-carboxylic acid tert-butyl ester was prepared by replacing (1R,4R,5S)-5-(7-(benzo[b]thiophen-3-yl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester as the starting material. LC-MS calculated for C₄₂ H₄₇ FN₅ O₆ S (M+H)⁺ : m/z=768.3; found 768.5.

步骤6.3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-4-((3-氟-1-甲基氮杂环丁烷-3-基)甲氧基)-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺Step 6. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide

在0℃向(3-氟-1-甲基氮杂环丁烷-3-基)甲醇(11μl，0.10mmol)于THF(0.50ml)中的溶液中添加叔丁醇钾(1M/THF，0.08ml，0.08mmol)，并且将反应混合物搅拌5min。随后添加(1R,4R,5S)-5-(8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(40mg，0.052mmol)于THF(0.50mL)中的溶液并且使反应混合物升温至室温。To a solution of (3-fluoro-1-methylazetidin-3-yl)methanol (11 μl, 0.10 mmol) in THF (0.50 ml) was added potassium tert-butoxide (1 M/THF, 0.08 ml, 0.08 mmol) at 0°C and the reaction mixture was stirred for 5 min. A solution of (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (40 mg, 0.052 mmol) in THF (0.50 mL) was then added and the reaction mixture was allowed to warm to room temperature.

30min后，通过LC-MS确认起始物质的完全转化并且将反应混合物冷却至0℃。将HCl(4M/1,4-二噁烷，0.39ml，1.56mmol)缓慢添加至溶液中。在室温下搅拌反应混合物10min，随后升温至50℃。在搅拌1h之后，通过L-CMS观测到完全脱保护并且通过制备型HPLC(pH 2)分离所需产物。以两种非对映异构体形式分离标题化合物。After 30min, the complete conversion of the starting material was confirmed by LC-MS and the reaction mixture was cooled to 0°C. HCl (4M/1,4-dioxane, 0.39ml, 1.56mmol) was slowly added to the solution. The reaction mixture was stirred at room temperature for 10min, then warmed to 50°C. After stirring for 1h, complete deprotection was observed by L-CMS and the desired product was separated by preparative HPLC (pH 2). The title compound was separated in two diastereoisomer forms.

非对映异构体1。峰1。LC-MS计算值C₃₉H₄₁F₂N₆O₃(M+H)⁺:m/z＝679.3；实验值679.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₉ H₄₁ F₂ N₆ O₃ (M+H)⁺ : m/z = 679.3; found 679.3.

非对映异构体2。峰2。LC-MS计算值C₃₉H₄₁F₂N₆O₃(M+H)⁺:m/z＝679.3；实验值679.3。Diastereomer 2. Peak 2. LC-MS Calcd. for C₃₉ H₄₁ F₂ N₆ O₃ (M+H)⁺ : m/z = 679.3; found 679.3.

实施例14：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 14: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例13、步骤4中所描述的程序，用(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(实施例1，步骤3)替代(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-(3-(二甲基氨基)-3-氧代丙基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯作为起始物质来制备。LC-MS计算值C₃₈H₄₀FN₄O₄S(M+H)⁺:m/z＝667.3；实验值667.2。This compound was prepared according to the procedure described in Example 13, Step 4, using (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 1, Step 3) instead of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-(3-(dimethylamino)-3-oxopropyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate as the starting material. LC^{-MS calculated for C38H40FN4O4S (M+H)+}_:m/ z = 667.3; found_667.2 .

步骤2. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(17mg，0.025mmol)、(5-甲基吡嗪-2-基)硼酸(8.79mg，0.064mmol)、四(三苯基膦)-钯(0)(5.89mg，5.10μmol)、3-甲基水杨酸铜(I)(19.70mg，0.092mmol)的混合物中添加二噁烷(1.0mL)。将反应混合物用N₂充气并且加热至120℃持续20小时。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。以两种非对映异构体形式分离标题化合物。To a mixture of (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (17 mg, 0.025 mmol), (5-methylpyrazin-2-yl)boronic acid (8.79 mg, 0.064 mmol), tetrakis(triphenylphosphine)-palladium(0) (5.89 mg, 5.10 μmol), 3-methylsalicylate copper(I) (19.70 mg, 0.092 mmol) was added dioxane (1.0 mL). The reaction mixture was purged with_N2 and heated to 120°C for 20 hours. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in 1:1 DCM/TFA (3 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2). The title compound was isolated in two diastereoisomeric forms.

非对映异构体1。峰1。LC-MS计算值C₃₅H₃₀FN₆O(M+H)⁺:m/z＝569.2；实验值569.3。Diastereomer 1. Peak 1. LC-MS calculated for C₃₅ H₃₀ FN₆ O (M+H)⁺ : m/z = 569.2; found 569.3.

非对映异构体2。峰2。LC-MS计算值C₃₅H₃₀FN₆O(M+H)⁺:m/z＝569.2；实验值569.3。Diastereomer 2. Peak 2. LC-MS calculated for C₃₅ H₃₀ FN₆ O (M+H)⁺ : m/z = 569.2; found 569.3.

实施例15：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 15: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1:(1R,4R,5S)-5-(2-((4-((苯甲基氧基)羰基)-2-氧代哌嗪-1-基)甲基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(2-((4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)methyl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例10、步骤1中所描述的程序，使用3-氧代-4-(丙-2-炔-1-基)哌嗪-1-甲酸苯甲酯代替1-(丙-2-炔-1-基)吡咯烷-2-酮来制备。LC-MS计算值C₄₈H₄₇F₂N₆O₅S(M+H)⁺:m/z＝857.3；实验值857.3。This compound was prepared according to the procedure described in Example 10, Step 1, using benzyl 3-oxo-4-(prop-2-yn-1-yl)piperazine-1-carboxylate instead of 1-(_prop -2-yn-₁ -yl)_pyrrolidin -2-_one . LC-MS calculated for_{C48H47F2N6O5S} (M+H)⁺ : m/z=857.3; found 857.3.

步骤2：(1R,4R,5S)-5-(2-((4-((苯甲基氧基)羰基)-2-氧代哌嗪-1-基)甲基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(2-((4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)methyl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例14、步骤2中所描述的程序，使用三甲基硼氧杂环己烷代替(5-甲基吡嗪-2-基)硼酸来制备。LC-MS计算值C₄₈H₄₇F₂N₆O₅(M+H)⁺:m/z＝825.4；实验值825.4。This compound was prepared according to the procedure described in Example 14, Step 2, using trimethylboroxane instead of (5-methylpyrazin-_2- yl)boronic acid. LC-MS Calcd_. for_C48H47F2N6O5 (M+H)₊^: m/z = 825.4; Found 825.4.

步骤3：(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

在H₂下将(1R,4R,5S)-5-(2-((4-((苯甲基氧基)羰基)-2-氧代哌嗪-1-基)甲基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(0.243g，0.294mmol)和Pd(OH)₂(150mg)在MeOH(5mL)中的混合物在室温下搅拌6h。在减压下浓缩反应混合物。通过快速柱色谱纯化粗产物，得到所需产物。LC-MS计算值C₄₀H₄₁F₂N₆O₃(M+H)⁺:m/z＝691.3；实验值691.3。A mixture of (1R,4R,5S)-tert-butyl 5-(2-((4-((benzyloxy)carbonyl)-2-oxopiperazin-1-yl)methyl)-8-(2-cyanoethyl)-6-fluoro-7-(₇ -fluoronaphthalen-1-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.243 g, 0.294 mmol) and Pd(OH)₂ (150 mg) in MeOH (5 mL) was stirred at room temperature for 6 h under H 2. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography to give the desired product. LC-MS calculated for C₄₀ H₄₁ F₂ N₆ O₃ (M+H)⁺ : m/z=691.3; found 691.3.

步骤4：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 4: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(30mg，0.043mmol)、甲醛溶液(0.1mL，37wt.％于H₂O中)、0.1mL AcOH和氰基硼氢化钠(13.65mg，0.217mmol)在MeOH(2mL)中的溶液在室温下搅拌1h。浓缩反应混合物。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₃₆H₃₅F₂N₆O(M+H)⁺:m/z＝605.3；实验值605.5。A solution of (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (30 mg, 0.043 mmol), formaldehyde solution (0.1 mL, 37 wt.% in H₂ O), 0.1 mL of AcOH and sodium cyanoborohydride (13.65 mg, 0.217 mmol) in MeOH (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated. The residue was stirred in 1:1 DCM/TFA (3 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2) to give the desired product. LC-MS calcd_{forC36H35F2N6O} (M₊ H₎⁺ : m/z = 605.3; found 605.5.

实施例16：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 16: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1:(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例4、步骤2中所描述的程序，使用4-异丙基-1-(丙-2-炔-1-基)哌嗪-2-酮(中间体15)和(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-2-乙氧基-8-氟-3-碘喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体16)代替戊-4-炔酸甲酯和(1R,4R)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₄H₄₃BrFN₆O₄(M+H)⁺:m/z＝697.2；实验值697.2。This compound was prepared according to the procedure described in Example 4, Step 2, using 4-isopropyl-1-(prop-2-yn-1-yl)piperazin-2-one (Intermediate 15) and (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-2-ethoxy-8-fluoro-3-iodoquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 16) instead of methyl pent-4-ynoate and (1R,4R)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate. LC-MS calculated for C₃₄ H₄₃ BrFN₆ O₄ (M+H)⁺ : m/z = 697.2; found 697.2.

步骤2：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例12中所描述的程序，使用5-(7-溴-8-(2-氰基乙基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₅H₃₈Cl₂FN₆O₃(M+H)⁺:m/z＝679.2；实验值679.5。This compound was prepared according to the procedure described in Example 12 using tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate. LC-MS calculated for C₃₅ H₃₈ Cl₂ FN₆ O₃ (M+H)⁺ : m/z=679.2; found 679.5.

实施例17：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 17: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基亚磺酰基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylsulfinyl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例10、步骤2中所描述的程序，使用4-(丙-2-炔-1-基)吗啉-3-酮代替1-(丙-2-炔-1-基)吡咯烷-2-酮来制备。LC-MS计算值C₄₀H₄₀F₂N₅O₅S(M+H)⁺:m/z＝740.3；实验值740.3。This compound was prepared according to the procedure described in Example 10, Step 2, using 4-(prop-2-yn-1-yl)morpholin-3-one instead of 1-(prop-₂ -yn-_1- yl)pyrrolidin-₂ -one. LC-MS Calcd. for_{C40H40F2N5O5S} (M+H)⁺ : m/z=740.3; Found 740.3.

步骤2：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基亚磺酰基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(25mg，0.034mmol)、N,N,3-三甲基氮杂环丁烷-3-胺盐酸盐(25.3mg，0.135mmol)和N,N-二异丙基乙胺(29.5μL，0.169mmol)于NMP(1mL)中的溶液在120℃搅拌3h。浓缩反应混合物。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₄₀H₄₂F₂N₇O₂(M+H)⁺:m/z＝690.3；实验值690.4。A solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylsulfinyl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (25 mg, 0.034 mmol), N,N,3-trimethylazetidin-3-amine hydrochloride (25.3 mg, 0.135 mmol) and N,N-diisopropylethylamine (29.5 μL, 0.169 mmol) in NMP (1 mL) was stirred at 120° C. for 3 h. The reaction mixture was concentrated. The residue was_stirred in 1:1 DCM/TFA (3 mL)_for30 min, concentrated, and purified by preparative HPLC (pH 2) to give the desired product. LC-MS Calcd_. for_C40H42F2N7O2 (M+H)⁺ : m/z = 690.3; found 690.4.

实施例18：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-2-(1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 18: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例4、步骤2中所描述的程序，使用4-(丁-3-炔-2-基)吗啉-3-酮(中间体14)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇代替4-异丙基-1-(丙-2-炔-1-基)哌嗪-2-酮和2-(2,3-二氯-5-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷来制备。以非对映异构体混合物形式分离所述化合物。LC-MS计算值C₃₇H₃₇FN₅O₄(M+H)⁺:m/z＝634.3；实验值634.3。This compound was prepared according to the procedure described in Example 4, Step 2, using 4-(but-3-yn-2-yl)morpholin-3-one (Intermediate 14) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol instead of 4-isopropyl-1-(prop-2-yn-1-yl)piperazin-2-one and 2-(2,3-dichloro-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan. The compound was isolated as a mixture of diastereomers. LC-MS calculated for C₃₇ H₃₇ FN₅ O₄ (M+H)⁺ : m/z=634.3; found 634.3.

实施例19：3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 19: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：(内)-5-((7-溴-2-氯-8-氟-6-碘-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (endo)-tert-butyl 5-((7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向7-溴-2,4-二氯-8-氟-6-碘-3-硝基喹啉(15g，32.5mmol，中间体1)和(内)-5-氨基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(6.76g，34.1mmol)在MeCN(325ml)中的溶液中添加休尼格氏碱(6.80ml，39.0mmol)，并且将反应混合物加热至60℃持续1h。添加冰屑和水(100mL)并且搅拌悬浮液15min。过滤固体，用水冲洗，并且在真空下风干过夜，得到所需产物。LC-MS计算值C₁₉H₁₉BrClFIN₄O₄(M+H)⁺:m/z＝626.9；实验值626.9。To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline (15 g, 32.5 mmol, intermediate 1) and (endo)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (6.76 g, 34.1 mmol) in MeCN (325 ml) was added Hunig's base (6.80 ml, 39.0 mmol) and the reaction mixture was heated to 60° C. for 1 h. Ice chips and water (100 mL) were added and the suspension was stirred for 15 min. The solid was filtered, rinsed with water, and air-dried under vacuum overnight to give the desired product. LC-MS calculated for C₁₉ H₁₉ BrClFIN₄ O₄ (M+H)⁺ : m/z=626.9; Found 626.9.

步骤2：(内)-5-((7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (endo)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例2、步骤1中所描述的程序，利用(内)-5-((7-溴-2-氯-8-氟-6-碘-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(甲基磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₂₆H₃₃BrFIN₅O₅(M+H)⁺:m/z＝720.1；实验值720.0。This compound was prepared according to the procedure described in Example 2, Step 1, using (endo)-5-((7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester instead of (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(methylsulfonyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]_hexane -2-carboxylic acid tert_{-butyl ester. LC-MS calculated for C26H33BrFIN5O5(M} +H)⁺ : m/z=720.1; found 720.0.

步骤3：(内)-5-((7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-硝基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (endo)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体2、步骤2中所描述的程序，利用(内)-5-((7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₁H₄₁BrFIN₅O₇(M+H)⁺:m/z＝820.1；实验值820.1。This compound was prepared according to the procedure described in Intermediate 2, Step 2, using (endo)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate instead of (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-_{2-carboxylate. LC-MS calculated for C31H41BrFIN5O7(M+} H)⁺ : m/z=820.1; found 820.1.

步骤4：(内)-5-((3-氨基-7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4: (endo)-tert-butyl 5-((3-amino-7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体2、步骤3中所描述的程序，利用(内)-5-((7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-硝基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-((7-溴-8-氟-6-碘-2-(甲基硫基)-3-硝基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₁H₄₃BrFIN₅O₅(M+H)⁺:m/z＝790.2；实验值790.0。This compound was prepared according to the procedure described in Intermediate 2, Step 3, using (endo)-tert-butyl 5-((7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate instead of tert-butyl (1R,4R,5S)-5-((₇ -bromo-8-fluoro-6-iodo-2-(methylthio)-3-nitroquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-_2- carboxylate. LC-MS calculated for_{C31H43BrFIN5O5} (M+H)⁺ : m/z=790.2; found 790.0.

步骤5：(内)-5-((3-氨基-7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5: (endo)-tert-butyl 5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体2、步骤4中所描述的程序，利用(内)-5-((3-氨基-7-溴-8-氟-6-碘-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-((3-氨基-7-溴-8-氟-6-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₄H₄₇BrFN₆O₅(M+H)⁺:m/z＝717.3；实验值717.2。This compound was prepared according to the procedure described in Intermediate 2, Step 4, using (endo)-tert-butyl 5-((3-amino-7-bromo-8-fluoro-6-iodo-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate instead of tert-butyl (1R,4R,5S)-5-((3-amino-7-bromo-8-fluoro-6-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-_{2-carboxylate. LC-MS calculated for C34H47BrFN6O5(M} +H)⁺ : m/z=717.3; found 717.2.

步骤6：(内)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6: (endo)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃经5分钟向(内)-5-((3-氨基-7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.82g，2.54mmol)在乙酸(19ml)和水(7mL)中的混合物中逐滴添加t-BuONO(1.5mL，12.7mmol)以控制鼓泡。在添加之后，在室温下搅拌反应物1h。使反应混合物分配于水(100mL)与EtOAc(100mL)之间并且分离各层。将有机层用饱和NaCl洗涤，经MgSO₄干燥并且浓缩。产物不经纯化即使用。LC-MS计算值C₃₄H₄₆BrFN₅O₅⁺(M+H)⁺:m/z＝702.3；实验值702.3。To a mixture of (endo)-tert-butyl 5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.82 g, 2.54 mmol) in acetic acid (19 ml) and water (7 mL) was added t-BuONO (1.5 mL, 12.7 mmol) dropwise over 5 min at 0 °C to control bubbling. After the addition, the reaction was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL) and the layers were separated. The organic layer was washed with saturated NaCl, dried over MgSO₄ and concentrated. The product was used without purification. LC-MS calcd for C₃₄ H₄₆ BrFN₅ O₅⁺ (M+H)⁺ : m/z = 702.3; found 702.3.

步骤7：(内)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 7: (endo)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据中间体5中所描述的程序，利用(内)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₂₉H₃₈BrFN₅O₃⁺(M+H)⁺:m/z＝602.2；实验值602.3。This compound was prepared according to the procedure described for Intermediate 5 utilizing (endo)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate in place of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2_- carboxylate. LC-MS Calcd_. for_{C29H38BrFN5O3+} (M+H)^+: m/z=602.2; Found 602.3.

步骤8：(内)-5-((6-(2-氰基乙基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 8: (endo)-tert-butyl 5-((6-(2-cyanoethyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(内)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(770mg，1.28mmol)、2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(422mg，1.34mmol)(中间体13)、四(三苯基膦)钯(0)(148mg，0.13mmol)和碳酸钠(406mg，3.83mmol)在1,4-二噁烷(7ml)和水(1.7ml)中的混合物用N₂充气并且加热至80℃持续15h。在冷却至室温之后，用EtOAc和水稀释反应混合物。将有机层用盐水洗涤，在减压下浓缩并且通过快速柱色谱(0至100％EtOAc/己烷)纯化，得到标题化合物(397mg，44％产率)。LC-MS计算值C₄₁H₄₉FN₅O₅(M+H)⁺:m/z＝710.4；实验值710.4。A mixture of (endo)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (770 mg, 1.28 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (422 mg, 1.34 mmol) (Intermediate 13), tetrakis(triphenylphosphine)palladium(0) (148 mg, 0.13 mmol) and sodium carbonate (406 mg, 3.83 mmol) in 1,4-dioxane (7 ml) and water (1.7 ml) was sparged with_N2 and heated to 80 °C for 15 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, concentrated under reduced pressure and purified by flash column chromatography (0 to 100% EtOAc/hexanes) to give the title compound (397 mg, 44% yield). LC-MS calculated for C₄₁ H₄₉ FN₅ O₅ (M+H)⁺ : m/z=710.4; found 710.4.

步骤9：(内)-5-((6-(2-氰基乙基)-8-氟-3-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 9: (endo)-tert-butyl 5-((6-(2-cyanoethyl)-8-fluoro-3-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(内)-5-((6-(2-氰基乙基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(397mg，0.559mmol)在DCM(7.99ml)中的溶液中添加三氟乙酸银(185mg，0.839mmol)，并且将混合物冷却至0℃。添加一氯化碘(559μl，0.559mmol)并且在0℃搅拌反应混合物30min。用饱和硫代硫酸钠淬灭反应物并且用EtOAc萃取。分离各层，并且将有机层用盐水洗涤，经硫酸镁干燥，过滤并浓缩。通过快速色谱(0至5％MeOH/DCM)纯化粗残余物，得到标题化合物(233.5mg，0.279mmol，50.0％产率)。LC-MS计算值C₄₁H₄₈FIN₅O₅(M+H)⁺:m/z＝836.3；实验值836.2。To a solution of (endo)-tert-butyl 5-((6-(2-cyanoethyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (397 mg, 0.559 mmol) in DCM (7.99 ml) was added silver trifluoroacetate (185 mg, 0.839 mmol) and the mixture was cooled to 0° C. Iodine monochloride (559 μl, 0.559 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched with saturated sodium thiosulfate and extracted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (0 to 5% MeOH/DCM) to give the title compound (_233.5 mg, 0.279 mmol, 50.0% yield).LC-MS_Calcd for_C41H48FIN5O5 (M+H)⁺ : m/z₌ 836.3; found 836.2.

步骤10：(内)-5-((6-(2-氰基乙基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-(吡啶-3-基乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 10: (endo)-tert-butyl 5-((6-(2-cyanoethyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-(pyridin-3-ylethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物根据实施例13、步骤1中所描述的程序，分别利用(内)-5-((6-(2-氰基乙基)-8-氟-3-碘-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯和3-乙炔基吡啶代替(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯和N,N-二甲基戊-4-炔酰胺来制备。LC-MS计算值C₄₈H₅₂FN₆O₅(M+H)⁺:m/z＝811.4；实验值811.3。This compound was prepared according to the procedure described in Example 13, Step 1, utilizing tert-butyl (endo)-5-((6-(2-cyanoethyl)-8-fluoro-3-iodo-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate and 3-ethynylpyridine instead of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate and N,N-dimethylpent-4-ynamide, respectively. LC-MS calculated_{forC48H52FN6O5} (M+_H)⁺ : m/z = 811.4; found 811.3.

步骤11：3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 11: 3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

向(内)-5-((6-(2-氰基乙基)-8-氟-7-(3-(甲氧基甲氧基)萘-1-基)-2-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-3-(吡啶-3-基乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(255mg，0.314mmol)的反应小瓶中添加1,3-双(2,6-二异丙基苯基-咪唑-2-亚基)氯化金(I)(39.1mg，0.063mmol)和六氟锑酸银(324mg，0.943mmol)。将小瓶抽空并且用氮气回填，并且添加THF(6.29ml)。将反应混合物加热至70℃持续8h，随后使其通过硫醇塞并且浓缩。将粗残余物溶解于EtOH(2.5mL)和含4N HCl的二噁烷(1.0mL)中，并且搅拌1h，其指出反应物用碳酸氢钠水溶液(5mL)淬灭并且分配于水(50mL)与DCM(50mL)之间。分离各层，并且将有机层经硫酸钠干燥，过滤，并且浓缩。通过制备型HPLC(pH2)纯化粗物质。LC-MS计算值C₄₁H₄₀FN₆O₂(M+H)⁺:m/z＝667.3；实验值667.3。To a reaction vial of (endo)-tert-butyl 5-((6-(2-cyanoethyl)-8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-3-(pyridin-3-ylethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (255 mg, 0.314 mmol) was added 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride (39.1 mg, 0.063 mmol) and silver hexafluoroantimonate (324 mg, 0.943 mmol). The vial was evacuated and backfilled with nitrogen, and THF (6.29 ml) was added. The reaction mixture was heated to 70° C. for 8 h, then passed through a plug of thiol and concentrated. The crude residue was dissolved in EtOH (2.5 mL) and 4N HCl in dioxane (1.0 mL) and stirred for 1 h, at which point the reaction was quenched with aqueous sodium bicarbonate (5 mL) and partitioned between water (50 mL) and DCM (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by preparative HPLC (pH 2). LC-MS calculated for C₄₁ H₄₀ FN₆ O₂ (M+H)⁺ : m/z=667.3; found 667.3.

实施例20.3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7,8-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 20. 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物经由以下方案以(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(实施例4，步骤4)作为起始物质来制备：在1打兰小瓶中，将(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(20mg，0.027mmol)、2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(15.73mg，0.054mmol)和XPhos Pd-G4(4.67mg，5.42μmol)溶解于1mL与敞开4:1二噁烷/0.5M K₃PO₄水溶液。用氮气吹扫小瓶顶部空间并且在80℃搅拌混合物1h。此时，用MeOH稀释混合物并且通过制备型LCMS(XBridgeC18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到两个经合并并且冻干的峰。用TFA(0.4mL)处理冻干粉末30min，接着用MeOH(4.5mL)稀释并且再次通过制备型LCMS纯化，得到呈两个峰的所需产物。This compound was prepared via the following scheme starting from tert-butyl (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Example 4, Step 4): In a 1 dram vial, (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate was added. cyclobutan-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (20 mg, 0.027 mmol), 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.73 mg, 0.054 mmol) and XPhos Pd-G4 (4.67 mg, 5.42 μmol) were dissolved in 1 mL with open 4:1 dioxane/0.5M K₃ PO₄ aqueous solution. The headspace of the vial was purged with nitrogen and the mixture was stirred at 80° C. for 1 h. At this point, the mixture was diluted with MeOH and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give two peaks that were combined and lyophilized. The lyophilized powder was treated with TFA (0.4 mL) for 30 min, then diluted with MeOH (4.5 mL) and purified again by preparative LCMS to give the desired product as two peaks.

非对映异构体1。峰1。LC-MS计算值C₄₂H₄₄F₃N₆O₂(M+H)⁺:m/z＝721.3；实验值721.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₄₂ H₄₄ F₃ N₆ O₂ (M+H)⁺ : m/z = 721.3; found 721.3.

非对映异构体2。峰2。LC-MS计算值C₄₂H₄₄F₃N₆O₂(M+H)⁺:m/z＝721.3；实验值721.3。Diastereomer 2. Peak 2. LC-MS Calcd. for C₄₂ H₄₄ F₃ N₆ O₂ (M+H)⁺ : m/z = 721.3; found 721.3.

实施例21. 3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(6,7-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 21. 3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物使用实施例20中所概述的方案，用2-(6,7-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替代2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷来制备。This compound was prepared using the protocol outlined in Example 20, substituting 2-(6,7-difluoronaphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane for 2-(7,8-difluoronaphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.

非对映异构体1。峰1。LC-MS计算值C₄₂H₄₄F₃N₆O₂(M+H)⁺:m/z＝721.3；实验值721.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₄₂ H₄₄ F₃ N₆ O₂ (M+H)⁺ : m/z = 721.3; found 721.3.

非对映异构体2。峰2。LC-MS计算值C₄₂H₄₄F₃N₆O₂(M+H)⁺:m/z＝721.3；实验值721.3。Diastereomer 2. Peak 2. LC-MS Calcd. for C₄₂ H₄₄ F₃ N₆ O₂ (M+H)⁺ : m/z = 721.3; found 721.3.

实施例22. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 22. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1. 6-氟萘-1-胺Step 1. 6-Fluoronaphthalen-1-amine

A部分：在40mL小瓶中，将6-氟-1-萘甲酸(0.500g，2.63mmol，1.0equiv.)溶解于敞开甲苯(10ml)中。添加分子筛(3g)，接着添加叔丁醇(2.5mL)、DIPEA(2.3mL，13.15mmol，5.0equiv.)和二苯基磷酰基叠氮化物(DPPA，0.85mL，3.94mmol，1.5equiv.)。用氮气吹扫顶部空间并且将混合物密封并加热至110℃过夜。经由过滤混合物，并且真空去除挥发物。通过自动化FCC(0至30％EtOAc/庚烷)纯化残余物，得到呈白色固体的(6-氟萘-1-基)氨基甲酸叔丁酯(575mg，2.20mmol，84％)。Part A: In a 40 mL vial, 6-fluoro-1-naphthoic acid (0.500 g, 2.63 mmol, 1.0 equiv.) was dissolved in open toluene (10 ml). Molecular sieves ( 3 g), followed by tert-butyl alcohol (2.5 mL), DIPEA (2.3 mL, 13.15 mmol, 5.0 equiv.) and diphenylphosphoryl azide (DPPA, 0.85 mL, 3.94 mmol, 1.5 equiv.). The headspace was purged with nitrogen and the mixture was sealed and heated to 110 °C overnight. The mixture was filtered and the volatiles were removed in vacuo.The residue was purified by automated FCC (0 to 30% EtOAc/heptane) to give tert-butyl (6-fluoronaphthalen-1-yl)carbamate (575 mg, 2.20 mmol, 84%) as a white solid.

B部分：将(6-氟萘-1-基)氨基甲酸叔丁酯(575mg，2.20mmol，在A部分中制备)溶解于纯TFA(20mL)中并且在室温下搅拌30min。真空去除挥发物并且用饱和NaHCO₃溶液(30mL)处理残余物并萃取至DCM(3×15mL)中。合并有机萃取物，用盐水(10mL)洗涤，经MgSO₄干燥，并且真空干燥，得到呈白色固体的6-氟萘-1-胺(339mg，2.10mmol，95％)，其不经进一步纯化即用于后续步骤中。Part B: tert-butyl (6-fluoronaphthalene-1-yl)carbamate (575 mg, 2.20 mmol, prepared in Part A) was dissolved in pure TFA (20 mL) and stirred at room temperature for 30 min. The volatiles were removed in vacuo and the residue was treated with saturated NaHCO solution (₃₀ mL) and extracted into DCM (₃ ×15 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgSO, and dried in vacuo to give 6-fluoronaphthalene-1-amine (339 mg, 2.10 mmol, 95%) as a white solid, which was used in subsequent steps without further purification.

步骤2. 2,4-二溴-6-氟萘-1-胺Step 2. 2,4-Dibromo-6-fluoronaphthalen-1-amine

在室温下向6-氟萘-1-胺(3.28g，20.35mmol)在乙酸(100mL)中的敞开溶液中添加溴(2.29ml，44.4mmol)，并且在85℃搅拌反应物1.5h。冷却至室温后，经烧结漏斗过滤反应混合物(浆液)，将滤饼用1NNaOH并且接着用水大量洗涤，并且经过滤器干燥，得到呈灰白色固体的标题化合物(6.32g，19.81mmol，97％)。LCMS计算值C₁₀H₇Br₂FN(M+H)⁺:m/z＝317.9,319.9,321.9(1:2:1)；实验值：317.8,319.9,321.9。To an open solution of 6-fluoronaphthalen-1-amine (3.28 g, 20.35 mmol) in acetic acid (100 mL) was added bromine (2.29 ml, 44.4 mmol) at room temperature and the reaction was stirred at 85°C for 1.5 h. After cooling to room temperature, the reaction mixture (slurry) was filtered through a sintered funnel, the filter cake was washed extensively with 1_NNaOH and then water, and dried over the filter to give the title compound (6.32 g, 19.81 mmol, 97%) as an off-white solid. LCMS calculated for_C10H7Br2FN (M+H)⁺ : m/z=317.9, 319.9, 321.9 (1:2:1); Found: 317.8, 319.9, 321.9.

步骤3. 5-溴-7-氟萘并[1,2-d][1,2,3]噁二唑Step 3. 5-Bromo-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole

在250mL圆底烧瓶中，将2,4-二溴-6-氟萘-1-胺(6.32g，19.81mmol)溶解于乙酸(75ml)/丙酸(15mL)混合物中并且在0℃敞开搅拌。经2min将亚硝酸钠(1.709g，1124.77mmol)分数份添加至反应混合物中。使混合物升温至室温并且搅拌1小时。此时，在搅拌下将混合物倒入冰水(350mL)中并且通过过滤收集沉淀物并且用冷水洗涤。经过滤器干燥物质，产生5.15g呈淡橙色粉末的噁二唑(19.28mmol，97％)。LCMS计算值C₁₀H₅BrFN₂O(M+H)⁺:m/z＝267.0,269.0；实验值：266.9,268.9。In a 250 mL round bottom flask, 2,4-dibromo-6-fluoronaphthalene-1-amine (6.32 g, 19.81 mmol) was dissolved in an acetic acid (75 ml)/propionic acid (15 mL) mixture and stirred open at 0°C. Sodium nitrite (1.709 g, 1124.77 mmol) was added to the reaction mixture in portions over 2 min. The mixture was allowed to warm to room temperature and stirred for 1 hour. At this point, the mixture was poured into ice water (350 mL) with stirring and the precipitate was collected by filtration and washed with cold water. The material was dried over the filter to produce 5.15 g of oxadiazole (19.28 mmol, 97%) as a light orange powder. LCMS calculated for C₁₀ H₅ BrFN₂ O (M+H)⁺ : m/z = 267.0, 269.0; Found: 266.9, 268.9.

步骤4. 4-溴-6-氟萘-2醇Step 4. 4-Bromo-6-fluoronaphthalen-2-ol

在250mL圆底烧瓶中，将5-溴-7-氟萘并[1,2-d][1,2,3]噁二唑(5.15g，19.28mmol)溶解于敞开乙醇(100ml)中。在0℃经10min分数份添加硼氢化钠(1.459g，38.6mmol)至反应混合物中。在完成添加之后，使反应物升温至室温并且再搅拌3h。随后添加水(100mL)并且用DCM(3×100mL)萃取反应混合物。合并有机层并且将产物萃取至1NNaOH(100mL)中。将NaOH溶液逐滴添加至1N HCl(200mL，于冰上预冷却)的快速搅拌溶液以沉淀所需产物。过滤固体并且在真空下干燥，得到呈灰白色固体的标题化合物(3.68g，15.27mmol，79％)。¹H NMR(500MHz,DMSO-d₆)δ10.17(s,1H),7.87(dd,J＝9.1,5.7Hz,1H),7.64(dd,J＝10.9,2.6Hz,1H),7.53(d,J＝2.2Hz,1H),7.41(td,J＝8.7,2.6Hz,1H),7.27(d,J＝2.3Hz,1H)。¹⁹F NMR(471MHz,DMSO-d₆)δ-116.42。In a 250mL round-bottom flask, 5-bromo-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole (5.15g, 19.28mmol) was dissolved in open ethanol (100ml). Sodium borohydride (1.459g, 38.6mmol) was added to the reaction mixture at 0°C over 10min fractions. After the addition was completed, the reactant was warmed to room temperature and stirred for another 3h. Water (100mL) was subsequently added and the reaction mixture was extracted with DCM (3×100mL). The organic layers were combined and the product was extracted into 1N NaOH (100mL). NaOH solution was added dropwise to a rapidly stirred solution of 1N HCl (200mL, pre-cooled on ice) to precipitate the desired product. The solid was filtered and dried under vacuum to give the title compound (3.68g, 15.27mmol, 79%) as an off-white solid.¹ H NMR (500MHz, DMSO-d₆ ) δ10.17(s,1H),7.87(dd,J＝9.1,5.7Hz,1H),7.64(dd,J＝10.9,2.6Hz,1H),7.53(d,J＝2.2Hz,1H),7.41(td,J＝8.7,2.6Hz,1H),7.27(d ,J=2.3Hz,1H).¹⁹ F NMR (471MHz, DMSO-d₆ ) δ-116.42.

步骤5. 6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇Step 5. 6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol

在40mL小瓶中，将4-溴-6-氟萘-2-醇(300mg，1.245mmol)、双(频哪醇基)二硼(411mg，1.618mmol)、Pd(dppf)Cl₂·CH₂Cl₂(102mg，0.124mmol)和乙酸钾(244mg，2.489mmol)溶解于二噁烷(5ml)中。将混合物在氮气下加盖并且在80℃搅拌4h。将反应混合物用EtOAc稀释，过滤并浓缩。将粗物质溶解于DCM中并且通过FCC(0至50％EtOAc/己烷)纯化，得到呈白色固体的标题化合物。LCMS计算值C₁₆H₁₉BFO₃(M+H)⁺:m/z＝289.1；实验值289.0。In a 40 mL vial, 4-bromo-6-fluoronaphthalen-2-ol (300 mg, 1.245 mmol), bis(pinacolato)diboron (411 mg, 1.618 mmol), Pd(dppf)Cl₂ ·CH₂ Cl₂ (102 mg, 0.124 mmol) and potassium acetate (244 mg, 2.489 mmol) were dissolved in dioxane (5 ml). The mixture was capped under nitrogen and stirred at 80° C. for 4 h. The reaction mixture was diluted with EtOAc, filtered and concentrated. The crude material was dissolved in DCM and purified by FCC (0 to 50% EtOAc/hexanes) to give the title compound as a white solid. LCMS calculated for C₁₆ H₁₉ BFO₃ (M+H)⁺ : m/z=289.1; found 289.0.

步骤6. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 6. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物使用实施例20中所概述的方案开始，用6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇替代2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷和用(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(实施例2，步骤1)替代(1R,4R,5S)-5-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-7-溴-8-(2-氰基乙基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。This compound was prepared using the protocol outlined in Example 20, substituting 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol for 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan and (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[ 3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Example 2, Step 1) was prepared instead of (1R,4R,5S)-5-(2-(3-(azetidin-1-yl)-3-oxopropyl)-7-bromo-8-(2-cyanoethyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester.

非对映异构体1。峰1。LC-MS计算值C₃₇H₃₈F₂N₅O₂(M+H)⁺:m/z＝622.3；实验值622.2。Diastereomer 1. Peak 1. LC-MS Calcd. for C₃₇ H₃₈ F₂ N₅ O₂ (M+H)⁺ : m/z = 622.3; found 622.2.

非对映异构体2。峰2。LC-MS计算值C₃₇H₃₈F₂N₅O₂(M+H)⁺:m/z＝622.3；实验值622.2。1H NMR(500MHz,DMSO-d₆)δ10.11(s,1H),9.8(s,1H),9.5(s,1H),8.09(s,1H),7.94(dd,J＝9.2,5.8Hz,1H),7.43-7.34(m,2H),7.17(d,J＝2.4Hz,1H),6.90(s,1H),6.66(s,1H),5.58(dt,J＝12.5,6.3Hz,1H),5.41-5.37(m,1H),5.09-5.04(m,1H),3.89-3.80(m,2H),3.57-3.42(m,3H),3.24(m,1H)3.04(s,3H),2.97(s,2H),2.74-2.63(m,2H),2.55(s,3H),2.29(d,J＝8.6Hz,2H),1.90(q,J＝12.8,7.3Hz,3H),1.61(d,J＝9.1Hz,1H),1.49(d,J＝6.1Hz,3H)。¹⁹FNMR(471MHz,DMSO-d₆)δ-117.63,-123.48。Diastereomer 2. Peak 2. LC-MS calculated value for C₃₇ H₃₈ F₂ N₅ O₂ (M+H)⁺ : m/z=622.3; found value 622.2. 1H NMR (500 MHz, DMSO-d₆ ) δ 10.11 (s, 1H), 9.8 (s, 1H), 9.5 (s, 1H), 8.09 (s, 1H), 7.94 (dd, J=9.2, 5.8 Hz, 1H), 7.43-7.34 (m, 2H), 7.17 (d, J=2.4 Hz, 1H), 6.90 (s, 1H), 6.66 (s, 1H), 5.58 (dt, J=12.5, 6.3 Hz, 1H), 5.41-5.37 (m, 1H), 5.09-5.04 ( m,1H),3.89-3.80(m,2H),3.57-3.42(m,3H),3.24(m,1H)3.04(s,3H),2.97(s,2H),2.74-2.63(m,2H),2.55(s,3H),2.29(d,J＝8.6Hz,2H),1.90(q, J＝12.8,7.3Hz,3H), 1.61(d,J＝9.1Hz,1H), 1.49(d,J＝6.1Hz,3H).¹⁹ FNMR (471MHz, DMSO-d₆ ) δ -117.63, -123.48.

实施例23a和实施例23b.1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈Example 23a and Example 23b. 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile

步骤1. 2-氨基-4-溴-3-氟苯甲酸乙酯Step 1. Ethyl 2-amino-4-bromo-3-fluorobenzoate

向2-氨基-4-溴-3-氟苯甲酸(22.7g，92mmol)在乙醇(184mL)中的溶液中缓慢添加硫酸(9.82mL，184mmol)。将所得混合物加热至回流持续2天。冷却至室温后，将反应混合物用水稀释并且用6M NaOH(22mL)调节至pH 7。真空去除有机溶剂。用乙酸乙酯和水稀释所得混合物。将有机层用0.5N NaOH溶液、盐水洗涤，经Na₂SO₄干燥，过滤并且真空浓缩，得到所需产物(23.2g，96％)。LCMS计算值C₉H₁₀BrFNO₂(M+H)⁺m/z＝262.0,264.0；实验值262.0,264.0。To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (22.7 g, 92 mmol) in ethanol (184 mL) was slowly added sulfuric acid (9.82 mL, 184 mmol). The resulting mixture was heated to reflux for 2 days. After cooling to room temperature, the reaction mixture was diluted with water and adjusted to pH 7 with 6M NaOH (22 mL). The organic solvent was removed in vacuo. The resulting mixture was diluted with ethyl acetate and water. The organic layer was washed with 0.5N NaOH solution, brine, dried over Na₂ SO₄ , filtered and concentrated in vacuo to give the desired product (23.2 g, 96%). LCMS calculated for C₉ H₁₀ BrFNO₂ (M+H)⁺ m/z=262.0, 264.0; Found 262.0, 264.0.

步骤2. 2-氨基-3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯甲酸乙酯Step 2. Ethyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

在氮气氛围下将2-氨基-4-溴-3-氟苯甲酸乙酯(21.8g，83mmol)、双(频哪醇基)二硼(25.3g，100mmol)、二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)二氯甲烷加合物(6.79g，8.32mmol)和乙酸钾(17.96g，183mmol)于二噁烷(416ml)中的混合物在100℃搅拌5h。经由过滤粗混合物，并且用乙酸乙酯洗涤。浓缩滤液。通过快速色谱纯化残余物，得到所需产物(24g，93％)。LCMS计算值C₁₅H₂₂BFNO₄(M+H)⁺m/z＝310.2；实验值310.1。A mixture of ethyl 2-amino-4-bromo-3-fluorobenzoate (21.8 g, 83 mmol), bis(pinacolato)diboron (25.3 g, 100 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (6.79 g, 8.32 mmol) and potassium acetate (17.96 g, 183 mmol) in dioxane (416 ml) was stirred at 100° C. for 5 h under nitrogen atmosphere. The crude mixture was filtered and washed with ethyl acetate. The filtrate was_concentrated . The residue was purified by flash chromatography to give the desired product (₂₄ g, 93%). LCMS calculated for_C15H22BFNO4 (M+H)⁺ m/z = 310.2; found 310.1.

步骤3. 8-氰基异喹啉2-氧化物Step 3. 8-Cyanoisoquinoline 2-oxide

在0℃向异喹啉-8-甲腈(3.70g，24.00mmol)于CH₂Cl₂(240ml)中的溶液中添加m-CPBA(7.10g，28.8mmol)。在0℃搅拌反应混合物2h。用饱和NaHCO₃溶液稀释反应混合物。用DCM(3×)萃取水层。将合并的有机层经Na₂SO₄干燥，过滤并浓缩。通过快速色谱(用0至100％乙酸乙酯/己烷洗脱)纯化粗物质，得到所需产物(3.2g，78％)。LC-MS计算值C₁₀HN₂O(M)⁺:m/z＝170.1；实验值170.1。To a solution of isoquinoline-8-carbonitrile (3.70 g, 24.00 mmol) in CH₂ Cl₂ (240 ml) was added m-CPBA (7.10 g, 28.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with saturated NaHCO₃ solution. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried over Na₂ SO₄ , filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0 to 100% ethyl acetate/hexanes) to give the desired product (3.2 g, 78%). LC-MS calculated for C₁₀ HN₂ O (M)⁺ : m/z = 170.1; found 170.1.

步骤4. 1-氯异喹啉-8-甲腈Step 4. 1-Chloroisoquinoline-8-carbonitrile

向8-氰基异喹啉2-氧化物(5.30g，31.1mmol)和2,6-二甲基吡啶(7.26ml，62.3mmol)于CH₂Cl₂(62.3ml)中的溶液中添加POCl₃(5.81ml，62.3mmol)。在室温下搅拌反应混合物2h。通过添加饱和NaHCO₃(80mL)淬灭反应混合物。有机层经MgSO₄干燥并且浓缩，得到粗产物。用乙酸乙酯/己烷湿磨粗产物，得到呈白色固体的所需产物(4.0g，68％)。LC-MS计算值C₁₀H₆ClN₂(M+H)⁺:m/z＝189.0；实验值189.0。To a solution of 8-cyanoisoquinoline 2-oxide (5.30 g, 31.1 mmol) and 2,6-lutidine (7.26 ml, 62.3 mmol) in CH₂ Cl₂ (62.3 ml) was added POCl₃ (5.81 ml, 62.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated NaHCO₃ (80 mL). The organic layer was dried over MgSO₄ and concentrated to give the crude product. The crude product was triturated with ethyl acetate/hexanes to give the desired product (4.0 g, 68%) as a white solid. LC-MS calculated for C₁₀ H₆ ClN₂ (M+H)⁺ : m/z=189.0; found 189.0.

步骤5. 2-氨基-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯Step 5. Ethyl 2-amino-4-(8-cyanoisoquinolin-1-yl)-3-fluorobenzoate

将1-氯异喹啉-8-甲腈(6.60g，35.0mmol)、2-氨基-3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯甲酸乙酯(11.4g，36.7mmol)、SPhos Pd G4(1.39g，1.75mmol)和磷酸三钾水合物(17.7g，77mmol)在1,4-二噁烷(120mL)和水(24mL)中的混合物在80℃搅拌2h。用乙酸乙酯和水稀释溶液。浓缩有机层。粗物质不经纯化即用于下一步骤中。LC-MS计算值C₁₉H₁₅FN₃O₂(M+H)⁺:m/z＝336.1；实验值336.1。A mixture of 1-chloroisoquinoline-8-carbonitrile (6.60 g, 35.0 mmol), ethyl 2-amino-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (11.4 g, 36.7 mmol), SPhos Pd G4 (1.39 g, 1.75 mmol) and potassium phosphate tripotassium hydrate (17.7 g, 77 mmol) in 1,4-dioxane (120 mL) and water (24 mL) was stirred at 80° C. for 2 h. The solution was diluted with ethyl acetate and water. The organic layer was concentrated. The crude material was used in the next step without purification. LC-MS calculated for C₁₉ H₁₅ FN₃ O₂ (M+H)⁺ : m/z=336.1; found 336.1.

步骤6. 2-氨基-5-氯-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯Step 6. Ethyl 2-amino-5-chloro-4-(8-cyanoisoquinolin-1-yl)-3-fluorobenzoate

在室温下向2-氨基-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯(11.7g，34.9mmol)在DMF(116ml)中的溶液中添加NCS(5.12g，38.4mmol)。在80℃加热混合物15h。将反应混合物冷却至室温并且用水稀释。通过过滤收集沉淀物并且用水和乙酸乙酯/己烷(1:2)洗涤。用乙酸乙酯萃取滤液。浓缩有机层。通过过滤收集固体并且用乙酸乙酯/己烷(1:2)洗涤，得到所需产物(10.2g，79％)。LC-MS计算值C₁₉H₁₄ClFN₃O₂(M+H)⁺:m/z＝370.1；实验值370.1。To a solution of ethyl 2-amino-4-(8-cyanoisoquinolin-1-yl)-3-fluorobenzoate (11.7 g, 34.9 mmol) in DMF (116 ml) was added NCS (5.12 g, 38.4 mmol) at room temperature. The mixture was heated at 80°C for 15 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was collected by filtration and washed with water and ethyl acetate/hexane (1:2). The filtrate was extracted with ethyl acetate. The organic layer was concentrated. The solid was collected by filtration and washed with ethyl acetate/hexane (1:2) to give the desired product (10.2 g, 79%). LC-MS calculated for C₁₉ H₁₄ ClFN₃ O₂ (M+H)⁺ : m/z=370.1; found 370.1.

步骤7. 5-氯-4-(8-氰基异喹啉-1-基)-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟苯甲酸乙酯Step 7. Ethyl 5-chloro-4-(8-cyanoisoquinolin-1-yl)-2-(3-ethoxy-3-oxopropionylamino)-3-fluorobenzoate

在0℃向2-氨基-5-氯-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯(10.3g，27.9mmol)和TEA(5.05ml，36.2mmol)在DCM(280mL)中的溶液中逐滴添加3-氯-3-氧代丙酸乙酯(3.92ml，30.6mmol)。将所得混合物在0℃搅拌并且通过LC-MS监测。再逐滴添加一当量的3-氯-3-氧代丙酸乙酯(3.92ml，30.6mmol)并且搅拌1h。用水和DCM稀释反应物。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。通过快速色谱纯化残余物，得到所需产物(9.5g，70％)。LC-MS计算值C₂₄H₂₀ClFN₃O₅(M+H)⁺:m/z＝484.1；实验值484.1。To a solution of ethyl 2-amino-5-chloro-4-(8-cyanoisoquinolin-1-yl)-3-fluorobenzoate (10.3 g, 27.9 mmol) and TEA (5.05 ml, 36.2 mmol) in DCM (280 mL) was added ethyl 3-chloro-3-oxopropanoate (3.92 ml, 30.6 mmol) dropwise at 0°C. The resulting mixture was stirred at 0°C and monitored by LC-MS. One more equivalent of ethyl 3-chloro-3-oxopropanoate (3.92 ml, 30.6 mmol) was added dropwise and stirred for 1 h. The reaction was diluted with water and_DCM . The organic layer was separated and dried over_Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography to give the desired product (9.5 g, 70%). LC-MS calculated_{forC24H20ClFN3O5} (_M +H⁾⁺_: m/z = 484.1; found 484.1.

步骤8. 6-氯-7-(8-氰基异喹啉-1-基)-8-氟-2,4-二羟基喹啉-3-甲酸乙酯Step 8. Ethyl 6-chloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate

将乙醇钠(21％/EtOH，19.9ml，53.3mmol)的溶液逐滴添加至5-氯-4-(8-氰基异喹啉-1-基)-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟苯甲酸乙酯(8.6g，17.8mmol)于EtOH(80ml)中的溶液。在室温下搅拌所得混合物2h。向反应烧瓶中添加1N HCl以调节pH至3。在真空下去除溶剂。收集所得沉淀物并且用乙酸乙酯洗涤，得到呈白色固体的所需产物(7.4g，95％)。LC-MS计算值C₂₂H₁₄ClFN₃O₄(M+H)⁺:m/z＝438.1；实验值438.1。A solution of sodium ethoxide (21%/EtOH, 19.9 ml, 53.3 mmol) was added dropwise to a solution of ethyl 5-chloro-4-(8-cyanoisoquinolin-1-yl)-2-(3-ethoxy-3-oxopropionamido)-3-fluorobenzoate (8.6 g, 17.8 mmol) in EtOH (80 ml). The resulting mixture was stirred at room temperature for 2 h. 1 N HCl was added to the reaction flask to adjust the pH to 3. The solvent was removed under vacuum. The resulting precipitate was collected and washed with ethyl acetate to give the desired product (7.4 g, 95%) as a white solid. LC-MS calculated for C₂₂ H₁₄ ClFN₃ O₄ (M+H)⁺ : m/z=438.1; found 438.1.

步骤9. 2,4,6-三氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯Step 9. Ethyl 2,4,6-trichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoroquinoline-3-carboxylate

向反应烧瓶中添加6-氯-7-(8-氰基异喹啉-1-基)-8-氟-2,4-二羟基喹啉-3-甲酸乙酯(7.4g，16.9mmol)和POCl₃(31.5ml，338mmol)。在110℃搅拌所得混合物2h。通过与甲苯共沸(3次)去除POCl₃，并且用DCM和饱和NaHCO₃溶液稀释残余物。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。用乙酸乙酯/己烷(1:1)湿磨粗物质，得到呈白色固体的所需产物(7.24g，90％)。LC-MS计算值C₂₂H₁₂Cl₃FN₃O₂(M+H)⁺:m/z＝474.0,476.0；实验值474.0,476.0。To the reaction flask was added ethyl 6-chloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate (7.4 g, 16.9 mmol) and POCl₃ (31.5 ml, 338 mmol). The resulting mixture was stirred at 110° C. for 2 h. POCl₃ was removed by azeotroping with toluene (3 times), and the residue was diluted with DCM and saturated NaHCO₃ solution. The organic layer was separated and dried over Na₂ SO₄ , filtered and concentrated. The crude material was triturated with ethyl acetate/hexanes (1:1) to give the desired product (7.24 g, 90%) as a white solid. LC-MS calculated for C₂₂ H₁₂ Cl₃ FN₃ O₂ (M+H)⁺ : m/z=474.0, 476.0; found 474.0, 476.0.

步骤10. 4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯Step 10. 4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoroquinoline-3-carboxylic acid ethyl ester

向2,4,6-三氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯(7.24g，15.25mmol)在DMF(100ml)中的溶液中添加(2S,4S)-4-氨基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(中间体9，6.56g，18.30mmol)和DIEA(5.3ml，30.5mmol)。在65℃搅拌所得混合物过夜。用乙酸乙酯和水稀释反应混合物。将有机层用水和盐水洗涤，经Na₂SO₄干燥，过滤，并且浓缩。通过硅胶柱(用0至30％梯度的乙酸乙酯/己烷洗脱)纯化粗物质，得到呈淡黄色泡沫的所需产物(11.5g，95％)。LC-MS计算值C₄₀H₄₉Cl₂FN₅O₅Si(M+H)⁺:m/z＝796.3,798.3；实验值796.3,798.3。To a solution of ethyl 2,4,6-trichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoroquinoline-3-carboxylate (7.24 g, 15.25 mmol) in DMF (100 ml) was added tert-butyl (2S,4S)-4-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (Intermediate 9, 6.56 g, 18.30 mmol) and DIEA (5.3 ml, 30.5 mmol). The resulting mixture was stirred at 65 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and_brine , dried over_Na2S04 , filtered, and concentrated. The crude material was purified by silica gel column (eluted with a gradient of 0 to 30% ethyl acetate/hexanes) to give the desired product (11.5 g, 95%) as a light yellow foam. LC-MS calculated_{forC40H49Cl2FN5O5Si} (M+H)⁺ : m/z = 796.3_,798.3 ; found 796.3_, 798.3.

步骤11.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-(羟基甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 11. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)piperidine-1-carboxylate

在-78℃向4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯(2.45g，3.07mmol)于甲苯(30.7ml)中的溶液中添加含1.0M DIBAL-H的DCM(9.84ml，9.84mmol)。使所得混合物经2h时段升温至-20℃，用甲醇(1.3mL)淬灭。在≤10℃下将罗谢尔盐水溶液(由14.7g(6wt)罗谢尔盐和50mL水制备)添加至溶液中。在15至25℃剧烈搅拌两相混合物≥1h并且分离，得到有机层。经Na₂SO₄干燥有机层，过滤并浓缩。产物不经纯化即使用。LC-MS计算值C₃₈H₄₇Cl₂FN₅O₄Si(M+H)⁺:m/z＝754.3,756.3；实验值754.3,756.3。To a solution of ethyl 4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoroquinoline-3-carboxylate (2.45 g, 3.07 mmol) in toluene (30.7 ml) was added 1.0 M DIBAL-H in DCM (9.84 ml, 9.84 mmol) at -78°C. The resulting mixture was allowed to warm to -20°C over a period of 2 h and quenched with methanol (1.3 mL). An aqueous solution of Rochelle's salt (prepared from 14.7 g (6 wt) Rochelle's salt and 50 mL water) was added to the solution at ≤10°C. The biphasic mixture was stirred vigorously at 15 to 25°C for ≥1 h and separated to give an organic layer. The_organic layer_was dried over_Na2SO4 , filtered and concentrated. The product was used without purification. LC-MS_{calculatedforC38H47Cl2FN5O4Si} (M+H)⁺ : m/z = 754.3_, 756.3; found 754.3, 756.3.

步骤12.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-甲酰基喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 12. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-formylquinolin-4-yl)amino)piperidine-1-carboxylate

向(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-(羟基甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯(2.32g，3.07mmol)在DCM(23ml)和乙腈(7.7ml)中的溶液中添加乙酸(0.53ml，9.22mmol)和IBX(2.58g，9.22mmol)。在38℃搅拌所得混合物22h。过滤反应混合物并且用DCM洗涤。浓缩滤液并且通过硅胶柱(用0至20％梯度的乙酸乙酯/己烷洗脱)纯化，得到呈两个峰形式的所需产物。To a solution of tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)piperidine-1-carboxylate (2.32 g, 3.07 mmol) in DCM (23 ml) and acetonitrile (7.7 ml) was added acetic acid (0.53 ml, 9.22 mmol) and IBX (2.58 g, 9.22 mmol). The resulting mixture was stirred at 38 °C for 22 h. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated and purified by silica gel column (eluting with a gradient of 0 to 20% ethyl acetate/hexanes) to give the desired product as two peaks.

非对映异构体1(1.05g，45％)。峰1。LC-MS计算值C₃₈H₄₅Cl₂FN₅O₄Si(M+H)⁺:m/z＝752.3,754.3；实验值752.3,754.3。Diastereomer 1 (1.05 g, 45%). Peak 1. LC-MS calculated for C₃₈ H₄₅ Cl₂ FN₅ O₄ Si (M+H)⁺ : m/z = 752.3, 754.3; found 752.3, 754.3.

非对映异构体2(1.05g，45％)。峰2。LC-MS计算值C₃₈H₄₅Cl₂FN₅O₄Si(M+H)⁺:m/z＝752.3,754.3；实验值752.3,754.3。Diastereomer 2 (1.05 g, 45%). Peak 2. LC-MS calculated for C₃₈ H₄₅ Cl₂ FN₅ O₄ Si (M+H)⁺ : m/z = 752.3, 754.3; found 752.3, 754.3.

步骤13.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-((E)-(羟基亚氨基)甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 13. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-((E)-(hydroxyimino)methyl)quinolin-4-yl)amino)piperidine-1-carboxylate

向(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-甲酰基喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯(0.85g，1.13mmol)(来自步骤12的非对映异构体1)在DCM(11ml)和EtOH(11ml)中的混合物中添加羟胺盐酸盐(0.26g，3.73mmol)和吡啶(0.30ml，3.73mmol)。在40℃搅拌反应混合物16小时。真空蒸发溶剂。用DCM和水稀释残余物并且分离各层。用DCM萃取水层。将合并的有机层用CuSO₄水溶液、盐水洗涤，经MgSO₄干燥，过滤并且真空浓缩。通过硅胶柱色谱纯化残余物，得到所需产物(0.5g，57％)。LC-MS计算值C₃₈H₄₆Cl₂FN₆O₄Si(M+H)⁺:m/z＝767.3,769.3；实验值767.3,769.3。To a mixture of tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-formylquinolin-4-yl)amino)piperidine-1-carboxylate (0.85 g, 1.13 mmol) (Diastereomer 1 from Step 12) in DCM (11 ml) and EtOH (11 ml) was added hydroxylamine hydrochloride (0.26 g, 3.73 mmol) and pyridine (0.30 ml, 3.73 mmol). The reaction mixture was stirred at 40 °C for 16 hours. The solvent was evaporated in vacuo. The residue was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with aqueous_CuSO4 , brine, dried over_MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica_gel column chromatography to give the desired product (0.5_g , 57%). LC-MS Calcd_{.forC38H46Cl2FN6O4Si} (M+H)⁺ : m/z = 767.3, 769.3; Found 767.3, 769.3.

非对映异构体2以与非对映异构体1类似的方式使用来自最后一个步骤的峰2来制备。LC-MS计算值C₃₈H₄₆Cl₂FN₆O₄Si(M+H)⁺:m/z＝767.3,769.3；实验值767.3,769.3。Diastereomer 2_was prepared in an analogous manner to Diastereomer 1 using Peak 2 from the last step. LC-MS Calcd_{.forC38H46Cl2FN6O4Si} (M+H)⁺ : m/z = 767.3,_769.3 ; Found 767.3, 769.3.

步骤14.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(4,8-二氯-7-(8-氰基异喹啉-1-基)-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯Step 14. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,8-dichloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate

在0℃向(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-((E)-(羟基亚氨基)甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯(486mg，0.633mmol)(来自步骤13的非对映异构体1)于CH₂Cl₂(5mL)中的溶液中添加2-氨基吡啶(113mg，1.20mmol)和MsCl(84μl,1.08mmol)。在0℃搅拌所得混合物2小时，随后升温至室温过夜。用水稀释所得混合物。将有机层用盐水洗涤，经MgSO₄干燥，过滤并浓缩。残余物不经纯化即使用。LC-MS计算值C₃₈H₄₄Cl₂FN₆O₃Si(M+H)⁺:m/z＝749.3,751.3；实验值749.3,751.3。To a solution of tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-((E)-(hydroxyimino)methyl)quinolin-4-yl)amino)piperidine-1-carboxylate (486 mg, 0.633 mmol) (Diastereomer 1 from Step 13) in_CH2Cl2 (5 mL) was added₂ -aminopyridine (113 mg, 1.20 mmol) and MsCl (84 μl, 1.08 mmol) at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then warmed to room temperature overnight. The resulting mixture was diluted with water. The organic layer was washed with brine, dried over_MgSO4 , filtered and concentrated. The residue was used without purification. LC-MS calculated for C₃₈ H₄₄ Cl₂ FN₆ O₃ Si (M+H)⁺ : m/z = 749.3, 751.3; found 749.3, 751.3.

非对映异构体2以与非对映异构体1类似的方式使用来自步骤13的峰2来制备。LC-MS计算值C₃₈H₄₄Cl₂FN₆O₃Si(M+H)⁺:m/z＝749.3,751.3；实验值749.3,751.3。Diastereomer 2_was prepared in_an analogous manner to Diastereomer 1 using Peak 2 from Step 13. LC-MS Calcd_{.forC38H44Cl2FN6O3Si} (M+H)⁺ : m/z = 749.3, 751.3; Found 749.3, 751.3.

步骤15.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯Step 15. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate

将硫代甲醇钠(133mg，1.901mmol)添加至(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(4,8-二氯-7-(8-氰基异喹啉-1-基)-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯(475mg，0.634mmol)(来自最后一个步骤的非对映异构体1)在MeOH(6.3ml)/1,4-二噁烷(6.3ml)中的混合物，并且将反应混合物在90℃搅拌18h。用饱和NH₄Cl稀释混合物并且用EtOAc萃取。将合并的有机层经MgSO₄干燥，过滤，浓缩并且产物不经纯化即使用。LC-MS计算值C₃₉H₄₇ClFN₆O₃SSi(M+H)⁺:m/z＝761.3；实验值761.3。Sodium thiomethoxide (133 mg, 1.901 mmol) was added to a mixture of tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,8-dichloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate (475 mg, 0.634 mmol) (Diastereomer 1 from the last step) in MeOH (6.3 ml)/1,4-dioxane (6.3 ml) and the reaction mixture was stirred at 90° C. for 18 h. The mixture was diluted with saturated NH₄ Cl and extracted with EtOAc. The combined organic layers were dried over MgSO₄ , filtered, concentrated and the product was used without purification. LC-MS calculated for_{C39H47ClFN6O3SSi} (M+_H)+^: m/z = 761.3; found 761.3.

非对映异构体2以与非对映异构体1类似的方式使用来自最后一个步骤的峰2来制备。LC-MS计算值C₃₉H₄₇ClFN₆O₃SSi(M+H)⁺:m/z＝761.3,；实验值761.3。Diastereomer 2 was prepared in an analogous manner to diastereomer 1 using peak 2 from the last step. LC-MS calcd for C₃₉ H₄₇ ClFN₆ O₃ SSi (M+H)⁺ : m/z = 761.3,; found 761.3.

步骤16.(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯Step 16. tert-Butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate

向(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯(482mg，0.633mmol)(来自最后一个步骤的非对映异构体1)于THF(6.33ml)中的溶液中添加含1.0M TBAF的THF(633μl，0.63mmol)。在60℃搅拌所得混合物1h。在冷却至室温之后，用水和乙酸乙酯稀释反应混合物。分离有机层并且用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱纯化残余物，得到所需产物(0.39g，95％)。LC-MS计算值C₃₃H₃₃ClFN₆O₃S(M+H)⁺:m/z＝647.2；实验值647.2。To a solution of tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate (482 mg, 0.633 mmol) (diastereomer 1 from the last step) in THF (6.33 ml) was added 1.0 M TBAF in THF (633 μl, 0.63 mmol). The resulting mixture was stirred at 60° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried over Na₂ SO₄ , filtered and concentrated. The residue was purified by flash chromatography to give the desired product (0.39 g, 95%). LC-^{MS calcd for C33H33ClFN6O3S (M+H)+}_:m/z = 647.2; found 647.2.

非对映异构体2以与非对映异构体1类似的方式使用来自最后一个步骤的峰2来制备。LC-MS计算值C₃₃H₃₃ClFN₆O₃S(M+H)⁺:m/z＝647.2；实验值647.2。Diastereomer 2_was prepared in_an analogous manner to diastereomer 1 using peak 2 from the last step_. LC-MS calcd for_{C33H33ClFN6O3S} (M+H)⁺ : m/z = 647.2; found 647.2.

步骤17.(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 17. tert-Butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

向(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯(392mg，0.61mmol)在DCM(6.0ml)中的溶液中添加戴斯-马丁高碘烷(283mg，0.67mmol)。将所得混合物搅拌1h。向反应烧瓶中添加饱和NaHCO₃并且搅拌10min。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。将粗物质溶解于THF(20mL)中，接着向反应烧瓶中添加氢氧化铵(1.37ml，9.81mmol)，随后添加碘(157mg，0.618mmol)。在室温下搅拌所得混合物2h。用乙酸乙酯和饱和NaS₂O₃溶液稀释反应溶液。分离有机层并且用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱纯化残余物，得到所需产物(0.32g，82％)。LC-MS计算值C₃₃H₃₀ClFN₇O₂S(M+H)⁺:m/z＝642.2；实验值642.2。To a solution of tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate (392 mg, 0.61 mmol) in DCM (6.0 ml) was added Dess-Martin periodinane (283 mg, 0.67 mmol). The resulting mixture was stirred for 1 h. Saturated NaHCO₃ was added to the reaction flask and stirred for 10 min. The organic layer was separated and dried over Na₂ SO₄ , filtered and concentrated. The crude material was dissolved in THF (20 mL) and then ammonium hydroxide (1.37 ml, 9.81 mmol) was added to the reaction flask followed by iodine (157 mg, 0.618 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and_{saturatedNaS2O3} solution. The organic layer was separated and washed with_brine , dried over_Na2SO4 , filtered and concentrated. The residue_was purified by flash chromatography to give the desired product (_0.32 g, 82%). LC-MS calculated for_{C33H30ClFN7O2S} (M+_H )⁺ : m/z=642.2; found 642.2.

非对映异构体2以与非对映异构体1类似的方式使用来自最后一个步骤的峰2来制备。LC-MS计算值C₃₃H₃₀ClFN₇O₂S(M+H)⁺:m/z＝642.2；实验值642.2。Diastereomer_{2 was prepared in an analogous manner to diastereomer 1 using peak 2 from the last step. LC-MS calcd for C33H30ClFN7O2S(M} +_H )⁺ : m/z = 642.2; found 642.2.

步骤18. 1-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈Step 18. 1-(8-Chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile

在0℃将m-CPBA(77％，43.9mg，0.25mmol)添加至(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(142mg，0.22mmol)于CH₂Cl₂(2.2ml)中的溶液，并且接着将反应物在此温度下搅拌20min。通过添加饱和Na₂S₂O₃淬灭反应物。用乙酸乙酯稀释反应混合物，并且分离各层。将有机层用饱和NaHCO₃溶液、盐水洗涤，过滤并浓缩。粗物质直接用于下一步骤中。m-CPBA (77%, 43.9 mg, 0.25 mmol) was added to a solution of tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (142 mg, 0.22 mmol) in CH₂ Cl₂ (2.2 ml) at 0° C. and the reaction was then stirred at this temperature for 20 min. The reaction was quenched by the addition of saturated Na₂ S₂ O_3. The reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated NaHCO₃ solution, brine, filtered and concentrated. The crude material was used directly in the next step.

将LiHMDS(318μl，0.318mmol)添加至(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(41.0mg，0.32mmol)于THF(1mL)中的溶液中。在室温下搅拌所得混合物30min。将第一溶液添加至(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基亚磺酰基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(95mg，0.14mmol)于THF(2.0ml)中的溶液，并且接着将反应物在60℃搅拌2h。用乙酸乙酯和水稀释反应混合物。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。用1:1DCM/TFA(2mL)处理残余物1h。真空蒸发溶剂。通过制备型LCMS(XBridge C18柱，用一梯度的乙腈/水(含有0.1％TFA)洗脱，流速为60mL/min)纯化残余物，得到呈两个峰的所需产物(60mg，58％)。LC-MS计算值C₃₄H₃₃ClFN₈O(M+H)⁺:m/z＝623.2；实验值623.2。LiHMDS (318 μl, 0.318 mmol) was added to a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (41.0 mg, 0.32 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 30 min. The first solution was added to a solution of tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylsulfinyl)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (95 mg, 0.14 mmol) in THF (2.0 ml), and the reaction was then stirred at 60 °C for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and dried over Na₂ SO₄ , filtered and concentrated. The residue was treated with 1:1 DCM/TFA (2 mL) for 1 h. The solvent was evaporated in vacuo. The residue was purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired product (60 mg, 58%) as two peaks. LC-MS calculated for C₃₄ H₃₃ ClFN₈ O (M+H)⁺ : m/z=623.2; found 623.2.

非对映异构体2以与非对映异构体1类似的方式使用来自最后一个步骤的峰2来制备。LC-MS计算值C₃₄H₃₃ClFN₈O(M+H)⁺:m/z＝623.2；实验值623.2。Diastereomer 2 was prepared in an analogous manner to_diastereomer 1 using peak 2 from the last step. LC-MS calcd_{for C34H33ClFN8O(} M+H)⁺ : m/z = 623.2; found 623.2.

步骤19. 1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈Step 19. 1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile

向双(2,2,2-三氟乙酸)1-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈(7.0mg，8.2μmol)在DCM(1.0ml)中的溶液中添加乙酰氯(0.5M/DCM，19.7μl，9.87μmol)和DIPEA(5.8μl，33μmol)。在室温下搅拌所得混合物1h。真空去除溶剂。将残余物溶解于甲醇和1N HCl(0.1mL)中并且使用制备型LCMS(XBridge C18柱，用一梯度的乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到所需非对映异构体1。To a solution of bis(2,2,2-trifluoroacetic acid)1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile (7.0 mg, 8.2 μmol) in DCM (1.0 ml) was added acetyl chloride (0.5 M/DCM, 19.7 μl, 9.87 μmol) and DIPEA (5.8 μl, 33 μmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. The residue was dissolved in methanol and 1 N HCl (0.1 mL) and purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired diastereomer 1.

非对映异构体2以类似方式，使用双(2,2,2-三氟乙酸)1-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈(来自最后一个步骤的峰2)来合成。Diastereomer 2 was synthesized in a similar manner using bis(2,2,2-trifluoroacetic acid)1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile (peak 2 from the last step).

实施例23a。非对映异构体1。峰1。LCMS计算值C₃₆H₃₅ClFN₈O₂(M+H)⁺m/z＝665.3；实验值665.3。Example 23a. Diastereomer 1. Peak 1. LCMS calcd for C₃₆ H₃₅ ClFN₈ O₂ (M+H)⁺ m/z = 665.3; found 665.3.

实施例23b。非对映异构体2。峰2。LCMS计算值C₃₆H₃₅ClFN₈O₂(M+H)⁺m/z＝665.3；实验值665.3。Example 23b. Diastereomer 2. Peak 2. LCMS calcd for C₃₆ H₃₅ ClFN₈ O₂ (M+H)⁺ m/z = 665.3; found 665.3.

实施例24a和实施例24b.8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Example 24a and Example 24b. 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

步骤1：2-氨基-4-溴-5-氯-3-氟苯甲酸甲酯Step 1: Methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate

在室温下将硫酸(7.76ml，146mmol)缓慢添加至2-胺-4-溴-5-氯-3-氟苯甲酸(19.5g，72.8mmol)在MeOH(146ml)中的溶液中。将所得混合物加热至80℃过夜。随后将混合物冷却至室温并且缓慢倒入饱和NaHCO₃中。将混合物在室温下搅拌30min，随后用EtOAc萃取。有机层经MgSO₄干燥，过滤，浓缩，并且不经进一步纯化即用于下一步骤中。LC-MS计算值C₈H₇BrClFNO₂(M+H)⁺:m/z＝281.9,283.9；实验值281.9,283.9。Sulfuric acid (7.76 ml, 146 mmol) was slowly added to a solution of 2-amine-4-bromo-5-chloro-3-fluorobenzoic acid (19.5 g, 72.8 mmol) in MeOH (146 ml) at room temperature. The resulting mixture was heated to 80 °C overnight. The mixture was then cooled to room temperature and slowly poured into saturated NaHCO_3. The mixture was stirred at room temperature for 30 min and then extracted with EtOAc. The organic layer was dried over MgSO₄ , filtered, concentrated, and used in the next step without further purification. LC-MS calculated for C₈ H₇ BrClFNO₂ (M+H)⁺ : m/z=281.9, 283.9; Found 281.9, 283.9.

步骤2：7-溴-6-氯-8-氟-4-羟基-2-氧代-1,2-二氢喹啉-3-甲酸乙酯Step 2: 7-Bromo-6-chloro-8-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid ethyl ester

在室温下将3-氯-3-氧代丙酸乙酯(9.60ml，75.0mmol)逐滴添加至2-氨基-4-溴-5-氯-3-氟苯甲酸甲酯(19.25g，68.1mmol)和TEA(14.25ml，102mmol)在DCM(150mL)中的溶液中。在搅拌1h之后，再添加3-氯-3-氧代丙酸乙酯(1.745ml，13.63mmol)。在再搅拌1h之后，用水淬灭反应物，接着用乙酸乙酯萃取。有机层经干燥，过滤，随后浓缩。将浓缩残余物再溶解于EtOH(150ml)中并且添加含乙醇钠的乙醇(53.4ml，143mmol)。在室温下搅拌反应混合物1h。将反应混合物倒入水(1L)中并且酸化至pH约3。经由过滤收集所得沉淀物，得到所需产物(18.39g，74.0％)。LC-MS计算值C₁₂H₉BrClFNO₄(M+H)⁺:m/z＝363.9,365.9；实验值363.9,365.9。At room temperature, 3-chloro-3-oxopropionic acid ethyl ester (9.60ml, 75.0mmol) is added dropwise to a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid methyl ester (19.25g, 68.1mmol) and TEA (14.25ml, 102mmol) in DCM (150mL). After stirring for 1h, 3-chloro-3-oxopropionic acid ethyl ester (1.745ml, 13.63mmol) is added. After stirring for another 1h, the reactant is quenched with water and then extracted with ethyl acetate. The organic layer is dried, filtered, and then concentrated. The concentrated residue is redissolved in EtOH (150ml) and ethanol (53.4ml, 143mmol) containing sodium ethoxide is added. The reaction mixture is stirred at room temperature for 1h. The reaction mixture is poured into water (1L) and acidified to pH about 3. The resulting precipitate is collected via filtration to obtain the desired product (18.39g, 74.0%). LC-MS calculated for C₁₂ H₉ BrClFNO₄ (M+H)⁺ : m/z = 363.9, 365.9; found 363.9, 365.9.

步骤3：7-溴-2,4,6-三氯-8-氟喹啉3-甲酸乙酯Step 3: Ethyl 7-bromo-2,4,6-trichloro-8-fluoroquinoline 3-carboxylate

将7-溴-6-氯-8-氟-2,4-二羟基喹啉-3-甲酸乙酯(2.0g，5.49mmol)溶解于POCl₃(10.2ml，110mmol)中并且添加DIPEA(1.92ml，10.97mmol)。在100℃搅拌所得混合物2h。在冷却至室温之后，通过缓慢倒入至快速搅拌的冰水(约250mL)中来淬灭反应物，搅拌30min，接着经由过滤收集固体，得到呈棕色固体的所需产物(1.66g，75％)。LC-MS计算值C₁₂H₇BrCl₃FNO₂(M+H)⁺:m/z＝399.9,401.9,403.9；实验值399.9,401.9,403.9。Ethyl 7-bromo-6-chloro-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate (2.0 g, 5.49 mmol) was dissolved in POCl₃ (10.2 ml, 110 mmol) and DIPEA (1.92 ml, 10.97 mmol) was added. The resulting mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched by slowly pouring into rapidly stirred ice water (about 250 mL), stirred for 30 min, and then the solid was collected by filtration to give the desired product as a brown solid (1.66 g, 75%). LC-MS calculated for C₁₂ H₇ BrCl₃ FNO₂ (M+H)⁺ : m/z=399.9, 401.9, 403.9; Found 399.9, 401.9, 403.9.

步骤4. 7-溴-4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-8-氟喹啉-3-甲酸乙酯Step 4. 7-Bromo-4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-8-fluoroquinoline-3-carboxylic acid ethyl ester

向7-溴-2,4,6-三氯-8-氟喹啉-3-甲酸乙酯(8.7g，21.7mmol)在DMF(80ml)中的溶液中添加(2S,4S)-4-氨基-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(中间体9，9.33g，26.0mmol)和DIEA(7.6ml，43.3mmol)。在65℃搅拌所得混合物5h。冷却至室温后，添加乙酸乙酯和水。将有机层用水(2×)和盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱(用0％至25％乙酸乙酯/己烷洗脱)纯化残余物，得到呈泡沫的所需产物(14.6g，93％)。LC-MS计算值C₃₀H₄₄BrCl₂FN₃O₅Si(M+H)⁺:m/z＝722.2,724.2；实验值722.2,724.2。To a solution of ethyl 7-bromo-2,4,6-trichloro-8-fluoroquinoline-3-carboxylate (8.7 g, 21.7 mmol) in DMF (80 ml) was added tert-butyl (2S,4S)-4-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (Intermediate 9, 9.33 g, 26.0 mmol) and DIEA (7.6 ml, 43.3 mmol). The resulting mixture was stirred at 65 °C for 5 h. After cooling to room temperature, ethyl acetate and water were added. The organic layer was washed with water (2x) and_brine , dried over_Na2S04 , filtered and concentrated. The residue was purified by flash chromatography (eluting with 0% to 25% ethyl acetate/hexanes) to give the desired product as a foam (14.6 g, 93%). LC-MS calculated for C₃₀ H₄₄ BrCl₂ FN₃ O₅ Si (M+H)⁺ : m/z = 722.2, 724.2; found 722.2, 724.2.

步骤5.(2S,4S)-4-((7-溴-2,6-二氯-8-氟-3-(羟基甲基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 5. tert-Butyl (2S,4S)-4-((7-bromo-2,6-dichloro-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

在-78℃向7-溴-4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-8-氟喹啉-3-甲酸乙酯(14.6g，20.18mmol)于甲苯(200ml)中的溶液中添加含1.0MDIBAL-H的DCM(60.5ml，60.5mmol)。在-78℃搅拌所得混合物40min并且使其升温至0℃持续1.5h，并且用甲醇(6.8ml，167mmol)淬灭。在≤10℃下将罗谢尔盐水溶液(由88g(6wt)罗谢尔盐和200mL水制备)添加至溶液中。在15至25℃剧烈搅拌两相混合物≥1h并且分离，得到有机层。分离两相混合物。将有机层用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。按原样使用粗物质。LC-MS计算值C₂₈H₄₂BrCl₂FN₃O₄Si(M+H)⁺:m/z＝680.1,682.1；实验值680.1,682.1。To a solution of ethyl 7-bromo-4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-8-fluoroquinoline-3-carboxylate (14.6 g, 20.18 mmol) in toluene (200 ml) was added 1.0 M DIBAL-H in DCM (60.5 ml, 60.5 mmol) at -78°C. The resulting mixture was stirred at -78°C for 40 min and allowed to warm to 0°C for 1.5 h and quenched with methanol (6.8 ml, 167 mmol). An aqueous solution of Rochelle's salt (prepared from 88 g (6 wt) of Rochelle's salt and 200 mL of water) was added to the solution at ≤10°C. The biphasic mixture was stirred vigorously at 15 to 25°C for ≥1 h and separated to give an organic layer. The biphasic mixture was separated. The organic layer was washed with_brine , dried over_Na2SO4 , filtered and concentrated. The crude material was used as is. LC-MS Calcd_. for_{C28H42BrCl2FN3O4Si} (M+H)⁺ : m/z₌ 680.1_,682.1 ; Found 680.1, 682.1.

步骤6.(2S,4S)-4-((7-溴-2,6-二氯-8-氟-3-甲酰基喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 6. tert-Butyl (2S,4S)-4-((7-bromo-2,6-dichloro-8-fluoro-3-formylquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

向(2S,4S)-4-((7-溴-2,6-二氯-8-氟-3-(羟基甲基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(13.0g，19.07mmol)在DCM(150ml)和乙腈(50ml)中的溶液中添加IBX(16.02g，57.2mmol)和乙酸(3.28ml，57.2mmol)。在35℃搅拌所得反应混合物16h。过滤反应混合物并且浓缩滤液。用EtOAc湿磨所得残余物，经由过滤收集所得沉淀物，在真空下干燥，得到呈淡黄色固体的所需产物(9.4g，73％，经2个步骤)。LC-MS计算值C₂₈H₄₀BrCl₂FN₃O₄Si(M+H)⁺:m/z＝678.1,680.1；实验值678.1,680.1。To a solution of tert-butyl (2S,4S)-4-((7-bromo-2,6-dichloro-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (13.0 g, 19.07 mmol) in DCM (150 ml) and acetonitrile (50 ml) was added IBX (16.02 g, 57.2 mmol) and acetic acid (3.28 ml, 57.2 mmol). The resulting reaction mixture was stirred at 35 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was triturated with EtOAc and the resulting precipitate was collected by filtration and dried under vacuum to give the desired product as a light yellow solid (9.4 g, 73% over 2 steps). LC-MS calculated_{forC28H40BrCl2FN3O4Si} (M+H)⁺ : m/z = 678.1_,680.1 ; found 678.1_, 680.1.

步骤7.(2S,4S)-4-((7-溴-6-氯-8-氟-3-甲酰基-2-(甲基硫基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 7. tert-Butyl (2S,4S)-4-((7-bromo-6-chloro-8-fluoro-3-formyl-2-(methylthio)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

将硫代甲醇钠(0.947g，13.51mmol)添加至(2S,4S)-4-((7-溴-2,6-二氯-8-氟-3-甲酰基喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(3.06g，4.50mmol)在MeOH(45.0ml)/DCM(45.0ml)中的混合物中，并且接着在室温下搅拌1h。用饱和NH₄Cl稀释混合物并且用EtOAc萃取。合并的有机层经MgSO₄干燥，过滤，浓缩，并且通过硅胶柱(用0至15％梯度的己烷/EtOAc洗脱)来纯化残余物，得到呈白色固体的所需产物(3.05g，98％)。LC-MS计算值C₂₉H₄₃BrClFN₃O₄SSi(M+H)⁺:m/z＝690.2,692.2；实验值690.2,692.2。Sodium thiomethoxide (0.947 g, 13.51 mmol) was added to a mixture of tert-butyl (2S,4S)-4-((7-bromo-2,6-dichloro-8-fluoro-3-formylquinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (3.06 g, 4.50 mmol) in MeOH (45.0 ml)/DCM (45.0 ml) and then stirred at room temperature for 1 h. The mixture was diluted with saturated_NH4Cl and extracted with EtOAc. The combined organic layers were dried over_MgSO4 , filtered, concentrated, and the residue was purified by silica gel column (eluting with a gradient of 0 to 15% hexanes/EtOAc) to give the desired product (3.05 g, 98%) as a white solid. LC-MS calculated for_{C29H43BrClFN3O4SSi} (M+H)₊^: m/z = 690.2_,692.2 ; found 690.2, 692.2.

步骤8.(2S,4S)-4-((7-溴-6-氯-8-氟-3-((E)-2-甲氧基乙烯基)-2-(甲基硫基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯Step 8. tert-Butyl (2S,4S)-4-((7-bromo-6-chloro-8-fluoro-3-((E)-2-methoxyvinyl)-2-(methylthio)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate

在室温下在氮气氛围下向(甲氧基甲基)氯化三苯基鏻(451mg，1.32mmol)于甲苯(3mL)中的溶液中添加叔丁醇钾(1M/THF，1.5mL，1.5mmol)。在搅拌30分钟之后，将(2S,4S)-4-((7-溴-6-氯-8-氟-3-甲酰基-2-(甲基硫基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(350mg，0.506mmol)于THF(1.0mL)中的溶液插管至反应烧瓶中。在室温下搅拌所得溶液1h。用1N HCl淬灭反应物并且用乙酸乙酯稀释。用乙酸乙酯萃取水层一次。将合并的有机溶液用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过硅胶色谱(用0至20％梯度的乙酸乙酯/己烷洗脱)纯化残余物，得到所需产物(0.32g，88％)。LC-MS计算值C₃₁H₄₇BrClFN₃O₄SSi(M+H)⁺:m/z＝718.2,720.2；实验值718.3,720.3。Potassium tert-butoxide (1M/THF, 1.5 mL, 1.5 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium chloride (451 mg, 1.32 mmol) in toluene (3 mL) at room temperature under nitrogen atmosphere. After stirring for 30 minutes, a solution of (2S, 4S)-tert-butyl 4-((7-bromo-6-chloro-8-fluoro-3-formyl-2-(methylthio)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (350 mg, 0.506 mmol) in THF (1.0 mL) was cannulated into a reaction flask. The resulting solution was stirred at room temperature for 1 h. The reactant was quenched with 1N HCl and diluted with ethyl acetate. The aqueous layer was extracted once with ethyl acetate. The combined organic solution was washed with brine, dried over Na₂ SO₄ , filtered and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of 0 to 20% ethyl acetate in hexanes) to give the desired product (0.32 g,₈₈ %). LC-MS Calcd_. for_{C31H47BrClFN3O4SSi} (M+H)⁺ : m/z = 718.2_, 720.2; Found 718.3, 720.3.

步骤9.(2S,4S)-4-(7-溴-8-氯-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯Step 9. tert-Butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate

向烧瓶中添加(2S,4S)-4-((7-溴-6-氯-8-氟-3-((E)-2-甲氧基乙烯基)-2-(甲基硫基)喹啉-4-基)氨基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-1-甲酸叔丁酯(320mg，0.445mmol)、含4.0M HCl的二噁烷(2.25ml，8.90mmol)和乙醇(3.0ml)。在70℃搅拌反应混合物1h。真空去除溶剂。将残余物溶解于甲醇中。添加Boc-酐(155μl，0.667mmol)和TEA(248μl，1.780mmol)，并且搅拌反应混合物2h。去除溶剂并且通过硅胶柱色谱纯化粗产物，得到所需产物(198mg，78％)。LC-MS计算值C₂₄H₂₉BrClFN₃O₃S(M+H)⁺:m/z＝572.1,574.1；实验值572.1,574.1。To a flask was added tert-butyl (2S,4S)-4-((7-bromo-6-chloro-8-fluoro-3-((E)-2-methoxyvinyl)-2-(methylthio)quinolin-4-yl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-1-carboxylate (320 mg, 0.445 mmol), 4.0 M HCl in dioxane (2.25 ml, 8.90 mmol) and ethanol (3.0 ml). The reaction mixture was stirred at 70° C. for 1 h. The solvent was removed in vacuo. The residue was dissolved in methanol. Boc-anhydride (155 μl, 0.667 mmol) and TEA (248 μl, 1.780 mmol) were added and the reaction mixture was stirred for 2 h. The solvent was removed and the crude product was purified by silica gel column chromatography to give the desired product (198 mg, 78%). LC-MS calculated for C₂₄ H₂₉ BrClFN₃ O₃ S (M+H)⁺ : m/z = 572.1, 574.1; found 572.1, 574.1.

步骤10.(2S,4S)-4-(7-溴-8-氯-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 10. Tert-butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

向(2S,4S)-4-(7-溴-8-氯-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯(215mg，0.375mmol)于CH₂Cl₂(3.8ml)中的溶液中添加戴斯-马丁高碘烷(175mg，0.413mmol)。将所得混合物搅拌1h。向反应烧瓶中添加饱和NaHCO₃并且搅拌10min。分离有机层，并且经Na₂SO₄干燥，过滤并浓缩。将粗物质溶解于THF(4mL)中，向反应烧瓶中添加氢氧化铵(845μl，6.08mmol)，随后添加碘(97mg，0.383mmol)。在室温下搅拌所得混合物3h。用乙酸乙酯和饱和NaS₂O₃溶液稀释反应溶液。分离有机层并且用盐水洗涤，经Na₂SO₄干燥，过滤并浓缩。通过快速色谱纯化残余物，得到所需产物(0.19g，89％)。LC-MS计算值C₂₄H₂₆BrClFN₄O₂S(M+H)⁺:m/z＝567.1,569.1；实验值567.1,569.1。To a solution of tert-butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate (215 mg, 0.375 mmol) in CH₂ Cl₂ (3.8 ml) was added Dess-Martin periodinane (175 mg, 0.413 mmol). The resulting mixture was stirred for 1 h. Saturated NaHCO₃ was added to the reaction flask and stirred for 10 min. The organic layer was separated and dried over Na₂ SO₄ , filtered and concentrated. The crude material was dissolved in THF (4 mL), and ammonium hydroxide (845 μl, 6.08 mmol) was added to the reaction flask followed by iodine (97 mg, 0.383 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was diluted with ethyl acetate and saturated NaS₂ O₃ solution. The organic layer was separated and washed with_brine , dried over_Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography to give the desired product (0.19_g , 89%). LC-MS Calcd_. for_{C24H26BrClFN4O2S} (M+H)⁺ : m/z = 567.1_, 569.1; Found 567.1, 569.1.

步骤11.(2S,4S)-4-(7-溴-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 11. tert-Butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

在0℃将m-CPBA(68.1mg，0.395mmol)添加至(2S,4S)-4-(7-溴-8-氯-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(195mg，0.343mmol)于CH₂Cl₂(3.4ml)中的溶液，并且接着将反应物在此温度下搅拌20min。通过添加饱和Na₂S₂O₃溶液淬灭反应物，将其用乙酸乙酯稀释并且用饱和NaHCO₃、盐水洗涤，过滤，干燥并浓缩，并且将粗物质直接用于下一步骤中。m-CPBA (68.1 mg, 0.395 mmol) was added to a solution of tert-butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-(methylsulfanyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (195 mg, 0.343 mmol) in CH₂ Cl₂ (3.4 ml) at 0° C., and the reaction was then stirred at this temperature for 20 min. The reaction was quenched by the addition of saturated Na₂ S₂ O₃ solution, diluted with ethyl acetate and washed with saturated NaHCO₃ , brine, filtered, dried and concentrated, and the crude material was used directly in the next step.

将LiHMDS(776μl，0.776mmol)添加至(S)-1-((S)-1-甲基吡咯烷-2-基)乙-1-醇(100mg，0.776mmol)于THF(1mL)中的溶液中。在室温下搅拌所得混合物30min。将第一溶液添加至(2S,4S)-4-(7-溴-8-氯-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(206mg，0.353mmol)于THF(2.0ml)中的溶液，并且接着将反应物在60℃搅拌2h。用乙酸乙酯和水稀释反应混合物。经Na₂SO₄干燥有机层，过滤并浓缩。通过硅胶柱纯化残余物，得到所需产物(131mg，57％)。LCMS计算值C₃₀H₃₇BrClFN₅O₃(M+H)⁺m/z＝648.2,650.2；实验值648.2,650.2。LiHMDS (776 μl, 0.776 mmol) was added to a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (100 mg, 0.776 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 30 min. The first solution was added to a solution of (2S, 4S)-4-(7-bromo-8-chloro-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.353 mmol) in THF (2.0 ml), and the reactant was then stirred at 60 ° C for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was dried over Na₂ SO₄ , filtered and concentrated. The residue was purified by silica gel column to give the desired product (131 mg, 57%). LCMS calcd for_{C30H37BrClFN5O3} (M+H)⁺ m/z = 648.2_,650.2 ; found 648.2_, 650.2.

步骤12. 8-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Step 12. 8-(8-Chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

向微波小瓶中装入(2S,4S)-4-(7-溴-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯(99mg，0.153mmol)、8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1-萘甲腈(42.6mg，0.153mmol)、甲磺酸根基(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯)(2'-甲基氨基-1,1'-联苯-2-基)钯(II)二氯甲烷加合物(12.1mg，0.015mmol)、磷酸钾(64.8mg，0.305mmol)和1,4-二噁烷(1.4ml)/水(0.14ml)。用N₂吹扫反应混合物并且在75℃加热2h。用乙酸乙酯和水稀释反应混合物。将有机层分离，经Na₂SO₄干燥，过滤并浓缩。将所得残余物溶解于DCM(1ml)和TFA(1ml)中。在搅拌1h之后，真空去除溶剂，通过制备型LCMS(XBridge C18柱，用一梯度的乙腈/水(含有0.1％TFA)洗脱，流速为60mL/min)纯化残余物，得到呈两个峰的所需产物(30mg，32％)。A microwave vial was charged with tert-butyl (2S,4S)-4-(7-bromo-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate (99 mg, 0.153 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- Naphthonitrile (42.6 mg, 0.153 mmol), mesylate (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium (II) dichloromethane adduct (12.1 mg, 0.015 mmol), potassium phosphate (64.8 mg, 0.305 mmol) and 1,4-dioxane (1.4 ml)/water (0.14 ml). The reaction mixture was purged with_N2 and heated at 75°C for 2 h. The reaction mixture was diluted with ethyl_acetate and water. The organic layer was separated, dried over_Na2SO4 , filtered and concentrated. The resulting residue was dissolved in DCM (1 ml) and TFA (1 ml). After stirring for 1 h, the solvent was removed in vacuo and the residue was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired product as two peaks (30 mg, 32%).

非对映异构体1。峰1。LC-MS计算值C₃₆H₃₅ClFN₆O(M+H)⁺:m/z＝621.3；实验值621.3Diastereomer 1. Peak 1. LC-MS calculated value C₃₆ H₃₅ ClFN₆ O (M+H)⁺ : m/z = 621.3; found value 621.3

非对映异构体2。峰2。LC-MS计算值C₃₆H₃₅ClFN₆O(M+H)⁺:m/z＝621.3；实验值621.3Diastereomer 2. Peak 2. LC-MS calculated for C₃₆ H₃₅ ClFN₆ O (M+H)⁺ : m/z = 621.3; found 621.3

步骤13. 8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈Step 13. 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile

向双(2,2,2-三氟乙酸)8-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈(10.0mg，12μmol)在DMF(1.0ml)中的溶液中添加含1.0M乙酰氯的DCM(14.1μl，0.014mmol)和DIPEA(8.2μl，0.047mmol)。在室温下搅拌所得混合物1h。将反应物用甲醇和1N HCl(0.1mL)稀释并且使用制备型LCMS(XBridge C18柱，用一梯度的乙腈/水(含有0.1％TFA)洗脱，流速为60mL/min)纯化残余物，得到所需非对映异构体1。To a solution of bis(2,2,2-trifluoroacetic acid)8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile (10.0 mg, 12 μmol) in DMF (1.0 ml) was added 1.0 M acetyl chloride in DCM (14.1 μl, 0.014 mmol) and DIPEA (8.2 μl, 0.047 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with methanol and 1 N HCl (0.1 mL) and the residue was purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired diastereomer 1.

非对映异构体2以类似方式，使用双(2,2,2-三氟乙酸)8-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈(来自最后一个步骤的峰2)来合成。Diastereomer 2 was synthesized in a similar manner using bis(2,2,2-trifluoroacetic acid)8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile (peak 2 from the last step).

实施例24a。非对映异构体1。峰1。LCMS计算值C₃₈H₃₇ClFN₆O₂(M+H)⁺m/z＝663.3；实验值663.3。Example 24a. Diastereomer 1. Peak 1. LCMS calcd for C₃₈ H₃₇ ClFN₆ O₂ (M+H)⁺ m/z = 663.3; found 663.3.

实施例24b。非对映异构体2。峰2。LCMS计算值C₃₈H₃₇ClFN₆O₂(M+H)⁺m/z＝663.3；实验值663.3。Example 24b. Diastereomer 2. Peak 2. LCMS calcd for C₃₈ H₃₇ ClFN₆ O₂ (M+H)⁺ m/z = 663.3; found 663.3.

实施例25. 8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈Example 25. 8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile

步骤1. 2-氨基-4-(8-氰基萘-1-基)-3-氟苯甲酸乙酯Step 1. Ethyl 2-amino-4-(8-cyanonaphthalen-1-yl)-3-fluorobenzoate

标题化合物根据针对实施例23a和23b所描述的程序，在步骤5中利用8-溴-1-萘甲腈代替1-氯异喹啉-8-甲腈来合成。LCMS计算值C₂₀H₁₆FN₂O₂(M+H)⁺m/z＝335.1；实验值335.1。The title compound was synthesized according to the procedure described for Examples 23a and 23b, utilizing 8-bromo-1-naphthocarbonitrile instead of 1-_{chloroisoquinoline} -₈ -carbonitrile in step 5. LCMS calcd for_C20H16FN2O2 (M+H)⁺ m/_z = 335.1; found 335.1.

步骤2. 2-氨基-5-氯-4-(8-氰基萘-1-基)-3-氟苯甲酸乙酯Step 2. Ethyl 2-amino-5-chloro-4-(8-cyanonaphthalen-1-yl)-3-fluorobenzoate

标题化合物针对实施例23a和23b所描述的程序，在步骤6中利用2-氨基-4-(8-氰基萘-1-基)-3-氟苯甲酸乙酯代替2-氨基-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯来合成。LCMS计算值C₂₀H₁₅ClFN₂O₂(M+H)⁺m/z＝369.1；实验值369.1。The title compound was synthesized following the procedures described for Examples 23a and 23b utilizing ethyl 2-amino-4-(8-cyanonaphthalen-1-yl)-3-fluorobenzoate instead of ethyl 2-amino-4-(8-cyanoisoquinolin_-1 -yl)_-3 -fluorobenzoate in step 6. LCMS calcd for_{C20H15ClFN2O2} (M+H)⁺ m/z = 369.1; found 369.1.

步骤3. 5-氯-4-(8-氰基萘-1-基)-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟苯甲酸乙酯Step 3. Ethyl 5-chloro-4-(8-cyanonaphthalen-1-yl)-2-(3-ethoxy-3-oxopropionylamino)-3-fluorobenzoate

此化合物根据实施例23a和23b中所描述的程序，在步骤7中用2-氨基-5-氯-4-(8-氰基萘-1-基)-3-氟苯甲酸乙酯替代2-氨基-5-氯-4-(8-氰基异喹啉-1-基)-3-氟苯甲酸乙酯来制备。LC-MS计算值C₂₅H₂₁ClFN₂O₅(M+H)⁺:m/z＝483.1；实验值483.1。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting ethyl 2-amino-5-chloro-4-(8-cyanonaphthalen-1-yl)-3-fluorobenzoate for ethyl 2-amino-5-chloro-4-(8-_{cyanoisoquinolin-1-yl)-3-fluorobenzoate in step 7. LC-MS calculated for C25H21ClFN2O5(M+} H)⁺ : m/z=483.1; found 483.1.

步骤4. 6-氯-7-(8-氰基萘-1-基)-8-氟-2,4-二羟基喹啉-3-甲酸乙酯Step 4. Ethyl 6-chloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤8中用5-氯-4-(8-氰基萘-1-基)-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟苯甲酸乙酯替代5-氯-4-(8-氰基异喹啉-1-基)-2-(3-乙氧基-3-氧代丙酰氨基)-3-氟苯甲酸乙酯来制备。LC-MS计算值C₂₃H₁₅ClFN₂O₄(M+H)⁺:m/z＝437.1；实验值437.1。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting ethyl 5-chloro-4-(8-cyanonaphthalen-1-yl)-2-(3-ethoxy-3-oxopropionylamino)-3-fluorobenzoate for ethyl 5-chloro-4-(8-_{cyanoisoquinolin-1-yl)-2-(3-ethoxy-3-oxopropionylamino)-3-fluorobenzoate in step 8. LC-MS calculated for C23H15ClFN2O4(M+} H)⁺ : m/z=437.1; found 437.1.

步骤5. 2,4,6-三氯-7-(8-氰基萘-1-基)-8-氟喹啉-3-甲酸乙酯Step 5. Ethyl 2,4,6-trichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoroquinoline-3-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤9中用6-氯-7-(8-氰基萘-1-基)-8-氟-2,4-二羟基喹啉-3-甲酸乙酯替代6-氯-7-(8-氰基异喹啉-1-基)-8-氟-2,4-二羟基喹啉-3-甲酸乙酯来制备。LC-MS计算值C₂₃H₁₃Cl₃FN₂O₂(M+H)⁺:m/z＝473.0,475.0；实验值473.1,475.1。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting ethyl 6-chloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate for ethyl 6-chloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-2,4-dihydroxyquinoline-3-carboxylate in step 9. LC-MS calculated for C₂₃ H₁₃ Cl₃ FN₂ O₂ (M+H)⁺ : m/z = 473.0, 475.0; found 473.1, 475.1.

步骤6. 4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-7-(8-氰基萘-1-基)-8-氟喹啉-3-甲酸乙酯Step 6. Ethyl 4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoroquinoline-3-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤10中用2,4,6-三氯-7-(8-氰基萘-1-基)-8-氟喹啉-3-甲酸乙酯替代2,4,6-三氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯来制备。LC-MS计算值C₄₁H₅₀Cl₂FN₄O₅Si(M+H)⁺:m/z＝795.3,797.3；实验值795.5,797.5。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting ethyl 2,4,6-trichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoroquinoline-3-carboxylate for ethyl 2,4,6_- trichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoroquinoline-₃ -carboxylate in step 10. LC-MS calculated for_{C41H50Cl2FN4O5Si} (M+H)⁺ : m/z=795.3_,797.3 ; found 795.5, 797.5.

步骤7.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-(羟基甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 7. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤11中用4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-7-(8-氰基萘-1-基)-8-氟喹啉-3-甲酸乙酯替代4-(((2S,4S)-1-(叔丁氧基羰基)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)哌啶-4-基)氨基)-2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟喹啉-3-甲酸乙酯来制备。LC-MS计算值C₃₉H₄₈Cl₂FN₄O₄Si(M+H)⁺:m/z＝753.3,755.3；实验值753.4,755.5。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting ethyl 4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoroquinoline-3-carboxylate for ethyl 4-(((2S,4S)-1-(tert-butoxycarbonyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-4-yl)amino)-2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoroquinoline-3-carboxylate in step 11. LC-MS calculated for C₃₉ H₄₈ Cl₂ FN₄ O₄ Si (M+H)⁺ : m/z = 753.3, 755.3; found 753.4, 755.5.

步骤8.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-甲酰基喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 8. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-formylquinolin-4-yl)amino)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤12中用(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-(羟基甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯替代(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-(羟基甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₉H₄₆Cl₂FN₄O₄Si(M+H)⁺:m/z＝751.3,753.3；实验值751.4,753.4。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)piperidine-1-carboxylate for tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-(hydroxymethyl)quinolin-4-yl)amino)piperidine-1-carboxylate in step 12. LC-MS calculated_{forC39H46Cl2FN4O4Si} (M+H)⁺ : m/z = 751.3,_753.3 ; found_751.4, 753.4.

步骤9.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-((E)-(羟基亚氨基)甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯Step 9. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-((E)-(hydroxyimino)methyl)quinolin-4-yl)amino)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤13中用(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-甲酰基喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯替代(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-甲酰基喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₉H₄₇Cl₂FN₅O₄Si(M+H)⁺:m/z＝766.3,768.3；实验值766.4,768.4。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-formylquinolin-4-yl)amino)piperidine-1-carboxylate for tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-formylquinolin-4-yl)amino)piperidine-1-carboxylate in step 13. LC-MS calculated for C₃₉ H₄₇ Cl₂ FN₅ O₄ Si (M+H)⁺ : m/z = 766.3, 768.3; found 766.4, 768.4.

步骤10.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(4,8-二氯-7-(8-氰基萘-1-基)-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯Step 10. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,8-dichloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤14中用(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基萘-1-基)-8-氟-3-((E)-(羟基亚氨基)甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯替代(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-((2,6-二氯-7-(8-氰基异喹啉-1-基)-8-氟-3-((E)-(羟基亚氨基)甲基)喹啉-4-基)氨基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₉H₄₅Cl₂FN₅O₃Si(M+H)⁺:m/z＝748.3,750.3；实验值748.4,750.4。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanonaphthalen-1-yl)-8-fluoro-3-((E)-(hydroxyimino)methyl)quinolin-4-yl)amino)piperidine-1-carboxylate for tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((2,6-dichloro-7-(8-cyanoisoquinolin-1-yl)-8-fluoro-3-((E)-(hydroxyimino)methyl)quinolin-4-yl)amino)piperidine-1-carboxylate in Step 14. LC-MS calculated for C₃₉ H₄₅ Cl₂ FN₅ O₃ Si (M+H)⁺ : m/z = 748.3, 750.3; found 748.4, 750.4.

步骤11.(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯Step 11. tert-Butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤15中用(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(4,8-二氯-7-(8-氰基萘-1-基)-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯替代(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(4,8-二氯-7-(8-氰基异喹啉-1-基)-6-氟-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₄₀H₄₈ClFN₅O₃SSi(M+H)⁺:m/z＝760.3；实验值760.3。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,8-dichloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate for tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,8-dichloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate in Step 15. LC-MS calculated_{forC40H48ClFN5O3SSi} (M+_H)⁺ : m/z = 760.3; found 760.3.

步骤12.(2S,4S)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯Step 12. Tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤16中用(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯替代(2S,4S)-2-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₄H₃₄ClFN₅O₃S(M+H)⁺:m/z＝646.2；实验值646.2。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate for tert-butyl (2S,4S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)piperidine-1-carboxylate in Step 16. LC-^{MS calcd for C34H34ClFN5O3S (M+H)+}_:m/z = 646.2; found 646.2.

步骤13.(2S,4S)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯Step 13. Tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate

此化合物根据实施例23a和23b中所描述的程序，在步骤17中用(2S,4S)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯替代(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(2-羟基乙基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₄H₃₁ClFN₆O₂S(M+H)⁺:m/z＝641.2；实验值641.2。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting (2S,4S)-tert-butyl 4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)piperidine-1-carboxylate for tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(2-hydroxyethyl)_piperidine -_1- carboxylate in step 17. LC-MS calculated for_{C34H31ClFN6O2S} (M+H)⁺ : m/z=641.2; found 641.2.

步骤14. 8-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈Step 14. 8-(8-Chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile

此化合物根据实施例23a和23b中所描述的程序，在步骤18中用(2S,4S)-4-(8-氯-7-(8-氰基萘-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯替代(2S,4S)-4-(8-氯-7-(8-氰基异喹啉-1-基)-6-氟-4-(甲基硫基)-1H-吡唑并[4,3-c]喹啉-1-基)-2-(氰基甲基)哌啶-1-甲酸叔丁酯来制备。LC-MS计算值C₃₅H₃₄ClFN₇O(M+H)⁺:m/z＝622.2；实验值622.2。This compound was prepared according to the procedures described in Examples 23a and 23b, substituting (2S,4S)-tert-butyl 4-(8-chloro-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-1-yl)-2-(cyanomethyl)piperidine-1-carboxylate for tert-butyl (2S,4S)-4-(8-chloro-7-(8-cyanoisoquinolin-1-yl)-6-fluoro-4-(methylthio)-1H-pyrazolo[4,3-c]quinolin-_{1-yl)-2-(cyanomethyl)piperidine-1-carboxylate in step 18. LC-MS calculated for C35H34ClFN7O(M} +H)⁺ : m/z=622.2; found 622.2.

步骤15. 8-(1-((2S,4S)-1-乙酰基-2-(氰基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈Step 15. 8-(1-((2S,4S)-1-acetyl-2-(cyano)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile

标题化合物根据针对实施例23a和23b中所描述的程序，在步骤19中用双(2,2,2-三氟乙酸)8-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈替代双(2,2,2-三氟乙酸)1-(8-氯-1-((2S,4S)-2-(氰基甲基)哌啶-4-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈来合成。The title compound was synthesized according to the procedure described for Examples 23a and 23b, substituting bis(2,2,2-trifluoroacetic acid)8-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile for bis(2,2,2-trifluoroacetic acid)1-(8-chloro-1-((2S,4S)-2-(cyanomethyl)piperidin-4-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile in step 19.

LCMS计算值C₃₇H₃₆ClFN₇O₂(M+H)⁺m/z＝664.3实验值664.3.¹H NMR(500MHz,DMSO,旋转异构体的混合物)δ9.79(s,1H),8.54-8.49(m,3H),8.34(d,J＝8.1Hz,1H),8.16(d,J＝7.1Hz,1H),7.88(t,J＝7.7Hz,1H),7.81-7.70(m,2H),5.81-5.73(m,1H),5.49(m,1H),5.20(m,0.5H),4.67(m,1H),4.03(d,J＝14.0Hz,0.5H),3.87-3.81(m,1H),3.69-3.60(m,2H),3.58-3.52(m,1H),3.27-3.07(m,5H),2.36-2.04(m,9H),1.91(m,2H),1.53(d,J＝6.0Hz,3H)。LCMS calculated value for C₃₇ H₃₆ ClFN₇ O₂ (M+H)⁺ m/z＝664.3 Found value 664.3.¹ H NMR (500 MHz, DMSO, mixture of rotamers) δ9.79 (s, 1H), 8.54-8.49 (m, 3H), 8.34 (d, J＝8.1 Hz, 1H), 8.16 (d, J＝7.1 Hz, 1H), 7.88 (t, J＝7.7 Hz, 1H), 7.81-7.70 (m, 2H), 5.81-5.73 (m, 1H), 5.49 (m, 1H), 5.5 .20(m,0.5H),4.67(m,1H),4.03(d,J＝14.0Hz,0.5H),3.87-3.81(m,1H),3.69-3.60(m,2H),3.58-3.52(m,1H),3.27-3.07(m,5H),2.36-2.04(m,9 H), 1.91 (m, 2H), 1.53 (d, J = 6.0Hz, 3H).

实施例26：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 26: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)萘-2-醇(10.5mg，34μmol，如实施例22中所描述来制备)、Pd(PPh₃)₄(2.0mg，1.7μmol)和碳酸钠(9.1mg，86μmol)的混合物中添加(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(10mg，17μmol，实施例1，步骤5)于二噁烷(1ml)中的溶液。添加水(0.3ml)，并且将反应混合物用N₂充气并且加热至100℃持续1h。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(3mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₂H₂₆F₂N₇O⁺(M+H)⁺:m/z＝562.2；实验值562.6。¹H NMR(600MHz,DMSO-d₆)δ9.54(s,1H),8.46(s,1H),8.25(s,1H),7.97(dd,J＝9.2,5.8Hz,1H),7.45-7.40(m,1H),7.39(d,J＝2.4Hz,1H),7.34(s,1H),7.24(d,J＝2.4Hz,1H),6.94(d,J＝10.7Hz,1H),5.53(s,1H),5.07(s,1H),3.93-3.87(m,2H),3.42(s,1H),3.08-3.01(m,1H),2.98(s,1H),2.82-2.71(m,3H),2.63(s,3H),2.36-2.30(m,1H),1.60(d,J＝9.1Hz,1H)。To a mixture of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (10.5 mg, 34 μmol, prepared as described in Example 22), Pd(_PPh3 )₄ (2.0 mg, 1.7 μmol) and sodium carbonate (9.1 mg, 86 μmol) was added a solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (10 mg, 17 μmol, Example 1, Step 5) in dioxane (1 ml). Water (0.3 ml) was added, and the reaction mixture was aerated with_N2 and heated to 100°C for 1 h. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in 1:1 DCM_/ TFA (3 mL)_for30 min, concentrated, and purified by preparative HPLC (pH 2). LC-MS calculated for_C32H26F2N7O⁺ (M+H)⁺ : m/z=562.2; found 562.6.^1H NMR (600 MHz, DMSO-_d6 )δ9.54(s,1H),8.46(s,1H),8.25(s,1H),7.97(dd,J＝9.2,5.8Hz,1H),7.45-7.40(m,1H),7.39(d,J＝2.4Hz,1H),7.34(s,1H),7.24(d,J＝2.4Hz,1H),6. 94(d,J＝10.7Hz,1 H),5.53(s,1H),5.07(s,1H),3.93-3.87(m,2H),3.42(s,1H),3.08-3.01(m,1H),2.98(s,1H),2.82-2.71(m,3H),2.63(s,3H),2.36-2.30(m,1H), 1.60(d,J=9.1Hz,1H).

实施例27. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 27. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例2、步骤2中所描述的程序，利用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(中间体10)代替5,7-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂-硼杂环戊-2-基)-1H-吲哚-1-甲酸叔丁酯来制备。LC-MS计算值C₃₇H₃₈F₂N₅O⁺(M+H)⁺:m/z＝606.3；实验值606.3。This compound was prepared according to the procedure described in Example 2, Step 2, using 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 10) instead of 5,7-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester. LC-MS calculated for C₃₇ H₃₈ F₂ N₅ O⁺ (M+H)⁺ : m/z = 606.3; found 606.3.

实施例28.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基吡咯烷-1-甲酰胺Example 28. (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide

步骤1.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)ethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体5，1.0g，1.545mmol)和中间体17(0.481g，2.008mmol)的混合物中添加DMF(7.7ml)和三乙胺(0.646ml，4.63mmol)，随后添加双(三苯基膦)氯化钯(II)(0.108g，0.154mmol)和碘化铜(I)(0.294g，1.545mmol)。抽空反应烧瓶，用氮气回填，随后在75℃搅拌2h。用水和少量30％氢氧化铵水溶液淬灭反应混合物，随后用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱纯化粗产物，得到所需产物(834mg，71％)。LC-MS计算值C₃₅H₄₆BrFN₅O₄SSi(M+H)⁺:m/z＝758.0/760.0；实验值758.0/760.0。To a mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 1.0 g, 1.545 mmol) and Intermediate 17 (0.481 g, 2.008 mmol) was added DMF (7.7 ml) and triethylamine (0.646 ml, 4.63 mmol), followed by bis(triphenylphosphine)palladium(II) chloride (0.108 g, 0.154 mmol) and copper(I) iodide (0.294 g, 1.545 mmol). The reaction flask was evacuated, backfilled with nitrogen, and then stirred at 75 °C for 2 h. The reaction mixture was quenched with water and a small amount of 30% aqueous ammonium hydroxide solution, then extracted with ethyl acetate. The organic layer was washed with_water and brine,_dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography to give the desired product (834 mg,₇₁ %). LC-MS calculated for_{C35H46BrFN5O4SSi} (M+H)⁺ : m/z=758.0/760.0; found 758.0/760.0.

步骤2.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(834mg，1.10mmol)在DMF(5.5ml)中的溶液中添加碳酸铯(1.07g，3.30mmol)，并且将反应混合物加热至90℃持续2h。用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱纯化粗产物，得到所需产物(532mg，64％)。LC-MS计算值C₃₅H₄₆BrFN₅O₄SSi(M+H)⁺:m/z＝758.0/760.0；实验值758.0/760.0。To a solution of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)ethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (834 mg, 1.10 mmol) in DMF (5.5 ml) was added cesium carbonate (1.07 g, 3.30 mmol) and the reaction mixture was heated to 90 °C for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography to give the desired product (532 mg, 64%). LC-MS calculated_{forC35H46BrFN5O4SSi} (M+H)₊ : m/_z =758.0/^760.0 ; found 758.0/760.0.

步骤3.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(532mg，0.701mmol)在DCM(3.5ml)中的溶液中添加m-CPBA(173mg，0.771mmol)，并且将反应混合物在室温下搅拌30min，随后用饱和碳酸氢钠淬灭。用水稀释混合物并且用DCM萃取。经硫酸钠干燥有机层并且浓缩。将粗产物溶解于DMF(3mL)中并且添加1H-1,2,4-三唑(58.1mg，0.841mmol)和碳酸铯(685mg，2.103mmol)。将反应混合物加热至80℃持续30min，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(505mg，92％)。LC-MS计算值C₃₆H₄₅BrFN₈O₄Si(M+H)⁺:m/z＝779.2/781.2；实验值779.2/781.2。To a solution of (1R, 4R, 5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (532 mg, 0.701 mmol) in DCM (3.5 ml) was added m-CPBA (173 mg, 0.771 mmol) and the reaction mixture was stirred at room temperature for 30 min and then quenched with saturated sodium bicarbonate. The mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was dissolved in DMF (3 mL) and 1H-1,2,4-triazole (58.1 mg, 0.841 mmol) and cesium carbonate (685 mg, 2.103 mmol) were added. The reaction mixture was heated to 80 °C for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (505 mg, 92%). LC-MS calculated for C₃₆ H₄₅ BrFN₈ O₄ Si (M+H)⁺ : m/z=779.2/781.2; Found 779.2/781.2.

步骤4.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(二甲基氨甲酰基)吡咯烷-2-基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(dimethylcarbamoyl)pyrrolidin-2-yl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(755mg，0.968mmol)于四氢呋喃(4.84ml)中的溶液中添加TBAF(1162μl，1.162mmol)并且将反应混合物加热至65℃持续2h。向此溶液的等分试样(150mg，0.236mmol)中添加三乙胺(99μl，0.708mmol)和二甲基胺甲酰氯(28.2μl,0.307mmol)，并且在室温下搅拌反应混合物30min，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱纯化粗产物，得到所需产物(65mg，39％)。LC-MS计算值C₃₃H₃₈BrFN₉O₃(M+H)⁺:m/z＝706.2/708.2；实验值706.2/708.2。To a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (755 mg, 0.968 mmol) in tetrahydrofuran (4.84 ml) was added TBAF (1162 μl, 1.162 mmol) and the reaction mixture was heated to 65 °C for 2 h. To an aliquot of this solution (150 mg, 0.236 mmol) was added triethylamine (99 μl, 0.708 mmol) and dimethylcarbamoyl chloride (28.2 μl, 0.307 mmol), and the reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography to give the desired product (65 mg, 39%). LC-MS calculated for C₃₃ H₃₈ BrFN₉ O₃ (M+H)⁺ : m/z=706.2/708.2; found 706.2/708.2.

步骤5.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基吡咯烷-1-甲酰胺Step 5. (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(二甲基氨甲酰基)吡咯烷-2-基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(65mg，0.092mmol)、(2,3-二氯苯基)硼酸(35.1mg，0.184mmol)、四(三苯基膦)钯(0)(10.63mg，9.20μmol)和碳酸钠(29.2mg，0.276mmol)的混合物中添加1,4-二噁烷(0.800ml)/水(0.200ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且将残余物溶解于1:1DCM/TFA(1mL)中。在静置30min之后，用MeOH稀释混合物并且通过制备型HPLC(pH2)纯化，得到所需产物。LC-MS计算值C₃₄H₃₃Cl₂FN₉O(M+H)⁺:m/z＝672.2；实验值672.2。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(dimethylcarbamoyl)pyrrolidin-2-yl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (65 mg, 0.092 mmol), ( To a mixture of 2,3-dichlorophenyl)boronic acid (35.1 mg, 0.184 mmol), tetrakis(triphenylphosphine)palladium(0) (10.63 mg, 9.20 μmol) and sodium carbonate (29.2 mg, 0.276 mmol) was added 1,4-dioxane (0.800 ml)/water (0.200 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100° C. overnight. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the residue was dissolved in 1:1 DCM/TFA (1 mL). After standing for 30 min, the mixture was diluted with MeOH and purified by preparative HPLC (pH 2) to give the desired product. LC-MS calculated for C₃₄ H₃₃ Cl₂ FN₉ O (M+H)⁺ : m/z=672.2; found 672.2.

实施例29.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 29. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

步骤1.(1R,4R,5S)-5-(7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(实施例28，步骤3；227mg，0.291mmol)、(2-氯-3-甲基苯基)硼酸(74.4mg，0.437mmol)、四(三苯基膦)钯(0)(33.6mg，0.029mmol)和碳酸钠(93mg，0.873mmol)的混合物中添加1,4-二噁烷(1.2ml)/水(0.300ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。用DCM稀释混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速柱色谱纯化粗残余物，得到所需产物(111mg，46％)。LC-MS计算值C₄₃H₅₁ClFN₈O₄Si(M+H)⁺:m/z＝825.3；实验值825.3。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Example 28, Step 3; 227 mg, To a mixture of 1,4-dioxane (1.2 ml)/water (0.300 ml) was added 2-(2-chloro-3-methylphenyl)boronic acid (74.4 mg, 0.437 mmol), tetrakis(triphenylphosphine)palladium(0) (33.6 mg, 0.029 mmol) and sodium carbonate (93 mg, 0.873 mmol), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100° C. overnight. The mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude residue was purified by flash column chromatography to give the desired product (111 mg, 46%). LC-MS calculated for C₄₃ H₅₁ ClFN₈ O₄ Si (M+H)⁺ : m/z=825.3; found 825.3.

步骤2：(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 2: (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester

向(1R,4R,5S)-5-(7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(111mg，0.134mmol)于THF(0.672ml)中的溶液中添加TBAF(161μl，0.161mmol)，并且将反应混合物加热至65℃持续2小时，随后冷却至室温。添加三乙胺(56.2μl，0.403mmol)和氯甲酸甲酯(15.62μl，0.202mmol)，并且在室温下搅拌反应混合物30min，接着用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。将粗产物溶解于1:1DCM/TFA(2mL)中并且在室温下搅拌30min，接着用MeOH稀释并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₃₄H₃₃ClFN₈O₂(M+H)⁺:m/z＝639.2；实验值639.2。To a solution of tert-butyl (1R,4R,5S)-5-(7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (111 mg, 0.134 mmol) in THF (0.672 ml) was added TBAF (161 μl, 0.161 mmol) and the reaction mixture was heated to 65 °C for 2 hours then cooled to room temperature. Triethylamine (56.2 μl, 0.403 mmol) and methyl chloroformate (15.62 μl, 0.202 mmol) were added, and the reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was dissolved in 1:1 DCM/TFA (2 mL) and stirred at room temperature for 30 min, then diluted with MeOH and purified by preparative HPLC (pH 2) to give the desired product. LC-MS calculated for C₃₄ H₃₃ ClFN₈ O₂ (M+H)⁺ : m/z=639.2; Found 639.2.

实施例30.(1S,3R,5S)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯Example 30. Methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

步骤1.(1S,3R,5S)-3-(羟基甲基)-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 1. Tert-butyl (1S,3R,5S)-3-(Hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

在0℃向(1S,3R,5S)-2-(叔丁氧基羰基)-2-氮杂双环[3.1.0]己烷-3-甲酸(4.9g，21.56mmol)于THF(71.9ml)中的溶液中添加三乙胺(3.61ml，25.9mmol)和氯甲酸异丁酯(2.83ml，21.56mmol)，并且使反应混合物升温至室温并且搅拌1h。随后过滤反应物并且用THF洗涤固体。将滤液冷却至0℃并且逐滴添加硼氢化钠(1.631g，43.1mmol)于水(约5mL)中的溶液。在室温下搅拌反应混合物30min，接着用1NHCl淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(4.6g，100％)。LC-MS计算值C₇H₁₂NO₃⁺(M+H-C₄H₈)⁺:m/z＝158.1；实验值158.1。Triethylamine (3.61 ml, 25.9 mmol) and isobutyl chloroformate (2.83 ml, 21.56 mmol) were added to a solution of (1S, 3R, 5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (4.9 g, 21.56 mmol) in THF (71.9 ml) at 0 ° C, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reactant was then filtered and the solid was washed with THF. The filtrate was cooled to 0 ° C and a solution of sodium borohydride (1.631 g, 43.1 mmol) in water (about 5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, then quenched with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (4.6 g, 100%). LC-MS calculated for C₇ H₁₂ NO₃⁺ (M + HC₄ H₈ )⁺ : m/z = 158.1; found 158.1.

步骤2.(1S,3R,5S)-3-甲酰基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 2. (1S,3R,5S)-tert-butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

向乙二酰氯(2.077ml，23.73mmol)在DCM(60mL)中的-78℃溶液中逐滴添加DMSO(3.37ml，47.5mmol)在DCM(4mL)中的溶液。在-78℃搅拌反应混合物45min，接着逐滴添加(1S,3R,5S)-3-(羟基甲基)-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(4.6g，21.57mmol)在DCM(5mL)中的溶液。在-78℃搅拌反应混合物2h，随后缓慢添加三乙胺(9.02ml，64.7mmol)。在-78℃搅拌反应混合物1h，接着升温至室温并且再搅拌1h。随后将反应物用1N HCl淬灭并且用DCM萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₇H₁₀NO₃⁺(M+H-C₄H₈)⁺:m/z＝156.1；实验值156.1。A solution of DMSO (3.37 ml, 47.5 mmol) in DCM (4 mL) was added dropwise to a -78 °C solution of oxalyl chloride (2.077 ml, 23.73 mmol) in DCM (60 mL). The reaction mixture was stirred at -78 °C for 45 min, followed by dropwise addition of a solution of (1S, 3R, 5S)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (4.6 g, 21.57 mmol) in DCM (5 mL). The reaction mixture was stirred at -78 °C for 2 h, followed by slow addition of triethylamine (9.02 ml, 64.7 mmol). The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for another 1 h. The reactant was then quenched with 1N HCl and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₇ H₁₀ NO₃⁺ (M + HC₄ H₈ )⁺ : m/z = 156.1; found 156.1.

步骤3.(1S,3R,5S)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 3. Tert-butyl (1S,3R,5S)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

在0℃向(1S,3R,5S)-3-甲酰基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(4.6g，21.77mmol)在MeOH(72.6ml)中的溶液中逐滴添加碳酸钾(6.02g，43.5mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(3.27ml，21.77mmol)。使反应混合物升温至室温过夜，接着浓缩。将粗残余物分配于水与乙酸乙酯之间。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至50％丙酮/己烷)纯化粗产物，得到所需产物(3.46g，77％)。LC-MS计算值C₈H₁₀NO₂⁺(M+H-C₄H₈)⁺:m/z＝152.1；实验值152.1。To a solution of (1S,3R,5S)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (4.6 g, 21.77 mmol) in MeOH (72.6 ml) at 0°C was added potassium carbonate (6.02 g, 43.5 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.27 ml, 21.77 mmol) dropwise. The reaction mixture was allowed to warm to room temperature overnight and then concentrated. The crude residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 50% acetone/hexanes) to give the desired product (3.46 g, 77%). LC-MS calculated for C₈ H₁₀ NO₂⁺ (M+HC₄ H₈ )⁺ : m/z=152.1; found 152.1.

步骤4.(1S,3R,5S)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯Step 4. Methyl (1S,3R,5S)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

将(1S,3R,5S)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(1g，4.82mmol)于HCl(4N于二噁烷中，2.412ml，9.65mmol)中的溶液在室温下搅拌30min，随后用THF(16.08ml)稀释并且冷却至0℃。添加三乙胺(3.36ml，24.12mmol)和氯甲酸甲酯(0.448ml，5.79mmol)并且使反应混合物升温至室温并且搅拌1h，接着用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(797mg，100％)。LC-MS计算值C₉H₁₂NO₂⁺(M+H)⁺:m/z＝166.1；实验值166.1。A solution of (1S,3R,5S)-tert-butyl 3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (1 g, 4.82 mmol) in HCl (4N in dioxane, 2.412 ml, 9.65 mmol) was stirred at room temperature for 30 min, then diluted with THF (16.08 ml) and cooled to 0°C. Triethylamine (3.36 ml, 24.12 mmol) and methyl chloroformate (0.448 ml, 5.79 mmol) were added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (797 mg, 100%). LC-MS calculated for C₉ H₁₂ NO₂⁺ (M+H)⁺ : m/z=166.1; found 166.1.

步骤5.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((1S,3R,5S)-2-(甲氧基羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((1S,3R,5S)-2-(methoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(1.5g，2.317mmol)和(1S,3R,5S)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯(0.574g，3.48mmol)的混合物中添加DMF(5.79ml)和三乙胺(0.969ml，6.95mmol)，随后添加四(三苯基膦)钯(0)(0.268g，0.232mmol)和碘化铜(I)(0.441g，2.317mmol)。抽空反应烧瓶，用氮气回填，随后在70℃搅拌2h。随后添加碳酸铯(1.510g，4.63mmol)并且将反应混合物加热至80℃持续2h。用水和少量氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至60％丙酮/己烷)纯化粗产物，得到所需产物(924mg，58％)。LC-MS计算值C₃₂H₃₆BrFN₅O₄S⁺(M+H)⁺:m/z＝684.2/686.2；实验值684.2/686.2。To a mixture of intermediate 5 (1.5 g, 2.317 mmol) and (1S, 3R, 5S)-3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester (0.574 g, 3.48 mmol) was added DMF (5.79 ml) and triethylamine (0.969 ml, 6.95 mmol), followed by tetrakis (triphenylphosphine) palladium (0) (0.268 g, 0.232 mmol) and copper (I) iodide (0.441 g, 2.317 mmol). The reaction flask was evacuated, backfilled with nitrogen, and then stirred at 70 ° C for 2 h. Cesium carbonate (1.510 g, 4.63 mmol) was then added and the reaction mixture was heated to 80 ° C for 2 h. The reactants were quenched with water and a small amount of saturated aqueous solution of ammonium hydroxide, then diluted with ethyl acetate and filtered through a plug of celite. The filtrate layers were separated and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0_to 60% acetone/hexanes) to give the desired product (924 mg, 58%). LC-MS Calcd_. for_{C32H36BrFN5O4S+} (M+H)⁺ : m/z⁼ 684.2/686.2; Found 684.2/686.2.

步骤6.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1S,3R,5S)-2-(甲氧基羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1S,3R,5S)-2-(methoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((1S,3R,5S)-2-(甲氧基羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(924mg，1.350mmol)、(2,3-二氯苯基)硼酸(309mg，1.620mmol)、氟化钾(235mg，4.05mmol)和Pd-132(96mg，0.135mmol)的混合物中添加1,4-二噁烷(3.60ml)/水(0.900ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌2h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速柱色谱(0至65％丙酮/己烷)纯化粗产物，得到所需产物。LC-MS计算值C₃₈H₃₉Cl₂FN₅O₄S⁺(M+H)⁺:m/z＝750.2/752.2；实验值750.2/752.2。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((1S,3R,5S)-2-(methoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (924 mg, 1. To a mixture of 1,4-dioxane (3.60 ml)/water (0.900 ml) was added 2,3-dichlorophenyl)boronic acid (350 mmol), (2,3-dichlorophenyl)boronic acid (309 mg, 1.620 mmol), potassium fluoride (235 mg, 4.05 mmol) and Pd-132 (96 mg, 0.135 mmol), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C for 2 h. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by flash column chromatography (0 to 65% acetone/hexanes) to give the desired product. LC-MS calculated for C₃₈ H₃₉ Cl₂ FN₅ O₄ S⁺ (M+H)⁺ : m/z=750.2/752.2; found 750.2/752.2.

步骤7.(1S,3R,5S)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯Step 7. Methyl (1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1S,3R,5S)-2-(甲氧基羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(592mg，0.789mmol)、N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺(436mg，1.577mmol)、四(三苯基膦)钯(0)(91mg，0.079mmol)和3-甲基水杨酸铜(I)(508mg，2.366mmol)的混合物中添加1,4-二噁烷(1.971ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过3h。用水和氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至80％丙酮/己烷)纯化粗产物。将纯化产物溶解于1:1TFA/DCM(10mL)中并且在室温下搅拌1h，接着浓缩。用乙腈稀释粗残余物并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₄₀H₃₇Cl₂FN₇O₃⁺(M+H)⁺:m/z＝752.2/754.2；实验值752.2/754.2。¹HNMR(600MHz,DMSO)δ9.48(s,1H),9.16(s,1H),8.47(d,J＝7.3Hz,1H),8.21(s,1H),8.14(s,1H),7.85(dd,J＝8.1,1.3Hz,1H),7.83(d,J＝8.1Hz,1H),7.59(t,J＝7.9Hz,1H),7.51(d,J＝6.6Hz,1H),6.82(s,1H),5.60(s,1H),5.14(d,J＝7.7Hz,1H),4.89(d,J＝4.9Hz,1H),3.91(s,1H),3.73(s,3H),3.54(dd,J＝8.1,3.9Hz,2H),3.43(s,1H),3.07(s,3H),3.05(s,3H),2.96-2.82(m,2H),2.70(dt,J＝15.5,7.1Hz,1H),2.58(dd,J＝12.1,9.1Hz,1H),2.33(d,J＝8.4Hz,1H),2.11-1.99(bs,1H),1.61(d,J＝8.9Hz,2H),0.94(dt,J＝9.8,5.1Hz,1H),0.67(s,1H)。To tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1S,3R,5S)-2-(methoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (592 mg, 0.789 mmol), N,N-dimethyl 1,4-dioxane (1.971 ml) was added to a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (436 mg, 1.577 mmol), tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.079 mmol) and 3-methylsalicylic acid copper(I) (508 mg, 2.366 mmol), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 ° C for 3 h. The reactants were quenched with water and a saturated aqueous solution of ammonium hydroxide, then diluted with ethyl acetate and filtered through a celite plug. The filtrate layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 80% acetone/hexane). The purified product was dissolved in 1:1 TFA/DCM (10 mL) and stirred at room temperature for 1 h, then concentrated. The crude residue was diluted with acetonitrile and purified by preparative HPLC (pH 2) to give the desired product. LC-MS Calcd. for C₄₀ H₃₇ Cl₂ FN₇ O₃⁺ (M+H)⁺ : m/z = 752.2/754.2; Found 752.2/754.2.¹ HNMR (600MHz, DMSO) δ9.48(s,1H),9.16(s,1H),8.47(d,J＝7.3Hz,1H),8.21(s,1H),8.14(s,1H),7.85(dd,J＝8.1,1.3Hz,1H),7.83(d,J＝8.1Hz,1H),7.59(t, J＝7.9Hz,1H),7.51(d,J＝6.6Hz,1H),6.82(s,1H),5.60(s,1H),5.14(d,J＝7.7Hz,1H),4.89(d,J＝4.9Hz,1H),3.91(s ,1H),3.73(s,3H),3.54(dd,J＝8.1,3.9Hz,2H),3.43(s,1H),3.07(s,3H),3.05(s,3H),2.96-2.82(m,2H),2.70(dt,J＝15.5,7.1Hz,1H),2.58(dd,J＝1 2.1, 9.1Hz, 1H), 2.33 (d, J = 8.4Hz, 1H), 2.11-1.99 (bs, 1H), 1.61 (d, J = 8.9Hz, 2H), 0.94 (dt, J = 9.8, 5.1Hz, 1H), 0.67 (s, 1H).

实施例31. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 31. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizine-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：N-甲氧基-N-甲基-5-氧代-1,2,3,5-四氢吲哚嗪-3-甲酰胺Step 1: N-methoxy-N-methyl-5-oxo-1,2,3,5-tetrahydroindole-3-carboxamide

向小瓶中装入市售的5-氧代-1,2,3,5-四氢吲哚嗪-3-甲酸(250mg，1.395mmol)、N,O-二甲基羟胺盐酸盐(204mg，2.093mmol)、DMF(7ml)和DIEA(0.675ml，3.86mmol)。在室温下搅拌反应混合物5min，接着添加HATU(562mg，1.479mmol)。在室温下搅拌反应混合物1h。将反应混合物用水淬灭并且萃取至DCM中。合并的有机洗脱份经硫酸镁干燥，过滤并浓缩。通过快速柱色谱(0至20％MeOH/DCM)纯化粗残余物，得到呈白色结晶固体的产物(0.249g，80％产率)。LCMS计算值C₁₁H₁₅N₂O₃⁺(M+H)⁺:m/z＝223.1；实验值223.1。A vial was charged with commercially available 5-oxo-1,2,3,5-tetrahydroindole-3-carboxylic acid (250 mg, 1.395 mmol), N,O-dimethylhydroxylamine hydrochloride (204 mg, 2.093 mmol), DMF (7 ml) and DIEA (0.675 ml, 3.86 mmol). The reaction mixture was stirred at room temperature for 5 min, followed by the addition of HATU (562 mg, 1.479 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted into DCM. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (0 to 20% MeOH/DCM) to give the product as a white crystalline solid (0.249 g, 80% yield). LCMS calculated for C₁₁ H₁₅ N₂ O₃⁺ (M+H)⁺ : m/z=223.1; Found 223.1.

步骤2：5-氧代-1,2,3,5-四氢吲哚嗪-3-甲醛Step 2: 5-Oxo-1,2,3,5-tetrahydroindole-3-carbaldehyde

经10分钟向N-甲氧基-N-甲基-5-氧代-1,2,3,5-四氢吲哚嗪-3-甲酰胺(0.25g)的经冷却(-45℃)THF(11.2mL)溶液中添加1M氢化锂铝于THF(1.34mL)中的溶液。在-45℃搅拌反应混合物30分钟，在0℃搅拌90分钟，接着冷却至-45℃，并且添加硫酸氢钾(0.305g)于水(1.0mL)中的溶液。使混合物升温至室温，过滤并浓缩。粗物质不经进一步纯化即用于下一步骤中(0.2g，100％产率)。LCMS计算值C₉H₁₀NO₂(M+H)⁺:m/z＝164.1；实验值164.1。To a cooled (-45°C) THF (11.2 mL) solution of N-methoxy-N-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxamide (0.25 g) was added a 1 M solution of lithium aluminum hydride in THF (1.34 mL) over 10 minutes. The reaction mixture was stirred at -45°C for 30 minutes, at 0°C for 90 minutes, then cooled to -45°C, and a solution of potassium hydrogen sulfate (0.305 g) in water (1.0 mL) was added. The mixture was allowed to warm to room temperature, filtered, and concentrated. The crude material was used in the next step without further purification (0.2 g, 100% yield). LCMS calculated for C₉ H₁₀ NO₂ (M+H)⁺ : m/z=164.1; found 164.1.

步骤3:3-乙炔基-2,3-二氢吲哚嗪-5(1H)-酮Step 3: 3-ethynyl-2,3-dihydroindole-5(1H)-one

向5-氧代-1,2,3,5-四氢吲哚嗪-3-甲醛(0.215g，1.32mmol)于甲醇(6.6ml)中的经冷却(0℃)溶液中添加碳酸钾(0.364g，2.64mmol)，随后直接添加(1-重氮-2-氧代丙基)膦酸二甲酯(0.217ml，1.45mmol)。在0℃搅拌反应溶液2小时。用水淬灭反应物并且用DCM萃取。合并的有机洗脱份经硫酸镁干燥，接着浓缩。通过快速柱色谱(0至20％MeOH/DCM)纯化粗物质，得到所需产物(0.114g，54％产率)。LCMS计算值C₁₀H₁₀NO(M+H)⁺:m/z＝160.1；实验值160.1To a cooled (0°C) solution of 5-oxo-1,2,3,5-tetrahydroindolizine-3-carbaldehyde (0.215 g, 1.32 mmol) in methanol (6.6 ml) was added potassium carbonate (0.364 g, 2.64 mmol) followed directly by the addition of dimethyl (1-diazo-2-oxopropyl)phosphonate (0.217 ml, 1.45 mmol). The reaction solution was stirred at 0°C for 2 hours. The reaction was quenched with water and extracted with DCM. The combined organic fractions were dried over magnesium sulfate and then concentrated. The crude material was purified by flash column chromatography (0 to 20% MeOH/DCM) to give the desired product (0.114 g, 54% yield). LCMS calculated for C₁₀ H₁₀ NO (M+H)⁺ : m/z = 160.1; Found 160.1

步骤4.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(硫基)-2-(-5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(thio)-2-(-5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物以类似于中间体18的方式，用3-乙炔基-2,3-二氢吲哚嗪-5(1H)-酮替代(R)-2-乙炔基吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯来制备。LCMS计算值C₃₉H₃₇Cl₂FN₅O₃S⁺(M+H)⁺:m/z＝744.2/746.2；实验值744.2/746.2。This compound was prepared in a manner analogous to Intermediate 18, substituting 3-ethynyl-2,3-dihydroindoleazin-₅ (1H)-one for (R)-2_- ethynylpyrrolidine-₁ -carboxylic acid 2-(trimethylsilyl)ethyl ester. LCMS Calcd. for_{C39H37Cl2FN5O3S}⁺ (M+H)⁺ : m/z₌ 744.2/746.2; Found 744.2/746.2.

步骤5. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 5. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

在0℃向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-(5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(20mg，0.027mmol)在DCM(0.269ml)中的溶液中添加m-CPBA(7.22mg，0.032mmol)，并且将反应混合物在室温下搅拌30min，随后用饱和碳酸氢钠淬灭并且用DCM萃取。经硫酸钠干燥有机层并且浓缩。将粗产物溶解于THF(0.8mL)中并且冷却至0℃。逐滴添加溴化甲基镁(3M于二乙醚中，8.95μl，0.027mmol)，并且在0℃搅拌反应混合物1h，随后用饱和氯化铵淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。使粗产物在1:1DCM/TFA(1mL)中静置15min，随后用MeOH稀释并且通过制备型HPLC(pH 2)纯化，得到所需产物。LCMS计算值C₃₄H₂₉Cl₂FN₅O⁺(M+H)⁺:m/z＝612.2/614.2；实验值612.2/614.2。在纯化后分离单个异构体。不确定吡咯2-位置处的立体化学。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-(5-oxo-1,2,3,5-tetrahydroindolazine-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (20 mg, 0.027 mmol) in DCM (0.269 ml) at 0°C was added m-CPBA (7.22 mg, 0.032 mmol) and the reaction mixture was stirred at room temperature for 30 min, then quenched with saturated sodium bicarbonate and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was dissolved in THF (0.8 mL) and cooled to 0°C. Methylmagnesium bromide (3M in diethyl ether, 8.95 μl, 0.027 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 1 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was allowed to stand in 1:1 DCM/TFA (1 mL) for 15 min, then diluted with MeOH and purified by preparative HPLC (pH 2) to give the desired product. LCMS calculated for C₃₄ H₂₉ Cl₂ FN₅ O⁺ (M+H)⁺ : m/z=612.2/614.2; Found 612.2/614.2. Single isomers were isolated after purification. The stereochemistry at the 2-position of pyrrole was uncertain.

实施例32.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 32. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向中间体18(416mg，0.504mmol)、N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺(279mg，1.009mmol)、四(三苯基膦)钯(0)(58.3mg，0.050mmol)和3-甲基水杨酸铜(I)(325mg，1.513mmol)的混合物中添加1,4-二噁烷(2.5ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。将反应物用水和氢氧化铵饱和水溶液淬灭，随后用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速色谱(0至7％MeOH/DCM)纯化粗产物，得到所需产物(465mg，99％)。LC-MS计算值C₄₈H₅₅Cl₂FN₇O₅Si⁺(M+H)⁺:m/z＝926.3/928.3；实验值926.3/928.3。To a mixture of intermediate 18 (416 mg, 0.504 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (279 mg, 1.009 mmol), tetrakis(triphenylphosphine)palladium(0) (58.3 mg, 0.050 mmol) and 3-methylsalicylic acid copper(I) (325 mg, 1.513 mmol) was added 1,4-dioxane (2.5 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 ° C overnight. The reactants were quenched with water and saturated aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 7% MeOH/DCM) to give the desired product (465 mg, 99%). LC^{-MS calculated for C48H55Cl2FN7O5Si+(M+H)+}_:m^/_z=926.3 /928.3; found 926.3/928.3.

步骤2.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 2. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(465mg，0.502mmol)于THF(2.5ml)中的溶液中添加TBAF(1M于THF中，602μl，0.602mmol)，并且将反应混合物加热至65℃持续1h，随后冷却至0℃。向反应混合物中添加三乙胺(210μl，1.506mmol)和氯甲酸甲酯(58.3μl，0.753mmol)，并且在室温下搅拌反应混合物30min，接着用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速色谱(0至100％丙酮/己烷)纯化粗产物，得到所需中间体。使其在1:1TFA/DCM(1mL)中静置15min，随后用MeOH稀释并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₃₉H₃₇Cl₂FN₇O₃⁺(M+H)⁺:m/z＝740.2/742.2；实验值740.2/742.2。¹H NMR(600MHz,DMSO)δ9.79-9.61(m,1H),9.15(s,1H),8.47(t,J＝6.9Hz,1H),8.31-8.08(m,2H),7.89-7.75(m,2H),7.59(t,J＝7.9Hz,1H),7.50(d,J＝6.5Hz,1H),6.67(s,1H),5.67(s,1H),5.17(t,J＝8.5Hz,1H),4.90(dd,J＝13.3,5.7Hz,1H),4.01-3.90(m,2H),3.72-3.60(m,4H),3.52-3.38(m,2H),3.07(s,3H),3.04(s,3H),2.94-2.80(m,2H),2.71(dt,J＝15.2,7.1Hz,1H),2.40-2.32(m,2H),1.94-1.80(m,2H),1.75-1.57(m,2H)。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (465 mg, 0.502 mmol) in THF (2.5 ml) was added TBAF (1 M in THF, 602 μl, 0.602 mmol) and the reaction mixture was heated to 65 °C for 1 h then cooled to 0 °C. Triethylamine (210 μl, 1.506 mmol) and methyl chloroformate (58.3 μl, 0.753 mmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 100% acetone/hexane) to give the desired intermediate. It was allowed to stand in 1:1 TFA/DCM (1 mL) for 15 min, then diluted with MeOH and purified by preparative HPLC (pH 2) to give the desired product. LC-MS calculated for C₃₉ H₃₇ Cl₂ FN₇ O₃⁺ (M+H)⁺ : m/z=740.2/742.2; Found 740.2/742.2.¹ H NMR (600MHz, DMSO) δ9.79-9.61(m,1H),9.15(s,1H),8.47(t,J＝6.9Hz,1H),8.31-8.08(m,2H),7.89-7.75(m,2H),7.59(t,J＝7.9Hz,1H),7.50(d,J＝6.5Hz,1H ),6.67(s,1H),5.67(s,1H),5.17(t,J＝8.5Hz,1H),4.90( dd,J＝13.3,5.7Hz,1H),4.01-3.90(m,2H),3.72-3.60(m,4H),3.52-3.38(m,2H),3.07(s,3H),3.04(s,3H),2.94-2.80(m,2H),2.71(dt,J＝15.2,7. 1Hz,1H),2.40-2.32(m,2H),1.94-1.80(m,2H),1.75-1.57(m,2H).

实施例33.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 33. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

此化合物以类似于实施例32的方式，用N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺替代步骤2中的N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺来制备。LC-MS计算值C₃₈H₃₅Cl₂FN₇O₃⁺(M+H)⁺:m/z＝726.2/728.2；实验值726.2/728.2。¹H NMR(600MHz,DMSO)δ9.17(d,J＝1.7Hz,1H),8.48(dd,J＝8.1,2.1Hz,1H),8.20(s,1H),7.87-7.76(m,2H),7.58(t,J＝7.9Hz,1H),7.49(d,J＝7.6Hz,1H),6.68(s,1H),5.63(s,1H),5.18(d,J＝8.1Hz,1H),4.93(s,1H),3.98(s,1H),3.70(m,5H),3.47(q,J＝9.8Hz,2H),3.08(s,5H),2.88(dq,J＝12.7,5.6Hz,2H),2.77-2.68(m,1H),2.37(d,J＝8.4Hz,2H),1.89(s,2H),1.66(d,J＝9.2Hz,1H)。This compound was prepared in a manner similar to Example 32, using N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide instead of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide in step 2. LC-MS calculated for C₃₈ H₃₅ Cl₂ FN₇ O₃⁺ (M+H)⁺ : m/z=726.2/728.2; found 726.2/728.2.¹ H NMR (600MHz, DMSO) δ9.17(d,J＝1.7Hz,1H),8.48(dd,J＝8.1,2.1Hz,1H),8.20(s,1H),7.87-7.76(m,2H),7.58(t,J＝7.9Hz,1H),7.49(d,J＝7.6Hz,1H),6.68(s, 1H),5.63(s,1H),5.18(d,J=8.1 Hz,1H),4.93(s,1H),3.98(s,1H),3.70(m,5H),3.47(q,J＝9.8Hz,2H),3.08(s,5H),2.88(dq,J＝12.7,5.6Hz,2H),2.77-2.68(m,1H),2.37(d,J＝8.4Hz ,2H),1.89(s,2H),1.66(d,J＝9.2Hz,1H).

实施例34. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-氟苯基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 34. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(7-(2-氯-3-氟苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-(2-chloro-3-fluorophenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物以类似于中间体18的方式，用(2-氯-3-氟苯基)硼酸替代步骤2中的(2,3-二氯苯基)硼酸来制备。LC-MS计算值C₄₁H₄₉ClF₂N₅O₄SSi⁺(M+H)⁺:m/z＝808.2；实验值808.2。This compound was prepared in^{a manner analogous to Intermediate 18, substituting (2-chloro-3-fluorophenyl)boronic acid for (2,3-dichlorophenyl)boronic acid in step 2. LC-MS Calcd. for C41H49ClF2N5O4SSi+}_(M+H)⁺ : m/z=808.2; Found 808.2.

步骤2.(1R,4R,5S)-5-(7-(2-氯-3-氟苯基)-8-(2-氰基乙基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-(2-chloro-3-fluorophenyl)-8-(2-cyanoethyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-(2-氯-3-氟苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(434mg，0.537mmol)于THF(2.7ml)中的溶液中添加TBAF(1M于THF中，644μl，0.644mmol)，并且将反应混合物在65℃搅拌1h。随后将混合物冷却至室温，并且添加三乙胺(224μl，1.610mmol)和环丙烷碳酰氯(48.8μl，0.537mmol)。将反应混合物在室温下搅拌30min，随后用水淬灭并且用乙酸乙酯萃取。有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(30至100％丙酮/己烷)纯化粗产物，得到所需产物(335mg，85％)。LC-MS计算值C₃₉H₄₁ClF₂N₅O₃S⁺(M+H)⁺:m/z＝732.2；实验值732.2。To a solution of tert-butyl (1R,4R,5S)-5-(7-(2-chloro-3-fluorophenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (434 mg, 0.537 mmol) in THF (2.7 ml) was added TBAF (1 M in THF, 644 μl, 0.644 mmol) and the reaction mixture was stirred at 65° C. for 1 h. The mixture was then cooled to room temperature and triethylamine (224 μl, 1.610 mmol) and cyclopropanecarbonyl chloride (48.8 μl, 0.537 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (30 to 100% acetone/hexanes) to give the desired product (335 mg, 85%). LC-MS calculated for C₃₉ H₄₁ ClF₂ N₅ O₃ S⁺ (M+H)⁺ : m/z=732.2; found 732.2.

步骤3. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-氟苯基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 3. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

在0℃向(1R,4R,5S)-5-(7-(2-氯-3-氟苯基)-8-(2-氰基乙基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(335mg，0.457mmol)在DCM(2.287ml)中的溶液中添加m-CPBA(103mg，0.595mmol)，并且将反应混合物在室温下搅拌30min，随后用饱和碳酸氢钠淬灭并且用DCM萃取。经硫酸钠干燥有机层并且浓缩。向粗产物中添加THF(2.5mL)并且冷却混合物至0℃。逐滴添加溴化甲基镁(3M于二乙醚中，305μl，0.915mmol)并且使反应混合物在0℃搅拌30min，随后用氯化铵饱和水溶液淬灭。用乙酸乙酯萃取混合物，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。将粗产物溶解于DCM/TFA(1:1；2mL)中，接着在室温下搅拌30min，用MeOH稀释并且通过制备型HPLC(pH 10，接着pH 2)纯化，得到所需产物。LC-MS计算值C₃₄H₃₃ClF₂N₅O⁺(M+H)⁺:m/z＝600.2；实验值600.2。¹H NMR(600MHz,DMSO)δ8.18(d,J＝6.7Hz,1H),7.59(dd,J＝7.9,3.9Hz,2H),7.49-7.40(m,1H),6.40(s,1H),5.34(d,J＝7.2Hz,1H),4.90(s,1H),4.39-4.20(m,1H),3.98(s,1H),3.73(s,1H),3.59-3.46(m,2H),2.87(d,J＝6.3Hz,2H),2.82-2.69(m,7H),2.30(s,1H),1.96(s,2H),1.86(s,2H),1.25-1.17(m,1H),0.81(m,4H)。To a solution of (1R,4R,5S)-5-(7-(2-chloro-3-fluorophenyl)-8-(2-cyanoethyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (335 mg, 0.457 mmol) in DCM (2.287 ml) at 0°C was added m-CPBA (103 mg, 0.595 mmol) and the reaction mixture was stirred at room temperature for 30 min, then quenched with saturated sodium bicarbonate and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. THF (2.5 mL) was added to the crude product and the mixture was cooled to 0°C. Methylmagnesium bromide (3M in diethyl ether, 305 μl, 0.915 mmol) was added dropwise and the reaction mixture was stirred at 0°C for 30 min, then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was dissolved in DCM/TFA (1:1; 2 mL), then stirred at room temperature for 30 min, diluted with MeOH and purified by preparative HPLC (pH 10, then pH 2) to give the desired product. LC-MS calculated for C₃₄ H₃₃ ClF₂ N₅ O⁺ (M+H)⁺ : m/z=600.2; found 600.2.¹ H NMR (600MHz, DMSO) δ8.18(d,J＝6.7Hz,1H),7.59(dd,J＝7.9,3.9Hz,2H),7.49-7.40(m,1H),6.40(s,1H),5.34(d,J＝7.2Hz,1H),4.90(s,1H),4.39-4.20( m,1H),3.98(s,1H),3.73(s,1H),3.59-3.46(m,2H),2.87(d,J＝6.3Hz,2H),2.82-2.69(m,7H),2.30(s,1H),1.96(s,2H),1.86(s,2H),1.25-1.17(m ,1H),0.81(m,4H).

实施例35. 8-(2-((R)-1-乙酰基吡咯烷-2-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-(2-甲基吡啶-4-基)-1H-吡咯并[3,2-c]喹啉-7-基)-1,2,3,4-四氢萘-1-甲腈Example 35. 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

步骤1.(R)-1-(2-乙炔基吡咯烷-1-基)乙-1-酮Step 1. (R)-1-(2-ethynylpyrrolidin-1-yl)ethan-1-one

在0℃将乙酸酐(1.72ml，18.2mmol)逐滴添加至(R)-2-乙炔基吡咯烷盐酸盐(2g，15.2mmol)和三乙胺(4.66ml，33.4mmol)在DCM(20ml)中的溶液中，并且在0℃搅拌所得混合物30分钟。用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用1N HCl、1N NaOH、水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₈H₁₂NO(M+H)⁺:m/z＝138.2；实验值138.2。Acetic anhydride (1.72 ml, 18.2 mmol) was added dropwise to a solution of (R)-2-ethynylpyrrolidine hydrochloride (2 g, 15.2 mmol) and triethylamine (4.66 ml, 33.4 mmol) in DCM (20 ml) at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, 1N NaOH, water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₈ H₁₂ NO (M+H)⁺ : m/z=138.2; found 138.2.

步骤2.(1R,4R,5S)-5-((3-(((R)-1-乙酰基吡咯烷-2-基)乙炔基)-7-溴-8-氟-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-((3-(((R)-1-acetylpyrrolidin-2-yl)ethynyl)-7-bromo-8-fluoro-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-8-氟-3-碘-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体7，700mg，1.151mmol)、(R)-1-(2-乙炔基吡咯烷-1-基)乙酸-1-酮(316mg，2.301mmol)、双(三苯基膦)氯化钯(II)(162mg，0.230mmol)、碘化铜(I)(219mg，1.151mmol)和DIPEA(2.010ml，11.51mmol)在DMF(15ml)中的混合物在70℃搅拌2小时。完成后，将反应混合物用乙酸乙酯稀释，随后用水(3次)和盐水洗涤。有机相经无水硫酸钠干燥，过滤并浓缩。通过快速色谱(用0至100％梯度的乙酸乙酯/己烷洗脱)纯化粗物质，得到产物(700mg，98％产率)。LC-MS计算值C₂₉H₃₅BrFN₄O₃S(M+H)⁺:m/z＝617.2；实验值617.1。A mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-8-fluoro-3-iodo-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 7, 700 mg, 1.151 mmol), (R)-1-(2-ethynylpyrrolidin-1-yl)acet-1-one (316 mg, 2.301 mmol), bis(triphenylphosphine)palladium(II) chloride (162 mg, 0.230 mmol), copper(I) iodide (219 mg, 1.151 mmol) and DIPEA (2.010 ml, 11.51 mmol) in DMF (15 ml) was stirred at 70°C for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate followed by washing with water (3 times) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (eluting with a gradient of 0 to 100% ethyl acetate_in hexanes) to give the product (₇₀₀ mg, 98% yield). LC-MS_Calcd for_{C29H35BrFN4O3S} (M+H)⁺ : m/z = 617.2; found 617.1.

步骤3.(1R,4R,5S)-5-(2-((R)-1-乙酰基吡咯烷-2-基)-7-溴-6-氟-8-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(2-((R)-1-acetylpyrrolidin-2-yl)-7-bromo-6-fluoro-8-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((3-(((R)-1-乙酰基吡咯烷-2-基)乙炔基)-7-溴-8-氟-6-甲基-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(600mg，0.972mmol)和Cs₂CO₃(950mg，2.91mmol)在DMF(12ml)中的混合物在100℃搅拌1h。冷却至室温后，用乙酸乙酯稀释反应混合物，随后用水(3次)和盐水洗涤。有机相经无水硫酸钠干燥，过滤并浓缩，得到粗产物(600mg，100％产率)，其不经进一步纯化即用于下一步骤中。LC-MS计算值C₂₉H₃₅BrFN₄O₃S(M+H)⁺:m/z＝617.2；实验值617.1。A mixture of (1R,4R,5S)-tert-butyl 5-((3-(((R)-1-acetylpyrrolidin-2-yl)ethynyl)-7-bromo-8-fluoro-6-methyl-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (600 mg, 0.972 mmol) and Cs₂ CO₃ (950 mg, 2.91 mmol) in DMF (12 ml) was stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and subsequently washed with water (3 times) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product (600 mg, 100% yield) which was used in the next step without further purification. LC-MS calculated_{forC29H35BrFN4O3S} (M+_H)⁺ : m/z = 617.2; found 617.1.

步骤4.(1R,4R,5S)-5-(2-((R)-1-乙酰基吡咯烷-2-基)-7-(8-氰基-5,6,7,8-四氢萘-1-基)-6-氟-8-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(2-((R)-1-acetylpyrrolidin-2-yl)-7-(8-cyano-5,6,7,8-tetrahydronaphthalen-1-yl)-6-fluoro-8-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-(2-((R)-1-乙酰基吡咯烷-2-基)-7-溴-6-氟-8-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(125mg，0.202mmol)、双(二-叔丁基(4-二甲基氨基苯基)膦)二氯钯(II)(43.0mg，0.061mmol)、8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,2,3,4-四氢萘-1-甲腈(172mg，0.607mmol)和K₃PO₄(129mg，0.607mmol)于二噁烷(5ml)和水(1ml)中的混合物在100℃搅拌1h。将反应物冷却至室温并且真空去除溶剂，并且通过快速色谱(用0至100％乙酸乙酯/己烷梯度洗脱)纯化残余物，得到所需产物(100mg，71％产率)。LC-MS计算值C₄₀H₄₅FN₅O₃S(M+H)⁺:m/z＝694.3；实验值694.3。Tert-butyl (1R,4R,5S)-5-(2-((R)-1-acetylpyrrolidin-2-yl)-7-bromo-6-fluoro-8-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (125 mg, 0.202 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (43.0 mg, 0.061 mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (172 mg, 0.607 mmol) and K₃ PO₄ A mixture of (129 mg, 0.607 mmol) in dioxane (5 ml) and water (1 ml) was stirred at 100°C for 1 h. The reaction was cooled to room temperature and the solvent was removed in vacuo, and the residue was purified by flash chromatography (eluting with a gradient of 0 to 100% ethyl acetate in hexanes) to give the desired product (100 mg, 71% yield). LC-MS calculated for C₄₀ H₄₅ FN₅ O₃ S (M+H)⁺ : m/z = 694.3; found 694.3.

步骤5：8-(2-((R)-1-乙酰基吡咯烷-2-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-(2-甲基吡啶-4-基)-1H-吡咯并[3,2-c]喹啉-7-基)-1,2,3,4-四氢萘-1-甲腈Step 5: 8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile

将(1R,4R,5S)-5-(2-((R)-1-乙酰基吡咯烷-2-基)-7-(8-氰基-5,6,7,8-四氢萘-1-基)-6-氟-8-甲基-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(100mg，0.144mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(95mg，0.432mmol)、3-甲基水杨酸铜(I)(111mg，0.519mmol)和Pd(PPh₃)₄(50.0mg，0.043mmol)于二噁烷(5ml)中的混合物在105℃搅拌2h。冷却至室温后，经由硅藻土过滤反应混合物，并且真空浓缩滤液。将残余物溶解于TFA(2ml)和DCM(2ml)中并且在室温下搅拌30min。将反应混合物用CH₃CN稀释，接着通过制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末形式的TFA盐形式的产物。Tert-butyl (1R,4R,5S)-5-(2-((R)-1-acetylpyrrolidin-2-yl)-7-(8-cyano-5,6,7,8-tetrahydronaphthalen-1-yl)-6-fluoro-8-methyl-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.144 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (95 mg, 0.432 mmol), 3-methylsalicylate copper(I) (111 mg, 0.519 mmol) and Pd(PPh₃ )₄ A mixture of (50.0 mg, 0.043 mmol) in dioxane (5 ml) was stirred at 105 ° C for 2 h. After cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 ml) and DCM (2 ml) and stirred at room temperature for 30 min. The reaction mixture was diluted with CH₃ CN and then purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to obtain the product in the form of a TFA salt in the form of a white amorphous powder.

非对映异构体1。峰1。LC-MS计算值C₄₀H₄₀FN₆O(M+H)⁺:m/z＝639.3；实验值639.3。Diastereomer 1. Peak 1. LC-MS Calcd. for C₄₀ H₄₀ FN₆ O (M+H)⁺ : m/z = 639.3; found 639.3.

非对映异构体2。峰2。LC-MS计算值C₄₀H₄₀FN₆O(M+H)⁺:m/z＝639.3；实验值639.3。此为所需峰。¹H NMR(600MHz,DMSO-d₆)δ9.30(s,1H),8.81(d,J＝5.5Hz,1H),8.20(s,1H),8.18(s,1H),8.05-7.96(m,2H),7.46(t,J＝7.6Hz,1H),7.35(d,J＝7.7Hz,1H),7.14(d,J＝7.3Hz,1H),6.64(s,1H),5.62(d,J＝2.9Hz,1H),5.24(d,J＝8.1Hz,1H),4.62(d,J＝6.0Hz,1H),3.96(dt,J＝6.4,3.2Hz,1H),3.89(t,J＝4.3Hz,1H),3.83(t,J＝9.2Hz,1H),3.77(s,1H),3.55(td,J＝10.0,7.0Hz,1H),3.46-3.40(m,1H),3.06-2.87(m,2H),2.73(s,3H),2.41-2.35(m,4H),2.34-2.25(m,1H),2.15(s,3H),2.13-2.09(m,1H)2.05-1.78(m,5H),1.75-1.67(m,1H),1.58(d,J＝9.2Hz,1H)。Diastereomer 2. Peak 2. LC-MS calculated for C₄₀ H₄₀ FN₆ O (M+H)⁺ : m/z = 639.3; found 639.3. This is the desired peak.¹ H NMR (600 MHz, DMSO-d₆ )δ9.30(s,1H),8.81(d,J＝5.5Hz,1H),8.20(s,1H),8.18(s,1H),8.05-7.96(m,2H),7.46(t,J＝7.6Hz,1H),7.35(d,J＝7.7Hz,1H),7.14(d,J＝7.3Hz,1H) ,6.64(s,1H),5.62(d,J＝2.9Hz,1H),5.24(d,J＝8.1Hz,1H),4.62(d,J＝6.0Hz,1H),3.96(dt,J＝6.4,3.2Hz,1H),3.8 9(t,J＝4.3Hz,1H),3.83(t,J＝9.2Hz,1H),3.77(s,1H),3.55(td,J＝10.0,7.0Hz,1H),3.46-3.40(m,1H),3.06-2.87(m,2H),2.73(s,3H),2.41-2.35(m ,4H),2.34-2.25(m,1H),2.15(s,3H),2.13-2.09(m,1H)2.05-1.78(m,5H),1.75-1.67(m,1H),1.58(d,J＝9.2Hz,1H).

非对映异构体3。峰3。LC-MS计算值C₄₀H₄₀FN₆O(M+H)⁺:m/z＝639.3；实验值639.3。Diastereomer 3. Peak 3. LC-MS Calcd. for C₄₀ H₄₀ FN₆ O (M+H)⁺ : m/z = 639.3; found 639.3.

实施例36：5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺Example 36: 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide

步骤1：(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazin-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.70g，4.17mmol，中间体5)、(R)-1-(丁-3-炔-2-基)吡嗪-2(1H)-酮(1.24g，8.34mmol，中间体20)、四(三苯基膦)钯(0)(0.96g，0.83mmol)、CuI(0.32g，1.67mmol)和N,N-二异丙基乙胺(7.3mL，41.7mmol)在DMF(21.0mL)中的混合物用N₂充气并且加热至70℃持续1h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用乙酸乙酯萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.1。A mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.70 g, 4.17 mmol, Intermediate 5), (R)-1-(but-3-yn-2-yl)pyrazin-2(1H)-one (1.24 g, 8.34 mmol, Intermediate 20), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol), CuI (0.32 g, 1.67 mmol) and N,N-diisopropylethylamine (7.3 mL, 41.7 mmol) in DMF (21.0 mL) was sparged with_N2 and heated to 70°C for 1 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with ethyl acetate, washed with brine, concentrated and purified by flash chromatography (0 to 100%_EtOAc /_hexanes ) to give the title compound. LC-MS Calcd_. for_{C31H33BrFN6O3S} (M+H)⁺ : m/z = 667.1; found 667.1.

步骤2：(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.00g，3.00mmol)和碳酸铯(2.93g，9.00mmol)在DMA(6.0mL)中的混合物在100℃加热0.5h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EA萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.2。A mixture of (1R, 4R, 5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazine-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.00 g, 3.00 mmol) and cesium carbonate (2.93 g, 9.00 mmol) in DMA (6.0 mL) was heated at 100 ° C for 0.5 h. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EA, washed with brine, concentrated and purified by flash chromatography (0 to 100% EtOAc/hexanes) to give the title compound. LC^{-MS calculated for C31H33BrFN6O3S (M+H)+}_:m/z = 667.1; found 667.2.

步骤3：(1R,4R,5S)-5-(7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(173mg，0.26mmol)、(3-氯-2-甲基苯基)硼酸(88mg，0.52mmol)、四(三苯基膦)钯(0)(45mg，0.039mmol)、磷酸钾(220mg，1.04mmol)于二噁烷(1.2mL)和水(0.12mL)中的混合物用N₂充气并且在100℃加热2h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EA萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₈H₃₉ClFN₆O₃S(M+H)⁺:m/z＝713.2；实验值713.3。A mixture of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (173 mg, 0.26 mmol), (3-chloro-2-methylphenyl)boronic acid (88 mg, 0.52 mmol), tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol), potassium phosphate (220 mg, 1.04 mmol) in dioxane (1.2 mL) and water (0.12 mL) was sparged with_N2 and heated at 100°C for 2 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EA, washed with brine_, concentrated and purified by flash chromatography (0 to 100%_EtOAc /_hexanes ) to give the title compound. LC-MS calcd for_{C38H39ClFN6O3S} (M+H)⁺ : m/z = 713.2; found 713.3.

步骤4:5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺Step 4: 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide

将(1R,4R,5S)-5-(7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(50mg，0.070mmol)、N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺(74mg，0.28mmol)、四(三苯基膦)-钯(0)(41mg，0.035mmol)、3-甲基水杨酸铜(I)(68mg，0.32mmol)于二噁烷(0.35mL)中的混合物用N₂充气并且加热至120℃持续1h。完成后，经由硅藻土过滤反应混合物并且浓缩。向残余物中添加一滴MeCN和2M HCl于二噁烷中的溶液(2mL)。搅拌混合物30min，并且通过制备型HPLC(pH 2)纯化。以一对滞转异构体形式分离标题化合物。对两种滞转异构体的混合物的TFA盐收集¹H NMR。¹HNMR(600MHz,DMSO-d₆)δ9.51(br,2H),9.31(dd,J＝5.8,2.2Hz,1H),9.08(dd,J＝5.8,2.2Hz,1H),8.90(m,1H),8.88(m,1H),8.68(td,J＝8.6,2.3Hz,1H),8.47(td,J＝8.6,2.3Hz,1H),8.34(br,2H),8.31(d,J＝8.1Hz,1H),8.25-8.16(m,5H),7.98(m,1H),7.65-7.60(m,2H),7.58(dd,J＝8.5,4.5Hz,1H),7.52(d,J＝4.2Hz,1H),7.47-7.39(m,2H),7.36-7.29(m,2H),7.26(d,J＝7.5Hz,1H),7.01-6.91(m,1H),6.40(dd,J＝10.5Hz,1H),6.30(m,1H),6.09(m,1H),5.74(m,1H),5.26(m,1H),5.16(m,1H),4.95(m,1H),4.02(m,1H),3.81(m,1H),3.40(m,2H),3.04(m,2H),2.89-2.63(m,12H),2.18(m,3H),2.13(m,2H),2.06(m,3H)1.85(m,3H),1.79(m,3H),1.52(d,J＝9.2Hz,2H)。A mixture of (1R,4R,5S)-5-(7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (50 mg, 0.070 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (74 mg, 0.28 mmol), tetrakis(triphenylphosphine)-palladium(0) (41 mg, 0.035 mmol), 3-methylsalicylic acid copper(I) (68 mg, 0.32 mmol) in dioxane (0.35 mL) was added with N₂ was aerated and heated to 120 °C for 1 h. Upon completion, the reaction mixture was filtered through celite and concentrated. A drop of MeCN and a solution of 2M HCl in dioxane (2 mL) were added to the residue. The mixture was stirred for 30 min and purified by preparative HPLC (pH 2). The title compound was isolated as a pair of hysteresis isomers.¹ H NMR was collected for the TFA salt of the mixture of two hysteresis isomers.¹ HNMR (600 MHz, DMSO-d₆ )δ9.51(br,2H),9.31(dd,J＝5.8,2.2Hz,1H),9.08(dd,J＝5.8,2.2Hz,1H),8.90(m,1H),8.88(m,1H),8.68(td,J＝8.6,2.3Hz,1H),8.47(td,J＝8.6,2.3Hz,1H ),8.34(br,2H),8.31(d,J＝8.1Hz,1H),8.25-8.16(m,5H),7.98(m,1H),7.65-7.60(m,2H),7.58(dd,J＝8.5,4.5Hz,1H),7.52(d,J＝4.2Hz,1H),7.47-7. 39(m,2H),7.3 4 .95(m,1H) ,4.02(m,1H),3.81(m,1H),3.40(m,2H),3.04(m,2H),2.89-2.63(m,12H),2.18(m,3H),2.13(m,2H),2.06(m,3H)1.85(m,3H),1.79(m,3H),1.52(d ,J=9.2Hz,2H).

滞转异构体1。峰1。LC-MS计算值C₃₉H₃₅ClFN₈O₂(M+H)⁺:m/z＝701.3；实验值701.2。Anisomeric form 1. Peak 1. LC-MS calculated for C₃₉ H₃₅ ClFN₈ O₂ (M+H)⁺ : m/z = 701.3; found 701.2.

滞转异构体2。峰2。LC-MS计算值C₃₉H₃₅ClFN₈O₂(M+H)⁺:m/z＝701.3；实验值701.2。Anisomeric form 2. Peak 2. LC-MS calculated for C₃₉ H₃₅ ClFN₈ O₂ (M+H)⁺ : m/z = 701.3; found 701.2.

实施例37：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 37: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazine-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物根据实施例36、步骤3中所描述的程序，使用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷代替(3-氯-2-甲基苯基硼酸来制备。LC-MS计算值C₄₁H₃₉F₂N₆O₃S(M+H)⁺:m/z＝733.3；实验值733.2。This compound was prepared according to the procedure described in Example 36, Step 3, using 2-(7-fluoronaphthalen-1-yl)_-4,4,5,5 -tetramethyl-1,3,2-dioxaborolane instead of (3-chloro-₂ -methylphenylboronic acid._LC -_MS calculated for_{C41H39F2N6O3S} (M+H)⁺ : m/z = 733.3; found 733.2.

步骤2：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例36、步骤4中所描述的程序，使用(1R,4R,5S)-5-(8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯代替(1R,4R,5S)-5-(7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯和使用5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶代替N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺来制备。以两种滞转异构体的混合物形式分离标题化合物。LC-MS计算值C₄₃H₃₈F₂N₇O₂(M+H)⁺:m/z＝722.3；实验值722.2。对两种滞转异构体的混合物的TFA盐收集¹H NMR。¹H NMR(500MHz,DMSO-d₆)δ9.45(br,2H),9.21(d,J＝5.3Hz,1H),9.19(br,2H),9.03(d,J＝5.3Hz,1H),8.49(t,J＝6.6Hz,1H),8.35-8.15(m,7H),8.08(m,1H),7.94(d,J＝8.0Hz,1H),7.85(d,J＝7.9Hz,1H),7.76-7.65(m,4H),7.61(d,J＝6.6Hz,1H),7.58-7.49(m,4H),7.32(m,1H),7.14(d,J＝10.2Hz,1H),7.09(d,J＝9.4Hz,1H),7.06-6.94(m,1H),6.88(d,J＝10.2Hz,1H),6.46(d,J＝3.0Hz,1H),6.33(m,1H),6.12(m,1H),5.74(m,1H),5.38-5.24(m,1H),5.18(d,J＝12.1Hz,1H),5.15-4.95(m,1H),4.01(m,1H),3.95-3.80(m,1H),3.59(br,2H),3.40(m,2H),3.04(m,2H),2.95-2.66(m,8H),2.16(m,2H),1.89(m,3H),1.80(m,3H),1.55(s,6H),1.52(m,2H),1.50(s,6H)。This compound was prepared according to the procedure described in Example 36, Step 4, using (1R,4R,5S)-5-(8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester instead of (1R,4R,5S)-5-(7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate. Prepared by using tert-butyl 4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate and using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-((trimethylsilyl)oxy)propan-2-yl)pyridine instead of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide. The title compound was isolated as a mixture of two atropisomers. LC-MS calculated for C₄₃ H₃₈ F₂ N₇ O₂ (M+H)⁺ : m/z = 722.3; found 722.2.¹ H NMR was collected on the TFA salt of the mixture of two alagostomers.¹ H NMR (500 MHz, DMSO-d₆ )δ9.45(br,2H),9.21(d,J＝5.3Hz,1H),9.19(br,2H),9.03(d,J＝5.3Hz,1H),8.49(t,J＝6.6Hz,1H),8.35-8.15(m,7H),8.08(m,1H),7.94(d,J＝8.0Hz,1H) ,7.85(d,J＝7.9Hz,1H),7.76-7.65(m,4H),7.61(d,J＝6.6Hz,1H),7.58-7.49(m,4H),7.32(m,1H),7.14(d,J＝10.2Hz,1H),7.09(d,J＝9.4Hz,1H),7.06- 6.94(m,1H),6 .88(d,J＝10.2Hz,1H),6.46(d,J＝3.0Hz,1H),6.33(m,1H),6.12(m,1H),5.74(m,1H),5.38-5.24(m,1H),5.18(d,J＝12.1Hz,1H),5.15-4.95(m,1H),4 .01(m,1H),3.95-3.80(m,1H),3.59(br,2H),3.40(m,2H),3.04(m,2H),2.95-2.66(m,8H),2.16(m,2H),1.89(m,3H),1.80(m,3H),1.55(s,6H),1. 52(m,2H),1.50(s,6H).

实施例38：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪-2-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 38: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例36、步骤4中所描述的程序，使用2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡嗪代替N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺来制备。以一对滞转异构体形式分离标题化合物。This compound was prepared according to the procedure described in Example 36, Step 4, using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine instead of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide. The title compound was isolated as a pair of anisomeric forms.

滞转异构体1。峰1。LC-MS计算值C₃₇H₃₃ClFN₈O(M+H)⁺:m/z＝659.2；实验值659.2。Anisomeric form 1. Peak 1. LC-MS calculated for C₃₇ H₃₃ ClFN₈ O (M+H)⁺ : m/z = 659.2; found 659.2.

滞转异构体2。峰2。LC-MS计算值C₃₇H₃₃ClFN₈O(M+H)⁺:m/z＝659.2；实验值659.2。Anisomeric form 2. Peak 2. LC-MS calculated for C₃₇ H₃₃ ClFN₈ O (M+H)⁺ : m/z = 659.2; found 659.2.

实施例39.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(5-氟-6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 39. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

步骤1.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(5.63g，7.42mmol，实施例28，步骤1)在DMF(37.1ml)中的溶液中添加碳酸铯(7.25g，22.26mmol)，并且将反应混合物加热至90℃持续2h。在通过LCMS观测到完全环化之后，添加氟化铯(4.51g，29.7mmol)并且将反应混合物加热至90℃。3h之后，用DCM和5％LiCl水溶液稀释反应物。将有机物相继用5％LiCl水溶液和盐水洗涤三次，经硫酸镁干燥并且浓缩。粗物质不经另外纯化即直接使用。LC-MS计算值C₂₉H₃₄BrFN₅O₂S⁺(M+H)⁺:m/z＝614.2/616.2；实验值614.2/616.2。To a solution of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)ethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.63 g, 7.42 mmol, Example 28, Step 1) in DMF (37.1 ml) was added cesium carbonate (7.25 g, 22.26 mmol) and the reaction mixture was heated to 90° C. for 2 h. After complete cyclization was observed by LCMS, cesium fluoride (4.51 g, 29.7 mmol) was added and the reaction mixture was heated to 90° C. After 3 h, the reaction was diluted with DCM and 5% aqueous LiCl. The organics were washed three times sequentially with 5% aqueous LiCl and brine,_dried over_magnesium sulfate and concentrated. The crude material was used directly without additional purification. LC-MS Calcd._{forC29H34BrFN5O2S}⁺ (M+H)⁺ : m/z=614.2/616.2; Found 614.2/616.2.

步骤2.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.5g，4.07mmol)于THF(20.3ml)中的溶液中添加N,N-二异丙基乙胺(4.26ml，24.4mmol)和氯甲酸甲酯(0.63ml，8.14mmol)。将反应溶液在室温下搅拌30min，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至60％丙酮/己烷的梯度洗脱来分离所需产物。LC-MS计算值C₃₁H₃₆BrFN₅O₄S⁺(M+H)⁺:m/z＝672.2/674.2；实验值672.1/674.1。To a solution of (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.5 g, 4.07 mmol) in THF (20.3 ml) was added N,N-diisopropylethylamine (4.26 ml, 24.4 mmol) and methyl chloroformate (0.63 ml, 8.14 mmol) at 0°C. The reaction solution was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product was isolated by flash column chromatography with a gradient elution of 0 to 60% acetone/hexane. LC-MS calculated_{for C31H36BrFN5O4S+}⁽ M+H)₊ : m/z=672.2/^674.2 ; found_672.1 /674.1.

步骤3.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.03g，3.02mmol)、(2,3-二氯苯基)硼酸(1.15g，6.04mmol)、氟化钾(0.526g，9.05mmol)和Pd-132(214mg，0.302mmol)的混合物中添加1,4-二噁烷(12.1ml)/水(3.02ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌1h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速色谱(0至80％丙酮/己烷)纯化粗产物，得到所需产物(1.90g，85％)。LC-MS计算值C₃₇H₃₉Cl₂FN₅O₄S⁺(M+H)⁺:m/z＝738.2/740.2；实验值738.1/740.1。To a mixture of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.03 g, 3.02 mmol), (2,3-dichlorophenyl)boronic acid (1.15 g, 6.04 mmol), potassium fluoride (0.526 g, 9.05 mmol) and Pd-132 (214 mg, 0.302 mmol) was added 1,4-dioxane (12.1 ml)/water (3.02 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C for 1 h. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by flash chromatography (₀ to 80% acetone/hexanes) to give the desired product (1.90 g, 85%)._LC- MS_Calcd for_{C37H39Cl2FN5O4S}⁺ (M+H)⁺ : m/z=738.2/740.2; Found 738.1/740.1.

步骤4.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(5-氟-6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 4. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(20mg，0.027mmol)、中间体21(27mg，0.135mmol)、四(三苯基膦)钯(0)(3.1mg，2.71μmol)和3-甲基水杨酸铜(I)(17mg，0.081mmol)的混合物中添加1,4-二噁烷(0.22ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。将粗产物在1:1TFA/DCM(1ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₈H₃₄Cl₂F₂N₇O₃⁺(M+H)⁺:m/z＝744.2/746.2；实验值744.1/746.1。To a mixture of (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (20 mg, 0.027 mmol), intermediate 21 (27 mg, 0.135 mmol), tetrakis(triphenylphosphine)palladium(0) (3.1 mg, 2.71 μmol) and 3-methylsalicylatecopper(I) (17 mg, 0.081 mmol) was added 1,4-dioxane (0.22 ml) and the reaction flask was evacuated, backfilled with nitrogen and then stirred at 100°C overnight. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was stirred in 1:1 TFA/DCM (1 ml) for 30 min, then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₈ H₃₄ Cl₂ F₂ N₇ O₃⁺ (M+H)⁺ : m/z=744.2/746.2; found 744.1/746.1.

实施例40.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 40. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向中间体18(380mg，0.46mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶(232mg，0.69mmol)、四(三苯基膦)钯(0)(53mg，0.046mmol)和3-甲基水杨酸铜(I)(297mg，1.38mmol)的混合物中添加1,4-二噁烷(3.7ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。将反应物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速色谱(0至7％MeOH/DCM)纯化粗产物，得到所需产物。LC-MS计算值C₄₈H₅₆Cl₂FN₆O₅Si⁺(M+H)⁺:m/z＝913.3/915.3；实验值913.4/915.3。To a mixture of intermediate 18 (380 mg, 0.46 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-((trimethylsilyl)oxy)propan-2-yl)pyridine (232 mg, 0.69 mmol), tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol) and 3-methylsalicylatecopper(I) (297 mg, 1.38 mmol) was added 1,4-dioxane (3.7 ml) and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 °C overnight. The reaction was quenched with water and saturated aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 7% MeOH/DCM) to give the desired product. LC^{-MS calculated for C48H56Cl2FN6O5Si+(M+H)+}_:m^/_z=913.3 /915.3; found 913.4/915.3.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(306mg，0.34mmol)在DMF(1.67ml)中的溶液中添加氟化铯(203mg，1.34mmol)，并且将反应混合物加热至90℃。1h之后，用DCM和5％LiCl水溶液稀释反应物。将有机物相继用5％LiCl水溶液和盐水洗涤三次，经硫酸镁干燥并且浓缩。粗物质不经另外纯化即直接使用。LC-MS计算值C₄₂H₄₄Cl₂FN₆O₃⁺(M+H)⁺:m/z＝769.3/771.3；实验值769.3/771.3。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (306 mg, 0.34 mmol) in DMF (1.67 ml) was added cesium fluoride (203 mg, 1.34 mmol) and the reaction mixture was heated to 90°C. After 1 h, the reaction was diluted with DCM and 5% aqueous LiCl. The organics were washed three times with 5% aqueous LiCl and brine, dried over magnesium sulfate and concentrated. The^{crude material was used directly without further purification. LC-MS calcd for C42H44Cl2FN6O3+}_(M+H )⁺ : m/_z =769.3/771.3; found 769.3/771.3.

步骤3.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 3. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(25mg，0.032mmol)于THF(0.16ml)中的经冷却至0℃的溶液中添加N,N-二异丙基乙胺(0.045ml，0.325mmol)和氯甲酸甲酯(3.76μl，0.049mmol)。将反应溶液在室温下搅拌30min，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。将粗产物在1:1TFA/DCM(1ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₉H₃₈Cl₂FN₆O₃⁺(M+H)⁺:m/z＝727.2/729.2；实验值727.3/729.3。¹H NMR(TFA盐，600MHz,DMSO-d₆)δ9.53-9.40(m,1H),9.10(d,J＝2.2Hz,1H),8.54-8.48(m,1H),8.23-8.19(m,2H),8.02(d,J＝8.4Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.54-7.46(m,1H),6.71-6.64(m,1H),5.65(s,1H),5.17(t,J＝7.9Hz,1H),4.92(dd,J＝15.7,6.0Hz,1H),4.04-3.91(m,1H),3.74-3.59(m,5H),3.55-3.38(m,2H),3.10-3.03(m,1H),2.96-2.81(m,2H),2.75-2.64(m,1H),2.42-2.29(m,2H),1.93-1.80(m,2H),1.75-1.59(m,2H),1.57(s,6H)。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (25 mg, 0.032 mmol) in THF (0.16 ml) cooled to 0°C was added N,N-diisopropylethylamine (0.045 ml, 0.325 mmol) and methyl chloroformate (3.76 μl, 0.049 mmol). The reaction solution was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was stirred in 1:1 TFA/DCM (1 ml) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₉ H₃₈ Cl₂ FN₆ O₃⁺ (M+H)⁺ : m/z=727.2/729.2; found 727.3/729.3.¹ H NMR (TFA salt, 600 MHz, DMSO-d₆ )δ9.53-9.40(m,1H),9.10(d,J＝2.2Hz,1H),8.54-8.48(m,1H),8.23-8.19(m,2H),8.02(d,J＝8.4Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz, 1H),7.54-7.46(m,1H),6.71-6.64(m,1H),5.65(s,1H),5.17(t,J＝7.9 Hz,1H),4.92(dd,J＝15.7,6.0Hz,1H),4.04-3.91(m,1H),3.74-3.59(m,5H),3.55-3.38(m,2H),3.10-3.03(m,1H),2.96-2.81(m,2H),2.75-2.64(m,1 H),2.42-2.29(m,2H),1.93-1.80(m,2H),1.75-1.59(m,2H),1.57(s,6H).

实施例41.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸乙酯Example 41. Ethyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

此化合物以类似于实施例40的方式，用氯甲酸乙酯替代步骤3中的氯甲酸甲酯来制备。LC-MS计算值C₄₀H₄₀Cl₂FN₆O₃⁺(M+H)⁺:m/z＝741.3/743.2；实验值741.4/743.4.¹H NMR(TFA盐，旋转异构体，600MHz,DMSO-d₆)δ9.38-9.26(m,1H),9.08(s,1H),8.47-8.39(m,1H),8.21-8.11(m,2H),7.97(dd,J＝10.9,8.2Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.50(t,J＝7.9Hz,1H),6.63(s,1H),5.64(s,1H),5.15(d,J＝8.1Hz,1H),4.98-4.88(m,2H),4.22-4.05(m,2H),4.02-3.92(m,1H),3.71-3.57(m,2H),3.55-3.37(m,2H),3.10-3.02(m,1H),2.95-2.82(m,2H),2.72-2.63(m,1H),2.44-2.31(m,2H),1.96-1.80(m,2H),1.72-1.59(m,2H),1.55(s,6H),1.27(t,J＝7.0Hz,2H),1.17(t,J＝7.1Hz,1H)。This compound was prepared in a manner similar to Example 40, substituting ethyl chloroformate for methyl chloroformate in step 3. LC-MS calculated for C₄₀ H₄₀ Cl₂ FN₆ O₃⁺ (M+H)⁺ : m/z=741.3/743.2; found 741.4/743.4.¹ H NMR (TFA salt, rotamer, 600 MHz, DMSO-d₆ )δ9.38-9.26(m,1H),9.08(s,1H),8.47-8.39(m,1H),8.21-8.11(m,2H),7.97(dd,J＝10.9,8.2Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz,1H ),7.50(t,J＝7.9Hz,1H),6.63(s,1H),5.64(s,1H),5.15(d,J＝8.1Hz,1H),4.98-4.88(m,2H),4. 22-4.05(m,2H),4.02-3.92(m,1H),3.71-3.57(m,2H),3.55-3.37(m,2H),3.10-3.02(m,1H),2.95-2.82(m,2H),2.72-2.63(m,1H),2.44-2.31(m, 2H), 1.96-1.80 (m, 2H), 1.72-1.59 (m, 2H), 1.55 (s, 6H), 1.27 (t, J = 7.0Hz, 2H), 1.17 (t, J = 7.1Hz, 1H).

实施例42. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d₃)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 42. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d₃ )-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.51g，2.46mmol，实施例39，步骤1)和N,N-二异丙基乙胺(1.29ml，7.37mmol)于THF(12.3ml)中的溶液中添加三光气(0.292g，0.983mmol)。在室温下搅拌反应物1h，此时添加3,3-二氟氮杂环丁烷盐酸盐(0.382g，2.95mmol)和N,N-二异丙基乙胺(1.29ml，7.37mmol)。在50℃搅拌反应混合物30min。随后用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至70％丙酮/己烷洗脱来纯化粗产物。LC-MS计算值C₃₃H₃₇BrF₃N₆O₃S⁺(M+H)⁺:m/z＝733.2/735.2；实验值733.1/735.1。To a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.51 g, 2.46 mmol, Example 39, Step 1) and N,N-diisopropylethylamine (1.29 ml, 7.37 mmol) in THF (12.3 ml) was added triphosgene (0.292 g, 0.983 mmol) at 0° C. The reaction was stirred at room temperature for 1 h, at which time 3,3-difluoroazetidine hydrochloride (0.382 g, 2.95 mmol) and N,N-diisopropylethylamine (1.29 ml, 7.37 mmol) were added. The reaction mixture was stirred at 50°C for 30 min. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 70% acetone/hexanes. LC-MS calculated for C₃₃ H₃₇ BrF₃ N₆ O₃ S⁺ (M+H)⁺ : m/z=733.2/735.2; found 733.1/735.1.

步骤2.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.12g，1.53mmol)在乙酸乙酯(30.5ml)中的溶液中添加m-CPBA(0.790g，2.29mmol)，并且将反应混合物在室温下搅拌30min，随后用饱和碳酸氢钠淬灭并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且浓缩。粗产物不经另外纯化即直接使用。LC-MS计算值C₃₃H₃₇BrF₃N₆O₄S⁺(M+H)⁺:m/z＝749.2/751.2；实验值749.2/751.1。To a solution of (1R, 4R, 5S)-5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1.12 g, 1.53 mmol) in ethyl acetate (30.5 ml) at 0°C was added m-CPBA (0.790 g, 2.29 mmol), and the reaction mixture was stirred at room temperature for 30 min, then quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The crude product was used directly without further purification. LC^{-MS calculated for C33H37BrF3N6O4S+(M+H)+}_:m^/_z=749.2 /751.2; found 749.2/751.1.

步骤3.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d₃)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d₃ )-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.14g，1.52mmol)于THF(7.6mL)中的溶液中逐滴添加(甲基-d₃)碘化镁(1M于二乙醚中，1.98ml，1.98mmol)。在0℃搅拌反应混合物30min。再添加一当量的(甲基-d₃)碘化镁溶液。在30min之后，观测到完全起始物质转化并且用氯化铵饱和水溶液淬灭反应物。用乙酸乙酯萃取混合物，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至70％乙酸乙酯/己烷洗脱来纯化粗产物。LC-MS计算值C₃₃H₃₄D₃BrF₃N₆O₃⁺(M+H)⁺:m/z＝704.2/706.2；实验值704.2/706.2。To a solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.14 g, 1.52 mmol) in THF (7.6 mL) was added (methyl-d₃ )magnesium iodide (1 M in diethyl ether, 1.98 ml, 1.98 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min. One more equivalent of (methyl-d₃ )magnesium iodide solution was added. After 30 min, complete starting material conversion was observed and the reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product_{was purified by flash column chromatography eluting with 0 to 70% ethyl acetate/hexanes. LC-MS Calcd. for C33H34D3BrF3N6O3+(M+} H)⁺ : m/^z₌ 704.2/706.2; Found 704.2/706.2.

步骤4. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d₃)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 4. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d₃ )-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d₃)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(0.150g，0.213mmol)、(2,3-二氯苯基)硼酸(0.081g，0.426mmol)、氟化钾(0.037g，0.639mmol)和Pd-132(15mg，0.021mmol)的混合物中添加1,4-二噁烷(0.85ml)/水(0.21ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃下搅拌2h。将反应混合物用乙酸乙酯和SiliaMetS硫醇官能化硅胶(Silicycle，PN R51030B，200mg)稀释，随后在室温下搅拌5分钟。经由硅藻土塞过滤浆液。用水稀释滤液。用乙酸乙酯萃取混合物，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过制备型HPLC(pH 10)分离粗产物。在通过EZ-2蒸发器浓缩之后，将产物在1:1TFA/DCM(3ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH2)纯化所需产物。LC-MS计算值C₃₄H₂₉D₃Cl₂F₃N₆O⁺(M+H)⁺:m/z＝670.2/672.2；实验值670.3/672.3。¹H NMR(TFA盐，600MHz,DMSO-d₆)δ9.48-9.37(m,1H),8.23-8.11(m,2H),7.86(dd,J＝8.2,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.47(dd,J＝7.6,1.5Hz,1H),6.96(s,1H),5.64-5.57(m,1H),5.29-5.22(m,1H),4.87(d,J＝6.0Hz,1H),4.60-4.48(m,4H),4.00-3.94(m,1H),3.82-3.75(m,1H),3.65-3.57(m,1H),3.47-3.38(m,2H),3.09-3.01(m,1H),2.92-2.81(m,2H),2.72-2.63(m,1H),2.37-2.27(m,2H),1.98-1.90(m,1H),1.78-1.67(m,2H),1.62-1.57(m,1H)。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d₃ To a mixture of tert-butyl 1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (0.150 g, 0.213 mmol), (2,3-dichlorophenyl)boronic acid (0.081 g, 0.426 mmol), potassium fluoride (0.037 g, 0.639 mmol) and Pd-132 (15 mg, 0.021 mmol) was added 1,4-dioxane (0.85 ml)/water (0.21 ml) and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 ° C for 2 h. The reaction mixture was diluted with ethyl acetate and SiliaMetS thiol functionalized silica gel (Silicycle, PN R51030B, 200 mg) and then stirred at room temperature for 5 minutes. The slurry was filtered through a plug of celite. The filtrate was diluted with water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was separated by preparative HPLC (pH 10). After concentration by EZ-2 evaporator, the product was stirred in 1:1 TFA/DCM (3 ml) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₄ H₂₉ D₃ Cl₂ F₃ N₆ O⁺ (M+H)⁺ :m/z＝670.2/672.2; Found 670.3/672.3.¹ H NMR (TFA salt, 600 MHz, DMSO-d₆ )δ9.48-9.37(m,1H),8.23-8.11(m,2H),7.86(dd,J＝8.2,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.47(dd,J＝7.6,1.5Hz,1H),6.96(s,1H),5.64-5.57(m,1H) ,5.29-5.22(m,1H),4.87(d,J＝6.0Hz,1H),4.60-4.48(m,4H ),4.00-3.94(m,1H),3.82-3.75(m,1H),3.65-3.57(m,1H),3.47-3.38(m,2H),3.09-3.01(m,1H),2.92-2.81(m,2H),2.72-2.63(m,1H),2.37-2.2 7(m,2H),1.98-1.90(m,1H),1.78-1.67(m,2H),1.62-1.57(m,1H).

实施例43. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 43. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.24g，2.95mmol，实施例39，步骤1)在DMF(14.8mL)中的溶液中添加氟化铯(1.79g，11.8mmol)，并且将反应混合物加热至90℃持续1h。随后用DCM和5％LiCl水溶液稀释反应溶液。将有机物用5％LiCl水溶液、随后盐水洗涤三次，经硫酸镁干燥并且浓缩。将残余物溶解于THF(14.8mL)中并且冷却至0℃。添加N,N-二异丙基乙胺(1.55ml，8.86mmol)，随后添加添加三光气(0.350g，1.18mmol)并且在室温下搅拌反应物1h。随后，添加3,3-二氟氮杂环丁烷盐酸盐(0.459g，3.54mmol)和N,N-二异丙基乙胺(1.55mL，8.86mmol)，并且将反应混合物在50℃搅拌30min.完成后，接着用水淬灭反应物并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱，用0至70％丙酮/己烷洗脱来纯化粗产物。LC-MS计算值C₃₃H₃₇BrF₃N₆O₃S⁺(M+H)⁺:m/z＝733.2/735.2；实验值733.1/735.1。To a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.24 g, 2.95 mmol, Example 39, Step 1) in DMF (14.8 mL) was added cesium fluoride (1.79 g, 11.8 mmol) and the reaction mixture was heated to 90 °C for 1 h. The reaction solution was then diluted with DCM and 5% aqueous LiCl. The organics were washed three times with 5% aqueous LiCl followed by brine, dried over magnesium sulfate and concentrated. The residue was dissolved in THF (14.8 mL) and cooled to 0 °C. N,N-diisopropylethylamine (1.55 ml, 8.86 mmol) was added followed by triphosgene (0.350 g, 1.18 mmol) and the reaction was stirred at room temperature for 1 h. Subsequently, 3,3-difluoroazetidine hydrochloride (0.459 g, 3.54 mmol) and N,N-diisopropylethylamine (1.55 mL, 8.86 mmol) were added and the reaction mixture was stirred at 50°C for 30 min. After completion, the reaction was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with 0 to 70% acetone/hexane. LC-MS calculated for C₃₃ H₃₇ BrF₃ N₆ O₃ S⁺ (M+H)⁺ : m/z=733.2/735.2; found 733.1/735.1.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

此化合物以类似于实施例39、步骤3的方式，用(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯替代(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₉H₄₀Cl₂F₃N₆O₃S⁺(M+H)⁺:m/z＝799.2/801.2；实验值799.2/801.2。This compound was prepared in a manner analogous to Example 39, Step 3, using (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester instead of (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester. LC-MS calculated_{forC39H40Cl2F3N6O3S}⁺ (M+H)₊^: m_/ z₌ 799.2/801.2; found_799.2 /801.2.

步骤3. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 3. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

在0℃向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(30mg，0.038mmol)在乙酸乙酯(0.75mL)中的溶液中添加m-CPBA(32mg，0.094mmol)，并且将反应混合物在室温下搅拌30min，随后用饱和碳酸氢钠淬灭并且用乙酸乙酯萃取。经硫酸钠干燥有机层并且浓缩。将残余物溶解于乙酸(0.75mL)中并且添加锌(30mg，0.459mmol)。将混合物加热至70℃持续16h。用DCM稀释反应混合物，经由硅藻土塞过滤并浓缩。将粗产物在1:1TFA/DCM(1mL)中搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₃H₃₀Cl₂F₃N₆O⁺(M+H)⁺:m/z＝653.2/655.2；实验值653.2/655.1。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (30 mg, 0.038 mmol) in ethyl acetate (0.75 mL) at 0°C was added m-CPBA (32 mg, 0.094 mmol), and the reaction mixture was stirred at room temperature for 30 min, then quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in acetic acid (0.75 mL) and zinc (30 mg, 0.459 mmol) was added. The mixture was heated to 70°C for 16 h. The reaction mixture was diluted with DCM, filtered through a plug of celite and concentrated. The crude product was stirred in 1:1 TFA/DCM (1 mL) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₃ H₃₀ Cl₂ F₃ N₆ O⁺ (M+H)⁺ : m/z=653.2/655.2; found 653.2/655.1.

实施例44：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 44: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1:(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(3-氧代-N-吗啉基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(3-oxo-N-morpholinyl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体5，3g，4.63mmol)、(R)-4-(丁-3-炔-2-基)吗啉-3-酮(中间体19，1.42g，9.27mmol)、DIPEA(8.09mL，46.3mmol)、Pd(PPh₃)₄(1.07g，0.927mmol)和碘化铜(I)(0.353g，1.854mmol)在DMF(25mL)中的溶液在70℃搅拌1h。随后浓缩反应物并且通过快速色谱纯化，得到标题化合物。LC-MS计算值C₃₁H₃₆BrFN₅O₄S⁺(M+H)⁺:m/z＝672.2；实验值672.2。A solution of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 3 g, 4.63 mmol), (R)-4-(but-3-yn-2-yl)morpholin-3-one (Intermediate 19, 1.42 g, 9.27 mmol), DIPEA (8.09 mL, 46.3 mmol), Pd(_PPh3 )₄ (1.07 g, 0.927 mmol) and copper(I) iodide (0.353 g, 1.854 mmol) in DMF (25 mL) was stirred at 70°C for 1 h. The reaction was then concentrated and purified by flash chromatography to give the title compound. LC-_MS calcd_{for C31H36BrFN5O4S+}⁽ M+_H )⁺ : m/z=672.2; found 672.2.

步骤2：(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(3-氧代-N-吗啉基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3.2g，4.76mmol)和碳酸铯(4.65g，14.27mmol)在DMF(50mL)中的溶液在70℃搅拌1h。随后浓缩反应物并且通过快速色谱纯化，得到标题化合物。LC-MS计算值C₃₁H₃₆BrFN₅O₄S⁺(M+H)⁺:m/z＝672.2；实验值672.2。A solution of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(3-oxo-N-morpholinyl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3.2 g, 4.76 mmol) and cesium carbonate (4.65 g, 14.27 mmol) in DMF (50 mL) was stirred at 70°C for 1 h. The reaction was then concentrated and purified by flash chromatography to give the title compound. LC-MS calculated for C₃₁ H₃₆ BrFN₅ O₄ S⁺ (M+H)⁺ : m/z=672.2; found 672.2.

步骤3：(1R,4R,5S)-5-(7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.16g，3.21mmol)、(3-氯-2-甲基苯基)硼酸(1.09g，6.42mmol)、Pd(PPh₃)₄(0.742g，0.642mmol)和磷酸钾(1.70g，8.03mmol)在1,4-二噁烷(20mL)和水(4mL)中的溶液在80℃搅拌30min。随后浓缩反应物并且通过快速色谱纯化，得到标题化合物。LC-MS计算值C₃₈H₄₂ClFN₅O₄S⁺(M+H)⁺:m/z＝718.3；实验值718.3。A solution of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.16 g, 3.21 mmol), (3-chloro-2-methylphenyl)boronic acid (1.09 g, 6.42 mmol), Pd(_PPh3 )₄ (0.742 g, 0.642 mmol) and potassium phosphate (1.70 g, 8.03 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 80°C for 30 min. The reaction was then concentrated and purified by flash chromatography to give the title compound. LC-MS calcd_{forC38H42ClFN5O4S}⁺ (M+H₎₊^: m/z=718.3; found 718.3.

步骤4：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 4: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

将(1R,4R,5S)-5-(7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.25g，1.74mmol)、Pd(PPh₃)₄(1.00g，0.870mmol)、3-甲基水杨酸铜(I)(1.87g，8.70mmol)和2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡嗪(1.92g，8.70mmol)在1,4-二噁烷(10mL)中的溶液在120℃搅拌1h。经由硫醇siliaprep滤筒过滤反应混合物并且浓缩。将残余物在1:1DCM/TFA(30mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₇H₃₆ClFN₇O₂⁺(M+H)⁺:m/z＝664.3；实验值664.4。¹H NMR(500MHz,DMF-d₇)δ9.71(d,J＝1.5Hz,1H),8.81(d,J＝1.5Hz,1H),8.63(s,1H),7.84(s,1H),7.65(m,1H),7.49(m,2H),6.38(q,J＝6.3Hz,1H),5.07(m,1H),4.63(d,J＝5.9Hz,1H),4.21(d,J＝16.5Hz,1H),4.16(d,J＝16.5Hz,1H),3.82(m,1H),3.76(m,1H),3.59(m,1H),3.12(m,1H),3.10(m,1H),2.96(m,2H),2.91(m,1H),2.67(s,3H),2.60(m,1H),2.52(d,J＝8.6Hz,1H),2.19(s,3H),1.94(d,J＝7.0Hz,1H),1.69(d,J＝6.7Hz,3H),1.36(d,J＝8.6Hz,1H),1.22(d,J＝7.0Hz,1H)。Tert-butyl (1R,4R,5S)-5-(7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.25 g, 1.74 mmol), Pd(PPh₃ )₄ A solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (1.92 g, 8.70 mmol) in 1,4-dioxane (10 mL) was stirred at 120 °C for 1 h. The reaction mixture was filtered through a thiol siliaprep cartridge and concentrated. The residue was stirred in 1:1 DCM/TFA (30 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2). LC-MS calculated for C₃₇ H₃₆ ClFN₇ O₂⁺ (M+H)⁺ : m/z=664.3; found 664.4.¹ H NMR (500 MHz, DMF-d₇ )δ9.71(d,J＝1.5Hz,1H),8.81(d,J＝1.5Hz,1H),8.63(s,1H),7.84(s,1H),7.65(m,1H),7.49(m,2H),6.38(q,J＝6.3Hz,1H),5.07(m,1H),4.63(d,J＝5. 9Hz,1H),4.21(d,J＝16.5Hz,1H),4.16(d,J＝16.5Hz,1H),3.82(m,1H),3.76( m,1H),3.59(m,1H),3.12(m,1H),3.10(m,1H),2.96(m,2H),2.91(m,1H),2.67(s,3H),2.60(m,1H),2.52(d,J＝8.6Hz,1H),2.19(s,3H),1.94(d,J＝7 .0Hz, 1H), 1.69 (d, J = 6.7Hz, 3H), 1.36 (d, J = 8.6Hz, 1H), 1.22 (d, J = 7.0Hz, 1H).

实施例45. 5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺Example 45. 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide

此化合物根据实施例44中所描述的程序，使用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷代替步骤3中的(3-氯-2-甲基苯基)硼酸和使用N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺代替步骤4中的2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡嗪来制备。LC-MS计算值C₄₂H₃₈F₂N₇O₃(M+H)⁺:m/z＝726.3；实验值726.4。¹H NMR(TFA盐，滞转异构体的混合物，旋转异构体，600MHz,DMSO-d₆)δ9.53(m,1H),9.25(m,1H),8.89(m,1H),8.61(m,1H),8.43-8.14(m,4H),7.77-7.48(m,3H),7.26-6.80(m,2H),5.98-5.75(m,1H),5.71-5.40(m,1H),5.24-4.91(m,1H),4.26(m,2H),4.10-2.99(m,5H),2.98-2.53(m,7H),2.49-1.92(m,3H),1.71-1.49(m,4H)。This compound was prepared according to the procedure described in Example 44 using 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanane instead of (3-chloro-2-methylphenyl)boronic acid in step 3 and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide instead of 2-methyl-_5- (4,4,5,5-tetramethyl-_1,3,2 -dioxaborolan-2-yl)pyrazine in step 4. LC-_MS calculated for_C42H38F2N7O3 (_M +H)⁺ : m/z=726.3; found 726.4.¹ H NMR (TFA salt, mixture of anisomeric isomers, rotamers, 600 MHz, DMSO-d₆ ) δ 9.53 (m, 1H), 9.25 (m, 1H), 8.89 (m, 1H), 8.61 (m, 1H), 8.43-8.14 (m, 4H), 7.77-7.48 (m, 3H), 7.26-6.80 (m, 2H), 5.98-5.75 (m, 1H), 5.71-5.40 (m, 1H), 5.24-4.91 (m, 1H), 4.26 (m, 2H), 4.10-2.99 (m, 5H), 2.98-2.53 (m, 7H), 2.49-1.92 (m, 3H), 1.71-1.49 (m, 4H).

实施例46. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 46. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例44中所描述的程序，使用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷代替步骤3中的(3-氯-2-甲基苯基)硼酸和使用5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶代替步骤4中的2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡嗪来制备。LC-MS计算值C₄₃H₄₁F₂N₆O₃(M+H)⁺:m/z＝727.3；实验值727.4。¹H NMR(TFA盐，滞转异构体的混合物，旋转异构体，600MHz,DMSO-d₆)δ9.54(m,1H),9.15(m,1H),8.51-8.14(m,4H),7.93(m,1H),7.76-7.48(m,3H),7.26-6.82(m,2H),5.99-5.78(m,1H),5.69-5.36(m,1H),5.25-4.90(m,1H),4.24(m,2H),4.11-2.98(m,5H),2.98-2.54(m,4H),2.48-1.90(m,3H),1.73-1.38(m,10H)。This compound was prepared according to the procedure described in Example 44 using 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyl)oxy)propan-2-yl)pyridine instead of 2-methyl-5-(4,4,5,5-tetramethyl-_1,3,2- dioxaborolan-₂ -yl)pyrazine in step 4. LC-MS Calcd._{for C43H41F2N6O3(} M+H)⁺ : m/z=727.3; Found 727.4.¹ H NMR (TFA salt, mixture of anisomeric isomers, rotamers, 600 MHz, DMSO-d₆ ) δ 9.54 (m, 1H), 9.15 (m, 1H), 8.51-8.14 (m, 4H), 7.93 (m, 1H), 7.76-7.48 (m, 3H), 7.26-6.82 (m, 2H), 5.99-5.78 (m, 1H), 5.69-5.36 (m, 1H), 5.25-4.90 (m, 1H), 4.24 (m, 2H), 4.11-2.98 (m, 5H), 2.98-2.54 (m, 4H), 2.48-1.90 (m, 3H), 1.73-1.38 (m, 10H).

实施例47. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(5-甲基吡嗪-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 47. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

此化合物根据实施例44中所描述的程序，使用2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷代替步骤3中的(3-氯-2-甲基苯基)硼酸来制备。LC-MS计算值C₄₀H₃₆F₂N₇O₂(M+H)⁺:m/z＝684.3；实验值684.4。¹H NMR(TFA盐，滞转异构体的混合物，旋转异构体，600MHz,DMSO-d₆)δ9.59(m,1H),9.49(m,0.7H),9.20(m,0.3H),8.82(m,1H),8.40-8.30(m,1.5H),8.27-8.16(m,2.5H),7.87-7.61(m,4H),7.55(m,1H),7.16(m,0.5H),6.92(m,0.5H),5.93(m,0.7H),5.77(m,0.3H),5.67(m,0.3H),5.44(m,0.7H),5.21-4.89(m,1H),4.35-4.12(m,2.3H),4.05-3.38(m,3.3H),3.14-1.86(m,11H),1.74-1.46(m,4.4H)。This compound was prepared according to the procedure described in Example 44 using 2-(7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of (3-chloro-2-methylphenyl)boronic acid in step 3. LC-MS calculated for C₄₀ H₃₆ F₂ N₇ O₂ (M+H)⁺ : m/z=684.3; found 684.4.¹ H NMR (TFA salt, mixture of anisomeric isomers, rotamers, 600 MHz, DMSO-d₆ )δ9.59(m,1H),9.49(m,0.7H),9.20(m,0.3H),8.82(m,1H),8.40-8.30(m,1.5H),8.27-8.16(m,2.5H),7.87-7.61(m,4H),7.55(m,1H),7.16(m,0. 5H),6.92(m,0.5H), 5.93(m,0.7H),5.77(m,0.3H),5.67(m,0.3H),5.44(m,0.7H),5.21-4.89(m,1H),4.35-4.12(m,2.3H),4.05-3.38(m,3.3H),3.14-1.86(m,11H), 1.74-1.46(m,4.4H).

实施例48.(1R,3R,5R)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯Example 48. Methyl (1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

此化合物以类似于实施例30的方式，使用(1R,3R,5R)-2-氮杂双环[3.1.0]己烷-2,3-二甲酸2-(叔丁基)3-乙酯代替步骤1中的(1S,3R,5S)-2-氮杂双环[3.1.0]己烷-2,3-二甲酸2-(叔丁基)3-乙酯来制备。LC-MS计算值C₄₀H₃₇Cl₂FN₇O₃⁺(M+H)⁺:m/z＝752.2/754.2；实验值752.2/754.2。¹H NMR(600MHz,DMSO-d₆)δ9.91-9.76(m,1H),9.15-9.06(m,1H),8.42(t,J＝8.0Hz,1H),8.22(d,J＝7.5Hz,1H),8.07(s,1H),7.84(t,J＝8.9Hz,2H),7.64-7.56(m,1H),7.50(d,J＝6.6Hz,1H),6.53(d,J＝3.4Hz,1H),5.66(d,J＝10.5Hz,1H),5.41(d,J＝10.7Hz,1H),4.86(d,J＝6.1Hz,1H),3.93-3.77(m,2H),3.75(s,1H),3.67(d,J＝4.0Hz,1H),3.49-3.26(m,1H),3.10-3.05(m,4H),3.04(d,J＝1.9Hz,3H),2.91(dt,J＝12.6,6.6Hz,2H),2.87-2.79(m,1H),2.73(td,J＝15.7,7.4Hz,1H),2.31(s,1H),2.14-1.98(m,1H),1.71-1.56(m,2H),1.19(t,J＝7.3Hz,1H),0.71-0.61(m,1H),0.60-0.41(m,1H)。This compound was prepared in a manner similar to Example 30, using 2-(tert-butyl)3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate instead of 2-(tert-butyl)3-ethyl (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate in step 1. LC-MS calculated for C₄₀ H₃₇ Cl₂ FN₇ O₃⁺ (M+H)⁺ : m/z=752.2/754.2; found 752.2/754.2.¹ H NMR (600 MHz, DMSO-d₆ )δ9.91-9.76(m,1H),9.15-9.06(m,1H),8.42(t,J＝8.0Hz,1H),8.22(d,J＝7.5Hz,1H),8.07(s,1H),7.84(t,J＝8.9Hz,2H),7.64-7.56(m,1H),7.50(d, J＝6.6Hz,1H),6.53(d,J＝3.4Hz,1H),5.66(d,J＝10.5Hz,1H),5.41(d,J＝10.7Hz,1H),4.86(d,J＝6.1Hz,1H),3.93-3.77(m,2H),3.75( s,1H),3.67(d,J＝4.0Hz,1H),3.49-3.26(m,1H),3.10-3.05(m,4H),3.04(d,J＝1.9Hz,3H),2.91(dt,J＝12.6,6.6Hz,2H),2.87-2.79(m,1H),2.73(td ,J＝15.7,7.4Hz,1H),2.31(s,1H),2.14-1.98(m,1H),1.71-1.56(m,2H),1.19(t,J＝7.3Hz,1H),0.71-0.61(m,1H),0.60-0.41(m,1H).

实施例49. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 49. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,3R,5R)-3-(羟基甲基)-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 1. tert-Butyl (1R,3R,5R)-3-(Hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

在0℃向(1R,3R,5R)-2-氮杂双环[3.1.0]己烷-2,3-二甲酸2-(叔丁基)3-乙酯(4.243g，16.62mmol)于四氢呋喃(83ml)中的溶液中添加LAH(0.757g，19.94mmol，2M于THF中)并且在室温下搅拌反应混合物1h，接着冷却至0℃。通过连续添加760μL水、760μL 15％NaOH和2.3mL水来淬灭反应物。在室温下搅拌30min之后，用DCM稀释混合物并且经由硅藻土塞过滤。浓缩滤液。粗产物不经进一步纯化即用于下一步骤中(2.78g，79％)。LC-MS计算值C₁₁H₂₀NO₃⁺(M+H)⁺:m/z＝214.1；实验值214.2。To a solution of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl) 3-ethyl ester (4.243 g, 16.62 mmol) in tetrahydrofuran (83 ml) was added LAH (0.757 g, 19.94 mmol, 2M in THF) at 0°C and the reaction mixture was stirred at room temperature for 1 h, then cooled to 0°C. The reactants were quenched by the sequential addition of 760 μL of water, 760 μL of 15% NaOH, and 2.3 mL of water. After stirring at room temperature for 30 min, the mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated. The crude product was used in the next step without further purification (2.78 g, 79%). LC-MS calculated for C₁₁ H₂₀ NO₃⁺ (M+H)⁺ : m/z=214.1; found 214.2.

步骤2.(1R,3R,5R)-3-甲酰基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 2. (1R,3R,5R)-tert-butyl 3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

在-78℃向乙二酰氯(1.372mL，15.67mmol)在DCM(60mL)中的溶液逐滴添加DMSO(1.112mL，15.67mmol)，并且在-78℃搅拌反应混合物45min，随后逐滴添加来自前一步骤的(1R,3R,5R)-3-(羟基甲基)-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(2.78g，13mmol)在DCM(5mL)中的溶液。再继续搅拌45min，此时添加三乙胺(5.46mL，39.2mmol)。在-78℃再搅拌45min后，将反应混合物转移至冰浴中并且搅拌15min，随后用水淬灭并且用DCM萃取。将有机层用1N HCl、水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(2.5g，91％)。LC-MS计算值C₁₁H₁₈NO₃⁺(M+H)⁺:m/z＝212.1；实验值212.2。To a solution of oxalyl chloride (1.372 mL, 15.67 mmol) in DCM (60 mL) was added DMSO (1.112 mL, 15.67 mmol) dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 45 min, followed by dropwise addition of a solution of (1R, 3R, 5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.78 g, 13 mmol) in DCM (5 mL) from the previous step. Stirring was continued for another 45 min, at which time triethylamine (5.46 mL, 39.2 mmol) was added. After stirring for another 45 min at -78 °C, the reaction mixture was transferred to an ice bath and stirred for 15 min, then quenched with water and extracted with DCM. The organic layer was washed with 1N HCl, water, and brine, dried over sodium sulfate, and concentrated. The crude product was used in the next step without further purification (2.5 g, 91%). LC-MS calculated for C₁₁ H₁₈ NO₃⁺ (M+H)⁺ : m/z = 212.1; found 212.2.

步骤3.(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯Step 3. tert-Butyl (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

在0℃向(1R,3R,5R)-3-甲酰基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(2.498g，11.82mmol)在MeOH(60mL)中的液中添加碳酸钾(3.27g，23.65mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(1.775mL，11.82mmol)，并且在室温下搅拌反应混合物2h，随后浓缩。将残余物分配于水与乙酸乙酯之间，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₁₂H₁₈NO₂⁺(M+H)⁺:m/z＝208.1；实验值208.2。To a solution of (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.498 g, 11.82 mmol) in MeOH (60 mL) was added potassium carbonate (3.27 g, 23.65 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.775 mL, 11.82 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 h, then concentrated. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₁₂ H₁₈ NO₂⁺ (M+H)⁺ : m/z=208.1; found 208.2.

步骤4.(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸2-(三甲基甲硅烷基)乙酯Step 4. 2-(Trimethylsilyl)ethyl (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate

在室温下搅拌(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(2.451g，11.82mmol)于4N HCl/二噁烷(20mL)中的溶液2h，随后浓缩。将残余物溶解于乙腈(40mL)中并且添加三乙胺(8.24mL，59.1mmol)。在5min之后，以固体形式添加1-[2-三甲基甲硅烷基)乙氧基羰基氧基]吡咯烷-2,5-二酮(3.07g，11.82mmol)，并且搅拌反应混合物过夜。用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(0至50％乙酸乙酯/己烷)纯化粗产物，得到所需产物(1.94，65％)。LC-MS计算值C₁₃H₂₂NO₂Si⁺(M+H)⁺:m/z＝252.1；实验值252.2。A solution of (1R, 3R, 5R) -3- ethynyl -2- azabicyclo [3.1.0] hexane -2- tert-butyl formate (2.451 g, 11.82 mmol) in 4N HCl/ dioxane (20 mL) was stirred at room temperature for 2 h, then concentrated. The residue was dissolved in acetonitrile (40 mL) and triethylamine (8.24 mL, 59.1 mmol) was added. After 5 min, 1- [2- trimethylsilyl) ethoxycarbonyloxy] pyrrolidine -2,5- dione (3.07 g, 11.82 mmol) was added as a solid, and the reaction mixture was stirred overnight. The reactant was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (0 to 50% ethyl acetate/hexane) to obtain the desired product (1.94, 65%). LC-MS calculated for_C13H22NO2Si⁺₍ M₊ H)⁺ : m/z=252.1; found 252.2.

步骤5.(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. tert-Butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)ethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(2.9g，4.48mmol)和(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸2-(三甲基甲硅烷基)乙酯(1.689g，6.72mmol)的混合物中添加DMF(15mL)和三乙胺(1.873mL，13.44mmol)，随后添加双(三苯基膦)氯化钯(II)(0.314g，0.448mmol)和碘化铜(I)(0.853g，4.48mmol)。抽空反应烧瓶，用氮气回填，随后在70℃搅拌2h。用水和少量30％氢氧化铵水溶液淬灭反应混合物，随后用乙酸乙酯萃取。有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(0至40％丙酮/己烷)纯化粗产物，得到所需产物(2.54g，73％)。LC-MS计算值C₃₆H₄₆BrFN₅O₄SSi⁺(M+H)⁺:m/z＝770.2/772.2；实验值770.0/772.0。To a mixture of intermediate 5 (2.9 g, 4.48 mmol) and (1R, 3R, 5R)-3-ethynyl-2-azabicyclo [3.1.0] hexane-2-carboxylic acid 2- (trimethylsilyl) ethyl ester (1.689 g, 6.72 mmol) was added DMF (15 mL) and triethylamine (1.873 mL, 13.44 mmol), followed by bis (triphenylphosphine) palladium (II) chloride (0.314 g, 0.448 mmol) and copper (I) iodide (0.853 g, 4.48 mmol). The reaction flask was evacuated, backfilled with nitrogen, and then stirred at 70 ° C for 2 h. The reaction mixture was quenched with water and a small amount of 30% aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (0 to 40% acetone / hexane) to give the desired product (2.54 g, 73%). LC-MS calculated_{forC36H46BrFN5O4SSi}⁺ (M+H)⁺ : m_/z =770.2/772.2; found 770.0/772.0.

步骤6.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-(((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)乙炔基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.537g，3.29mmol)在DMF(15ml)中的溶液中添加碳酸铯(2.145g，6.58mmol)，并且将反应混合物加热至90℃持续2h。用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(0至40％丙酮/己烷)纯化粗产物，得到所需产物(1.7g，67％)。To a solution of tert-butyl (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-(((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.537 g, 3.29 mmol) in DMF (15 ml) was added cesium carbonate (2.145 g, 6.58 mmol) and the reaction mixture was heated to 90 °C for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (0 to 40% acetone/hexanes) to give the desired product (1.7 g, 67%).

LC-MS计算值C₃₆H₄₆BrFN₅O₄SSi⁺(M+H)⁺:m/z＝770.2/772.2；实验值770.0/772.0。LC-MS calculated_{forC36H46BrFN5O4SSi}⁺ (M+H)⁺ : m_/z =770.2/772.2; found 770.0/772.0.

步骤7.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 7. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.699g，2.204mmol)、(2,3-二氯苯基)硼酸(0.631g，3.31mmol)、氟化钾(0.384g，6.61mmol)和Pd-132(0.156g，0.220mmol)的混合物中添加1,4-二噁烷(6mL)/水(1.5mL)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌1h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过柱色谱(0至40％丙酮/己烷)纯化粗产物，得到所需产物(1.72g，93％)。LC-MS计算值C₄₂H₄₉Cl₂FN₅O₄SSi⁺(M+H)⁺:m/z＝836.3/838.3；实验值836.2/838.2。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1R,4R,5S)-2-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a mixture of 1,4-dioxane (6 mL)/water (1.5 mL) was added 1,4-dioxane (6 mL)/water (1.5 mL) and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 °C for 1 h. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by column chromatography (0 to 40% acetone/hexanes) to give the desired product (1.72 g, 93%). LC-MS calculated for C₄₂ H₄₉ Cl₂ FN₅ O₄ SSi⁺ (M+H)⁺ : m/z=836.3/838.3; found 836.2/838.2.

步骤8.(1R,4R,5S)-5-(8-(2-氰基乙基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 8. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.72g，2.055mmol)于四氢呋喃(10mL)中的溶液中添加TBAF(1M于THF中，2.466mL，2.466mmol)，并且将反应混合物在65℃搅拌1h，接着冷却至室温。添加三乙胺(0.859mL，6.17mmol)和环丙烷碳酰氯(0.279mL，3.08mmol)并且在室温下搅拌反应混合物30min，接着用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱(0至100％丙酮/己烷)纯化粗产物，得到所需产物。LC-MS计算值C₄₀H₄₁Cl₂FN₅O₃S⁺(M+H)⁺:m/z＝760.2/762.2；实验值760.2/762.2。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.72 g, 2.055 mmol) in tetrahydrofuran (10 mL) was added TBAF (1 M in THF, 2.466 mL, 2.466 mmol) and the reaction mixture was stirred at 65 °C for 1 h then cooled to room temperature. Triethylamine (0.859 mL, 6.17 mmol) and cyclopropanecarbonyl chloride (0.279 mL, 3.08 mmol) were added and the reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (0 to 100% acetone/hexanes) to give the desired product. LC-MS calculated for C₄₀ H₄₁ Cl₂ FN₅ O₃ S⁺ (M+H)⁺ : m/z=760.2/762.2; found 760.2/762.2.

步骤9.(1R,4R,5S)-5-(8-(2-氰基乙基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 9. tert-Butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(8-(2-氰基乙基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(925mg，1.216mmol)在DCM(6mL)中的溶液中添加m-CPBA(327mg，1.459mmol，77％w/w于水中)，并且将反应混合物在室温下搅拌30min，接着用饱和碳酸氢钠淬灭并且用DCM萃取。经硫酸钠干燥有机层并且浓缩。通过柱色谱(0至100％丙酮/己烷)纯化粗产物，得到所需产物(703mg，74％)。LC-MS计算值C₄₀H₄₁Cl₂FN₅O₄S⁺(M+H)⁺:m/z＝776.2/778.2；实验值776.2/778.2。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (925 mg, 1.216 mmol) in DCM (6 mL) at 0°C was added m-CPBA (327 mg, 1.459 mmol, 77% w/w in water) and the reaction mixture was stirred at room temperature for 30 min, then quenched with saturated sodium bicarbonate and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product_was purified by column chromatography (0 to 100% acetone/hexanes) to give_the desired product (₇₀₃ mg, 74%). LC-MS calcd for_{C40H41Cl2FN5O4S}⁺ (M+H)⁺ : m/_z =776.2/778.2; found 776.2/778.2.

步骤10. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 10. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-(甲基亚磺酰基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(403mg，0.519mmol)溶解于四氢呋喃(2.59ml)中并且冷却至-20℃。添加溴化甲基镁(3M于二乙醚中，346μl，1.038mmol)并且在-20℃搅拌反应混合物1h，接着用饱和氯化铵淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。使粗产物在1:1DCM/TFA(2mL)中静置15min，随后用MeOH稀释并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₃₅H₃₃Cl₂FN₅O⁺(M+H)⁺:m/z＝628.2/630.2；实验值628.2/630.2。¹H NMR(500MHz,DMSO-d₆)δ9.76(s,1H),8.15(s,1H),8.03(s,1H),7.85(d,J＝8.0Hz,1H),7.58(t,J＝7.8Hz,1H),7.46(d,J＝7.5Hz,1H),6.52(s,1H),5.62(s,1H),5.51(d,J＝10.7Hz,1H),4.81(d,J＝5.9Hz,1H),4.14(t,J＝2.5Hz,1H),3.90(s,1H),3.47(s,1H),3.35(s,1H),3.03(dt,J＝14.0,6.6Hz,1H),2.95-2.76(m,5H),2.71(dt,J＝15.1,7.2Hz,1H),2.35-2.29(m,1H),2.27(d,J＝9.1Hz,1H),1.97(dd,J＝12.9,2.6Hz,1H),1.79(dq,J＝12.2,6.5Hz,1H),1.58(d,J＝9.2Hz,1H),1.24(s,1H),1.00-0.89(m,3H),0.88-0.80(m,1H),0.76(q,J＝6.8Hz,1H),0.66(dt,J＝7.4,3.5Hz,1H)。Tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylsulfinyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (403 mg, 0.519 mmol) was dissolved in tetrahydrofuran (2.59 ml) and cooled to -20°C. Methylmagnesium bromide (3M in diethyl ether, 346 μl, 1.038 mmol) was added and the reaction mixture was stirred at -20°C for 1 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was allowed to stand in 1:1 DCM/TFA (2 mL) for 15 min, then diluted with MeOH and purified by preparative HPLC (pH 2) to give the desired product. LC-MS Calcd. for C₃₅ H₃₃ Cl₂ FN₅ O⁺ (M+H)⁺ : m/z=628.2/630.2; Found. 628.2/630.2.¹ H NMR (500 MHz, DMSO-d₆ )δ9.76(s,1H),8.15(s,1H),8.03(s,1H),7.85(d,J＝8.0Hz,1H),7.58(t,J＝7.8Hz,1H),7.46(d,J＝7.5Hz,1H),6.52(s,1H),5.62(s,1H),5.51(d,J＝10 .7Hz,1H),4.81(d,J＝5.9Hz,1H),4.14(t,J＝2.5Hz,1H),3.90(s,1H),3.47(s,1H),3.35(s,1H),3.03(dt,J＝14.0,6.6Hz,1H), 2.95-2.76(m,5H),2.71(dt,J＝15.1,7.2Hz,1H),2.35-2.29(m,1H),2.27(d,J＝9.1Hz,1H),1.97(dd,J＝12.9,2.6Hz,1H),1.79(dq,J＝12.2,6.5Hz,1H), 1.58(d,J＝9.2Hz,1H),1.24(s,1H),1.00-0.89(m,3H),0.88-0.80(m,1H),0.76(q,J＝6.8Hz,1H),0.66(dt,J＝7.4,3.5Hz,1H).

实施例50：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 50: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazine-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1：(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazin-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.70g，4.17mmol，中间体5)、(R)-1-(丁-3-炔-2-基)吡嗪-2(1H)-酮(1.24g，8.34mmol，中间体20)、四(三苯基膦)钯(0)(0.96g，0.83mmol)、CuI(0.32g，1.67mmol)和N,N-二异丙基乙胺(7.3mL，41.7mmol)在DMF(21.0mL)中的混合物用N₂充气并且加热至70℃持续1h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用乙酸乙酯萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.1。A mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.70 g, 4.17 mmol, Intermediate 5), (R)-1-(but-3-yn-2-yl)pyrazin-2(1H)-one (1.24 g, 8.34 mmol, Intermediate 20), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol), CuI (0.32 g, 1.67 mmol) and N,N-diisopropylethylamine (7.3 mL, 41.7 mmol) in DMF (21.0 mL) was sparged with_N2 and heated to 70°C for 1 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with ethyl acetate, washed with brine, concentrated and purified by flash chromatography (0 to 100%_EtOAc /_hexanes ) to give the title compound. LC-MS Calcd_. for_{C31H33BrFN6O3S} (M+H)⁺ : m/z = 667.1; found 667.1.

步骤2：(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.00g，3.00mmol)和碳酸铯(2.93g，9.00mmol)在DMA(6.0mL)中的混合物在100℃加热0.5h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EA萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.2。A mixture of (1R, 4R, 5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazine-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.00 g, 3.00 mmol) and cesium carbonate (2.93 g, 9.00 mmol) in DMA (6.0 mL) was heated at 100 ° C for 0.5 h. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EA, washed with brine, concentrated and purified by flash chromatography (0 to 100% EtOAc/hexanes) to give the title compound. LC-MS calculated_{forC31H33BrFN6O3S} (M+H₎⁺ : m/_z = 667.1; found 667.2.

步骤3：(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(150mg，0.23mmol)、(2,3-二氯苯基)硼酸(64mg，0.34mmol)、双(二-叔丁基(4-二甲基氨基苯基)膦)二氯钯(II)(13mg，0.022mmol)、氟化钾(191mg，0.90mmol)于二噁烷(0.70mL)和水(0.07mL)中的混合物用N₂充气并且在100℃加热1h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EA萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₇H₃₆Cl₂FN₆O₃S(M+H)⁺:m/z＝733.2；实验值733.1。A mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylsulfanyl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (150 mg, 0.23 mmol), (2,3-dichlorophenyl)boronic acid (64 mg, 0.34 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (13 mg, 0.022 mmol), potassium fluoride (191 mg, 0.90 mmol) in dioxane (0.70 mL) and water (0.07 mL) was sparged with_N2 and heated at 100°C for 1 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EA_, washed with brine_, concentrated and purified by flash chromatography (0 to 100%_EtOAc /hexanes) to give the title compound. LC-MS calcd for_{C37H36Cl2FN6O3S} (M+H)₊^: m/z = 733.2; found 733.1.

步骤4：3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 4: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(73mg，0.10mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶(100mg，0.30mmol)、四(三苯基膦)钯(0)(58mg，0.050mmol)、3-甲基水杨酸铜(I)(75mg，0.35mmol)于二噁烷(0.50mL)中的混合物用N₂充气并且加热至120℃持续1h。完成后，经由硅藻土过滤反应混合物并且浓缩。向残余物中添加一滴MeCN和2M HCl于二噁烷中的溶液(2mL)。搅拌混合物30min，并且通过制备型HPLC(pH 2)纯化。Tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (73 mg, 0.10 mmol), 5-(4, A mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-((trimethylsilyl)oxy)propane-2-yl)pyridine (100 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol), 3-methylsalicylate copper(I) (75 mg, 0.35 mmol) in dioxane (0.50 mL) was gassed with_N2 and heated to 120 °C for 1 h. After completion, the reaction mixture was filtered through celite and concentrated. A drop of MeCN and 2M HCl in dioxane (2 mL) was added to the residue. The mixture was stirred for 30 min and purified by preparative HPLC (pH 2).

滞转异构体1。峰1。LC-MS计算值C₃₉H₃₅Cl₂FN₇O₂(M+H)⁺:m/z＝722.2；实验值722.2。Anisomeric form 1. Peak 1. LC-MS calculated for C₃₉ H₃₅ Cl₂ FN₇ O₂ (M+H)⁺ : m/z = 722.2; found 722.2.

滞转异构体2。峰2。LC-MS计算值C₃₉H₃₅Cl₂FN₇O₂(M+H)⁺:m/z＝722.2；实验值722.2。¹H NMR(TFA盐，旋转异构体的混合物，500MHz,DMSO-d₆)δ9.60(br,0.6H),9.27(br,0.4H),9.21(m,0.6H),9.00(m,0.4H),8.51(m,0.6H),8.38(br,0.6H),8.14(br,0.4H),8.28(m,0.4H),8.25-8.18(m,2H),8.02-7.93(m,0.8H),7.91-7.81(m,1.6H),7.63-7.47(m,3H),7.28(d,J＝4.4Hz,0.6H),6.96(d,J＝4.4Hz,0.6H),6.42(s,0.4H),6.29(m,0.6H),6.10(m,0.4H),5.72(s,0.4H),5.26(m,0.6H),5.14(s,0.6H),5.05(br,1H),4.95(m,0.4H),4.00(m,0.4H),3.80(m,0.6H),3.54(m,0.4H),3.42(m,0.4H),3.06(m,0.6H),2.95-2.64(m,4H),2.37(m,0.4H),2.13(m,0.6H),1.95(m,0.4H),1.86(d,J＝6.3Hz,1.8H),1.77(d,J＝6.9Hz,1.2H),1.57-1.48(m,7.2H)。Anisomeric form 2. Peak 2. LC-MS calculated for C₃₉ H₃₅ Cl₂ FN₇ O₂ (M+H)⁺ : m/z=722.2; found 722.2.¹ H NMR (TFA salt, mixture of rotamers, 500 MHz, DMSO-d₆ )δ9.60(br,0.6H),9.27(br,0.4H),9.21(m,0.6H),9.00(m,0.4H),8.51(m,0.6H),8.38(br,0.6H),8.14(br,0.4H),8.28(m,0.4H),8.25-8.18(m,2H),8.02-7.93(m,0.8H),7.91-7.81(m,1.6H),7.63-7.47(m,3H),7.28(d,J＝4.4Hz,0.6H),6.96(d,J＝4.4Hz,0.6H),6.42(s,0.4H),6.29(m,0.6H),6.10( m,0.4H),5.72(s,0.4H),5.26(m,0.6H),5.14(s,0.6H),5.05(br,1H),4.95(m,0.4H),4.00(m,0.4H),3.80(m,0.6H),3.54(m,0.4H),3.42(m,0.4H), 3.06(m,0.6H),2.95-2.64(m,4H),2.37(m,0.4H),2.13(m,0.6H),1.95(m,0.4H),1.86(d,J＝6.3Hz,1.8H),1.77(d,J＝6.9Hz,1.2H),1.57-1.48(m,7. 2H).

实施例51.(2R,4S)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-4-氟吡咯烷-1-甲酸甲酯Example 51. Methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoropyrrolidine-1-carboxylate

步骤1.(2R,4S)-4-氟-2-(羟基甲基)吡咯烷-1-甲酸叔丁酯Step 1. tert-Butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

向(2R,4S)-1-(叔丁氧基羰基)-4-氟吡咯烷-2-甲酸(4.36g，18.69mmol)和三乙胺(2.87ml，20.56mmol)于THF(93ml)中的0℃溶液添加氯甲酸异丁酯(2.70ml，20.56mmol)，并且在室温下搅拌反应混合物1小时，随后过滤。用THF洗涤固体。将滤液冷却至0℃并且添加硼氢化钠于水(10mL)中的溶液。将反应混合物在室温下搅拌30min，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(2.3g，56％)。LC-MS计算值C₆H₁₁FNO₃⁺(M+H-C₄H₈)⁺:m/z＝164.1；实验值164.0。To a 0°C solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (4.36 g, 18.69 mmol) and triethylamine (2.87 ml, 20.56 mmol) in THF (93 ml) was added isobutyl chloroformate (2.70 ml, 20.56 mmol), and the reaction mixture was stirred at room temperature for 1 hour, then filtered. The solid was washed with THF. The filtrate was cooled to 0°C and a solution of sodium borohydride in water (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (2.3 g, 56%). LC-MS calculated for C₆ H₁₁ FNO₃⁺ (M+HC₄ H₈ )⁺ : m/z=164.1; found 164.0.

步骤2.(2R,4S)-4-氟-2-甲酰基吡咯烷-1-甲酸叔丁酯Step 2. tert-Butyl (2R,4S)-4-fluoro-2-formylpyrrolidine-1-carboxylate

在-78℃向乙二酰氯(1.800ml，20.57mmol)在DCM(62.3ml)中的溶液逐滴添加DMSO(2.92ml，41.1mmol)，并且在-78℃搅拌反应混合物45min，随后添加(2R,4S)-4-氟-2-(羟基甲基)吡咯烷-1-甲酸叔丁酯(4.1g，18.70mmol)在DCM(3mL)中的溶液，并且在-78℃再继续搅拌2h。随后添加三乙胺(7.82ml，56.1mmol)并且在-78℃搅拌反应混合物15min，随后升温至0℃并且再搅拌1h。将反应混合物用1NHCl淬灭并且用DCM萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中(4.0g，98％)。LC-MS计算值C₆H₉FNO₃⁺(M+H-C₄H₈)⁺:m/z＝162.1；实验值162.0。To a solution of oxalyl chloride (1.800 ml, 20.57 mmol) in DCM (62.3 ml) was added DMSO (2.92 ml, 41.1 mmol) dropwise at -78 °C, and the reaction mixture was stirred for 45 min at -78 °C, followed by addition of a solution of (2R, 4S)-tert-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.1 g, 18.70 mmol) in DCM (3 mL), and stirring was continued at -78 °C for another 2 h. Triethylamine (7.82 ml, 56.1 mmol) was then added and the reaction mixture was stirred at -78 °C for 15 min, then warmed to 0 °C and stirred for another 1 h. The reaction mixture was quenched with 1N HCl and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (4.0 g, 98%). LC-MS calculated_forC6H9FNO3⁺ (M+_HC4H8 )⁺ : m/z=_162.1 ; found_162.0 .

步骤3.(2R,4S)-2-乙炔基-4-氟吡咯烷-1-甲酸叔丁酯Step 3. tert-Butyl (2R,4S)-2-ethynyl-4-fluoropyrrolidine-1-carboxylate

向(2R,4S)-4-氟-2-甲酰基吡咯烷-1-甲酸叔丁酯(3.2g，14.73mmol)在MeOH(73.7ml)中的0℃溶液中添加碳酸钾(4.07g，29.5mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(2.211ml，14.73mmol)，并且在室温下搅拌反应混合物2h，随后浓缩。将残余物分配于水与乙酸乙酯之间，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过Biotage(0至50％丙酮/己烷)纯化粗产物，得到所需产物(1.51g，48％)。LC-MS计算值C₇H₉FNO₂⁺(M+H-C₄H₈)⁺:m/z＝158.1；实验值158.0。To a 0°C solution of (2R,4S)-4-fluoro-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (3.2 g, 14.73 mmol) in MeOH (73.7 ml) was added potassium carbonate (4.07 g, 29.5 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (2.211 ml, 14.73 mmol), and the reaction mixture was stirred at room temperature for 2 h, then concentrated. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Biotage (0 to 50% acetone/hexanes) to give the desired product (1.51 g, 48%). LC-MS calculated for C₇ H₉ FNO₂⁺ (M+HC₄ H₈ )⁺ : m/z=158.1; found 158.0.

步骤4.(2R,4S)-2-乙炔基-4-氟吡咯烷-1-甲酸甲酯Step 4. Methyl (2R,4S)-2-ethynyl-4-fluoropyrrolidine-1-carboxylate

在室温下搅拌(2R,4S)-2-乙炔基-4-氟吡咯烷-1-甲酸叔丁酯(500mg，2.345mmol)于4N HCl/二噁烷(5mL)中的溶液1h，随后浓缩。将残余物溶解于DCM(4.7ml)中并且冷却至0℃。添加三乙胺(1634μl，11.72mmol)和氯甲酸甲酯(218μl，2.81mmol)。在室温下搅拌反应混合物1h，随后用水淬灭并且用乙酸乙酯萃取。将有机层用盐水洗涤，经硫酸钠干燥并浓缩。粗产物不经进一步纯化即用于下一步骤中(377mg，94％)。LC-MS计算值C₈H₁₁FNO₂⁺(M+H)⁺:m/z＝172.1；实验值172.1。A solution of (2R,4S)-2-ethynyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.345 mmol) in 4N HCl/dioxane (5 mL) was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in DCM (4.7 ml) and cooled to 0 ° C. Triethylamine (1634 μl, 11.72 mmol) and methyl chloroformate (218 μl, 2.81 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification (377 mg, 94%). LC-MS calculated value C₈ H₁₁ FNO₂⁺ (M+H)⁺ : m/z=172.1; Found value 172.1.

步骤5.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,4S)-4-氟-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,4S)-4-fluoro-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(1.3g，2.008mmol)和(2R,4S)-2-乙炔基-4-氟吡咯烷-1-甲酸甲酯(0.447g，2.61mmol)的混合物中添加DMF(5.02ml)和三乙胺(0.840ml，6.02mmol)，随后添加四(三苯基膦)钯(0)(0.232g，0.201mmol)和碘化铜(I)(0.382g，2.008mmol)。抽空反应烧瓶，用氮气回填，随后在70℃搅拌2h。随后添加碳酸铯(1.309g，4.02mmol)并且将反应混合物加热至80℃持续2h。用水和少量氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至60％丙酮/己烷)纯化粗产物，得到所需产物(486mg，35％)。LC-MS计算值C₃₁H₃₅BrF₂N₅O₄S⁺(M+H)⁺:m/z＝690.2/692.2；实验值690.0/692.0。DMF (5.02 ml) and triethylamine (0.840 ml, 6.02 mmol) were added to a mixture of intermediate 5 (1.3 g, 2.008 mmol) and (2R, 4S)-2-ethynyl-4-fluoropyrrolidine-1-methyl carboxylate (0.447 g, 2.61 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.232 g, 0.201 mmol) and copper(I)iodide (0.382 g, 2.008 mmol). The reaction flask was evacuated, backfilled with nitrogen, and then stirred at 70 ° C for 2 h. Cesium carbonate (1.309 g, 4.02 mmol) was then added and the reaction mixture was heated to 80 ° C for 2 h. The reactant was quenched with water and a small amount of saturated aqueous solution of ammonium hydroxide, then diluted with ethyl acetate and filtered through a diatomaceous earth plug. The filtrate layer was separated and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The^{crude product was purified by flash column chromatography (0 to 60% acetone/hexanes) to give the desired product (486 mg, 35%). LC-MS Calcd for C31H35BrF2N5O4S+}_(M+H)⁺ : m/z=690.2/692.2; found 690.0/692.0.

步骤6.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((2R,4S)-4-氟-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((2R,4S)-4-fluoro-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,4S)-4-氟-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(486mg，0.704mmol)、(2,3-二氯苯基)硼酸(161mg，0.844mmol)、氟化钾(123mg，2.111mmol)和Pd-132(49.8mg，0.070mmol)的混合物中添加1,4-二噁烷(1.407ml)/水(0.352ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌2h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速柱色谱(0至65％丙酮/己烷)纯化粗产物，得到所需产物(368mg，69％)。LC-MS计算值C₃₇H₃₈Cl₂F₂N₅O₄S⁺(M+H)⁺:m/z＝756.2/758.2；实验值756.2/758.2。To a mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,4S)-4-fluoro-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (486 mg, 0.704 mmol), (2,3-dichlorophenyl)boronic acid (161 mg, 0.844 mmol), potassium fluoride (123 mg, 2.111 mmol) and Pd-132 (49.8 mg, 0.070 mmol) was added 1,4-dioxane (1.407 ml)/water (0.352 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C for 2 h. The reaction mixture_was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified_by flash column chromatography (₀ to 65% acetone/hexanes) to give the desired product (368 mg, 69%). LC-MS_{CalcdforC37H38Cl2F2N5O4S}⁺ (M+H)⁺ : m/z=756.2/758.2; Found 756.2/758.2.

步骤7.(2R,4S)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-4-氟吡咯烷-1-甲酸甲酯Step 7. Methyl (2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoropyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((2R,4S)-4-氟-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(353mg，0.467mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶(313mg，0.933mmol)、四(三苯基膦)钯(0)(53.9mg，0.047mmol)和3-甲基水杨酸铜(I)(300mg，1.400mmol)的混合物中添加1,4-二噁烷(1.5ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌3h。用水和氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至80％丙酮/己烷)纯化粗产物。将纯化产物溶解于1:1TFA/DCM(20mL)中并且在室温下搅拌1小时，随后浓缩。用乙腈稀释粗产物并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₃₉H₃₇Cl₂F₂N₆O₃⁺(M+H)⁺:m/z＝745.2/747.2；实验值745.2/747.2。To the mixture were (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((2R,4S)-4-fluoro-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (353 mg, 0.467 mmol), 5-(4,4,5,5-tetramethyl-1,3, 1,4-Dioxane (1.5 ml) was added to a mixture of 2-(2-((trimethylsilyl)oxy)propane-2-yl)pyridine (313 mg, 0.933 mmol), tetrakis(triphenylphosphine)palladium(0) (53.9 mg, 0.047 mmol) and 3-methylsalicylate copper(I) (300 mg, 1.400 mmol), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 ° C for 3 h. The reactants were quenched with water and saturated aqueous ammonium hydroxide solution, then diluted with ethyl acetate and filtered through a plug of celite. The filtrate layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 80% acetone/hexane). The purified product was dissolved in 1:1 TFA/DCM (20 mL) and stirred at room temperature for 1 hour, then concentrated. The crude product was diluted with acetonitrile and purified_{by preparative HPLC (pH 2) to give the desired product. LC-MS Calcd. for C39H37Cl2F2N6O3+(M+}^H )⁺ : m/z = 745.2/_747.2 ; Found 745.2/747.2.

实施例52.(2R,5R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-5-甲基吡咯烷-1-甲酸甲酯Example 52. Methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate

步骤1.(2R,5R)-2-(羟基甲基)-5-甲基吡咯烷-1-甲酸叔丁酯Step 1. tert-Butyl (2R,5R)-2-(Hydroxymethyl)-5-methylpyrrolidine-1-carboxylate

在0℃向(2R,5R)-1-(叔丁氧基羰基)-5-甲基吡咯烷-2-甲酸(5.015g，21.87mmol)于THF(109ml)中的溶液中添加三乙胺(3.35ml，24.06mmol)和氯甲酸异丁酯(3.16ml，24.06mmol)，并且将反应混合物在室温下搅拌1h，随后过滤。用THF洗涤固体并且将滤液冷却至0℃。随后逐滴添加硼氢化钠(1.655g，43.7mmol)于水(约10mL)中的溶液，并且在0℃搅拌反应混合物30min，接着用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₇H₁₄NO₃⁺(M+H-C₄H₈)⁺:m/z＝160.1；实验值160.1。To a solution of (2R, 5R)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (5.015 g, 21.87 mmol) in THF (109 ml) was added triethylamine (3.35 ml, 24.06 mmol) and isobutyl chloroformate (3.16 ml, 24.06 mmol) at 0 ° C, and the reaction mixture was stirred at room temperature for 1 h, then filtered. The solid was washed with THF and the filtrate was cooled to 0 ° C. A solution of sodium borohydride (1.655 g, 43.7 mmol) in water (about 10 mL) was then added dropwise, and the reaction mixture was stirred at 0 ° C for 30 min, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₇ H₁₄ NO₃⁺ (M + HC₄ H₈ )⁺ : m/z = 160.1; found 160.1.

步骤2.(2R,5R)-2-甲酰基-5-甲基吡咯烷-1-甲酸叔丁酯Step 2. tert-Butyl (2R,5R)-2-Formyl-5-methylpyrrolidine-1-carboxylate

在-78℃向乙二酰氯(2.106ml，24.06mmol)在DCM(80mL)中的溶液中逐滴添加DMSO(3.42ml，48.1mmol)在DCM(3.5mL)中的溶液，并且在-78℃搅拌反应混合物45min，随后逐滴添加(2R,5R)-2-(羟基甲基)-5-甲基吡咯烷-1-甲酸叔丁酯(4.71g，21.88mmol)在DCM(10mL)中的溶液，并且在-78℃再继续搅拌45min。随后逐滴添加三乙胺(9.15ml，65.6mmol)并且在-78℃继续搅拌30min，随后升温至0℃并且搅拌30min。将反应物用1N HCl淬灭并且用DCM萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₇H₁₂NO₃⁺(M+H-C₄H₈)⁺:m/z＝158.1；实验值158.1。To a solution of oxalyl chloride (2.106 ml, 24.06 mmol) in DCM (80 mL) was added dropwise a solution of DMSO (3.42 ml, 48.1 mmol) in DCM (3.5 mL) at -78 ° C, and the reaction mixture was stirred at -78 ° C for 45 min, followed by dropwise addition of a solution of (2R, 5R)-2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (4.71 g, 21.88 mmol) in DCM (10 mL), and stirring was continued at -78 ° C for another 45 min. Triethylamine (9.15 ml, 65.6 mmol) was then added dropwise and stirring was continued at -78 ° C for 30 min, then warmed to 0 ° C and stirred for 30 min. The reactant was quenched with 1N HCl and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₇ H₁₂ NO₃⁺ (M + HC₄ H₈ )⁺ : m/z = 158.1; found 158.1.

步骤3.(2R,5R)-2-乙炔基-5-甲基吡咯烷-1-甲酸叔丁酯Step 3. tert-Butyl (2R,5R)-2-ethynyl-5-methylpyrrolidine-1-carboxylate

向(2R,5R)-2-甲酰基-5-甲基吡咯烷-1-甲酸叔丁酯(4.67g，21.90mmol)在MeOH(109ml)中的0℃溶液中添加碳酸钾(6.05g，43.8mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(3.29ml，21.90mmol)，并且在室温下搅拌反应混合物过夜，随后浓缩。将残余物分配于水与乙酸乙酯之间并且分离各层。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。粗产物不经进一步纯化即用于下一步骤中。LC-MS计算值C₈H₁₂NO₂⁺(M+H-C₄H₈)⁺:m/z＝154.1；实验值154.1。To a 0°C solution of (2R,5R)-2-formyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (4.67 g, 21.90 mmol) in MeOH (109 ml) was added potassium carbonate (6.05 g, 43.8 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.29 ml, 21.90 mmol), and the reaction mixture was stirred at room temperature overnight and then concentrated. The residue was partitioned between water and ethyl acetate and the layers were separated. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C₈ H₁₂ NO₂⁺ (M+HC₄ H₈ )⁺ : m/z=154.1; found 154.1.

步骤4.(2R,5R)-2-乙炔基-5-甲基吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯Step 4. 2-(Trimethylsilyl)ethyl (2R,5R)-2-ethynyl-5-methylpyrrolidine-1-carboxylate

在室温下搅拌(2R,5R)-2-乙炔基-5-甲基吡咯烷-1-甲酸叔丁酯(4.5g，21.50mmol)于4N HCl/二噁烷(5mL)中的溶液1h，随后浓缩。将残余物悬浮于乙腈(108ml)中并且添加三乙胺(14.98ml，108mmol)。在室温下5min之后，一次性以固体形式添加1-[2-三甲基甲硅烷基)乙氧基羰基氧基]吡咯烷-2,5-二酮(5.58g，21.50mmol)，并且在室温下搅拌反应混合物2h，随后用水淬灭并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至50％乙酸乙酯/己烷)纯化粗产物，得到所需产物(3.95g，72％，经5个步骤)。LC-MS计算值C₁₃H₂₄NO₂Si⁺(M+H)⁺:m/z＝254.1；实验值254.1。A solution of (2R, 5R)-2-ethynyl-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester (4.5g, 21.50mmol) in 4N HCl/dioxane (5mL) was stirred at room temperature for 1h, then concentrated. The residue was suspended in acetonitrile (108ml) and triethylamine (14.98ml, 108mmol) was added. After 5min at room temperature, 1-[2-trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (5.58g, 21.50mmol) was added as a solid at one time, and the reaction mixture was stirred at room temperature for 2h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 50% ethyl acetate/hexane) to obtain the desired product (3.95g, 72% over 5 steps). LC-MS calcd_{for C13H24NO2Si+}⁽ M₊ H)⁺ : m/z=254.1; found 254.1.

步骤5.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,5R)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,5R)-5-methyl-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(1.8g，2.78mmol)在DMF(12ml)中的溶液中添加(2R,5R)-2-乙炔基-5-甲基吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯(1.3g，5.01mmol)、TEA(3.0mL，22.2mmol)、双(三苯基膦)氯化钯(II)(0.39g，0.556mmol)和CuI(0.58g，3.06mmol)。用N₂吹扫反应容器的顶部空间5min。将反应混合物加热至80℃持续2h，其后将粗反应混合物冷却至室温并且添加Cs₂CO₃(4.5g，13.9mmol)。将反应混合物加热回至80℃并且再搅拌1h。将反应混合物倒入水中并且将水层用EtOAc萃取，用盐水洗涤，经硫酸钠干燥，过滤并浓缩。通过快速柱色谱纯化粗产物，得到所需产物(1.3g，61％)。LC-MS计算值C₃₆H₄₈BrFN₅O₄SSi(M+H)⁺:m/z＝772.2/774.2；实验值772.2/774.2。To a solution of intermediate 5 (1.8 g, 2.78 mmol) in DMF (12 ml) was added 2-(trimethylsilyl)ethyl (2R,5R)-2-ethynyl-5-methylpyrrolidine-1-carboxylate (1.3 g, 5.01 mmol), TEA (3.0 mL, 22.2 mmol), bis(triphenylphosphine)palladium(II) chloride (0.39 g, 0.556 mmol) and CuI (0.58 g, 3.06 mmol). The headspace of the reaction vessel was purged with_N2 for 5 min. The reaction mixture was heated to 80 °C for 2 h, after which the crude reaction mixture was cooled to room temperature and_Cs2CO3 (4.5 g, 13.9_mmol ) was added. The reaction mixture was heated back to 80 °C and stirred for another 1 h. The reaction mixture was poured into water and the aqueous layer was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography to give the desired product (1.3 g, 61%). LC_- MS Calcd_{.forC36H48BrFN5O4SSi} (M+H)⁺ : m/z = 772.2/774.2; Found 772.2/774.2.

步骤6.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

在0℃向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,5R)-5-甲基-1-((2-(三甲基甲硅烷基)乙氧基)羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.3g，1.68mmol)于THF(10mL)中的溶液中添加TBAF(2.0mL，2.02mmol，1M于THF中)。将反应混合物加热至60℃并且搅拌30min。将反应混合物重新冷却至室温。此后，添加Et3N(0.59mL，4.21mmol)，随后添加添加氯甲酸甲酯(240mg，2.52mmol)。使反应混合物在室温下再搅拌20min。添加水并且用EtOAc萃取水层。将有机层用盐水洗涤，经硫酸钠干燥，过滤并浓缩。通过快速柱色谱纯化粗产物，得到所需产物(0.80g，76％)。LC-MS计算值C₃₂H₃₈BrFN₅O₄S(M+H)⁺:m/z＝686.2/688.2；实验值686.2/688.2。To a solution of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,5R)-5-methyl-1-((2-(trimethylsilyl)ethoxy)carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.3 g, 1.68 mmol) in THF (10 mL) at 0°C was added TBAF (2.0 mL, 2.02 mmol, 1 M in THF). The reaction mixture was heated to 60°C and stirred for 30 min. The reaction mixture was recooled to room temperature. Thereafter, Et3N (0.59 mL, 4.21 mmol) was added followed by methyl chloroformate (240 mg, 2.52 mmol). The reaction mixture was stirred at room temperature for another 20 min. Water was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography to give the desired product (0.80 g, 76%). LC-MS calculated for C₃₂ H₃₈ BrFN₅ O₄ S (M+H)⁺ : m/z = 686.2/688.2; found 686.2/688.2.

步骤7.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 7. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(803mg，1.17mmol)、(2,3-二氯苯基)硼酸(446mg，2.34mmol)、氟化钾(204mg，3.51mmol)和Pd-132(124mg，0.175mmol)的混合物中添加1,4-二噁烷(7mL)/水(1.5mL)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌1h。用DCM稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速柱色谱(0至40％丙酮/己烷)纯化粗产物，得到所需产物(498mg，57％)。LC-MS计算值C₃₈H₄₁Cl₂FN₅O₄S⁺(M+H)⁺:m/z＝752.2；实验值752.2。To a mixture of tert-butyl (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (803 mg, 1.17 mmol), (2,3-dichlorophenyl)boronic acid (446 mg, 2.34 mmol), potassium fluoride (204 mg, 3.51 mmol) and Pd-132 (124 mg, 0.175 mmol) was added 1,4-dioxane (7 mL)/water (1.5 mL), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C for 1 h. The reaction mixture was diluted with DCM and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by flash column chromatography (₀ to 40% acetone/hexanes) to give the desired product (498 mg, 57%)_. LC-MS Calcd_.^{for C38H41Cl2FN5O4S+}_(M +H)⁺ : m/z=752.2; Found 752.2.

步骤8.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 8. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(498mg，0.662mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶(666mg，1.99mmol),四(三苯基膦)钯(0)(382mg，0.331mmol)和3-甲基水杨酸铜(I)(568mg，2.65mmol)的混合物中添加1,4-二噁烷(7ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌3h。将反应混合物用水和氢氧化铵饱和水溶液淬灭，随后用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至15％MeOH/DCM)纯化粗产物，得到所需产物(398mg，72％)。LC-MS计算值C₄₅H₄₈Cl₂FN₆O₅⁺(M+H)⁺:m/z＝841.3；实验值841.3。To the mixture were tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (498 mg, 0.662 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(2-((trimethylsilyl)oxy)propane-2-yl)pyridine (666 mg, 1.99 mmol), tetrakis(triphenylphosphine)palladium(0) (382 mg, 0.331 mmol) and 3-methylsalicylate copper(I) (568 mg, 2.65 mmol) were added 1,4-dioxane (7 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100 ° C for 3 h. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 15% MeOH/DCM) to give the desired product (398 mg, 72%). LC-MS calcd_{forC45H48Cl2FN6O5+} (M₊ H)₊^: m/z⁼ 841.3; found 841.3.

步骤9.(2R,5R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-5-甲基吡咯烷-1-甲酸甲酯Step 9. Methyl (2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((2R,5R)-1-(甲氧基羰基)-5-甲基吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(398mg，0.473mmol)于CH₃CN(4mL)中的溶液中添加TFA(4mL)。在室温下搅拌混合物2h。此后，用更多CH₃CN稀释混合物并且通过制备型HPLC(pH 10)纯化，随后通过制备型HPLC(pH 2)纯化。LC-MS计算值C₄₀H₄₀Cl₂FN₆O₃⁺(M+H)⁺:m/z＝741.3；实验值741.3.¹HNMR(TFA盐，600MHz,DMSO-d₆)δ9.24(s,1H),9.05(s,1H),8.35(d,J＝8.2Hz,1H),8.24-8.10(m,2H),7.94(d,J＝8.3Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.49(d,J＝7.6Hz,1H),6.70(s,1H),5.63(s,1H),5.20-5.12(m,1H),4.96-4.84(s,1H),3.97-3.87(m,2H),3.75-3.56(m,3H),3.52-3.40(m,1H),3.10-3.03(m,1H),2.93-2.81(m,3H),2.72-2.61(m,1H),2.51-2.31(m,3H),2.14-1.99(m,1H),1.91-1.78(m,1H),1.63-1.57(m,1H),1.54(s,6H),1.38(d,J＝6.0Hz,3H)。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((2R,5R)-1-(methoxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (398 mg, 0.473 mmol) in CH₃ CN (4 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 2 h. Thereafter, the mixture was diluted with more CH₃ CN and purified by preparative HPLC (pH 10) followed by preparative HPLC (pH 2). LC-MS calculated value for C₄₀ H₄₀ Cl₂ FN₆ O₃⁺ (M+H)⁺ : m/z=741.3; found value 741.3.¹ H NMR (TFA salt, 600 MHz, DMSO-d₆ )δ9.24(s,1H),9.05(s,1H),8.35(d,J＝8.2Hz,1H),8.24-8.10(m,2H),7.94(d,J＝8.3Hz,1H),7.85(dd,J＝8.1,1.5Hz,1H),7.59(t,J＝7.9Hz,1H),7.49(d ,J＝7.6Hz,1H),6.70(s,1H),5.63(s,1H),5.20-5.12(m,1H),4.96-4.84(s,1H) ),3.97-3.87(m,2H),3.75-3.56(m,3H),3.52-3.40(m,1H),3.10-3.03(m,1H),2.93-2.81(m,3H),2.72-2.61(m,1H),2.51-2.31(m,3H),2.14-1.99 (m,1H),1.91-1.78(m,1H),1.63-1.57(m,1H),1.54(s,6H),1.38(d,J=6.0Hz,3H).

实施例53.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-3-氯-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 53. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.06g，2.79mmol，实施例39，步骤3)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-2-(2-((三甲基甲硅烷基)氧基)丙烷-2-基)吡啶(2.81g，8.37mmol)、四(三苯基膦)钯(0)(322mg，0.28mmol)和3-甲基水杨酸铜(I)(1.80g，8.37mmol)的混合物中添加1,4-二噁烷(28ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱，用0至100％丙酮/己烷洗脱来纯化粗产物。LC-MS计算值C₄₄H₄₆Cl₂FN₆O₅⁺(M+H)⁺:m/z＝827.3/829.3；实验值827.4/829.3。To tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.06 g, 2.79 mmol, Example 39, Step 3), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(2-((trimethylsilyl)oxy)propane-2-yl)pyridine (2.81 g, 8.37 mmol), tetrakis(triphenylphosphine)palladium(0) (322 mg, 0.28 mmol) and 3-methylsalicylatecopper(I) (1.80 g, 8.37 mmol) were added 1,4-dioxane (28 ml) and the reaction flask was evacuated, backfilled with nitrogen and then stirred at 100 °C overnight. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with 0 to 100% acetone/hexane. LC-MS calculated_{forC44H46Cl2FN6O5+} (M+H)₊ : m/_z⁼ 827.3/^829.3 ; found 827.4/829.3.

步骤2.(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-3-氯-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 2. Methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.70g，3.26mmol)在DMF(33ml)中的溶液中添加N-氯丁二酰亚胺(0.436g，3.26mmol)，并且将反应混合物加热至65℃持续2h。完成时，通过添加乙酸乙酯和水淬灭反应物。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。将粗产物在1:1TFA/DCM(1ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₉H₃₇Cl₃FN₆O₃⁺(M+H)⁺:m/z＝761.2/763.2；实验值761.1/763.1。To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropane-2-yl)pyridin-3-yl)-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.70 g, 3.26 mmol) in DMF (33 ml) was added N-chlorosuccinimide (0.436 g, 3.26 mmol) and the reaction mixture was heated to 65 °C for 2 h. Upon completion, the reaction was quenched by adding ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was stirred in 1:1 TFA/DCM (1 ml) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₉ H₃₇ Cl₃ FN₆ O₃⁺ (M+H)⁺ : m/z = 761.2/763.2; found 761.1/763.1.

实施例54a和54b：4-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-2-氟-N-甲基苯甲酰胺Examples 54a and 54b: 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide

步骤1：(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazin-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.70g，4.17mmol，中间体5)、(R)-1-(丁-3-炔-2-基)吡嗪-2(1H)-酮(1.24g，8.34mmol，中间体20)、四(三苯基膦)钯(0)(0.96g，0.83mmol)、CuI(0.32g，1.67mmol)和N,N-二异丙基乙胺(7.3mL，41.7mmol)在DMF(21.0mL)中的混合物用N₂充气并且加热至70℃持续1h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用乙酸乙酯萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.1。A mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.70 g, 4.17 mmol, Intermediate 5), (R)-1-(but-3-yn-2-yl)pyrazin-2(1H)-one (1.24 g, 8.34 mmol, Intermediate 20), tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol), CuI (0.32 g, 1.67 mmol) and N,N-diisopropylethylamine (7.3 mL, 41.7 mmol) in DMF (21.0 mL) was sparged with_N2 and heated to 70°C for 1 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with ethyl acetate, washed with brine, concentrated and purified by flash chromatography (0 to 100%_EtOAc /_hexanes ) to give the title compound. LC-MS Calcd_. for_{C31H33BrFN6O3S} (M+H)⁺ : m/z = 667.1; found 667.1.

步骤2：(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-3-((R)-3-(2-氧代吡嗪-1(2H)-基)丁-1-炔-1-基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.00g，3.00mmol)和碳酸铯(2.93g，9.00mmol)在DMA(6.0mL)中的混合物在100℃加热0.5h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用乙酸乙酯萃取，用盐水洗涤，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₁H₃₃BrFN₆O₃S(M+H)⁺:m/z＝667.1；实验值667.2。A mixture of (1R,4R,5S)-5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)-3-((R)-3-(2-oxopyrazine-1(2H)-yl)but-1-yn-1-yl)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (2.00 g, 3.00 mmol) and cesium carbonate (2.93 g, 9.00 mmol) in DMA (6.0 mL) was heated at 100 °C for 0.5 h. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with ethyl acetate, washed with brine, concentrated and purified by flash chromatography (0 to 100% EtOAc/hexanes) to give the title compound. LC-MS calculated_{forC31H33BrFN6O3S} (M+H₎⁺ : m/_z = 667.1; found 667.2.

步骤3：(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

将(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1g，1.498mmol)、(2,3-二氯苯基)硼酸(0.429g，2.247mmol)、Pd(amphos)Cl₂(0.106g，0.150mmol)、氟化钾(0.348g，5.99mmol)于二噁烷(15ml)和水(3.00ml)中的混合物用N₂充气并且在100℃加热2h。完成后，将反应混合物冷却至室温并且倒入水中。将水层用EtOAc萃取，用盐水洗涤，经Na₂SO₄干燥，浓缩并且通过快速色谱(0至100％EtOAc/己烷)纯化，得到标题化合物。LC-MS计算值C₃₇H₃₆Cl₂FN₆O₃S(M+H)⁺:m/z＝733.2；实验值733.2。A mixture of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-4-(methylsulfanyl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1 g, 1.498 mmol), (2,3-dichlorophenyl)boronic acid (0.429 g, 2.247 mmol), Pd(amphos)_Cl2 (0.106 g, 0.150 mmol), potassium fluoride (0.348 g, 5.99 mmol) in dioxane (15 ml) and water (3.00 ml) was sparged with_N2 and heated at 100°C for 2 h. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EtOAc_, washed with_brine , dried over_Na2SO4 , concentrated and purified by flash chromatography (0_to 100% EtOAc/hexanes) to give the title compound. LC-MS Calcd_{.forC37H36Cl2FN6O3S} (M+H)⁺ : m/z = 733.2; found 733.2.

步骤4:4-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-2-氟-N-甲基苯甲酰胺Step 4: 4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide

向小瓶中添加(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(400mg，0.545mmol)、3-甲基水杨酸铜(I)(351mg，1.636mmol)、tetrakis(63.0mg，0.055mmol)和(3-氟-4-(甲基氨甲酰基)苯基)硼酸(537mg，2.73mmol)。添加二噁烷(4ml)和水(2ml)。用氮气吹扫顶部空间并且密封小瓶。将容器加热至120℃持续2h，此时LCMS分析指示完全SM转化。To a vial was added tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (400 mg, 0.545 mmol), copper(I) 3-methylsalicylate (351 mg, 1.636 mmol), tetrakis (63.0 mg, 0.055 mmol), and (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (537 mg, 2.73 mmol). Dioxane (4 ml) and water (2 ml) were added. The headspace was purged with nitrogen and the vial was sealed. The vessel was heated to 120 °C for 2 h, at which time LCMS analysis indicated complete SM conversion.

用EtOAc和NH₄OH水溶液稀释粗混合物。分离有机层并且用水和盐水洗涤，随后经Na₂SO₄干燥并且浓缩。通过快速色谱(0至40％AcOEt/DCM)纯化残余物，得到产物。The crude mixture was diluted with EtOAc and aqueous NH₄ OH. The organic layer was separated and washed with water and brine, then dried over Na₂ SO₄ and concentrated. The residue was purified by flash chromatography (0 to 40% AcOEt/DCM) to give the product.

将中间体溶解于MeCN(2mL)和HCl(4M于二噁烷中)(2mL，8.00mmol)中。在室温下搅拌混合物20min，用乙腈/水稀释并且使用制备型LCMS(XBridge C18柱，使用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈TFA盐形式的所需产物。将产物分离为一对滞转异构体。对两种滞转异构体的混合物的TFA盐收集¹H NMR。¹H NMR(600MHz,DMSO-d₆)δ9.61(br,1H),9.31(br,1H),8.52(m,1H),8.42-8.35(m,3H),8.23-8.19(m,3H),8.02-7.93(m,4H),7.90(dd,J＝8.0,1.3Hz,2H),7.63-7.56(m,4H),7.45(s,2H),7.30(d,J＝4.5Hz,2H),6.96(d,J＝3.6Hz,1H),6.91(d,J＝4.5Hz,1H),6.32-6.28(m,3H),6.1(d,J＝7.5Hz,1H),5.74(m,1H),5.26(d,J＝6.6Hz,1H),5.15-5.13(m,2H),4.94(m,1H),4.02(m,1H),3.79(m,1H),3.10-3.04(m,1H),2.94-2.63(m,17H),2.13(dd,J＝9.3,2.3Hz,1H),1.95(d,J＝9.0Hz,1H),1.85(d,J＝6.0Hz,3H),1.78(d,J＝6.7Hz,3H),1.64(d,J＝8.6Hz,1H),1.53(d,J＝9.2Hz,1H)。The intermediate was dissolved in MeCN (2 mL) and HCl (4M in dioxane) (2 mL, 8.00 mmol). The mixture was stirred at room temperature for 20 min, diluted with acetonitrile/water and purified using preparative LCMS (XBridge C18 column, gradient elution with acetonitrile/water (containing 0.1% TFA) at a flow rate of 60 mL/min) to give the desired product as a TFA salt. The product was separated into a pair of asymmetric isomers.¹ H NMR was collected on the TFA salt of the mixture of two asymmetric isomers.¹ H NMR (600 MHz, DMSO-d₆ )δ9.61(br,1H),9.31(br,1H),8.52(m,1H),8.42-8.35(m,3H),8.23-8.19(m,3H),8.02-7.93(m,4H),7.90(dd,J＝8.0,1.3Hz,2H),7.63-7.56(m,4H),7 .45(s,2H),7.30(d,J＝4.5Hz,2H),6.96(d,J＝3.6Hz,1H),6.91(d,J＝4.5Hz,1H),6.32-6.28(m,3H),6.1(d,J＝7.5Hz,1H),5. 74(m,1H),5.26(d,J＝6.6Hz,1H),5.15-5.13(m,2H),4.94(m,1H),4.02(m,1H),3.79(m,1H),3.10-3.04(m,1H),2.94-2.63(m,17H),2.13(dd,J＝9.3, 2.3Hz, 1H), 1.95 (d, J = 9.0Hz, 1H), 1.85 (d, J = 6.0Hz, 3H), 1.78 (d, J = 6.7Hz, 3H), 1.64 (d, J = 8.6Hz, 1H), 1.53 (d, J = 9.2Hz, 1H).

实施例54a.滞转异构体1。峰1。LCMS计算值C₃₉H₃₂Cl₂F₂N₇O₂(M+H)⁺:m/z＝738.2；实验值738.2。Example 54a. Antimeter 1. Peak 1. LCMS calculated for C₃₉ H₃₂ Cl₂ F₂ N₇ O₂ (M+H)⁺ : m/z = 738.2; found 738.2.

实施例54b.滞转异构体2。峰2(所需产物)。LCMS计算值C₃₉H₃₂Cl₂F₂N₇O₂(M+H)⁺:m/z＝738.2；实验值738.2。Example 54b. Apomorphous isomer 2. Peak 2 (desired product). LCMS calculated for C₃₉ H₃₂ Cl₂ F₂ N₇ O₂ (M+H)⁺ : m/z = 738.2; found 738.2.

实施例55：((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)氨基甲酸甲酯Example 55: Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate

在0℃向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.032mmol)于四氢呋喃(0.321ml)中的溶液中添加(22.39μl，0.161mmol)和氯甲酸甲酯(7.46μl，0.096mmol)。在室温下搅拌反应混合物30分钟。完成后，真空浓缩反应物。将残余物溶解于TFA(1ml)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₀H₂₉Cl₂FN₅O₂(M+H)⁺:m/z＝580.2；实验值580.3。¹H NMR(600MHz,DMSO-d₆)9.21(s,1H),8.14-8.07(m,2H),8.02(s,1H),7.83(d,J＝7.8Hz,1H),7.57(t,J＝7.8Hz,1H),7.46(d,J＝7.8Hz,1H),6.80(s,1H),5.57(s,1H),4.91-4.79(m,2H),3.96-3.87(m,1H),3.66(s,3H),3.64-3.55(m,1H),3.46-3.38(m,1H),3.07-2.97(m,1H),2.91-2.83(m,2H),2.82(s,3H),2.97-2.69(m,1H),2.31(d,J＝8.5Hz,1H),1.57(d,J＝8.5Hz,1H),1.39(d,J＝6.8Hz,3H),To a solution of (1R, 4R, 5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Intermediate 22, 20 mg, 0.032 mmol) in tetrahydrofuran (0.321 ml) was added (22.39 μl, 0.161 mmol) and methyl chloroformate (7.46 μl, 0.096 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. After completion, the reactant was concentrated in vacuo. The residue was dissolved in TFA (1 ml) and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reaction was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate 60 mL/min) to give the product as a TFA salt in the form of a white amorphous powder. LC-MS calculated for C₃₀ H₂₉ Cl₂ FN₅ O₂ (M+H)⁺ : m/z=580.2; found 580.3.¹ H NMR (600 MHz, DMSO-d₆ )9.21(s,1H),8.14-8.07(m,2H),8.02(s,1H),7.83(d,J＝7.8Hz,1H),7.57(t,J＝7.8Hz,1H),7.46(d,J＝7.8Hz,1H),6.80(s,1H),5.57(s,1H),4.91-4. 79(m,2H),3.96-3.87(m,1H),3.66 (s,3H),3.64-3.55(m,1H),3.46-3.38(m,1H),3.07-2.97(m,1H),2.91-2.83(m,2H),2.82(s,3H),2.97-2.69(m,1H),2.31(d,J＝8.5Hz,1H),1.57(d ,J＝8.5Hz,1H),1.39(d,J＝6.8Hz,3H),

实施例56：N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-2,2-二氟乙酰胺Example 56: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.032mmol)于四氢呋喃(0.321ml)中的溶液中添加三乙胺(44.8μl，0.321mmol)和2,2-二氟乙酸酐(28.0mg，0.161mmol)。在室温下搅拌反应混合物30分钟。完成后，用水淬灭反应物并且用乙酸乙酯萃取。将有机层用水和盐水洗涤并且浓缩。将残余物溶解于TFA(1ml)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₀H₂₇Cl₂F₃N₅O(M+H)⁺:m/z＝600.2；实验值600.2。To a solution of (1R, 4R, 5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (intermediate 22, 20 mg, 0.032 mmol) in tetrahydrofuran (0.321 ml) was added triethylamine (44.8 μl, 0.321 mmol) and 2,2-difluoroacetic anhydride (28.0 mg, 0.161 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After completion, the reactant was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine and concentrated. The residue was dissolved in TFA (1 ml), and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reaction was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing_0.1 % TFA) at a flow rate of 60 mL/min) to give the product as a white_amorphous powder as a TFA salt_. LC-MS calculated for_{C30H27Cl2F3N5O} (M+H₎⁺ : m/z=600.2; found 600.2.

实施例57:(2S)-N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)四氢呋喃-2-甲酰胺Example 57: (2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.031mmol)和三乙胺((21.90μl，0.157mmol)在乙腈(0.628mL)中的溶液中添加(S)-四氢呋喃-2-甲酸(7.30mg，0.063mmol)和HATU(23.89mg，0.063mmol)。在室温下搅拌反应混合物1小时。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于TFA(1ml)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₃H₃₃Cl₂FN₅O₂(M+H)⁺:m/z＝620.2；实验值620.2。To a solution of (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methylamino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 22, 20 mg, 0.031 mmol) and triethylamine ((21.90 μl, 0.157 mmol) in acetonitrile (0.628 mL) was added (S)-tetrahydrofuran. -2-formic acid (7.30 mg, 0.063 mmol) and HATU (23.89 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in TFA (1 ml), and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reactant was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to obtain the product in the form of a TFA salt of a white amorphous powder. LC-MS calculated value C₃₃ H₃₃ Cl₂ FN₅ O₂ (M+H)⁺ :m/z＝620.2; Found value 620.2.

实施例58：N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)环丙烷磺酰胺Example 58: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.032mmol)于四氢呋喃(0.643ml)中的溶液中添加三乙胺(22.39μl，0.161mmol)和环丙烷磺酰氯(13.55mg，0.096mmol)。在室温下搅拌反应混合物30分钟。完成后，真空浓缩反应物。将残余物溶解于TFA(1ml)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₁H₃₁Cl₂FN₅O₂S(M+H)⁺:m/z＝626.2；实验值626.2。To a solution of (1R, 4R, 5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Intermediate 22, 20 mg, 0.032 mmol) in tetrahydrofuran (0.643 ml) was added triethylamine (22.39 μl, 0.161 mmol) and cyclopropanesulfonyl chloride (13.55 mg, 0.096 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Upon completion, the reactant was concentrated in vacuo. The residue was dissolved in TFA (1 ml) and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reaction was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water₍ containing_0.1 % TFA) at a flow rate of 60 mL/min) to give the product as a white_amorphous powder as a TFA salt_. LC-MS calculated for_{C31H31Cl2FN5O2S} (M+H)⁺ : m/z=626.2; found 626.2.

实施例59:N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)噻唑-4-甲酰胺Example 59: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.032mmol)在乙腈(0.643ml)中的溶液中添加三乙胺(22.39μl，0.161mmol)和噻唑-4-甲酸(8.30mg，0.064mmol)。在室温下搅拌反应混合物30分钟。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于TFA(1ml)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₂H₂₈Cl₂FN₆OS(M+H)⁺:m/z＝633.1；实验值633.2。To a solution of (1R, 4R, 5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (intermediate 22, 20 mg, 0.032 mmol) in acetonitrile (0.643 ml) was added triethylamine (22.39 μl, 0.161 mmol) and thiazole-4-carboxylic acid (8.30 mg, 0.064 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in TFA (1 ml), and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reaction was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing_0.1 % TFA)_at a flow rate of 60 mL/min) to give the product as a white_amorphous powder as a TFA salt. LC-MS calculated for_{C32H28Cl2FN6OS} (M+H)⁺ : m/z=633.1; found 633.2.

实施例60:N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-N-甲基环丙烷甲酰胺Example 60: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-(甲基氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体23，20mg，0.031mmol)于四氢呋喃(0.628ml)中的溶液中添加三乙胺(21.90μl，0.157mmol)和环丙烷碳酰氯(6.57mg，0.063mmol)。在室温下搅拌反应混合物30分钟。完成后，真空浓缩反应物。将残余物溶解于TFA(1mL)中，并且在室温下搅拌溶液10分钟以去除Boc保护基。随后用乙腈稀释反应物，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₃H₃₃Cl₂FN₅O(M+H)⁺:m/z＝604.2；实验值604.3。To a solution of (1R, 4R, 5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-(methylamino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Intermediate 23, 20 mg, 0.031 mmol) in tetrahydrofuran (0.628 ml) was added triethylamine (21.90 μl, 0.157 mmol) and cyclopropanecarbonyl chloride (6.57 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After completion, the reactant was concentrated in vacuo. The residue was dissolved in TFA (1 mL), and the solution was stirred at room temperature for 10 minutes to remove the Boc protecting group. The reaction was then diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water (containing_0.1 % TFA) at a flow rate of 60 mL/min) to give the product as a white_amorphous powder as a TFA salt_. LC-MS calculated for_{C33H33Cl2FN5O} (M+H)⁺ : m/z = 604.2; found 604.3.

实施例61.N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-甲基环丙烷-1-甲酰胺Example 61. N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide

步骤1.(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(250mg，0.31mmol，中间体22，步骤3)在DMF(1.60mL)中的溶液中添加氟化铯(190mg，1.25mmol)，并且将反应混合物在90℃加热1小时。冷却至室温后，用DCM和5％LiCl水溶液稀释反应物。将有机物相继用5％LiCl水溶液和盐水洗涤三次，经硫酸钠干燥并且浓缩。粗物质不经另外纯化即直接使用。LCMS计算值C₃₃H₃₅Cl₂FN₅O₂S(M+H)⁺:m/z＝654.2/656.2；实验值654.1/656.1。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (250 mg, 0.31 mmol, Intermediate 22, Step 3) in DMF (1.60 mL) was added cesium fluoride (190 mg, 1.25 mmol) and the reaction mixture was heated at 90 °C for 1 hour. After cooling to room temperature, the reaction was diluted with DCM and 5% aqueous LiCl. The organics were washed three times sequentially with 5% aqueous LiCl and brine, dried over sodium sulfate and concentrated. The crude material was used directly without additional purification. LCMS calcd_{forC33H35Cl2FN5O2S} (M+H)₊ : m_/ z = 654.2/^656.2 ; found_654.1 /656.1.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(250mg，0.38mmol)和三乙胺(0.27mL，1.91mmol)在乙腈(3.82mL)中的溶液中添加1-甲基环丙烷-1-甲酸(76mg，0.76mmol)和HATU(290mg，0.76mmol)。在室温下搅拌反应混合物1小时。完成后，将反应物倒入水中。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。通过快速柱色谱，用0至70％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(164mg，58％产率)。LCMS计算值C₃₈H₄₁Cl₂FN₅O₃S(M+H)⁺:m/z＝736.2/738.2；实验值736.2/738.2。To a solution of tert-butyl (1R,4R,5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (250 mg, 0.38 mmol) and triethylamine (0.27 mL, 1.91 mmol) in acetonitrile (3.82 mL) was added 1-methylcyclopropane-1-carboxylic acid (76 mg, 0.76 mmol) and HATU (290 mg, 0.76 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reactant was poured into water. The reaction mixture was extracted by ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated._The desired product (164 mg, 58% yield)_was isolated as a light yellow-brown solid by flash column chromatography eluting_with a gradient of 0 to 70% acetone/n-heptane. LCMS calcd for_{C38H41Cl2FN5O3S} (M+H)⁺ : m/_z = 736.2/738.2; found 736.2/738.2.

步骤3.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(164mg，0.22mmol)于二噁烷(2.23mL)中的溶液中添加3-甲基水杨酸铜(I)(143mg，0.67mmol)、四(三苯基膦)钯(0)(26mg，0.022mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(0.21mL，1.11mmol)。用氮气吹扫顶部空间并且将容器密封并且加热至100℃持续3h。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(145mg，89％产率)。LCMS计算值C₄₀H₄₃Cl₂FN₅O₃(M+H)⁺:m/z＝730.3/732.3；实验值730.2/732.2。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (164 mg, 0.22 mmol) in dioxane (2.23 mL) was added 3-methylsalicylate copper(I) (143 mg, 0.67 mmol), tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.21 mL, 1.11 mmol). The headspace was purged with nitrogen and the vessel was sealed and heated to 100°C for 3 h. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (145 mg, 89% yield) was isolated as a light yellow-brown solid by flash column chromatography eluting with a gradient of 0 to 80% acetone/n-heptane. LCMS calculated for C₄₀ H₄₃ Cl₂ FN₅ O₃ (M+H)⁺ : m/z=730.3/732.3; Found 730.2/732.2.

步骤4.(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁基Step 4. Tert-butyl (1R,4R,5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向小瓶中装入(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(145mg，0.20mmol)、搅拌棒、THF(1.59mL)和水(0.40mL)。向此悬浮液中添加锇酸钾二水合物(0.7mg，1.98μmol)。搅拌反应物五分钟，随后添加过碘酸钠(212mg，0.99mmol)。1h之后，通过LCMS检测到起始物质的完全转化。用水和DCM稀释反应混合物。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离所需产物。LCMS计算值C₃₉H₄₁Cl₂FN₅O₄(M+H)⁺:m/z＝732.2/734.2；实验值732.4/734.4。A vial was charged with (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (145 mg, 0.20 mmol), a stirring bar, THF (1.59 mL) and water (0.40 mL). To this suspension was added potassium osmate dihydrate (0.7 mg, 1.98 μmol). The reaction was stirred for five minutes, followed by the addition of sodium periodate (212 mg, 0.99 mmol). After 1 h, complete conversion of the starting material was detected by LCMS. The reaction mixture was diluted with water and DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product was isolated by flash column chromatography eluting with a gradient of 0 to 80% acetone/n-heptane. LCMS calculated for C₃₉ H₄₁ Cl₂ FN₅ O₄ (M+H)⁺ : m/z = 732.2/734.2; found 732.4/734.4.

步骤5.N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-甲基环丙烷-1-甲酰胺Step 5. N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide

向(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-甲基环丙烷-1-甲酰氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(30mg，0.041mmol)在DCM(0.15mL)和甲酸/三乙胺复合物(0.03mL，5:2)中的溶液中添加RuCl(对异丙基甲苯)[(R,R)-Ts-DPEN](1.8mg，2.87μmol)。在室温下搅拌混合物16h。将粗物质在1:1TFA/DCM(0.5ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH2)纯化所需产物。LC-MS计算值C₃₄H₃₅Cl₂FN₅O₂⁺(M+H)⁺:m/z＝634.2/636.2；实验值634.5/636.3。¹HNMR(600MHz,DMSO)δ9.23(s,1H),8.10(s,1H),8.06(s,1H),7.84(dd,J＝8.2,1.5Hz,1H),7.57(t,J＝7.9Hz,1H),7.46(dd,J＝7.6,1.6Hz,1H),6.70(s,1H),5.53(s,1H),5.49(d,J＝11.0Hz,1H),5.12(q,J＝6.6Hz,1H),4.85(d,J＝6.0Hz,1H),4.03-3.97(m,1H),3.90-3.85(m,1H),3.55-3.49(m,1H),3.41-3.35(m,1H),3.05-2.98(m,1H),2.91-2.77(m,3H),2.65(dt,J＝15.7,7.2Hz,1H),2.28(d,J＝9.0Hz,1H),1.94(dd,J＝13.0,2.6Hz,1H),1.85-1.77(m,1H),1.61(s,3H),1.56-1.50(m,4H),1.23-1.17(m,1H),0.91-0.79(m,3H),0.69-0.62(m,2H)。To a solution of (1R, 4R, 5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-methylcyclopropane-1-carboxamido)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (30 mg, 0.041 mmol) in DCM (0.15 mL) and formic acid/triethylamine complex (0.03 mL, 5:2) was added RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN](1.8 mg, 2.87 μmol). The mixture was stirred at room temperature for 16 h. The crude material was stirred in 1:1 TFA/DCM (0.5 ml) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₄ H₃₅ Cl₂ FN₅ O₂⁺ (M+H)⁺ : m/z = 634.2/636.2; found^634.5 /636.3. HNMR (600MHz, DMSO) δ9.23(s,1H),8.10(s,1H),8.06(s,1H),7.84(dd,J＝8.2,1.5Hz,1H),7.57(t,J＝7.9Hz,1H),7.46(dd,J＝7.6,1.6Hz,1H),6.70(s,1H),5.5 3(s,1H),5.49(d,J＝11.0Hz,1H),5.12(q,J＝6.6Hz,1H),4.85(d,J＝6.0Hz,1H),4.03-3.97(m,1H),3.90-3.85(m,1 H),3.55-3.49(m,1H),3.41-3.35(m,1H),3.05-2.98(m,1H),2.91-2.77(m,3H),2.65(dt,J＝15.7,7.2Hz,1H),2.28(d,J＝9.0Hz,1H),1.94(dd,J＝13.0 ,2.6Hz,1H),1.85-1.77(m,1H),1.61(s,3H),1.56-1.50(m,4H),1.23-1.17(m,1H),0.91-0.79(m,3H),0.69-0.62(m,2H).

实施例62. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 62. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(2-((1R,3R,5R)-2-氮杂双环[3.1.0]己烷-3-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-5-(2-((1R,3R,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物以类似于实施例61、步骤1的方式，用(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((1R,3R,5R)-2-((2-(三甲基甲硅烷基)乙氧基)羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯替代(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯来制备。LC-MS计算值C₃₆H₃₇Cl₂FN₅O₂S⁺(M+H)⁺:m/z＝692.2/694.2；实验值692.1/694.1。This compound was reacted with (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((1R,3R,5R)-2-((2-(trimethylsilyl)ethoxy)carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[3.1.0]hexan-3-yl]-1H-pyrrolo[3,2-c]quinolin-1-yl] ... tert-Butyl bicyclo[2.1.1]hexane-2-carboxylate was prepared instead of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2_- c]quinolin_- 1-yl)-2-azabicyclo[2.1.1]hexane-_{2-carboxylate. LC-MS calculated for C36H37Cl2FN5O2S+}⁽ M+H)⁺ : m/z=692.2/694.2; found 692.1/694.1.

步骤2.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(2-((1R,3R,5R)-2-氮杂双环[3.1.0]己烷-3-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(200mg，0.29mmol)和三乙胺(0.20mL，1.44mmol)在乙腈(2.9mL)中的溶液中添加1-甲基环丙烷-1-甲酸(58mg，0.58mmol)和HATU(220mg，0.58mmol)。在室温下搅拌反应混合物1小时。完成后，将反应物倒入水中。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。通过快速柱色谱，用0至70％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(142mg，64％产率)。LCMS计算值C₄₁H₄₃Cl₂FN₅O₃S(M+H)⁺:m/z＝774.2/776.2；实验值774.3/776.3。To a solution of tert-butyl (1R,4R,5S)-5-(2-((1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (200 mg, 0.29 mmol) and triethylamine (0.20 mL, 1.44 mmol) in acetonitrile (2.9 mL) was added 1-methylcyclopropane-1-carboxylic acid (58 mg, 0.58 mmol) and HATU (220 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reactant was poured into water. The reaction mixture was extracted by ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated._The desired product (142 mg, 64% yield) was isolated as a light yellow-brown solid by flash column chromatography eluting_with a gradient of 0 to 70% acetone/n-heptane_. LCMS calcd for_{C41H43Cl2FN5O3S} (M+H)⁺ : m/_z = 774.2/776.2; found 774.3/776.3.

步骤3.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(142mg，0.18mmol)于二噁烷(1.83mL)中的溶液中添加3-甲基水杨酸铜(I)(118mg，0.55mmol)、四(三苯基膦)钯(0)(21mg，0.018mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(0.17mL，0.92mmol)。用氮气吹扫顶部空间并且将容器密封并且加热至100℃持续3h。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(78mg，55％产率)。LCMS计算值C₄₃H₄₅Cl₂FN₅O₃(M+H)⁺:m/z＝768.3/770.3；实验值768.2/770.2。To tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3-Methylsalicylic acid copper (I) (118 mg, 0.55 mmol), tetrakis (triphenylphosphine) palladium (0) (21 mg, 0.018 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (0.17 mL, 0.92 mmol) (142 mg, 0.18 mmol) were added to a solution of dioxane (1.83 mL). The head space was purged with nitrogen and the vessel was sealed and heated to 100 ° C for 3 h. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (78 mg, 55% yield) was isolated as a light yellow-brown solid by flash column chromatography with a gradient elution of 0 to 80% acetone/n-heptane. LCMS calcd_{forC43H45Cl2FN5O3} (M+H)₊ : m_/ z = 768.3/^770.3 ; found_768.2 /770.2.

步骤4.(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向小瓶中装入(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(78mg，0.10mmol)、搅拌棒、THF(0.81mL)和水(0.20mL)。向此悬浮液中添加锇酸钾二水合物(0.4mg，1.02μmol)。搅拌反应物五分钟，随后添加过碘酸钠(109mg，0.51mmol)。1h之后，通过LCMS检测到起始物质的完全转化。用水和DCM稀释反应混合物。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离所需产物。LCMS计算值C₄₂H₄₃Cl₂FN₅O₄(M+H)⁺:m/z＝770.3/772.3；实验值770.5/772.4。A vial was charged with tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (78 mg, 0.10 mmol), a stir bar, THF (0.81 mL), and water (0.20 mL). To this suspension was added potassium osmate dihydrate (0.4 mg, 1.02 μmol). The reaction was stirred for five minutes followed by the addition of sodium periodate (109 mg, 0.51 mmol). After 1 h, complete conversion of the starting material was detected by LCMS. The reaction mixture was diluted with water and DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product was isolated by flash column chromatography eluting with a gradient of 0 to 80% acetone/n-heptane. LCMS calculated for C₄₂ H₄₃ Cl₂ FN₅ O₄ (M+H)⁺ : m/z=770.3/772.3; found 770.5/772.4.

步骤5. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 5. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

向(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(29mg，0.038mmol)在DCM(0.13mL)和甲酸/三乙胺复合物(0.03mL，5:2)中的溶液中添加RuCl(对异丙基甲苯)[(R,R)-Ts-DPEN](1.7mg，2.63μmol)。在室温下搅拌混合物16h。将粗物质在1:1TFA/DCM(0.5ml)中搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₇H₃₇Cl₂FN₅O₂⁺(M+H)⁺:m/z＝672.2/674.2；实验值672.4/674.4。To a solution of tert-butyl (1R,4R,5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (29 mg, 0.038 mmol) in DCM (0.13 mL) and formic acid/triethylamine complex (0.03 mL, 5:2) was added RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] (1.7 mg, 2.63 μmol). The mixture was stirred at room temperature for 16 h. The crude material was stirred in 1:1 TFA/DCM (0.5 ml) for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS Calcd for C₃₇ H₃₇ Cl₂ FN₅ O₂⁺ (M+H)⁺ : m/z = 672.2/674.2; Found 672.4/674.4.

实施例63. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 63. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷盐酸盐Step 1. (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane hydrochloride

向(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-甲酸叔丁酯(实施例49，步骤3；4.88g，23.5mmol)于THF(80mL)中的溶液中添加含4N HCl的二噁烷(18mL)。在室温下搅拌溶液8至16h，直至通过LCMS所检测观测到起始物质完全转化，随后浓缩至近干燥。将粗固体在乙醚中制成浆液，通过过滤收集，随后风干(2.48g，73％产率)。LCMS计算值C₇H₁₀N(M+H)⁺:m/z＝108.1；实验值108.1。To a solution of tert-butyl (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (Example 49, Step 3; 4.88 g, 23.5 mmol) in THF (80 mL) was added 4N HCl in dioxane (18 mL). The solution was stirred at room temperature for 8 to 16 h until complete conversion of the starting material was observed by LCMS, then concentrated to near dryness. The crude solid was slurried in diethyl ether, collected by filtration, and air-dried (2.48 g, 73% yield). LCMS calculated for C₇ H₁₀ N (M+H)⁺ : m/z = 108.1; found 108.1.

步骤2.((1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-基)(1-氟环丙基)甲酮Step 2. ((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexan-2-yl)(1-fluorocyclopropyl)methanone

向(1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷盐酸盐(2.48g，17.3mmol)和三乙胺(12mL，86mmol)在乙腈(90mL)中的溶液中添加1-氟环丙烷-1-甲酸(3.59g，34.5mmol)和HATU(13.1g，34.5mmol)。在室温下搅拌反应混合物1小时。完成后，将反应物倒入水中。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。通过快速柱色谱，用0至50％丙酮/己烷的梯度洗脱分离出呈无色油状物的所需产物(2.71g，81％产率)。LCMS计算值C₁₁H₁₃FNO(M+H)⁺:m/z＝194.1；实验值194.1。To a solution of (1R, 3R, 5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane hydrochloride (2.48 g, 17.3 mmol) and triethylamine (12 mL, 86 mmol) in acetonitrile (90 mL) was added 1-fluorocyclopropane-1-carboxylic acid (3.59 g, 34.5 mmol) and HATU (13.1 g, 34.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reactant was poured into water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The desired product (2.71 g, 81% yield) was isolated as a colorless oil by flash column chromatography with a gradient elution of 0 to 50% acetone/hexane. LCMS calculated for C₁₁ H₁₃ FNO (M+H)⁺ : m/z=194.1; Found 194.1.

步骤3.(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向中间体5(2.5g，3.86mmol)和((1R,3R,5R)-3-乙炔基-2-氮杂双环[3.1.0]己烷-2-基)(1-氟环丙基)甲酮(970mg，5.02mmol)的混合物中添加DMF(19.3mL)和三乙胺(5.38mL，38.6mmol)，随后添加双(三苯基膦)氯化钯(II)(270mg，0.386mmol)和碘化铜(I)(736mg，3.86mmol)。用氮气吹扫反应烧瓶的顶部空间，随后在75℃搅拌2h。随后添加碳酸铯(6.29g，19.3mmol)并且将反应混合物加热至55℃持续16h。用水和少量氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至60％丙酮/正庚烷)纯化粗产物，得到所需产物(1.86g，68％)。LC-MS计算值C₃₄H₃₇BrF₂N₅O₃S⁺(M+H)⁺:m/z＝712.2/714.2；实验值712.3/714.3。To a mixture of intermediate 5 (2.5 g, 3.86 mmol) and ((1R, 3R, 5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl)(1-fluorocyclopropyl)methanone (970 mg, 5.02 mmol) was added DMF (19.3 mL) and triethylamine (5.38 mL, 38.6 mmol), followed by bis(triphenylphosphine)palladium(II) chloride (270 mg, 0.386 mmol) and copper(I) iodide (736 mg, 3.86 mmol). The headspace of the reaction flask was purged with nitrogen and then stirred at 75 °C for 2 h. Cesium carbonate (6.29 g, 19.3 mmol) was then added and the reaction mixture was heated to 55 °C for 16 h. The reaction was quenched with water and a small amount of saturated aqueous ammonium hydroxide solution, then diluted with ethyl acetate and filtered through a plug of celite. The filtrate layers were separated and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified_by flash column chromatography (0 to 60% acetone/n-heptane) to give the desired product (_1.86 g, 68%). LC-MS_Calcd for_{C34H37BrF2N5O3S}⁺ (M+H)⁺ : m/z₌ 712.2/714.2; Found 712.3/714.3.

步骤4.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(7-溴-8-(2-氰基乙基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3.92g，5.50mmol)、(2,3-二氯苯基)硼酸(1.36,7.15mmol)、氟化钾(959mg，16.5mmol)和Pd-132(389mg，0.55mmol)的混合物中添加1,4-二噁烷(44mL)/水(11mL)，并且抽空反应烧瓶，用氮气回填，随后在90℃搅拌1h。将反应混合物用乙酸乙酯稀释，用水和盐水洗涤，经硫酸钠干燥，并且接着浓缩。通过快速柱色谱(0至70％丙酮/正庚烷)纯化粗产物，得到所需产物(3.76g，88％)。LC-MS计算值C₄₀H₄₀Cl₂F₂N₅O₃S⁺(M+H)⁺:m/z＝778.2/780.2；实验值778.4/780.3。To (1R,4R,5S)-5-(7-bromo-8-(2-cyanoethyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (3 To a mixture of 1,4-dioxane (44 mL)/water (11 mL) was added 2,4-dioxane (44 mL), (2,3-dichlorophenyl)boronic acid (1.36, 7.15 mmol), potassium fluoride (959 mg, 16.5 mmol), and Pd-132 (389 mg, 0.55 mmol), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 90°C for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and then concentrated. The crude product was purified by flash column chromatography (0 to 70% acetone/n-heptane) to give the desired product (3.76 g, 88%). LC-MS calculated for C₄₀ H₄₀ Cl₂ F₂ N₅ O₃ S⁺ (M+H)⁺ : m/z=778.2/780.2; found 778.4/780.3.

步骤5.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3.76g，4.83mmol)于二噁烷(48mL)中的溶液中添加3-甲基水杨酸铜(I)(3.11g，14.5mmol)、四(三苯基膦)钯(0)(558mg，0.48mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(4.54mL，24.1mmol)。用氮气吹扫顶部空间并且将容器密封并且加热至100℃持续3h。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(2.84g，76％产率)。LCMS计算值C₄₂H₄₂Cl₂F₂N₅O₃(M+H)⁺:m/z＝772.3/774.3；实验值772.2/774.2。To tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3-Methylsalicylic acid copper (I) (3.11 g, 14.5 mmol), tetrakis (triphenylphosphine) palladium (0) (558 mg, 0.48 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (4.54 mL, 24.1 mmol) (3.76 g, 4.83 mmol) were added to a solution of 1,2-dioxaborolane (48 mL). The headspace was purged with nitrogen and the vessel was sealed and heated to 100 ° C for 3 h. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (2.84 g, 76% yield) was isolated as a light yellow-brown solid by flash column chromatography with a gradient elution of 0 to 80% acetone/n-heptane._LCMS calcd for_{C42H42Cl2F2N5O3} (M₊ H)₊ : m/_z = 772.3/_774.3 ; found 772.2/^774.2 .

步骤6.(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 6. (1R,4R,5S)-tert-butyl 5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向圆底烧瓶中装入(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(丙-1-烯-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.84g，3.68mmol)、搅拌棒、THF(30mL)和水(7.4mL)。向此悬浮液中添加锇酸钾二水合物(14mg，0.037μmol)。搅拌反应物五分钟，随后添加过碘酸钠(3.93g，18.4mmol)。1h之后，通过LCMS检测到起始物质的完全转化。用水和DCM稀释反应混合物。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离所需产物。LCMS计算值C₄₁H₄₀Cl₂F₂N₅O₄(M+H)⁺:m/z＝774.2/776.2；实验值774.1/776.2。A round bottom flask was charged with tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(prop-1-en-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.84 g, 3.68 mmol), a stir bar, THF (30 mL) and water (7.4 mL). To this suspension was added potassium osmate dihydrate (14 mg, 0.037 μmol). The reaction was stirred for five minutes followed by the addition of sodium periodate (3.93 g, 18.4 mmol). After 1 h, complete conversion of the starting material was detected by LCMS. The reaction mixture was diluted with water and DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product was isolated by flash column chromatography eluting with a gradient of 0 to 80% acetone/n-heptane. LCMS calculated for C₄₁ H₄₀ Cl₂ F₂ N₅ O₄ (M+H)⁺ : m/z=774.2/776.2; found 774.1/776.2.

步骤7.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 7. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(2.81g，3.63mmol)在DCM(6.05mL)和甲酸/三乙胺复合物(1.21mL，5:2)中的溶液中添加RuCl(对异丙基甲苯)[(R,R)-Ts-DPEN](231mg，0.36mmol)。在室温下搅拌混合物24h。在通过LCMS检测到起始物质完全转化后，添加饱和碳酸氢钠水溶液并且用DCM萃取有机物。将有机相用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至100％丙酮/正庚烷的梯度洗脱来分离所需产物(1.86g，66％产率)。LCMS计算值C₄₁H₄₂Cl₂F₂N₅O₄(M+H)⁺:m/z＝776.3/778.3；实验值776.3/778.3。To a solution of tert-butyl (1R,4R,5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.81 g, 3.63 mmol) in DCM (6.05 mL) and formic acid/triethylamine complex (1.21 mL, 5:2) was added RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] (231 mg, 0.36 mmol). The mixture was stirred at room temperature for 24 h. After complete conversion of the starting material was detected by LCMS, saturated aqueous sodium bicarbonate solution was added and the organics were extracted with DCM. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (1.86 g, 66% yield) was isolated by flash column chromatography with a gradient elution of 0 to 100% acetone/n-heptane. LCMS calculated for C₄₁ H₄₂ Cl₂ F₂ N₅ O₄ (M+H)⁺ : m/z=776.3/778.3; Found 776.3/778.3.

步骤8. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 8. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.86g，2.4mmol)在1:1TFA/DCM(10ml)中的溶液在室温下搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₆H₃₄Cl₂F₂N₅O₂⁺(M+H)⁺:m/z＝676.2/678.2；实验值676.3/678.2。¹H NMR(600MHz,DMSO-d₆)δ9.28(s,1H),8.11(s,1H),8.06(s,1H),7.84(dd,J＝8.1,1.5Hz,1H),7.58(t,J＝7.9Hz,1H),7.46(dd,J＝7.6,1.5Hz,1H),6.77(s,1H),5.64(d,J＝10.8Hz,1H),5.56(s,1H),5.15(q,J＝6.7Hz,1H),4.85(d,J＝6.0Hz,1H),4.13-4.07(m,1H),3.93-3.88(m,1H),3.54-3.48(m,1H),3.42-3.36(m,1H),3.06-2.98(m,1H),2.92-2.79(m,3H),2.66(dt,J＝15.6,7.2Hz,1H),2.29(d,J＝9.0Hz,1H),1.96(dd,J＝12.9,2.7Hz,1H),1.86-1.79(m,1H),1.62-1.50(m,2H),1.52(d,J＝6.5Hz,3H),1.50-1.41(m,2H),1.28-1.18(m,1H),0.80(dt,J＝8.9,6.0Hz,1H),0.71-0.64(m,1H)。A solution of tert-butyl (1R, 4R, 5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R, 3R, 5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.86 g, 2.4 mmol) in 1:1 TFA/DCM (10 ml) was stirred at room temperature for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated value for C₃₆ H₃₄ Cl₂ F₂ N₅ O₂⁺ (M+H)⁺ : m/z = 676.2/678.2; found value 676.3/678.2.¹ H NMR (600 MHz, DMSO-d₆ )δ9.28(s,1H),8.11(s,1H),8.06(s,1H),7.84(dd,J＝8.1,1.5Hz,1H),7.58(t,J＝7.9Hz,1H),7.46(dd,J＝7.6,1.5Hz,1H),6.77(s,1H),5.64(d,J＝10.8Hz, 1H),5.56(s,1H),5.15(q,J＝6.7Hz,1H),4.85(d,J＝6.0Hz,1H),4.13-4.07(m,1H),3.93-3.88(m,1H),3.54-3.48(m,1H),3.42- 3.36(m,1H),3.06-2.98(m,1H),2.92-2.79(m,3H),2.66(dt,J＝15.6,7.2Hz,1H),2.29(d,J＝9.0Hz,1H),1.96(dd,J＝12.9,2.7Hz,1H),1.86-1.79(m,1 H),1.62-1.50(m,2H),1.52(d,J＝6.5Hz,3H),1.50-1.41(m,2H),1.28-1.18(m,1H),0.80(dt,J＝8.9,6.0Hz,1H),0.71-0.64(m,1H).

实施例64. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 64. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物以类似于实施例63的方式，用甲基硼酸替代步骤5的4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷来制备。LC-MS计算值C₄₀H₄₀Cl₂F₂N₅O₃⁺(M+H)⁺:m/z＝746.2/748.2；实验值746.2/748.2。This compound was prepared in_a manner analogous to Example 63, substituting methylboronic acid for 4,4,5,5-tetramethyl-2-(prop-₁ -en-2-yl)-1,3,2_- dioxaborolane in step 5.^{LC-MS calcd for C40H40Cl2F2N5O3+}_(M+ H)⁺ : m/z=746.2/748.2; found 746.2/748.2.

步骤2. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 2. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

将(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(19mg，0.026mmol)在1:1TFA/DCM(0.5mL)中的溶液在室温下搅拌30min，随后浓缩。通过制备型HPLC(pH 2)纯化所需产物。LC-MS计算值C₃₅H₃₂Cl₂F₂N₅O⁺(M+H)⁺:m/z＝646.2/648.2；实验值646.1/648.1。A solution of (1R, 4R, 5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R, 3R, 5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (19 mg, 0.026 mmol) in 1:1 TFA/DCM (0.5 mL) was stirred at room temperature for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC^{-MS calculated for C35H32Cl2F2N5O+(M+H)+}_:m^/_z=646.2 /648.2; found 646.1/648.1.

实施例65.N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丙烷-1-甲酰胺Example 65. N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide

步骤1.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(丙-1-烯-2-基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(prop-1-en-2-yl)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(甲基硫基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.0g，1.25mmol，中间体22，步骤3)于二噁烷(12.5mL)中的溶液中添加3-甲基水杨酸铜(I)(806mg，3.76mmol)、四(三苯基膦)钯(0)(145mg，0.13mmol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼杂环戊烷(0.71mL，3.76mmol)。用氮气吹扫顶部空间并且将容器密封并且加热至100℃持续3h。将反应混合物用水和氢氧化铵饱和水溶液淬灭，接着用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离出呈淡黄棕色固体的所需产物(858mg，86％产率)。LCMS计算值C₄₁H₄₉Cl₂FN₅O₄Si(M+H)⁺:m/z＝792.3/794.3；实验值792.2/794.2。To (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(methylthio)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1.0 g, 1.25 mm ol, intermediate 22, step 3) was added to a solution of 3-methylsalicylate copper (I) (806 mg, 3.76 mmol), tetrakis (triphenylphosphine) palladium (0) (145 mg, 0.13 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (0.71 mL, 3.76 mmol) in dioxane (12.5 mL). The headspace was purged with nitrogen and the vessel was sealed and heated to 100 ° C for 3 h. The reaction mixture was quenched with water and saturated aqueous ammonium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (858 mg, 86% yield) was isolated as a light yellow-brown solid by flash column chromatography with a gradient elution of 0 to 80% acetone/n-heptane. LCMS calcd_{forC41H49Cl2FN5O4Si} (M₊ H)₊ : m_/ z = 792.3/^794.3 ; found 792.2/794.2.

步骤2.(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. (1R,4R,5S)-tert-butyl 5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向小瓶中装入(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(丙-1-烯-2-基)-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(858mg，1.08mmol)、搅拌棒、THF(8.66mL)和水(2.16mL)。向此悬浮液中添加锇酸钾二水合物(4.0mg，10.8μmol)。搅拌反应物五分钟，随后添加过碘酸钠(1.16g，5.41mmol)。1h之后，通过LCMS检测到起始物质的完全转化。用水和DCM稀释反应混合物。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱，用0至80％丙酮/正庚烷的梯度洗脱来分离所需产物(667mg，78％产率)。LCMS计算值C₄₀H₄₇Cl₂FN₅O₅Si(M+H)⁺:m/z＝794.3/796.3；实验值794.2/796.2。A vial was charged with (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(prop-1-en-2-yl)-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (858 mg, 1.08 mmol), a stirring bar, THF (8.66 mL) and water (2.16 mL). To this suspension was added potassium osmate dihydrate (4.0 mg, 10.8 μmol). The reaction was stirred for five minutes, followed by the addition of sodium periodate (1.16 g, 5.41 mmol). After 1 h, complete conversion of the starting material was detected by LCMS. The reaction mixture was diluted with water and DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (667 mg, 78% yield) was isolated by flash column chromatography eluting_with a gradient of 0 to 80% acetone/n_- heptane._LCMS calculated for_{C40H47Cl2FN5O5Si} (M+H)₊ : m/z=794.3/^796.3 ; found 794.2/796.2.

步骤3.(1R,4R,5S)-5-(4-乙酰基-2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-(4-acetyl-2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(667mg，0.84mmol)在DMF(4.2mL)中的溶液中添加氟化铯(510mg，3.36mmol)，并且在90℃加热反应混合物1小时。冷却至室温后，用DCM和5％LiCl水溶液稀释反应物。将有机物相继用5％LiCl水溶液和盐水洗涤三次，经硫酸钠干燥并且浓缩。粗物质不经另外纯化即直接使用。LCMS计算值C₃₄H₃₅Cl₂FN₅O₃(M+H)⁺:m/z＝650.2/652.2；实验值650.2/652.2。To a solution of (1R,4R,5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (667 mg, 0.84 mmol) in DMF (4.2 mL) was added cesium fluoride (510 mg, 3.36 mmol) and the reaction mixture was heated at 90 °C for 1 hour. After cooling to room temperature, the reaction was diluted with DCM and 5% aqueous LiCl solution. The organics were washed three times with 5% aqueous LiCl solution and brine, dried over sodium sulfate and concentrated. The crude material was used directly without additional purification. LCMS calcd_{forC34H35Cl2FN5O3} (M+H)⁺ : m/z =_650.2 /_652.2 ; found_650.2 /652.2.

步骤4.(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-甲酰氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 4. (1R,4R,5S)-tert-butyl 5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carboxamido)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(4-乙酰基-2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(350mg，0.54mmol)和三乙胺(0.38mL，2.69mmol)在乙腈(5.4mL)中的溶液中添加1-氟环丙烷-1-甲酸(112mg，1.08mmol)和HATU(409mg，1.08mmol)。在室温下搅拌反应混合物1小时。完成后，将反应物倒入水中。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。通过快速柱色谱，用0至80％丙酮/己烷的梯度洗脱来分离所需产物(205mg，52％产率)。LCMS计算值C₃₈H₃₈Cl₂F₂N₅O₄(M+H)⁺:m/z＝736.2/738.2；实验值736.2/738.1。To a solution of (1R, 4R, 5S)-5-(4-acetyl-2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (350 mg, 0.54 mmol) and triethylamine (0.38 mL, 2.69 mmol) in acetonitrile (5.4 mL) was added 1-fluorocyclopropane-1-carboxylic acid (112 mg, 1.08 mmol) and HATU (409 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 1 hour. After completion, the reactant was poured into water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The desired product (205 mg, 52% yield)_was isolated by flash column chromatography_eluting with_a gradient of 0 to 80% acetone/hexanes_. LCMS calcd for_{C38H38Cl2F2N5O4} (M₊ H)⁺ : m/z = 736.2/738.2; found 736.2/738.1.

步骤5.(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-甲酰氨基)乙基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 5. (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carboxamido)ethyl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-(4-乙酰基-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-甲酰氨基)乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(205mg，0.28mmol)在DCM(4.6mL)和甲酸/三乙胺复合物(0.93mL，5:2)中的溶液中添加RuCl(对异丙基甲苯)[(R,R)-Ts-DPEN](18mg，0.028mmol)。在室温下搅拌混合物16h。在通过LCMS检测到起始物质完全转化后，添加饱和碳酸氢钠水溶液并且用DCM萃取有机物。将有机相用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过制备型HPLC(pH 10)分离所需产物(106mg，52％产率)。LCMS计算值C₃₈H₄₀Cl₂F₂N₅O₄(M+H)⁺:m/z＝738.2/740.2；实验值738.2/740.2。To a solution of (1R, 4R, 5S)-5-(4-acetyl-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-formamido)ethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (205mg, 0.28mmol) in DCM (4.6mL) and formic acid/triethylamine complex (0.93mL, 5:2) was added RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN](18mg, 0.028mmol). The mixture was stirred at room temperature for 16h. After the complete conversion of the starting material was detected by LCMS, saturated sodium bicarbonate aqueous solution was added and the organic matter was extracted with DCM. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The desired product (106_mg , 52% yield)_was isolated_by preparative HPLC (pH 10)_.LCMS calcd for_{C38H40Cl2F2N5O4} (M+H)⁺ : m/z = 738.2/740.2; found 738.2/740.2.

步骤6.N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丙烷-1-甲酰胺Step 6. N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide

(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-甲酰氨基)乙基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(106mg，0.14mmol)在1:1TFA/DCM(0.6mL)中的溶液30min，随后浓缩。通过制备型HPLC(pH2)纯化所需产物。LC-MS计算值C₃₃H₃₂Cl₂F₂N₅O₂⁺(M+H)⁺:m/z＝638.2/640.2；实验值638.3/640.3。¹H NMR(600MHz,DMSO)δ9.46(s,1H),9.32(d,J＝7.5Hz,1H),8.16(s,1H),8.09(s,1H),7.84(dd,J＝8.1,1.6Hz,1H),7.58(t,J＝7.8Hz,1H),7.49(dd,J＝7.8,1.5Hz,1H),7.09(s,1H),5.62(s,1H),5.28-5.19(m,2H),4.86(d,J＝6.0Hz,1H),3.97-3.91(m,1H),3.64(t,J＝8.4Hz,1H),3.42(t,J＝9.1Hz,1H),3.10-2.95(m,1H),2.92-2.72(m,2H),2.72-2.63(m,1H),2.33(d,J＝8.8Hz,1H),1.62-1.53(m,4H),1.51(d,J＝6.9Hz,3H),1.50-1.39(m,2H),1.34-1.23(m,2H)。A solution of (1R,4R,5S)-tert-butyl 5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carboxamido)ethyl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (106 mg, 0.14 mmol) in 1:1 TFA/DCM (0.6 mL) was stirred for 30 min and then concentrated. The desired product was purified by preparative HPLC (pH 2). LC-MS calculated for C₃₃ H₃₂ Cl₂ F₂ N₅ O₂⁺ (M+H)⁺ : m/z=638.2/640.2; found 638.3/640.3.¹ H NMR (600MHz, DMSO) δ9.46(s,1H),9.32(d,J＝7.5Hz,1H),8.16(s,1H),8.09(s,1H),7.84(dd,J＝8.1,1.6Hz,1H),7.58(t,J＝7.8Hz,1H),7.49(dd,J＝7.8,1.5Hz,1 H),7.09(s,1H),5.62(s,1H),5.28-5.19(m,2H),4.86(d,J＝6.0Hz,1 H),3.97-3.91(m,1H),3.64(t,J＝8.4Hz,1H),3.42(t,J＝9.1Hz,1H),3.10-2.95(m,1H),2.92-2.72(m,2H),2.72-2.63(m,1H),2.33(d,J＝8.8Hz,1H),1 .62-1.53(m,4H),1.51(d,J=6.9Hz,3H),1.50-1.39(m,2H),1.34-1.23(m,2H).

实施例66.N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丁烷-1-甲酰胺Example 66. N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide

此化合物以类似于实施例67的方式，用1-氟环丁烷-1-甲酸替代步骤4中的1-氟环丙烷-1-甲酸来制备。LC-MS计算值C₃₄H₃₄Cl₂F₂N₅O₂⁺(M+H)⁺:m/z＝652.2/654.2；实验值652.1/654.2。This compound_was prepared in_a manner analogous to Example 67, substituting 1-fluorocyclobutane-1_- carboxylic acid for 1_- fluorocyclopropane-1-carboxylic acid in step 4. LC-MS calcd for_{C34H34Cl2F2N5O2+} (M+H)^+: m/z=652.2/654.2; found 652.1/654.2.

实施例67. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-2-(1-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)乙基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 67. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

步骤1.(1R,4R,5S)-5-((3-氨基-7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1. (1R,4R,5S)-tert-butyl 5-((3-amino-7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((3-氨基-7-溴-6-(2-氰基乙基)-8-氟-2-(甲基硫基)-喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(来自中间体2，步骤4，14.37g，22.57mmol,)、Pd(PPh₃)₄(2.61g，2.26mmol)和磷酸钾(14.37g，67.7mmol)于二噁烷(100ml)和水(20ml)中的混合物中添加(3-氯-2-甲基苯基)硼酸(7.69g，45.1mmol)。将反应混合物加热至100℃持续1小时。使反应混合物冷却至室温并且添加水和DCM。分离各层并且用DCM萃取水层。合并的有机洗脱份经MgSO₄塞过滤并浓缩。通过自动快速柱色谱(0至100％EtOAc/己烷)纯化粗残余物，得到标题化合物(11.1g，72％)。LC-MS计算值C₃₅H₄₂ClFN₅O₄S⁺(M+H)⁺:m/z＝682.3；实验值682.4.To a mixture of (1R,4R,5S)-5-((3-amino-7-bromo-6-(2-cyanoethyl)-8-fluoro-2-(methylsulfanyl)-quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (from Intermediate 2, Step 4, 14.37 g, 22.57 mmol,), Pd(_PPh3 )₄ (2.61 g, 2.26 mmol) and potassium phosphate (14.37 g, 67.7 mmol) in dioxane (100 ml) and water (20 ml) was added (3-chloro-2-methylphenyl)boronic acid (7.69 g, 45.1 mmol). The reaction mixture was heated to 100°C for 1 hour. The reaction mixture was cooled to room temperature and water and DCM were added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic fractions were filtered through a plug of MgSO₄ and concentrated. The crude residue was purified by automated flash column chromatography (0 to 100% EtOAc/hexanes) to afford the title compound (11.1 g, 72%). LC-MS calculated for C₃₅ H₄₂ ClFN₅ O₄ S⁺ (M+H)⁺ : m/z = 682.3; found 682.4.

步骤2.(1R,4R,5S)-5-((3-氨基-7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-2-甲基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2. tert-Butyl (1R,4R,5S)-5-((3-amino-7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-2-methylquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((3-氨基-7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-2-(甲基硫基)喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(11.1g，16.3mmol)、甲基硼酸(3.51g，58.6mmol)、Pd(PPh₃)₄(3.76g，3.25mmol)于二噁烷(100ml)中的溶液中添加3-甲基水杨酸铜(I)(12.6g，58.6mmol)。在110℃搅拌反应混合物1小时。使反应混合物冷却至室温，并且用NH₄OH饱和水溶液淬灭并且用DCM稀释。分离各层并且用DCM萃取有机层。合并的有机洗脱份经MgSO₄塞过滤并浓缩。通过自动快速柱色谱(0至100％EtOAc/己烷)纯化粗残余物，得到标题化合物(8.34g，79％)。LC-MS计算值C₃₅H₄₂ClFN₅O₄⁺(M+H)⁺:m/z＝650.3；实验值650.4。To a solution of tert-butyl (1R,4R,5S)-5-((3-amino-7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-2-(methylthio)quinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (11.1 g, 16.3 mmol), methylboronic acid (3.51 g, 58.6 mmol), Pd(PPh₃ )₄ (3.76 g, 3.25 mmol) in dioxane (100 ml) was added 3-methylsalicylate copper(I) (12.6 g, 58.6 mmol). The reaction mixture was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature and quenched with saturated aqueous NH₄ OH and diluted with DCM. The layers were separated and the organic layer was extracted with DCM. The combined organic fractions were filtered through a plug of MgSO₄ and concentrated. The crude residue was purified by_automated flash column chromatography (0 to 100% EtOAc/hexanes) to give the title compound (_8.34 g, 79%). LC-MS calcd for_{C35H42ClFN5O4}⁺ (M+H)₊^: m/z = 650.3; found 650.4.

步骤3.(1R,4R,5S)-5-((7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-3-碘-2-甲基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3. (1R,4R,5S)-tert-butyl 5-((7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate

向(1R,4R,5S)-5-((3-氨基-7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-2-甲基喹啉-4-基)(叔丁氧基羰基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(8.34g，12.83mmol)在乙腈(130ml)中的-20℃溶液中逐滴添加硫酸(50％v/v，3.44ml，32.1mmol)。逐滴添加亚硝酸钠(1.77g，25.7mmol)的浓缩水溶液，保持反应混合物温度在-20℃与-15℃之间。在添加之后，在-20℃快速搅拌反应混合物。逐滴添加碘化钾(8.52g，51.3mmol)的浓缩水溶液，使反应混合物温度保持在-20℃与-15℃之间。添加之后，用饱和硫代硫酸钠水溶液和饱和碳酸氢钠水溶液淬灭反应混合物，并且用DCM稀释。分离各层并且用DCM萃取有机层。合并的有机洗脱份经MgSO₄塞过滤并浓缩。在室温下向粗残余物中添加DCM(100ml)和TFA(100ml)。在室温下搅拌反应混合物1小时。浓缩反应混合物。将DCM(100ml)添加至粗残余物中并且再次浓缩溶液。将粗残余物溶解于THF(100ml)中，并且添加三乙胺(18.7ml，107mmol)和Boc₂O(2.8g，12.85mmol)。搅拌反应混合物1小时。用饱和碳酸氢钠水溶液淬灭反应混合物，并且用DCM稀释。分离各层并且用DCM萃取有机层。合并的有机洗脱份经MgSO₄塞过滤并浓缩。通过自动快速柱色谱(0至100％乙酸乙酯/己烷)纯化粗残余物，得到所需材料(2.8g，40％)。LC-MS计算值C₃₀H₃₂ClFIN₄O₂⁺(M+H)⁺:m/z＝661.1；实验值661.2。To a -20°C solution of tert-butyl (1R,4R,5S)-5-((3-amino-7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-2-methylquinolin-4-yl)(tert-butoxycarbonyl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8.34 g, 12.83 mmol) in acetonitrile (130 ml) was added sulfuric acid (50% v/v, 3.44 ml, 32.1 mmol) dropwise. A concentrated aqueous solution of sodium nitrite (1.77 g, 25.7 mmol) was added dropwise, maintaining the reaction mixture temperature between -20°C and -15°C. After the addition, the reaction mixture was rapidly stirred at -20°C. A concentrated aqueous solution of potassium iodide (8.52 g, 51.3 mmol) was added dropwise, maintaining the reaction mixture temperature between -20°C and -15°C. After addition, the reaction mixture was quenched with saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution, and diluted with DCM. Separate each layer and extract the organic layer with DCM. The organic eluent merged is filtered through_MgSO4 plug and concentrated. At room temperature, DCM (100ml) and TFA (100ml) are added to the crude residue. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated. DCM (100ml) is added to the crude residue and the solution is concentrated again. The crude residue is dissolved in THF (100ml), and triethylamine (18.7ml, 107mmol) and_Boc2O (2.8g, 12.85mmol) are added. The reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, and diluted with DCM. Separate each layer and extract the organic layer with DCM. The organic eluent merged is filtered through_MgSO4 plug and concentrated. The crude residue was purified by_automated flash column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired material (_2.8g , 40%). LC-MS calcd for_{C30H32ClFIN4O2}⁺ (M+H)⁺ : m/z = 661.1; found 661.2.

步骤4. 3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-2-(1-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)乙基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Step 4. 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

向(1R,4R,5S)-5-((7-(3-氯-2-甲基苯基)-6-(2-氰基乙基)-8-氟-3-碘-2-甲基喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(40mg，0.061mmol)在DMF(0.3ml)中的溶液中添加4-(丁-3-炔-2-基)-2,6-二甲基哒嗪-3(2H)-酮(中间体24，21.3mg，0.121mmol,)、碘化铜(I)(4.61mg，0.024mmol)、Pd(PPh₃)₄(14mg，0.012mmol)和DIPEA(0.1ml，0.6mmol)。将反应混合物用N₂充气1分钟，接着加热至55℃持续1小时。将反应混合物冷却至室温并且添加Cs₂CO₃(100mg，0.3mmol)。随后将反应混合物加热至90℃持续1小时。使反应混合物冷却至室温，接着用NH₄OH饱和水溶液淬灭并且用DCM稀释。分离各层并且用DCM萃取水层。合并的有机洗脱份经MgSO₄塞过滤并浓缩。将粗残余物溶解于DCM(0.3ml)和TFA(0.3ml)中并且搅拌1小时。浓缩反应混合物并且用MeCN稀释，过滤并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₃₅H₃₅ClFN₆O⁺(M+H)⁺:m/z＝609.3；实验值609.3。To a solution of tert-butyl (1R,4R,5S)-5-((7-(3-chloro-2-methylphenyl)-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-methylquinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (40 mg, 0.061 mmol) in DMF (0.3 ml) was added 4-(but-3-yn-2-yl)-2,6-dimethylpyridazin-3(2H)-one (Intermediate 24, 21.3 mg, 0.121 mmol,), copper(I) iodide (4.61 mg, 0.024 mmol), Pd(_PPh3 )₄ (14 mg, 0.012 mmol) and DIPEA (0.1 ml, 0.6 mmol). The reaction mixture was sparged with_N2 for 1 min and then heated to 55°C for 1 h. The reaction mixture was cooled to room temperature and Cs₂ CO₃ (100 mg, 0.3 mmol) was added. The reaction mixture was then heated to 90° C. for 1 hour. The reaction mixture was cooled to room temperature, then quenched with NH₄ OH saturated aqueous solution and diluted with DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic fractions were filtered through a plug of MgSO₄ and concentrated. The crude residue was dissolved in DCM (0.3 ml) and TFA (0.3 ml) and stirred for 1 hour. The reaction mixture was concentrated and diluted with MeCN, filtered and purified by preparative HPLC (pH 2). LC-MS calculated for C₃₅ H₃₅ ClFN₆ O⁺ (M+H)⁺ : m/z=609.3; found 609.3.

实施例68:N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)嘧啶-4-甲酰胺Example 68: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，600mg，0.964mmol)、嘧啶-4-甲酸(239mg，1.928mmol)、HATU(733mg，1.928mmol)在乙腈(9.64ml)中的溶液中添加三乙胺(672μl，4.82mmol)。在室温下搅拌反应混合物1h。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于DCM/TFA溶液(1:1比率，总共20ml)中，并且在室温下搅拌溶液2小时以去除Boc保护基。随后浓缩反应物并且用乙腈稀释，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₃H₂₉Cl₂FN₇O(M+H)⁺:m/z＝628.2；实验值628.2。¹HNMR(600MHz,DMSO-d₆)9.79(d,J＝7.5Hz,1H),9.48(s,1H),9.45-9.34(m,1H),9.16(d,J＝5.0Hz,1H),8.19(s,1H),8.11(d,J＝5.0Hz,1H),7.85(dd,J＝8.0,1.0Hz,1H),7.59(t,J＝8.0Hz,1H),7.49(dd,J＝8.0,1.0Hz,1H),6.98(s,1H),5.68(s,1H),5.40-5.32(m,1H),4.88(d,J＝6.0Hz,1H),4.05-3.98(m,1H),3.73-3.65(m,1H),3.53-3.44(m,1H),3.09-3.01(m,1H),2.95-2.79(m,5H),2.72-2.66(m,1H),2.34(d,J＝8.9Hz,1H),1.62(d,J＝8.9Hz,1H),1.60(d,J＝7.0Hz,3H)。To a solution of (1R,4R,5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Intermediate 22, 600 mg, 0.964 mmol), pyrimidine-4-carboxylic acid (239 mg, 1.928 mmol), HATU (733 mg, 1.928 mmol) in acetonitrile (9.64 ml) was added triethylamine (672 μl, 4.82 mmol). The reaction mixture was stirred at room temperature for 1 h. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted by ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM/TFA solution (1:1 ratio, 20 ml in total), and the solution was stirred at room temperature for 2 hours to remove the Boc protecting group. The reaction was then concentrated and diluted with acetonitrile and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to give the product as a TFA salt in the form of a white amorphous powder. LC-MS calculated value C₃₃ H₂₉ Cl₂ FN₇ O (M+H)⁺ : m/z=628.2; Found value 628.2.¹ HNMR (600 MHz, DMSO-d₆ )9.79(d,J＝7.5Hz,1H),9.48(s,1H),9.45-9.34(m,1H),9.16(d,J＝5.0Hz,1H),8.19(s,1H),8.11(d,J＝5.0Hz,1H),7.85(dd,J＝8.0,1.0Hz,1H),7.59(t,J ＝8.0Hz,1H),7.49(dd,J＝8.0,1.0Hz,1H),6.98(s,1H),5.68(s,1H),5 .40-5.32(m,1H),4.88(d,J＝6.0Hz,1H),4.05-3.98(m,1H),3.73-3.65(m,1H),3.53-3.44(m,1H),3.09-3.01(m,1H),2.95-2.79(m,5H),2.72-2.6 6(m,1H),2.34(d,J=8.9Hz,1H),1.62(d,J=8.9Hz,1H),1.60(d,J=7.0Hz,3H).

实施例69:N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)哒嗪-3-甲酰胺Example 69: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，100mg，0.161mmol)、哒嗪-3-甲酸(39.9mg，0.321mmol)、HATU(122mg，0.321mmol)在乙腈(1.606ml)中的溶液中添加三乙胺(112μl，0.803mmol)。在室温下搅拌反应混合物1h。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于DCM/TFA溶液(1:1比率，总共5ml)中，并且在室温下搅拌溶液2小时以去除Boc保护基。随后浓缩反应物并且用乙腈稀释，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₃H₂₉Cl₂FN₇O(M+H)⁺:m/z＝628.2；实验值628.3。To a solution of (1R,4R,5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (Intermediate 22, 100 mg, 0.161 mmol), pyridazine-3-carboxylic acid (39.9 mg, 0.321 mmol), HATU (122 mg, 0.321 mmol) in acetonitrile (1.606 ml) was added triethylamine (112 μl, 0.803 mmol). The reaction mixture was stirred at room temperature for 1 h. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted by ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM/TFA solution (1:1 ratio, 5 ml in total), and the solution was stirred at room temperature for 2 hours to remove the Boc protecting group. The reaction was then concentrated and diluted with acetonitrile, purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to give the product as a TFA salt in the form of a white amorphous powder. LC-MS calculated value C₃₃ H₂₉ Cl₂ FN₇ O (M+H)⁺ : m/z=628.2; Found value 628.3.

实施例70:N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-3,3-二氟氮杂环丁烷-1-甲酰胺Example 70: N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide

向(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22，20mg，0.032mmol)和DIPEA(5.61μl，0.032mmol)于四氢呋喃(0.643ml)中的溶液中添加三光气(5.72mg，0.019mmol)，并且在0℃搅拌反应物30分钟。此后，添加3,3-二氟氮杂环丁烷盐酸盐(4.16mg，0.032mmol)。随后在室温下搅拌反应混合物1h。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于TFA溶液(1ml)中，并且在室温下搅拌溶液30分钟以去除Boc保护基。随后浓缩反应物并且用乙腈稀释，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₂H₃₀Cl₂F₃N₆O(M+H)⁺:m/z＝641.2；实验值641.3。To a solution of (1R, 4R, 5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (intermediate 22, 20 mg, 0.032 mmol) and DIPEA (5.61 μl, 0.032 mmol) in tetrahydrofuran (0.643 ml) was added triphosgene (5.72 mg, 0.019 mmol), and the reactant was stirred at 0°C for 30 minutes. Thereafter, 3,3-difluoroazetidine hydrochloride (4.16 mg, 0.032 mmol) was added. The reaction mixture was then stirred at room temperature for 1 h. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in TFA solution (1 ml), and the solution was stirred at room temperature for 30 minutes to remove the Boc protecting group. The reaction was then concentrated and diluted with acetonitrile, and purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to give the product in the form of a TFA salt of a white amorphous powder. LC-MS calculated value C₃₂ H₃₀ Cl₂ F₃ N₆ O (M+H)⁺ : m/z=641.2; found value 641.3.

实施例71:3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-((1-甲基-1H-吡唑-4-基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈Example 71: 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile

将(1R,4R,5S)-5-(2-((R)-1-氨基乙基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体22,，20mg，0.032mmol)、1-甲基-4-碘-1H-吡唑(13.36mg，0.064mmol)、tBuBrettPhos PdG3(2.74mg，3.21μmol)、tBuBrettPhos(1.557mg，3.21μmol)和叔丁醇钠(4.63mg，0.048mmol)于二噁烷(0.643ml)中的反应混合物用N₂充气并且加热至100℃持续5小时。完成后，通过饱和碳酸氢钠溶液淬灭反应物。通过乙酸乙酯萃取反应混合物。将合并的有机层经硫酸钠干燥，过滤并浓缩。将残余物溶解于TFA溶液(1ml)中，并且在室温下搅拌溶液30分钟以去除Boc保护基。随后浓缩反应物并且用乙腈稀释，经制备型LCMS(XBridge C18柱，用乙腈/水(含有0.1％TFA)的梯度洗脱，流速为60mL/min)纯化，得到呈白色非晶形粉末的TFA盐形式的产物。LC-MS计算值C₃₂H₃₁Cl₂FN₇(M+H)⁺:m/z＝602.2；实验值602.3。A reaction mixture of tert-butyl (1R,4R,5S)-5-(2-((R)-1-aminoethyl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 22, 20 mg, 0.032 mmol), 1-methyl-4-iodo-1H-pyrazole (13.36 mg, 0.064 mmol), tBuBrettPhos PdG3 (2.74 mg, 3.21 μmol), tBuBrettPhos (1.557 mg, 3.21 μmol) and sodium tert-butoxide (4.63 mg, 0.048 mmol) in dioxane (0.643 ml) was sparged with_N2 and heated to 100°C for 5 h. After completion, the reactant was quenched by saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in TFA solution (1 ml), and the solution was stirred at room temperature for 30 minutes to remove the Boc protecting group. The reactant was then concentrated and diluted with acetonitrile, and purified by preparative LCMS (XBridge C18 column, gradient elution with acetonitrile/water (containing 0.1% TFA), flow rate of 60 mL/min) to obtain the product in the form of a white amorphous powder in the form of a TFA salt. LC-MS calculated value C₃₂ H₃₁ Cl₂ FN₇ (M+H)⁺ :m/z＝602.2; Found value 602.3.

实施例72. 5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-4-基)-N,N-二甲基吡啶甲酰胺Example 72. 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide

步骤1:(R)-(2-乙炔基吡咯烷-1-基)(1-氟环丙基)甲酮Step 1: (R)-(2-ethynylpyrrolidin-1-yl)(1-fluorocyclopropyl)methanone

向(R)-2-乙炔基吡咯烷盐酸盐(5g，38.0mmol)、1-氟环丙烷-1-甲酸(7.91g，76mmol)、HATU(28.9g，76mmol)在乙腈(190ml)中的溶液中添加三乙胺(26.5ml，190mmol)。在室温下搅拌反应物30分钟。用水淬灭反应物，并且用乙酸乙酯萃取。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过柱色谱，用0至50％丙酮/己烷洗脱来纯化粗产物，得到所需产物。LC-MS计算值C₁₀H₁₃FNO⁺(M+H)⁺:m/z＝182.1；实验值182.1。To a solution of (R)-2-ethynylpyrrolidine hydrochloride (5 g, 38.0 mmol), 1-fluorocyclopropane-1-carboxylic acid (7.91 g, 76 mmol), HATU (28.9 g, 76 mmol) in acetonitrile (190 ml) was added triethylamine (26.5 ml, 190 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with 0 to 50% acetone/hexane to give the desired product. LC-MS calculated for C₁₀ H₁₃ FNO⁺ (M+H)⁺ : m/z=182.1; found 182.1.

步骤2:(1R,4R,5S)-5-(7-溴-8-(氰基乙基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(7-bromo-8-(cyanoethyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-((7-溴-6-(2-氰基乙基)-8-氟-3-碘-2-(甲基硫基)喹啉-4-基)氨基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(中间体5，2.0g，3.09mmol)、(R)-(2-乙炔基吡咯烷-1-基)(1-氟环丙基)甲酮(0.728g，4.02mmol)、双(三苯基膦)氯化钯(II)(0.217g，0.309mmol)、碘化铜(I)(0.588g,3.09mmol)和三乙胺(4.3ml，30.9mmol)的混合物中添加DMF(20ml)。抽空反应烧瓶，用氮气回填，随后在75℃搅拌2h。随后添加Cs₂CO₃(5.03g，15.45mmol)并且在100℃搅拌12小时。冷却至室温后，用乙酸乙酯稀释反应混合物，随后用水(3次)和盐水洗涤。有机相经无水硫酸钠干燥，过滤并浓缩。通过快速色谱(用0至100％梯度的乙酸乙酯/己烷洗脱)纯化粗物质，得到产物(1.1g，50％产率)。LC-MS计算值C₃₃H₃₇BrF₂N₅O₃S⁺(M+H)⁺:m/z＝700.2/702.2；实验值700.1/702.2。To a mixture of (1R,4R,5S)-tert-butyl 5-((7-bromo-6-(2-cyanoethyl)-8-fluoro-3-iodo-2-(methylthio)quinolin-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylate (Intermediate 5, 2.0 g, 3.09 mmol), (R)-(2-ethynylpyrrolidin-1-yl)(1-fluorocyclopropyl)methanone (0.728 g, 4.02 mmol), bis(triphenylphosphine)palladium(II) chloride (0.217 g, 0.309 mmol), copper(I) iodide (0.588 g, 3.09 mmol) and triethylamine (4.3 ml, 30.9 mmol) was added DMF (20 ml). The reaction flask was evacuated, backfilled with nitrogen and then stirred at 75 °C for 2 h. Cs₂ CO₃ (5.03 g, 15.45 mmol) was then added and stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and then washed with water (3 times) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0 to 100% gradient of ethyl acetate/hexanes) to give the product (1.1 g, 50% yield). LC-MS calculated for C₃₃ H₃₇ BrF₂ N₅ O₃ S⁺ (M+H)⁺ : m/z=700.2/702.2; found 700.1/702.2.

步骤3:(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 3: (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(7-溴-8-(氰基乙基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(1.1g，1.57mmol)、(2,3-二氯苯基)硼酸(389mg，2.041mmol)、氟化钾(274mg，4.71mmol)和Pd-132(111mg，0.157mmol)的混合物中添加1,4-二噁烷(12.5ml)/水(3.2ml)，并且抽空反应烧瓶，用氮气回填，随后在90℃搅拌2h。用EtOAc稀释反应混合物并且经由硅藻土塞过滤。浓缩滤液并且通过快速柱色谱(0至65％乙酸乙酯/己烷)纯化粗产物，得到所需产物(0.861g，71.5％产率)。LC-MS计算值C₃₉H₄₀Cl₂F₂N₅O₃S⁺(M+H)⁺:m/z＝766.2/768.2；实验值766.2/768.2。To a mixture of (1R,4R,5S)-tert-butyl 5-(7-bromo-8-(cyanoethyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.1 g, 1.57 mmol), (2,3-dichlorophenyl)boronic acid (389 mg, 2.041 mmol), potassium fluoride (274 mg, 4.71 mmol) and Pd-132 (111 mg, 0.157 mmol) was added 1,4-dioxane (12.5 ml)/water (3.2 ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 90°C for 2 h. The reaction mixture was diluted with EtOAc and filtered through a plug of celite. The filtrate was concentrated and the crude product was purified by flash column chromatography (₀ to 65% ethyl acetate/hexanes) to give the desired product (0.861 g,_71.5 % yield).^{LC-MS Calcd. for C39H40Cl2F2N5O3S+(M+H)+}_:m/^z₌ 766.2/768.2; Found 766.2/768.2.

步骤4：5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-4-基)-N,N-二甲基吡啶甲酰胺Step 4: 5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-4-(甲基硫基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(861mg，1.123mmol)、N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶甲酰胺(620mg，2.246mmol)、四(三苯基膦)钯(0)(130mg，0.112mmol)和3-甲基水杨酸铜(I)(723mg，3.37mmol)的混合物中添加1,4-二噁烷(7.5ml)，并且抽空反应烧瓶，用氮气回填，随后在100℃搅拌过夜。用水和氢氧化铵饱和水溶液淬灭反应物，随后用乙酸乙酯稀释并且经由硅藻土塞过滤。分离滤液层，并且将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过快速柱色谱(0至80％EtOAc/己烷)纯化粗产物。将纯化产物溶解于1:1TFA/DCM(10mL)中并且在室温下搅拌1h，接着浓缩。用乙腈稀释粗残余物并且通过制备型HPLC(pH 2)纯化，得到所需产物。LC-MS计算值C₄₁H₃₈Cl₂F₂N₇O₂⁺(M+H)⁺:m/z＝768.2/770.2；实验值768.3/770.3。¹H NMR(500MHz,DMSO)δ9.28(s,1H),9.14(d,J＝2.1Hz,1H),8.46(dd,J＝8.1,2.2Hz,1H),8.21(s,1H),8.11(s,1H),7.86(dd,J＝8.1,1.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.59(t,J＝7.9Hz,1H),7.50(dd,J＝7.6,1.5Hz,1H),6.60(s,1H),5.66(s,1H),5.39(d,J＝7.3Hz,1H),4.91(d,J＝6.0Hz,1H),4.12-4.09(m,1H),4.02-3.96(m,1H),3.86-3.75(m,2H),3.45-3.42(m,1H),3.07(s,3H),3.06-3.02(m,4H),2.96-2.83(m,2H),2.74-2.65(m,1H),2.43-2.32(m,2H),2.01-1.97(m,1H),1.91-1.84(m,1H),1.80-1.75(m,1H),1.60(d,J＝9.2Hz,1H),1.48-1.35(m,2H),1.32-1.19(m,2H)。To the reaction mixture were tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-4-(methylthio)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (861 mg, 1.123 mmol), N,N-dimethyl-5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (620mg, 2.246mmol), tetrakis(triphenylphosphine)palladium(0) (130mg, 0.112mmol) and 3-methylsalicylic acid copper(I) (723mg, 3.37mmol) were added 1,4-dioxane (7.5ml), and the reaction flask was evacuated, backfilled with nitrogen, and then stirred at 100°C overnight. The reactants were quenched with water and saturated aqueous ammonium hydroxide solution, then diluted with ethyl acetate and filtered through a celite plug. The filtrate layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography (0 to 80% EtOAc/hexane). The purified product was dissolved in 1:1 TFA/DCM (10mL) and stirred at room temperature for 1h, then concentrated. The crude residue was diluted with acetonitrile and purified by preparative HPLC (pH 2) to give the desired product. LC-MS Calcd. for C₄₁ H₃₈ Cl₂ F₂ N₇ O₂⁺ (M+H)⁺ : m/z = 768.2/770.2; Found 768.3/770.3.¹ H NMR (500MHz, DMSO) δ9.28(s,1H),9.14(d,J＝2.1Hz,1H),8.46(dd,J＝8.1,2.2Hz,1H),8.21(s,1H),8.11(s,1H),7.86(dd,J＝8.1,1.6Hz,1H),7.82(d,J＝8.0Hz,1 H),7.59(t,J＝7.9Hz,1H),7.50(dd,J＝7.6,1.5Hz,1H),6.60(s,1H),5.66(s,1H),5.39(d,J＝7.3Hz,1H),4.91(d,J＝6.0Hz,1H) ,4.12-4.09(m,1H),4.02-3.96(m,1H),3.86-3.75(m,2H),3.45-3.42(m,1H),3.07(s,3H),3.06-3.02(m,4H),2.96-2.83(m,2H),2.74-2.65(m,1 H),2.43-2.32(m,2H),2.01-1.97(m,1H),1.91-1.84(m,1H),1.80-1.75(m,1H),1.60(d,J=9.2Hz,1H),1.48-1.35(m,2H),1.32-1.19(m,2H).

实施例73：(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(4-((二甲基氨基)甲基)-2,3-二氟苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Example 73: (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester

步骤1：(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(2,3-二氟-4-(甲氧基羰基)苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 1: (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(2,3-difluoro-4-(methoxycarbonyl)phenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

此化合物通过与针对(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(5-氟-6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯(实施例39)所描述相同的程序来制备。LC-MS计算值C₄₄H₄₁Cl₂F₃N₅O₆(M+H)⁺:m/z＝862.2；实验值862.2。This compound was prepared by the same procedure as described for methyl (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)_-1H -pyrrolo[3,2_- c]quinolin-_2- yl)pyrrolidine-1-carboxylate (Example₃₉ ). LC-MS calculated for_{C44H41Cl2F3N5O6} (M+H)⁺ : m/z=862.2; found 862.2.

步骤2:(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(2,3-二氟-4-(羟基甲基)苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯Step 2: (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(2,3-difluoro-4-(hydroxymethyl)phenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester

向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(2,3-二氟-4-(甲氧基羰基)苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(900mg，1.043mmol)于THF(10ml)中的溶液中添加硼氢化锂(1043μl，2.086mmol)。在室温下搅拌反应物过夜。将反应混合物用1M HCl溶液淬灭，用水稀释，接着用乙酸乙酯萃取两次。将有机层用水和盐水洗涤，经硫酸钠干燥并且浓缩。通过Biotage(0至10％甲醇/DCM)纯化粗产物，得到所需产物。LC-MS计算值C₄₃H₄₁Cl₂F₃N₅O₅(M+H)⁺:m/z＝834.2；实验值834.3To a solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(2,3-difluoro-4-(methoxycarbonyl)phenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (900 mg, 1.043 mmol) in THF (10 ml) was added lithium borohydride (1043 μl, 2.086 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with 1M HCl solution, diluted with water, and then extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by Biotage (0 to 10% methanol/DCM) to give the desired product. LC-MS calculated for C₄₃ H₄₁ Cl₂ F₃ N₅ O₅ (M+H)⁺ : m/z = 834.2; found 834.3

步骤3:(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(4-((二甲基氨基)甲基)-2,3-二氟苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯Step 3: (2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester

在0℃向(1R,4R,5S)-5-(8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(2,3-二氟-4-(羟基甲基)苯基)-6-氟-2-((R)-1-(甲氧基羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-1-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(140mg，0.168mmol)在DCM(5ml)中的溶液中添加甲磺酰氯(19.60μl，0.252mmol)和TEA(46.8μl，0.335mmol)。在0℃搅拌反应物30min，接着添加二甲胺(2.0M)于THF(419μl，0.839mmol)和TEA(46.8μl，0.335mmol)中的溶液。将反应混合物继续在室温下搅拌2h。将反应混合物用水淬灭，用DCM萃取。将有机层用盐水洗涤，经硫酸钠干燥并浓缩。将残余物在1:1DCM/TFA(4mL)中搅拌30min，浓缩，并且通过制备型HPLC(pH 2)纯化。LC-MS计算值C₄₀H₃₈Cl₂F₃N₆O₂(M+H)⁺:m/z＝761.7；实验值761.2。To a solution of tert-butyl (1R,4R,5S)-5-(8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(2,3-difluoro-4-(hydroxymethyl)phenyl)-6-fluoro-2-((R)-1-(methoxycarbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (140 mg, 0.168 mmol) in DCM (5 ml) at 0°C was added methanesulfonyl chloride (19.60 μl, 0.252 mmol) and TEA (46.8 μl, 0.335 mmol). The reaction was stirred at 0°C for 30 min, followed by the addition of a solution of dimethylamine (2.0 M) in THF (419 μl, 0.839 mmol) and TEA (46.8 μl, 0.335 mmol). The reaction mixture was continued to stir at room temperature for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was stirred in 1:1 DCM/TFA (4 mL) for 30 min, concentrated, and purified by preparative HPLC (pH 2). LC-MS calculated for C₄₀ H₃₈ Cl₂ F₃ N₆ O₂ (M+H)⁺ : m/z=761.7; Found 761.2.

实施例A.GDP-GTP交换测定Example A. GDP-GTP exchange assay

例示化合物的抑制剂效力在基于荧光的鸟嘌呤核苷酸交换测定中测定，所述测定测量在SOS1(鸟嘌呤核苷酸交换因子)存在下，bodipy-GDP(经荧光标记的GDP)与GppNHp(不可水解GTP类似物)的交换，以产生KRAS的活性状态。抑制剂在DMSO中连续稀释并且将0.1μL的体积转移至黑色低容量384孔板的孔中。将5μL/孔体积的在测定缓冲液(25mM Hepes pH7.5，50mM NaCl，10mM MgCl₂和0.01％Brij-35)中稀释至2.5nM的负载bodipy的KRAS G12D添加至板中，并且在环境温度下与抑制剂一起预孵育4小时。培养板上包括适当对照(无抑制剂或具有G12D抑制剂的酶)。通过在测定缓冲液中添加含有1mM GppNHp和300nM SOS1的5μL/孔体积来起始交换。负载bodipy的KRAS G12D、GppNHp和SOS1的10μL/孔反应浓度分别为2.5nM、500μM和150nM。反应板在环境温度下孵育2小时，其为在无抑制剂存在下完成GDP-GTP交换的估计时间。对于KRAS G12V突变体，使用类似鸟嘌呤核苷酸交换测定，其中负载bodipy的KRAS蛋白的最终浓度为2.5nM，并且在添加GppNHp-SOS1混合物之后进行3小时孵育。所描述的选择性结合G12D突变体的环肽(Sakamoto等人，BBRC 484.3(2017),605-611)或确认结合的内部化合物用作测定板中的阳性对照。在485nm激发和520nm发射下，在PheraStar读板仪(BMG Labtech)上测量荧光强度。The inhibitor potency of the exemplary compounds was determined in a fluorescence-based guanine nucleotide exchange assay that measures the exchange of bodipy-GDP (fluorescently labeled GDP) with GppNHp (non-hydrolyzable GTP analog) in the presence of SOS1 (guanine nucleotide exchange factor) to produce the active state of KRAS. The inhibitor was serially diluted in DMSO and a volume of 0.1 μL was transferred to a well of a black low-capacity 384-well plate. 5 μL/well volume of KRAS G12D loaded with bodipy diluted to 2.5 nM in assay buffer (25 mM Hepes pH 7.5, 50 mM NaCl, 10 mM MgCl₂ and 0.01% Brij-35) was added to the plate and pre-incubated with the inhibitor for 4 hours at ambient temperature. Appropriate controls (enzyme without inhibitor or with G12D inhibitor) were included on the culture plate. The exchange was initiated by adding a 5 μL/well volume containing 1 mM GppNHp and 300 nM SOS1 in the assay buffer. The 10 μL/well reaction concentrations of KRAS G12D, GppNHp and SOS1 loaded with bodipy were 2.5 nM, 500 μM and 150 nM, respectively. The reaction plate was incubated at ambient temperature for 2 hours, which is the estimated time for completing GDP-GTP exchange in the absence of inhibitors. For the KRAS G12V mutant, a similar guanine nucleotide exchange assay was used, in which the final concentration of the KRAS protein loaded with bodipy was 2.5 nM, and the GppNHp-SOS1 mixture was added for 3 hours. The described cyclic peptides (Sakamoto et al., BBRC 484.3 (2017), 605-611) that selectively bind to the G12D mutant or internal compounds that confirm binding are used as positive controls in the assay plate. Fluorescence intensity was measured on a PheraStar plate reader (BMG Labtech) at 485 nm excitation and 520 nm emission.

使用GraphPad prism或Genedata Screener SmartFit分析数据。IC₅₀值通过将数据拟合至四参数逻辑方程，产生具有可变希尔(Hill)系数的S形剂量-反应曲线来导出。Data were analyzed using GraphPad prism or Genedata Screener SmartFit._IC50 values were derived by fitting the data to a four-parameter logistic equation, generating sigmoidal dose-response curves with a variable Hill coefficient.

KRAS_G12D和KRAS_G12V交换测定IC₅₀数据提供于下表1中。符号指示IC₅₀≤100nM，指示IC₅₀>100nM但≤1μM；并且指示IC₅₀>1μM但≤5μM，指示IC₅₀>5μM但≤10μM。“NA”指示IC₅₀不可用。KRAS_G12D and KRAS_G12V exchange assay_IC50 data are provided in Table 1 below. Symbol Indication_IC50 ≤100nM, Indicates_IC50 >100nM but ≤1μM; and Indicates_IC50 >1μM but ≤5μM, Indicates_IC50 >5 μM but ≤10 μM. "NA" indicates_IC50 not available.

表1Table 1

实施例B：发光活力测定Example B: Luminescence activity assay

MIA PaCa-2(KRAS G12C；CRL-1420)、NCI-H358(KRAS G12C；CRL-5807)、A427(KRAS G12D；HTB53)、HPAFII(KRAS G12D；CRL-1997)、YAPC(KRAS G12V；DSMZ ACC382)、SW480(KRAS G12V；CRL-228)和NCI-H838(KRASWT；CRL-5844)细胞在补充有10％FBS的RPMI 1640培养基(Gibco/LifeTechnologies)中培养。将补充有2％FBS的RPMI 1640培养基中的每孔八百个细胞接种至含有50nL测试化合物点(最终浓度是1:500稀释液，0.2％DMSO中的最终浓度)的白色、透明底384孔Costar组织培养板中。将板在370℃、5％CO₂下孵育3天。在测定结束时，添加25μl/孔的CellTiter-Glo试剂(Promega)。在15分钟后用PHERAstar(BMG)读取发光。在GenedataScreener中使用SmartFit分析数据以获得IC₅₀值。MIA PaCa-2 (KRAS G12C; CRL-1420), NCI-H358 (KRAS G12C; CRL-5807), A427 (KRAS G12D; HTB53), HPAFII (KRAS G12D; CRL-1997), YAPC (KRAS G12V; DSMZ ACC382), SW480 (KRAS G12V; CRL-228) and NCI-H838 (KRASWT; CRL-5844) cells were cultured in RPMI 1640 medium (Gibco/LifeTechnologies) supplemented with 10% FBS. Eight hundred cells per well in RPMI 1640 medium supplemented with 2% FBS were inoculated into a white, clear-bottomed 384-well Costar tissue culture plate containing 50 nL test compound spots (final concentration was 1:500 dilution, final concentration in 0.2% DMSO). The plate was incubated at 370 ° C, 5% CO₂ for 3 days. At the end of the assay, 25 μl/well of CellTiter-Glo reagent (Promega) was added. Luminescence was read with PHERAstar (BMG) after 15 minutes. SmartFit was used to analyze the data in GenedataScreener to obtain IC₅₀ values.

实施例C：细胞pERK HTRF测定Example C: Cellular pERK HTRF Assay

MIA PaCa-2(KRAS G12C；CRL-1420)、NCI-H358(KRAS G12C；CRL-5807)、A427(KRAS G12D；HTB53)、HPAFII(KRAS G12D；CRL-1997)、YAPC(KRAS G12V；DSMZ ACC382)、SW480(KRAS G12V；CRL-228)和NCI-H838(KRASWT；CRL-5844)细胞购自ATCC并且在补充有10％FBS的RPMI 1640培养基(Gibco/Life Technologies)中维持。将细胞以每孔5000个细胞(8μL)涂铺于Greiner 384孔低容量、平底、经组织培养处理的白色板中并且在370℃、5％CO₂下孵育过夜。第二天早上，将测试化合物储备溶液在培养基中稀释成3倍最终浓度，并且将4μL添加至细胞，最终浓度为0.1％DMSO。将细胞与测试化合物一起在37℃、5％CO₂下孵育4小时(G12C和G12V)或2小时(G12D)。将4μL具有阻断试剂(Cisbio)的4倍裂解缓冲液添加至各孔中并且在室温下使板平缓(300rpm)旋转30分钟。将每孔4μL的Cisbio抗磷酸化ERK 1/2d2与抗磷酸化ERK 1/2穴状化合物(1:1)混合，并且添加至各孔，在室温下于暗处孵育过夜。在Pherastar读板器上在665nm和620nm波长下读取板。在Genedata Screener中使用SmartFit分析数据以获得IC₅₀值。MIA PaCa-2 (KRAS G12C; CRL-1420), NCI-H358 (KRAS G12C; CRL-5807), A427 (KRAS G12D; HTB53), HPAFII (KRAS G12D; CRL-1997), YAPC (KRAS G12V; DSMZ ACC382), SW480 (KRAS G12V; CRL-228) and NCI-H838 (KRASWT; CRL-5844) cells were purchased from ATCC and maintained in RPMI 1640 culture medium (Gibco/Life Technologies) supplemented with 10% FBS. Cells were plated in Greiner 384-well low-capacity, flat-bottomed, tissue culture-treated white plates at 5000 cells per well (8 μL) and incubated overnight at 370°C, 5% CO_2. The next morning, the test compound stock solution was diluted to 3 times the final concentration in culture medium, and 4 μL was added to the cells at a final concentration of 0.1% DMSO. The cells were incubated at 37°C, 5% CO₂ for 4 hours (G12C and G12V) or 2 hours (G12D) with the test compound. 4 μL of 4 times lysis buffer with blocking reagent (Cisbio) was added to each well and the plate was rotated gently (300rpm) for 30 minutes at room temperature. 4 μL of Cisbio anti-phospho-ERK 1/2d2 per well was mixed with anti-phospho-ERK 1/2 cryptate (1:1) and added to each well and incubated overnight at room temperature in the dark. Plates were read on a Pherastar plate reader at 665nm and 620nm wavelengths. Data were analyzed using SmartFit in Genedata Screener to obtain IC₅₀ values.

实施例D：全血pERK1/2HTRF测定Example D: Whole blood pERK1/2 HTRF assay

MIA PaCa-2细胞(KRAS G12C；CRL-1420)、HPAF-II(KRAS G12D；CRL-1997)和YAPC(KRAS G12V；DSMZ ACC382)在具有10％FBS的RPMI 1640(Gibco/Life Technologies)中维持。对于MIA PaCa-2测定，将细胞以每孔25000个细胞的100μL培养基接种至96孔组织培养板(Corning#3596)中，并且在测定前在37℃、5％CO₂下培养2天。对于HPAF-II和YAPC测定，将细胞以每孔50000个细胞的100μL培养基接种至96孔组织培养板中，并且在测定前培养1天。将全血添加至96孔板中的1μL化合物点中(于DMSO中制备)，并且通过上下移液平缓混合以使得血液中化合物的浓度为0.5％DMSO中所需浓度的1倍。自细胞中吸出培养基，并且每孔添加50μL含测试化合物的全血，在37℃、5％CO₂下分别孵育4小时用于MIA PaCa和YAPC测定；或孵育2小时用于HPAF-II测定。在倾倒血液之后，通过将PBS添加至孔边并且将PBS自板倾倒至纸巾上，轻敲板以充分沥干来将板轻缓地洗涤两次。随后添加五十微升/孔的具有阻断试剂(Cisbio)和全能核酸酶(Benzonase nuclease)(Sigma Cat#E1014-5KU，1:10000最终浓度)的1倍裂解缓冲液#1(Cisbio)，并且在室温下振荡(250rpm)孵育30分钟。在裂解之后，使用Assist Plus(Integra Biosciences,NH)将16μL裂解物转移至384孔Greiner小容量白色板中。使用Assist Plus将4μL的抗磷酸化ERK1/2d2与和抗磷酸化ERK 1/2穴状化合物(Cisbio)的1:1混合物添加至孔中并且在室温下于暗处孵育过夜。在Pherastar读板器上在665nm和620nm波长下读取板。在Genedata Screener中使用SmartFit分析数据以获得IC₅₀值。MIA PaCa-2 cells (KRAS G12C; CRL-1420), HPAF-II (KRAS G12D; CRL-1997) and YAPC (KRAS G12V; DSMZ ACC382) were maintained in RPMI 1640 (Gibco/Life Technologies) with 10% FBS. For the MIA PaCa-2 assay, cells were seeded into 96-well tissue culture plates (Corning #3596) at 25,000 cells per well in 100 μL of culture medium and cultured for 2 days at 37°C, 5%_CO2 before the assay. For the HPAF-II and YAPC assays, cells were seeded into 96-well tissue culture plates at 50,000 cells per well in 100 μL of culture medium and cultured for 1 day before the assay. Whole blood was added to 1 μL of compound spots (prepared in DMSO) in a 96-well plate and gently mixed by pipetting up and down to achieve a concentration of compound in the blood that was 1-fold the concentration required in 0.5% DMSO. The culture medium was aspirated from the cells, and 50 μL of whole blood containing the test compound was added to each well and incubated for 4 hours at 37°C, 5%_CO2 for MIA PaCa and YAPC determinations, respectively; or incubated for 2 hours for HPAF-II determinations. After pouring the blood, the plate was gently washed twice by adding PBS to the edge of the well and pouring PBS from the plate onto a paper towel, tapping the plate to fully drain. Fifty microliters/well of 1x lysis buffer #1 (Cisbio) with blocking reagent (Cisbio) and Benzonase nuclease (Sigma Cat#E1014-5KU, 1:10000 final concentration) was then added, and incubated at room temperature with shaking (250rpm) for 30 minutes. After lysis, 16 μL of lysate was transferred to a 384-well Greiner small volume white plate using Assist Plus (Integra Biosciences, NH). 4 μL of a 1:1 mixture of anti-phospho-ERK1/2d2 and anti-phospho-ERK 1/2 cryptate (Cisbio) was added to the wells using Assist Plus and incubated overnight in the dark at room temperature. The plate was read at 665nm and 620nm wavelengths on a Pherastar plate reader. Data was analyzed using SmartFit in Genedata Screener to obtain IC₅₀ values.

实施例E：Ras活化ElisaExample E: Ras Activation Elisa

96孔Ras活化ELISA试剂盒(Cell Biolabs Inc；#STA441)使用与96孔板结合的Raf1 RBD(Rho结合域)自细胞裂解物选择性地拉下Ras的活性形式。通过泛Ras抗体和HRP结合二次抗体检测所捕捉的GTP-Ras。The 96-well Ras Activation ELISA Kit (Cell Biolabs Inc; #STA441) uses the Raf1 RBD (Rho Binding Domain) bound to a 96-well plate to selectively pull down the active form of Ras from cell lysates. The captured GTP-Ras is detected by a pan-Ras antibody and an HRP-conjugated secondary antibody.

MIA PaCa-2(KRAS G12C；CRL-1420)、NCI-H358(KRAS G12C；CRL-5807)、A427(KRAS G12D；HTB53)、HPAFII(KRAS G12D；CRL-1997)、YAPC(KRAS G12V；DSMZ ACC382)、SW480(KRAS G12V；CRL-228)和NCI-H838(KRASWT；CRL-5844)细胞在具有10％FBS的RPMI 1640(Gibco/Life Technologies)中维持。将细胞以每孔25000个细胞的100μL培养基接种至96孔组织培养板(Corning#3596)中并且在37℃、5％CO₂下培养2天，使得其在测定开始时约80％汇合。在37℃，5％CO₂下用化合物处理细胞4小时或过夜。在收获时，用PBS洗涤细胞，充分沥干，并且随后在冰上用50μL 1倍裂解缓冲液(由试剂盒提供)加上所添加的Halt蛋白酶和磷酸酶抑制剂(1:100)裂解1小时。MIA PaCa-2 (KRAS G12C; CRL-1420), NCI-H358 (KRAS G12C; CRL-5807), A427 (KRAS G12D; HTB53), HPAFII (KRAS G12D; CRL-1997), YAPC (KRAS G12V; DSMZ ACC382), SW480 (KRAS G12V; CRL-228) and NCI-H838 (KRASWT; CRL-5844) cells were maintained in RPMI 1640 (Gibco/Life Technologies) with 10% FBS. The cells were seeded into 96-well tissue culture plates (Corning#3596) with 100 μL of culture medium at 25,000 cells per well and cultured for 2 days at 37°C, 5%_CO2 , so that they were about 80% confluent at the start of the assay. Cells were treated with compounds for 4 hours or overnight at 37°C, 5%_CO2 . At harvest, cells were washed with PBS, drained thoroughly, and then lysed on ice for 1 hour with 50 μL of 1x lysis buffer (provided by the kit) plus added Halt protease and phosphatase inhibitors (1:100).

将Raf-1 RBD在测定稀释剂中(在试剂盒中提供)以1:500稀释并且将100μL经稀释的Raf-1 RBD添加至Raf-1 RBD捕捉板的各孔中。将板用板密封膜覆盖并且在室温下在定轨振荡器上孵育1小时。用每孔250μL 1倍洗涤缓冲液洗涤板3次，每次洗涤之间彻底抽吸。一式两份地添加每孔50μL Ras裂解物样品(10-100μg)。在一对孔中添加“无细胞裂解物”对照用于背景测定。紧跟着各孔将50μL测定稀释剂添加至所有孔，并且将板在室温下在定轨振荡器上孵育1小时。用每孔250μL 1倍洗涤缓冲液洗涤培养板5次，每次洗涤之间彻底抽吸。将100μL经稀释的抗泛Ras抗体添加至各孔中，并且将板在室温下在定轨振荡器上孵育1小时。如前所述洗涤板5次。将100μL经稀释的二级抗体、HRP结合物添加至各孔中，并且将板在室温下在定轨振荡器上孵育1小时。如前所述洗涤培养板5次并且充分沥干。将100μL化学发光试剂(在试剂盒中提供)添加至各孔，包括空白孔。将板在室温下在定轨振荡器上孵育5分钟，之后在板光度计上读取各微孔的发光。在自所有值减去“无裂解物对照”的背景含量之后，计算相对于DMSO对照孔的抑制％。通过使用GraphPad Prism 7软件拟合抑制剂抑制百分比相对于抑制剂浓度对数的曲线来进行IC₅₀测定。Raf-1 RBD was diluted 1:500 in assay diluent (provided in the kit) and 100 μL of the diluted Raf-1 RBD was added to each well of the Raf-1 RBD capture plate. The plate was covered with a plate seal and incubated on an orbital shaker for 1 hour at room temperature. The plate was washed 3 times with 250 μL of 1x wash buffer per well, aspirating thoroughly between each wash. 50 μL of Ras lysate samples (10-100 μg) were added to each well in duplicate. A "cell-free lysate" control was added to a pair of wells for background determination. 50 μL of assay diluent was added to all wells immediately following each well, and the plate was incubated on an orbital shaker for 1 hour at room temperature. The culture plate was washed 5 times with 250 μL of 1x wash buffer per well, aspirating thoroughly between each wash. 100 μL of diluted anti-pan-Ras antibody was added to each well, and the plate was incubated on an orbital shaker for 1 hour at room temperature. The plate was washed 5 times as described above. 100 μ L of diluted secondary antibody, HRP conjugate are added in each well, and plate is hatched on orbital oscillator for 1 hour at room temperature. Wash culture plate 5 times as previously mentioned and fully drain. 100 μ L chemiluminescent reagent (provided in test kit) is added to each well, including blank well. Plate is hatched on orbital oscillator for 5 minutes at room temperature, then read the luminescence of each micropore on plate photometer. After deducting the background content of "no lysate control" from all values, calculate the inhibition % relative to DMSO control well._IC50 is measured by using GraphPad Prism 7 software fitting inhibitor to suppress percentage relative to the curve of inhibitor concentration logarithm.

实施例F：RAS-RAF和PI3K-AKT路径的抑制Example F: Inhibition of RAS-RAF and PI3K-AKT pathways

通过测量KRAS下游效应子细胞外信号调节激酶(ERK)、核糖体S6激酶(RSK)、AKT(也称为蛋白激酶B，PKB)和下游底物S6核糖体蛋白的磷酸化来测定化合物的细胞效力。The cellular potency of the compounds was determined by measuring phosphorylation of the KRAS downstream effectors extracellular signal-regulated kinase (ERK), ribosomal S6 kinase (RSK), AKT (also known as protein kinase B, PKB), and the downstream substrate S6 ribosomal protein.

为了测量磷酸化的细胞外信号调节激酶(ERK)、核糖体S6激酶(RSK)、AKT和S6核糖体蛋白，将细胞(关于细胞系和所产生的数据类型的细节进一步详述于表2中)以4×104个细胞/孔接种在Corning96孔组织培养处理板中的具有10％FBS的RPMI培养基中过夜。次日，将细胞在存在或不存在一定浓度范围的测试化合物的情况下在37℃、5％CO₂下孵育4小时。将细胞用PBS洗涤并且用具有蛋白酶和磷酸酶抑制剂(Thermo Fisher，78446)的1倍裂解缓冲液(Cisbio)裂解。使用以下抗体对10或20μg总蛋白裂解物进行SDS-PAGE和免疫墨点分析：磷酸化ERK1/2-Thr202/Tyr204(#9101L)、总ERK1/2(#9102L)、磷酸化AKT-Ser473(#4060L)、磷酸化p90RSK-Ser380(#11989S)和磷酸化S6核糖体蛋白-Ser235/Ser236(#2211S)，来自Cell Signaling Technologies(Danvers,MA)。To measure phosphorylated extracellular signal-regulated kinase (ERK), ribosomal S6 kinase (RSK), AKT and S6 ribosomal protein, cells (details on cell lines and data types generated are further detailed in Table 2) were seeded at 4×104 cells/well in RPMI medium with 10% FBS in Corning 96-well tissue culture treated plates overnight. The next day, cells were incubated at 37° C., 5% CO₂ for 4 hours in the presence or absence of a range of test compounds. Cells were washed with PBS and lysed with 1× lysis buffer (Cisbio) with protease and phosphatase inhibitors (Thermo Fisher, 78446). 10 or 20 μg of total protein lysate was subjected to SDS-PAGE and immunoblot analysis using the following antibodies: phospho-ERK1/2-Thr202/Tyr204 (#9101L), total ERK1/2 (#9102L), phospho-AKT-Ser473 (#4060L), phospho-p90RSK-Ser380 (#11989S), and phospho-S6 ribosomal protein-Ser235/Ser236 (#2211S) from Cell Signaling Technologies (Danvers, MA).

表2Table 2

细胞系Cell lines组织学HistologyKRAS更改KRAS changes读出Read outH358H358肺lungG12CG12CpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKMIA PaCa-2MIA PaCa-2胰腺pancreasG12CG12CpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKHPAF IIHPAF II胰腺pancreasG12DG12DpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKA427A427肺lungG12DG12DpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKAGSAGS胃StomachG12DG12DpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKPaTu 8988sPaTu 8988s胰腺pancreasG12VG12VpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKH441H441肺lungG12VG12VpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKYAPCYAPC胰腺pancreasG12VG12VpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSKSW480SW480结肠直肠ColorectalG12VG12VpERK、pAKT、p-S6、p-p90RSKpERK, pAKT, p-S6, p-p90RSK

实施例G：体内功效研究Example G: In vivo efficacy studies

MIA-PaCa-2(KRAS G12C)、H358(KRAS G12C)、HPAF-II(KRAS G12D)、AGS(KRASG12D)、SW480(KRAS G12V)或YAPC(KRAS G12V)人类癌症细胞获自美国典型培养物保藏中心(American Type Culture Collection)并且在补充有10％FBS的RPMI培养基中维持。对于功效研究实验，将5×106个细胞皮下接种至6至8周龄BALB/c裸小鼠(Charles RiverLaboratories,Wilmington,MA,USA)的右后侧腹中。当肿瘤体积为大约150-250mm3时，根据肿瘤体积对小鼠进行随机分组，并且经口施用化合物。使用式(L×W2)/2计算肿瘤体积，其中L和W分别指长度和宽度尺寸。使用式(1-(VT/VC))×100来计算肿瘤生长抑制，其中VT为处理组在处理最后一天的肿瘤体积，并且VC为对照组在处理最后一天的肿瘤体积。使用邓尼特多重比较检验(Dunnett's multiple comparisons test)的双向方差分析来确定处理组之间的统计差异(GraphPad Prism)。小鼠按每笼10至12只饲养，并且提供丰富的食物并使其暴露于12小时亮/暗循环。肿瘤体积超出限制(10％体重)的小鼠通过CO₂吸入以人道方式安乐死。将动物维持在由国际实验室动物护理评定和认证协会完全认可的障壁设施中。所有程序均按照关于人类护理和使用实验室动物的美国公众服务策略和Incyte动物护理和使用委员会指南进行。MIA-PaCa-2 (KRAS G12C), H358 (KRAS G12C), HPAF-II (KRAS G12D), AGS (KRASG12D), SW480 (KRAS G12V) or YAPC (KRAS G12V) human cancer cells were obtained from the American Type Culture Collection and maintained in RPMI medium supplemented with 10% FBS. For efficacy study experiments, 5×106 cells were subcutaneously inoculated into the right posterior flank of 6- to 8-week-old BALB/c nude mice (Charles River Laboratories, Wilmington, MA, USA). When the tumor volume was approximately 150-250 mm3, mice were randomized according to tumor volume and the compounds were administered orally. Tumor volume was calculated using the formula (L×W2)/2, where L and W refer to the length and width dimensions, respectively. Tumor growth inhibition was calculated using the formula (1-(VT/VC))×100, where VT was the tumor volume of the treatment group on the last day of treatment, and VC was the tumor volume of the control group on the last day of treatment. Two-way ANOVA with Dunnett's multiple comparisons test was used to determine statistical differences between treatment groups (GraphPad Prism). Mice were housed at 10 to 12 per cage and provided with abundant food and exposed to a 12-hour light/dark cycle. Mice with tumor volume exceeding the limit (10% of body weight) were humanely euthanized by_CO2 inhalation. Animals were maintained in a barrier facility fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. All procedures were performed in accordance with the U.S. Public Service Policy on the Care and Use of Laboratory Animals for Humans and the Incyte Animal Care and Use Committee Guidelines.

实施例H：Caco2测定Example H: Caco2 determination

Caco-2细胞在37℃、5％CO₂氛围中，在补充有10％(v/v)胎牛血清、1％(v/v)非必需氨基酸、青霉素(100U/mL)和链霉素(100μg/mL)的DMEM生长培养基中生长。通过用含有1μM EDTA的0.05％胰蛋白酶处理，每7天或4天对Caco-2的汇合细胞单层进行继代培养。将Caco-2细胞接种于96孔Transwell板中。Caco-2细胞的接种密度为14,000个细胞/孔。接种后每隔一天更换一次DMEM生长培养基。细胞单层用于Caco-2细胞在22与25天之间的转运测定。Caco-2 cells were grown in_DMEM growth medium supplemented with 10% (v/v) fetal bovine serum, 1% (v/v) non-essential amino acids, penicillin (100U/mL) and streptomycin (100μg/mL) at 37°C in a 5% CO2 atmosphere. Confluent cell monolayers of Caco-2 were subcultured every 7 days or 4 days by treatment with 0.05% trypsin containing 1μM EDTA. Caco-2 cells were seeded in 96-well Transwell plates. The seeding density of Caco-2 cells was 14,000 cells/well. DMEM growth medium was replaced every other day after seeding. Cell monolayers were used for transport assays of Caco-2 cells between 22 and 25 days.

去除细胞培养基并且用HBSS替换。为了测量TEER，将HBSS添加至供体隔室(顶端侧)和受体隔室(基底侧)。通过使用REMS自动进样器测量TEER以确保细胞单层的完整性。将TEER值≥300Ω·cm²的Caco-2细胞单层用于转运实验。为了确定吸收方向(A-B)中的P_app，将测试化合物(50μM)于HBSS中的溶液添加至供体隔室(顶端侧)，而将具有4％BSA的HBSS溶液添加至受体隔室(基底侧)。顶端体积为0.075mL，并且基底侧体积为0.25mL。在37℃、5％CO₂氛围中孵育期为120分钟。在孵育期结束时，自供体和受体侧移出样品并且添加等体积的乙腈用于蛋白沉淀。离心(3000rpm，Allegra X-14R离心机，来自Beckman Coulter,Indianapolis,IN)后收集上清液用于LCMS分析。根据以下等式确定渗透率值：Remove the cell culture medium and replace it with HBSS. In order to measure TEER, HBSS is added to the donor compartment (top side) and the receptor compartment (basal side). TEER is measured by using a REMS autosampler to ensure the integrity of the cell monolayer. Caco-2 cell monolayers with a TEER value of ≥300Ω·cm² are used for transport experiments. In order to determine the P_app in the absorption direction (AB), a solution of the test compound (50 μM) in HBSS is added to the donor compartment (top side), while a HBSS solution with 4% BSA is added to the receptor compartment (basal side). The top volume is 0.075 mL, and the basal side volume is 0.25 mL. The incubation period is 120 minutes at 37 ° C, 5% CO₂ atmosphere. At the end of the incubation period, the sample is removed from the donor and receptor sides and an equal volume of acetonitrile is added for protein precipitation. After centrifugation (3000 rpm, Allegra X-14R centrifuge, from Beckman Coulter, Indianapolis, IN), the supernatant was collected for LCMS analysis. The permeability value was determined according to the following equation:

P_app(cm/s)＝(F*VD)/(SA*MD)，P_app (cm/s)=(F*VD)/(SA*MD),

其中通量率(F，质量/时间)是由受体侧相关化合物累积量的斜率计算的，SA为细胞膜的表面积，VD为供体体积，并且MD为供体隔室中溶液的初始量。where the flux rate (F, mass/time) is calculated from the slope of the accumulation of the relevant compound on the acceptor side, SA is the surface area of the cell membrane, VD is the donor volume, and MD is the initial amount of solution in the donor compartment.

Caco-2数据提供于下表3和表4中。符号“+”指示Caco-2值≤0.5，“++”指示Caco-2值>0.5但≤1；并且“+++”指示Caco-2值>1。“NA”指示IC₅₀不可用。Caco-2 data are provided below in Tables 3 and 4. The symbol "+" indicates a Caco-2 value ≤ 0.5, "++" indicates a Caco-2 value > 0.5 but ≤ 1; and "+++" indicates a Caco-2 value > 1. "NA" indicates that an_IC50 is not available.

表3Table 3

实施例编号Example No.Caco-2Caco-211++++22++33++44++55++66++++77++++++88++99++1010++1111++1212++1313NANA1414++++1515++++1616++1717++1818++1919++2020++21twenty one++22twenty two++23twenty three++++24twenty four++2525++++++2626++2727++

表4Table 4

实施例I：人全血稳定性Example I: Human Whole Blood Stability

通过LC-MS/MS测定例示性化合物的全血稳定性。96孔Flexi-Tier^TM块(AnalyticalSales&Services,Inc,Flanders,NJ)用于孵育板，其含有1.0mL玻璃小瓶，每小瓶装有0.5mL血液(汇集性别，人全血，来源于BIOIVT,Hicksville,NY或类似)。血液在水浴中预热至37℃，持续30分钟。通过添加100μL超纯水/孔制备96深孔分析板。将50μL冷冻超纯水/孔添加至96深孔样品收集板并且用密封垫覆盖。将1μL的0.5mM化合物工作溶液(DMSO:水)添加至孵育板中的血液中，以达到1μM的最终浓度，通过移液器彻底混合，并且将50μL转移至样品收集板的T＝0孔中。使血液在水中静置2分钟，并且随后添加400μL终止溶液/孔(含有内标的乙腈)。将孵育板置于37℃下以150rpm振荡的Incu-Shaker CO₂ Mini孵育箱(BenchmarkScientific,Sayreville,NJ)中。在1、2和4小时，通过移液器将血液样品彻底混合，并且将50μL转移至样品收集板的相应孔中。使血液在水中静置2分钟，并且随后添加400μL的终止溶液/孔。将收集板密封并且以1700rpm涡旋3分钟(VX-2500Multi-Tube Vortexer,VWRInternational,Radnor,PA)，并且样品随后在收集板中以3500rpm离心10分钟(Allegra X-14R Centrifuge Beckman Coulter,Indianapolis,IN)。将100μL上清液/孔自样品收集板转移至分析板的相应孔中。最终板以1700rpm涡旋1分钟，并且通过LC-MS/MS分析样品。1、2和4小时样品相对于T＝0的峰面积比用于确定剩余百分比。剩余百分比与时间的自然对数用于确定斜率，以计算化合物在血液中的半衰期(t_1/2＝0.693/斜率)。Whole blood stability of exemplary compounds was determined by LC-MS/MS. A 96-well Flexi-Tier^TM block (Analytical Sales & Services, Inc, Flanders, NJ) was used to incubate the plate, which contained 1.0 mL glass vials, each containing 0.5 mL of blood (pooled gender, human whole blood, from BIOIVT, Hicksville, NY or similar). The blood was preheated to 37° C. in a water bath for 30 minutes. A 96-deep well assay plate was prepared by adding 100 μL of ultrapure water/well. 50 μL of chilled ultrapure water/well was added to a 96-deep well sample collection plate and covered with a sealing mat. 1 μL of 0.5 mM compound working solution (DMSO: water) was added to the blood in the incubation plate to achieve a final concentration of 1 μM, mixed thoroughly by pipetting, and 50 μL was transferred to the T=0 well of the sample collection plate. Blood was allowed to stand in water for 2 minutes, and then 400 μL stop solution/well (acetonitrile containing internal standard) was added. The incubation plate was placed in an Incu-Shaker CO₂ Mini incubator (BenchmarkScientific, Sayreville, NJ) vibrated at 150 rpm at 37°C. At 1, 2 and 4 hours, the blood sample was thoroughly mixed by a pipette, and 50 μL was transferred to the corresponding wells of the sample collection plate. Blood was allowed to stand in water for 2 minutes, and then 400 μL stop solution/well was added. The collection plate was sealed and vortexed at 1700 rpm for 3 minutes (VX-2500 Multi-Tube Vortexer, VWR International, Radnor, PA), and the sample was then centrifuged at 3500 rpm for 10 minutes in the collection plate (Allegra X-14R Centrifuge Beckman Coulter, Indianapolis, IN). 100 μL supernatant/well was transferred from the sample collection plate to the corresponding wells of the analysis plate. The final plate was vortexed at 1700 rpm for 1 minute and the samples were analyzed by LC-MS/MS. The peak area ratios of the 1, 2 and 4 hour samples relative to T=0 were used to determine the remaining percentage. The natural logarithm of the remaining percentage and time was used to determine the slope to calculate the half-life of the compound in the blood (t_1/2 =0.693/slope).

实施例J：体外固有清除率方案Example J: In vitro intrinsic clearance protocol

对于体外代谢稳定性实验，将测试化合物与人肝微粒体一起在37℃下孵育。孵育混合物在100mM磷酸盐缓冲液(pH 7.4)中含有测试化合物(1μM)、NADPH(2mM)和人肝微粒体(0.5mg蛋白/mL)。在添加NADPH前，将混合物在37℃下预孵育2分钟。添加NADPH后开始反应，并且在0、10、20和30分钟时用冰冷的甲醇淬灭。使用LC-MS/MS系统分析终止的孵育混合物。分析系统由Shimadzu LC-30AD二元泵系统和SIL-30AC自动进样器(Shimadzu ScientificInstruments,Columbia,MD)联合来自Applied Biosystems(Foster City,CA)的SciexTriple Quad 6500+质谱仪组成。测试化合物和内标的色谱分离使用来自ThermoFisherScientific(Waltham,MA)的Hypersil Gold C18柱(50×2.1mm，5μM，)达成。流动相A由0.1％甲酸/水组成，而流动相B由0.1％甲酸/乙腈组成。总LC-MS/MS运行时间可为2.75分钟，流速为0.75毫升/分钟。使用来自Applied Biosystems的Analyst软件(1.6.3版)进行峰面积积分和峰面积比率计算。For in vitro metabolic stability experiment, test compound is incubated at 37 ℃ together with human liver microsome.Hatch mixture contains test compound (1 μ M), NADPH (2 mM) and human liver microsome (0.5 mg protein/mL) in 100 mM phosphate buffer (pH 7.4).Before adding NADPH, mixture is pre-incubated for 2 minutes at 37 ℃.Reaction is started after adding NADPH, and quenched with ice-cold methanol at 0,10,20 and 30 minutes.Use LC-MS/MS system to analyze the incubation mixture terminated.Analytical system is made up of Shimadzu LC-30AD binary pump system and SIL-30AC automatic sampler (Shimadzu ScientificInstruments, Columbia, MD) in conjunction with SciexTriple Quad 6500+ mass spectrometer from Applied Biosystems (Foster City, CA). Chromatographic separation of test compounds and internal standards was performed using a Hypersil Gold C18 column (50×2.1 mm, 5 μM, 4 μg/mL) from Thermo Fisher Scientific (Waltham, MA). ). Mobile phase A consisted of 0.1% formic acid/water, while mobile phase B consisted of 0.1% formic acid/acetonitrile. The total LC-MS/MS run time could be 2.75 minutes with a flow rate of 0.75 ml/min. Peak area integration and peak area ratio calculations were performed using Analyst software (version 1.6.3) from Applied Biosystems.

体外固有清除率CL_int,体外是由测试化合物消失的t_1/2计算，即CL_int,_体外＝(0.693/t_1/2)×(1/C_蛋白)，其中C_蛋白为孵育期间的蛋白浓度，并且t_1/2是由浓度与时间曲线的对数线性回归分析的斜率(k)确定；因此，t_1/2＝ln2/k。通过使用基于生理的比例因子、肝微粒体蛋白浓度(45mg蛋白/g肝)和肝重量(21g/kg体重)，将CL_int,体外值缩放为人类的体内值。使用等式CL_int＝CL_int,体外×(mg蛋白/g肝重量)×(g肝重量/kg体重)。随后通过使用CL_int和肝血流量Q(在人类中20mL min^-1·kg^-1)在充分搅拌的肝模型中由CL_H＝(Q×CL_int)/(Q+CL_int)计算体内肝清除率(CL_H)，不考虑所有结合。肝提取率计算为CL_H除以Q。In vitro intrinsic clearance CL_{int, in vitro} is calculated by t_1/2 of disappearance of the test compound, i.e. CL_int ,_{in vitro} = (0.693/t_1/2 ) × (1/C_protein ), where C_protein is the protein concentration during incubation, and t_1/2 is determined by the slope (k) of the logarithmic linear regression analysis of the concentration versus time curve; therefore, t_1/2 = ln2/k. CL_{int, in vitro} values are scaled to human in vivo values by using physiologically based scaling factors, liver microsomal protein concentration (45 mg protein/g liver) and liver weight (21 g/kg body weight). The equation CL_int = CL_{in vitro} × (mg protein/g liver weight) × (g liver weight/kg body weight) is used. In vivo hepatic clearance (CL H ) was then calculated in a well-stirred liver model by CL_H =(Q×CL_int )/(Q+CL_int ) using CL_int and hepatic blood flow Q (20 mL min⁻¹ ·^kg₋₁ in humans), ignoring any binding. The hepatic extraction rate was calculated as CL_H divided by Q.

实施例K：体内药物动力学方案Example K: In vivo pharmacokinetic protocol

对于体内药物动力学实验，经静脉内或经由经口管饲向雄性Sprague Dawley大鼠或雄性和雌性食蟹猴施用测试化合物。对于静脉内(IV)给药，使用10％二甲基乙酰胺(DMAC)于酸化生理盐水中的制剂以0.5至1mg/kg给药测试化合物，对于大鼠经由IV推注，并且对于猴经由5分钟或10分钟IV输注。对于经口(PO)给药，使用含5％DMAC的0.5％甲基纤维素的柠檬酸盐缓冲液(pH 2.5)以1.0至3.0mg/kg给药测试化合物。在给药前和给药后至多24小时的多个时间点收集血液样品。使用EDTA作为抗凝血剂收集所有血液样品，并且离心获得血浆样品。测试化合物的血浆浓度通过LC-MS法测定。所测量的血浆浓度用于通过标准非房室法使用WinNonlin软件程序(8.0版，Pharsight Corporation)计算PK参数。For in vivo pharmacokinetic experiments, test compounds were administered intravenously or via oral gavage to male Sprague Dawley rats or male and female cynomolgus monkeys. For intravenous (IV) administration, test compounds were administered at 0.5 to 1 mg/kg using a formulation of 10% dimethylacetamide (DMAC) in acidified saline, for rats via IV push, and for monkeys via 5 minutes or 10 minutes IV infusion. For oral (PO) administration, test compounds were administered at 1.0 to 3.0 mg/kg using a citrate buffer (pH 2.5) of 0.5% methylcellulose containing 5% DMAC. Blood samples were collected at multiple time points up to 24 hours before and after administration. All blood samples were collected using EDTA as an anticoagulant, and plasma samples were obtained by centrifugation. The plasma concentration of the test compound was determined by LC-MS. The measured plasma concentration was used for the use of a standard non-compartmental method PK parameters were calculated using the WinNonlin software program (version 8.0, Pharsight Corporation).

在大鼠和猴中，进行测试化合物的盒式给药以获得初步PK参数。In rats and monkeys, cassette dosing of test compounds was performed to obtain preliminary PK parameters.

雄性比格犬(beagledog)的体内药物动力学实验可在上述条件下进行。In vivo pharmacokinetic studies in male beagle dogs can be conducted under the above conditions.

实施例L：CYP的时间依赖性抑制(TDI)方案Example L: Time-dependent inhibition (TDI) protocol of CYP

此测定被设计来表征随着测试化合物随时间代谢而增加的CYP抑制。其潜在机制包括形成紧密结合的准不可逆抑制性代谢物复合物或通过代谢物的共价加合物形成使P450酶失活。虽然此实验采用10倍稀释以降低代谢物浓度并且因此降低可逆抑制的影响，但作为极强效CYP抑制剂的代谢物可能(但不常见)导致阳性结果。This assay is designed to characterize CYP inhibition that increases as the test compound is metabolized over time. Potential mechanisms include the formation of tightly bound, quasi-irreversible inhibitory metabolite complexes or inactivation of P450 enzymes by covalent adduct formation of metabolites. Although this experiment uses a 10-fold dilution to reduce metabolite concentrations and thus reduce the impact of reversible inhibition, metabolites that are very potent CYP inhibitors may (but are uncommon) lead to positive results.

结果来自使用人肝微粒体(HLM)对CYP2C9、2C19、2D6和3A4(咪达唑仑(midazolam))的4倍Km浓度的CYP特异性探针底物的混合液。在NADPH再生系统存在(+N)或不存在(-N)的情况下，HLM可与浓度为10μM的测试化合物一起预孵育30分钟，稀释10倍，并且在底物混合液存在的情况下通过添加NADPH再生系统的新鲜等分试样孵育8分钟。代谢物标准品的校准曲线可用于使用LC-MS/MS定量测量酶活性。另外，与已知时间依赖性抑制剂替尼利酸(tienilic aicd)(CYP2C9)、噻氯匹定(ticlopidine)(CYP2C19)、帕罗西汀(paroxetine)(CYP2D6)和醋竹桃霉素(troleandomycin)(CYP3A4)一起孵育用作阳性对照，在具有或不具有NADPH再生系统的情况下预孵育30分钟。Results are from a cocktail of CYP-specific probe substrates at 4 times the Km concentration for CYP2C9, 2C19, 2D6, and 3A4 (midazolam) using human liver microsomes (HLM). HLMs were pre-incubated with test compounds at a concentration of 10 μM for 30 minutes in the presence (+N) or absence (-N) of an NADPH regeneration system, diluted 10-fold, and incubated for 8 minutes in the presence of the substrate cocktail by adding a fresh aliquot of the NADPH regeneration system. Calibration curves of metabolite standards can be used to quantitatively measure enzyme activity using LC-MS/MS. Additionally, incubations with known time-dependent inhibitors tienilic acid (CYP2C9), ticlopidine (CYP2C19), paroxetine (CYP2D6), and troleandomycin (CYP3A4) were used as positive controls, with or without a NADPH regeneration system for 30 min preincubation.

分析系统由Shimadzu LC-30AD二元泵系统和SIL-30AC自动进样器(ShimadzuScientific Instruments,Columbia,MD)联合来自Applied Biosystems(Foster City,CA)的Sciex Triple Quad 6500+质谱仪组成。测试化合物和内标的色谱分离可使用ACQUITYUPLC BEH 130A，2.1×50mm，1.7μm HPLC柱(Waters Corp,Milford,MA)达成。流动相A由0.1％甲酸/水组成，而流动相B由0.1％甲酸/乙腈组成。总LC-MS/MS运行时间将为2.50分钟，流速为0.9毫升/分钟。使用来自Applied Biosystems的Analyst软件(1.6.3版)进行峰面积积分和峰面积比率计算。The analysis system consists of a Shimadzu LC-30AD binary pump system and a SIL-30AC autosampler (Shimadzu Scientific Instruments, Columbia, MD) in combination with a Sciex Triple Quad 6500+ mass spectrometer from Applied Biosystems (Foster City, CA). Chromatographic separation of test compounds and internal standards can be achieved using an ACQUITY UPLC BEH 130A, 2.1×50 mm, 1.7 μm HPLC column (Waters Corp, Milford, MA). Mobile phase A consists of 0.1% formic acid/water, while mobile phase B consists of 0.1% formic acid/acetonitrile. The total LC-MS/MS run time will be 2.50 minutes with a flow rate of 0.9 ml/min. Peak area integration and peak area ratio calculations are performed using Analyst software (version 1.6.3) from Applied Biosystems.

将化合物与NADPH预孵育后剩余的对照CYP2C9、CYP2C19、CYP2D6和CYP3A4活性百分比针对相应的对照媒介物活性进行校正，并且随后基于0分钟计算为100％。使用各同功酶的剩余活性％的自然对数与时间的线性回归曲线来计算斜率。斜率等于酶损失率，或K_obs。The percentage of control CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity remaining after preincubation of the compound with NADPH was corrected for the corresponding control vehicle activity and then calculated as 100% based on 0 minutes. The slope was calculated using a linear regression curve of the natural logarithm of the % activity remaining for each isozyme versus time. The slope is equal to the enzyme loss rate, or K_obs .

除本文所描述的那些修改以外，根据前述描述，本发明的各种修改对本领域的技术人员而言将为显而易见的。此类修改也意图属于随附权利要求书的范围内。本申请中所引用的各参考文献包括但不限于所有专利、专利申请和公开，其以全文引用的方式并入本文中。In addition to those modifications described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. The various references cited in this application include, but are not limited to, all patents, patent applications, and disclosures, which are incorporated herein by reference in their entirety.

Claims (52)

Translated fromChinese

1.一种具有式(I)的化合物：1. A compound having formula (I):或其药学上可接受的盐，其中：or a pharmaceutically acceptable salt thereof, wherein:Y为N或CR⁶；Y is N or CR⁶ ;R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至9元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至9元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 9-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5-membered to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 and C(O)NR^c6 R^d6 ; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 9-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene are each optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;Cy²选自Cy² is selected from其中n为0、1或2；Where n is 0, 1 or 2;各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; orR^f3选自R^f3 is selected from其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;其限制条件为所述式I化合物不为The limiting condition is that the compound of formula I is not3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.2.如权利要求1所述的化合物或其药学上可接受的盐，其中2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, whereinY为N或CR⁶；Y is N or CR⁶ ;R¹选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a1；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；R¹ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, cyclopropyl, halo, D, CN and OR^a1 ; wherein the C_1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from R^g ;R²选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R^g的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, and OR^a2 ; wherein each of the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted with 1 or 2 substituents independently selected from R^g ;Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^f3、C(O)NR^c3R^d3、NR^c3R^j3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene, 5-membered to 6-membered heteroaryl-_C1-3 alkylene, halo, D, CN,^ORf3 , C(O)^NRc3Rd3 ,^NRc3Rj3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6^cycloalkyl , 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl,_C3-6 cycloalkyl-_C1-3 alkylene^, 4-membered to 6-membered heterocycloalkyl-_C1-3 alkylene, phenyl-_C1-3 alkylene and 5-membered to 6-membered heteroaryl-C_1-3 alkylene groups are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R⁵选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a5；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa5 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;R⁶选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基、5元至6元杂芳基-C_1-3亚烷基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_1-3烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、C_3-6环烷基-C_1-3亚烷基、4元至6元杂环烷基-C_1-3亚烷基、苯基-C_1-3亚烷基和5元至6元杂芳基-C_1-3亚烷基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；^R is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, 5- to 6-membered heteroaryl-C_1-3 alkylene, halo, D, CN, OR^a6 , and C(O)NR^c6 R^d6 ; wherein each of the C_1-3 alkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C_3-6 cycloalkyl-C_1-3 alkylene, 4- to 6-membered heterocycloalkyl-C_1-3 alkylene, phenyl-C_1-3 alkylene, and 5- to 6-membered heteroaryl-C_1-3 alkylene is optionally substituted by 1 or 2 independently selected R⁶⁰ is substituted by a substituent;R⁷选自H、C_1-3烷基、C_1-3卤烷基、环丙基、卤基、D、CN和OR^a7；其中所述C_1-3烷基和环丙基各自任选地被1或2个独立地选自R^g的取代基取代；^R7 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, cyclopropyl, halo, D, CN and^ORa7 ; wherein the_C1-3 alkyl and cyclopropyl are each optionally substituted with 1 or 2 substituents independently selected from^Rg ;Cy²选自Cy² is selected from其中n为0、1或2；Where n is 0, 1 or 2;各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;各R³³独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基、C_3-6环烷基、4元杂环烷基、6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³³ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;R^a1选自H、C_1-3烷基和C_1-3卤烷基；R^a1 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R^j3选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R is selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;或连接至同一N原子的R^c3和R^j3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^j3 attached to the same N atom together with the N atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R^f3选自C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；或R^f3 is selected from C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ; orR^f3选自R^f3 is selected from其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;或R^x和R^y与其所连接的C原子一起形成3元或4元环烷基；or R^x and R^y together with the C atom to which they are attached form a 3-membered or 4-membered cycloalkyl group;R^a5选自H、C_1-3烷基和C_1-3卤烷基；R^a5 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;R^a7选自H、C_1-3烷基和C_1-3卤烷基；R^a7 is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and各R^g独立地选自D、OH、CN、卤基、C_1-3烷基、C_1-3卤烷基、C_1-3烷氧基、C_1-3卤烷氧基、氨基、C_1-3烷氨基和二(C_1-3烷基)氨基；each^Rg is independently selected from D, OH, CN, halo,_C1-3 alkyl,_C1-3 haloalkyl,_C1-3 alkoxy,_C1-3 haloalkoxy, amino,_C1-3 alkylamino, and di(_C1-3 alkyl)amino;其限制条件为所述式I化合物不为The limiting condition is that the compound of formula I is not3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺。3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide.3.如权利要求1或2所述的化合物或其药学上可接受的盐，其中3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, whereinY为CR⁶；Y is CR⁶ ;R¹选自H、C_1-3烷基和C_1-3卤烷基；R¹ is selected from H, C_1-3 alkyl and C_1-3 haloalkyl;R²选自H、C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a2；其中所述C_1-3烷基任选地被1或2个独立地选自R^g的取代基取代；^R2 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, halo, D, CN and^ORa2 ; wherein the_C1-3 alkyl is optionally substituted by 1 or 2 substituents independently selected from^Rg ;Cy¹选自C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基；其中所述4元至10元杂环烷基和6元至10元杂芳基各自具有至少一个成环碳原子和1、2、3或4个独立地选自N、O和S的成环杂原子；其中6元至10元杂芳基和4元至10元杂环烷基的成环碳原子任选地被氧代取代以形成羰基；并且其中所述C_3-10环烷基、4元至10元杂环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1、2、3或4个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 4- to 10-membered heterocycloalkyl and the 6- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of the 6- to 10-membered heteroaryl and the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C_3-10 cycloalkyl, the 4- to 10-membered heterocycloalkyl, the C_6-10 aryl and the 6- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰ ;R³选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、C(O)NR^c3R^d3和NR^c3C(O)R^b3；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halo, D, CN, C(O)^NRc3Rd3 and^NRc3C (O)^Rb3 ; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered^{heterocycloalkyl} , phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from^R30 ;R⁵选自H、C_1-3烷基、C_1-3卤烷基和卤基；^R5 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl and halo;R⁶选自H、C_1-3卤烷基、C_3-6环烷基、4元至8元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a6和C(O)NR^c6R^d6；其中所述C_3-6环烷基、4元至8元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, halo, D, CN, OR^a6 , and C(O)NR^c6 R^d6 ; wherein the C_3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; orR⁶为C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;R⁷选自H、C_1-3烷基、C_1-3卤烷基、卤基和CN；R⁷ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, halo and CN;Cy²选自Cy² is selected from其中n为0、1或2；Where n is 0, 1 or 2;各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a10、C(O)R^b10、C(O)NR^c10R^d10、C(O)OR^a10、NR^c10R^d10和S(O)₂R^b10；each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a10 , C(O)R^b10 , C(O)NR^c10 R^d10 , C(O)OR^a10 , NR^c10 R^d10 and S(O)₂ R^b10 ;各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a20；Each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a20 ;各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基、5元至6元杂芳基、卤基、D、CN、OR^a30、C(O)R^b30、C(O)NR^c30R^d30、C(O)OR^a30、NR^c30R^d30和S(O)₂R^b30；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl, 5-membered to 6-membered heteroaryl, halogen, D, CN, OR^a30 , C(O)R^b30 , C(O)NR^c30 R^d30 , C(O)OR^a30 , NR^c30 R^d30 and S(O)₂ R^b30 ; wherein the C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a31、C(O)R^b31、C(O)NR^c31R^d31、C(O)OR^a31、NR^c31R^d31和S(O)₂R^b31；each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a31 , C(O)R^b31 , C(O)NR^c31 R^d31 , C(O)OR^a31 , NR^c31 R^d31 and S(O)₂ R^b31 ;各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN、OR^a61和NR^c61R^d61；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN, OR^a61 and NR^c61 R^d61 ;各R^a2独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a2 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^b3、R^c3和R^d3独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；each of R^b3 , R^c3 and R^d3 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein said C_1-3 alkyl, C_3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;或连接至同一N原子的R^c3和R^d3与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1、2或3个独立地选自R³⁰的取代基取代；or R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;各R^a6、R^c6和R^d6独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；Each of^Ra6 ,^Rc6 and^Rd6 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R60 ;各R^a10、R^b10、R^c10和R^d10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a10 , R^b10 , R^c10 and R^d10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a20独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a20 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;R^b20选自NH₂、C_1-3烷基和C_1-3卤烷基；R^b20 is selected from NH₂ , C_1-3 alkyl and C_1-3 haloalkyl;各R^a30、R^b30、R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a30 , R^b30 , R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a31、R^b31、R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；Each of R^a31 , R^b31 , R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代；以及or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group, which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ; and各R^a61、R^c61和R^d61独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^a61 , R^c61 and R^d61 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and各R^g独立地选自D、CN、卤基、C_1-3烷基和C_1-3卤烷基。Each^Rg is independently selected from D, CN, halo,_C1-3 alkyl and_C1-3 haloalkyl.4.如权利要求1或2所述的化合物或其药学上可接受的盐，其中4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, whereinY为CR⁶；Y is CR⁶ ;R¹为H；^R1 is H;R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and -CH₂ CH₂ CN;Cy¹选自C_3-10环烷基、C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_3-10环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；^R3 is selected from H,_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl; wherein each of the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, phenyl and 5-membered to 6-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from^R30 ;R⁵选自H和卤基；^R5 is selected from H and halogen;R⁶选自H、C_1-3卤烷基、4元至8元杂环烷基和5元至6元杂芳基；其中所述4元至8元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from H, C_1-3 haloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocycloalkyl and the 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; orR⁶为C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;R⁷为卤基；^R7 is halogen;Cy²为Cy² is各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D, CN and OR^a10 ;各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN、OR^a31和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a31 and NR^c31 R^d31 ;各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和CN；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and CN;各R^a10独立地选自H和C_1-3烷基；Each R^a10 is independently selected from H and C_1-3 alkyl;各R^a30、R^c30和R^d30独立地选自H和C_1-3烷基；Each of R^a30 , R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;各R^a31、R^c31和R^d31独立地选自H和C_1-3烷基；Each of R^a31 , R^c31 and R^d31 is independently selected from H and C_1-3 alkyl;各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .5.如权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, whereinY为CR⁶；Y is CR⁶ ;R¹为H；^R1 is H;R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;R³选自H、C_1-3烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R⁵选自H和卤基；^R5 is selected from H and halogen;R⁶选自4元至8元杂环烷基；其中所述4元至8元杂环烷基任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from 4- to 8-membered heterocycloalkyl; wherein the 4- to 8-membered heterocycloalkyl is optionally substituted by 1 or 2 substituents independently selected from R⁶⁰ ; orR⁶选自C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-3 alkyl; wherein the C_1-3 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;R⁷为卤基；^R7 is halogen;Cy²为Cy² is各R¹⁰独立地选自C_1-3烷基和卤基；Each R¹⁰ is independently selected from C_1-3 alkyl and halo;各R³⁰独立地选自C_1-3烷基、卤基、D和C(O)NR^c30R^d30；其中所述C_1-3烷基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from C_1-3 alkyl, halo, D and C(O)NR^c30 R^d30 ; wherein the C_1-3 alkyl is optionally substituted with 1 substituent independently selected from R³¹ ;各R³¹为OR^a31；each R³¹ is OR^a31 ;各R⁶⁰独立地选自C_1-3烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl, halogen, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl and halo;各R^c30和R^d30独立地选自H和C_1-3烷基；Each R^c30 and R^d30 is independently selected from H and C_1-3 alkyl;各R^a31独立地选自H和C_1-3烷基；以及Each R^a31 is independently selected from H and C_1-3 alkyl; and各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein said_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .6.如权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, whereinY为CR⁶；Y is CR⁶ ;R¹为H；^R1 is H;R²为-CH₂CH₂CN；R² is -CH₂ CH₂ CN;Cy¹为苯基；其中所述苯基任选地被1或2个独立地选自R¹⁰的取代基取代；Cy¹ is phenyl; wherein the phenyl is optionally substituted by 1 or 2 substituents independently selected from R¹⁰ ;R³选自H、甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基；其中所述甲基、苯基、1,2,4-三唑基、吡唑基和吡啶基各自任选地被1、2或3个独立地选自R³⁰的取代基取代；R³ is selected from H, methyl, phenyl, 1,2,4-triazolyl, pyrazolyl and pyridinyl; wherein the methyl, phenyl, 1,2,4-triazolyl, pyrazolyl and pyridinyl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ ;R⁵选自H和氯；^R5 is selected from H and chlorine;R⁶选自吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基；其中所述吡咯烷基、2-氮杂双环[3.1.0]己烷基和5-氧代-1,2,3,5-四氢吲哚嗪-3-基任选地被1或2个独立地选自R⁶⁰的取代基取代；或R⁶ is selected from pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl; wherein the pyrrolidinyl, 2-azabicyclo[3.1.0]hexanyl and 5-oxo-1,2,3,5-tetrahydroindoleazin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; orR⁶选自C_1-2烷基；其中所述C_1-2烷基被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from C_1-2 alkyl; wherein the C_1-2 alkyl is substituted by 1 or 2 substituents independently selected from R⁶⁰ ;R⁷为氟；^R7 is fluorine;Cy²为Cy² is各R¹⁰独立地选自甲基、氟和氯；each R¹⁰ is independently selected from methyl, fluoro and chloro;各R³⁰独立地选自甲基、氟、D和C(O)NR^c30R^d30；其中所述甲基任选地被1个独立地选自R³¹的取代基取代；Each R³⁰ is independently selected from methyl, fluorine, D and C(O)NR^c30 R^d30 ; wherein the methyl is optionally substituted with 1 substituent independently selected from R³¹ ;各R³¹为OR^a31；each R³¹ is OR^a31 ;各R⁶⁰独立地选自甲基、氟、3-氧代吗啉基、2-氧代吡嗪-1(2H)-基、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60和NR^c60S(O)₂R^b60；其中所述3-氧代吗啉基和2-氧代吡嗪-1(2H)-基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each R⁶⁰ is independently selected from methyl, fluoro, 3-oxomorpholinyl, 2-oxopyrazine-1(2H)-yl, C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 and NR^c60 S(O)₂ R^b60 ; wherein the 3-oxomorpholinyl and 2-oxopyrazine-1(2H)-yl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自甲基和氟；Each R⁶¹ is independently selected from methyl and fluoro;各R^c30和R^d30独立地选自H和甲基；Each R^c30 and R^d30 is independently selected from H and methyl;各R^a31独立地选自H和甲基；以及each R^a31 is independently selected from H and methyl; and各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-2烷基、C₁卤烷基、环丙基、四氢呋喃基和噻唑基；其中所述C_1-2烷基、环丙基、四氢呋喃基和噻唑基各自任选地被1或2个独立地选自R⁶¹的取代基取代；each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-2 alkyl,_C1 haloalkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl; wherein the_C1-2 alkyl, cyclopropyl, tetrahydrofuranyl and thiazolyl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成任选地被1或2个独立地选自R⁶¹的取代基取代的氮杂环丁烷基。Or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form an azetidinyl group optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .7.如权利要求1或2所述的化合物或其药学上可接受的盐，其中7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, whereinY为N或CR⁶；Y is N or CR⁶ ;R¹为H；^R1 is H;R²选自C_1-3烷基、C_1-3卤烷基、卤基、CN和-CH₂CH₂CN；R² is selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and -CH₂ CH₂ CN;Cy¹选自C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_6-10芳基和6元至10元杂芳基各自任选地被1、2或3个独立地选自R¹⁰的取代基取代；Cy¹ is selected from C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R¹⁰ ;R³选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代；^R3 is selected from_C1-3 alkyl,_C1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, 5-membered to 6-membered heteroaryl and^ORf3 ; wherein the_C1-3 alkyl, 4-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R30 ;R⁵为H；^R5 is H;R⁶选自H、C_1-3烷基、C_1-3卤烷基和5元至6元杂芳基；其中所述C_1-3烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ;R⁷为卤基；^R7 is halogen;Cy²选自Cy² is selected from各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OR^a10；Each R¹⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN and OR^a10 ;各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ ;各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基和NR^c31R^d31；Each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo and NR^c31 R^d31 ;R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基和CN；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代；R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo and CN; wherein each of the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents independently selected from R³¹ ;各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基和C(O)NR^c60R^d60；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, and C(O)NR^c60 R^d60 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ ;各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基和卤基；Each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl and halo;R^f3为C_1-3卤烷基；或R^f3 is C_1-3 haloalkyl; orR^f3选自R^f3 is selected from其中R^x为H或C_1-2烷基并且R^y为C_1-2烷基；wherein^Rx is H or_C1-2 alkyl and^Ry is_C1-2 alkyl;各R^a10独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^a10 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;R^b20选自C_1-3烷基和C_1-3卤烷基；R^b20 is selected from C_1-3 alkyl and C_1-3 haloalkyl;各R^c30和R^d30独立地选自H、C_1-3烷基和C_1-3卤烷基；Each R^c30 and R^d30 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl;各R^c31和R^d31独立地选自H、C_1-3烷基和C_1-3卤烷基；以及each of R^c31 and R^d31 is independently selected from H, C_1-3 alkyl and C_1-3 haloalkyl; and各R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基和4元至6元杂环烷基；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R⁶¹的取代基取代；Each of R^c60 and R^d60 is independently selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 4- to 6-membered heterocycloalkyl; wherein the C_1-3 alkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R⁶¹ ;或连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元或5元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。or any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered or 5-membered heterocycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .8.如权利要求1至7中任一项所述的化合物或其药学上可接受的盐，其中8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, whereinY为CR⁶；Y is CR⁶ ;R¹为H；^R1 is H;R²为C_1-3烷基，其被CN取代；^R2 is_C1-3 alkyl, which is substituted by CN;Cy¹为被1或2个独立地选自R¹⁰的取代基取代的苯基，其中各R¹⁰独立地为卤基；Cy¹ is phenyl substituted by 1 or 2 substituents independently selected from R¹⁰ , wherein each R¹⁰ is independently halogen;R³选自-CH₃、-CH(CH₃)-OH和经-C(CH₃)₂OH取代的6元杂芳基；R³ is selected from -CH₃ , -CH(CH₃ )-OH and a 6-membered heteroaryl substituted with -C(CH₃ )₂ OH;R⁵为H；^R5 is H;R⁶选自-6元杂环烷基-C(O)R^b60、-CH(CH₃)-R⁶⁰和-CH(CH₃)-NHC(O)R^b60；R⁶ is selected from -6-membered heterocycloalkyl-C(O)R^b60 , -CH(CH₃ )-R⁶⁰ and -CH(CH₃ )-NHC(O)R^b60 ;R⁷为卤基；^R7 is halogen;Cy²为Cy² isR⁶⁰为6元杂环烷基；R⁶⁰ is a 6-membered heterocycloalkyl group;R^b60为C_3-4环烷基，其被R⁶¹取代；以及R^b60 is a C_3-4 cycloalkyl group substituted by R⁶¹ ; andR⁶¹为卤基。^R61 is a halogen group.9.如权利要求1或2所述的化合物或其药学上可接受的盐，其中Y为N。9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is N.10.如权利要求1或2所述的化合物或其药学上可接受的盐，其中Y为CR⁶。10 . The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein Y is CR⁶ .11.如权利要求1或2所述的化合物或其药学上可接受的盐，其中R¹为H。11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is H.12.如权利要求1至3和9至11中任一项所述的化合物或其药学上可接受的盐，其中R²选自C_1-3烷基、卤基、CN和-CH₂CH₂CN。_12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 9 to 11, wherein^R2 is selected from_C1-3 alkyl, halo, CN and_-CH2CH2CN .13.如权利要求1至3和9至12中任一项所述的化合物或其药学上可接受的盐，其中Cy¹选自C_3-10环烷基、C_6-10芳基和6元至10元杂芳基；其中所述6元至10元杂芳基具有至少一个成环碳原子和1个独立地选自N和S的成环杂原子；并且其中所述C_3-10环烷基、C_6-10芳基和6元至10元杂芳基各自任选地被1或2个独立地选自R¹⁰的取代基取代。13. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3 and 9 to 12, wherein Cy¹ is selected from C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl; wherein the 6- to 10-membered heteroaryl has at least one ring-forming carbon atom and 1 ring-forming heteroatom independently selected from N and S; and wherein the C_3-10 cycloalkyl, C_6-10 aryl and 6- to 10-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰ .14.如权利要求1至3和9至13中任一项所述的化合物或其药学上可接受的盐，其中R³选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基和OR^f3；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R³⁰的取代基取代。14. A compound as described in any one of claims 1 to 3 and 9 to 13, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and OR^f3 ; wherein the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R³⁰ .15.如权利要求1至3和9至14中任一项所述的化合物或其药学上可接受的盐，其中R³选自H、C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基；其中所述C_1-3烷基、4元至6元杂环烷基、苯基和5元至6元杂芳基各自任选地被1、2或3个独立地选自R³⁰的取代基取代。15. A compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3 and 9 to 14, wherein R³ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R³⁰ .16.如权利要求1至3和9至15中任一项所述的化合物或其药学上可接受的盐，其中R⁵为H。16. The compound of any one of claims 1 to 3 and 9 to 15, or a pharmaceutically acceptable salt thereof, wherein R⁵ is H.17.如权利要求1至3和9至16中任一项所述的化合物或其药学上可接受的盐，其中R⁶选自H、C_1-3烷基、C_1-3卤烷基和5元至6元杂芳基；其中所述C_1-3烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代。17. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3 and 9 to 16, wherein R⁶ is selected from H, C_1-3 alkyl, C_1-3 haloalkyl and 5- to 6-membered heteroaryl; wherein the C_1-3 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ .18.如权利要求1至3和9至17中任一项所述的化合物或其药学上可接受的盐，其中R⁶选自H、C_1-3卤烷基、4元至8元杂环烷基和5元至6元杂芳基；其中所述4元至8元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶⁰的取代基取代；或18. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 and 9 to 17, wherein R⁶ is selected from H, C_1-3 haloalkyl, 4- to 8-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the 4- to 8-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R⁶⁰ ; orR⁶为C_1-3烷基；其中所述C_1-3烷基被1或2个独立地选自R⁶⁰的取代基取代。R⁶ is a C_1-3 alkyl group; wherein the C_1-3 alkyl group is substituted by 1 or 2 substituents independently selected from R⁶⁰ .19.如权利要求1至3和9至18中任一项所述的化合物或其药学上可接受的盐，其中R⁷为卤基。19. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 and 9 to 18, wherein R⁷ is halo.20.如权利要求1至3和9至19中任一项所述的化合物或其药学上可接受的盐，其中Cy²为Cy²-a。20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 9 to 19, wherein Cy² is Cy² -a.21.如权利要求1至3和9至20中任一项所述的化合物或其药学上可接受的盐，其中Cy²为Cy²-b。21. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 and 9 to 20, wherein Cy² is Cy² -b.22.如权利要求1至3和9至21中任一项所述的化合物或其药学上可接受的盐，其中n为0。22. The compound of any one of claims 1 to 3 and 9 to 21, or a pharmaceutically acceptable salt thereof, wherein n is 0.23.如权利要求1至3和9至22中任一项所述的化合物或其药学上可接受的盐，其中n为1。23. The compound of any one of claims 1 to 3 and 9 to 22, or a pharmaceutically acceptable salt thereof, wherein n is 1.24.如权利要求1至3和9至23中任一项所述的化合物或其药学上可接受的盐，其中各R¹⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN和OR^a10。24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3 and 9 to 23, wherein each^R10 is independently selected from_C1-3 alkyl,_C1-3 haloalkyl, halo, CN and^ORa10 .25.如权利要求1至3和9至24中任一项所述的化合物或其药学上可接受的盐，其中各R²⁰独立地选自C_1-3烷基、C_1-3卤烷基、卤基、D和CN。25. The compound of any one of claims 1 to 3 and 9 to 24, or a pharmaceutically acceptable salt thereof, wherein each R²⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, D and CN.26.如权利要求1至3和9至25中任一项所述的化合物或其药学上可接受的盐，其中各R³⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、卤基、D、CN、OR^a30、C(O)NR^c30R^d30和NR^c30R^d30；其中所述C_1-3烷基和4元至6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。26. A compound as described in any one of claims 1 to 3 and 9 to 25, or a pharmaceutically acceptable salt thereof, wherein each R³⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4-membered to 6-membered heterocycloalkyl, halo, D, CN, OR^a30 , C(O)NR^c30 R^d30 and NR^c30 R^d30 ; wherein the C_1-3 alkyl and 4-membered to 6-membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents independently selected from R³¹ .27.如权利要求1至3和9至26中任一项所述的化合物或其药学上可接受的盐，其中各R³¹独立地选自C_1-3烷基、C_1-3卤烷基、卤基、CN、OR^a31和NR^c31R^d31。27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3 and 9 to 26, wherein each R³¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, halo, CN, OR^a31 and NR^c31 R^d31 .28.如权利要求1至3和9至27中任一项所述的化合物或其药学上可接受的盐，其中R³³选自C_2-3烷基、C_1-3卤烷基、4元杂环烷基、6元杂环烷基、卤基和CN；其中所述C_2-3烷基、4元杂环烷基和6元杂环烷基各自任选地被1或2个独立地选自R³¹的取代基取代。28. A compound as described in any one of claims 1 to 3 and 9 to 27, or a pharmaceutically acceptable salt thereof, wherein R³³ is selected from C_2-3 alkyl, C_1-3 haloalkyl, 4-membered heterocycloalkyl, 6-membered heterocycloalkyl, halo and CN; wherein the C_2-3 alkyl, 4-membered heterocycloalkyl and 6-membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R³¹ .29.如权利要求1至3和9至28中任一项所述的化合物或其药学上可接受的盐，其中各R⁶⁰独立地选自C_1-3烷基、C_1-3卤烷基、4元至6元杂环烷基、5元至6元杂芳基、卤基、D、CN、OR^a60、C(O)R^b60、C(O)NR^c60R^d60、NR^c60C(O)R^b60、C(O)OR^a60、NR^c60C(O)OR^a60、NR^c60R^d60、NR^c60S(O)₂R^b60和S(O)₂R^b60；其中所述C_1-3烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代。29. A compound as described in any one of claims 1 to 3 and 9 to 28, or a pharmaceutically acceptable salt thereof, wherein each R⁶⁰ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, halo, D, CN, OR^a60 , C(O)R^b60 , C(O)NR^c60 R^d60 , NR^c60 C(O)R^b60 , C(O)OR^a60 , NR^c60 C(O)OR^a60 , NR^c60 R^d60 , NR^c60 S(O)₂ R^b60 and S(O)₂ R^b60 ; wherein the C_1-3 alkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1 or 2 substituents independently selected from R⁶¹ .30.如权利要求1至3和9至29中任一项所述的化合物或其药学上可接受的盐，其中各R⁶¹独立地选自C_1-3烷基、C_1-3卤烷基和卤基。30. The compound of any one of claims 1 to 3 and 9 to 29, or a pharmaceutically acceptable salt thereof, wherein each R⁶¹ is independently selected from C_1-3 alkyl, C_1-3 haloalkyl and halo.31.如权利要求1、2和9至30中任一项所述的化合物或其药学上可接受的盐，其中R^f3为C_1-3卤烷基。31. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1, 2 and 9 to 30, wherein^Rf3 is_C1-3 haloalkyl.32.如权利要求1、2和9至30中任一项所述的化合物或其药学上可接受的盐，其中R^f3为R^f3-a。32. The compound or pharmaceutically acceptable salt thereof of any one of claims 1, 2, and 9 to 30, wherein^Rf3 is^Rf3 -a.33.如权利要求1、2和9至30中任一项所述的化合物或其药学上可接受的盐，其中R^f3为R^f3-b。33. The compound or pharmaceutically acceptable salt thereof of any one of claims 1, 2, and 9 to 30, wherein^Rf3 is^Rf3 -b.34.如权利要求1、2、9至30、32和33中任一项所述的化合物或其药学上可接受的盐，其中R^x为H。34. The compound of any one of claims 1, 2, 9 to 30, 32 and 33, or a pharmaceutically acceptable salt thereof, wherein^Rx is H.35.如权利要求1、2、9至30、32和33中任一项所述的化合物或其药学上可接受的盐，其中R^x为C_1-2烷基。35. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1, 2, 9 to 30, 32 and 33, wherein^Rx is_C1-2 alkyl.36.如权利要求1至5和9至35中任一项所述的化合物或其药学上可接受的盐，其中各R^a60、R^b60、R^c60和R^d60独立地选自H、C_1-3烷基、C_1-3卤烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基；其中所述C_1-3烷基、C_3-6环烷基、4元至6元杂环烷基和5元至6元杂芳基各自任选地被1或2个独立地选自R⁶¹的取代基取代；或36. A compound as described in any one of claims 1 to 5 and 9 to 35, or a pharmaceutically acceptable salt thereof, wherein each of^Ra60 ,^Rb60 ,^Rc60 and^Rd60 is independently selected from H,_C1-3 alkyl,_C1-3 haloalkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; wherein the_C1-3 alkyl,_C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from^R61 ; or连接至同一N原子的任何R^c60和R^d60与其所连接的N原子一起形成4元、5元或6元杂环烷基，其任选地被1或2个独立地选自R⁶¹的取代基取代。Any R^c60 and R^d60 attached to the same N atom together with the N atom to which they are attached form a 4-membered, 5-membered or 6-membered heterocycloalkyl group which is optionally substituted with 1 or 2 substituents independently selected from R⁶¹ .37.如权利要求1所述的化合物，其中所述式I化合物选自37. The compound of claim 1, wherein the compound of formula I is selected from3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7-氯-3-羟基萘-1-基)-6-氟-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7-chloro-3-hydroxynaphthalen-1-yl)-6-fluoro-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(5,7-二氟-1H-吲哚-3-基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(5,7-difluoro-1H-indol-3-yl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(6-氟-5-甲基-1H-吲哚-3-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indol-3-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-((1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-2-基)甲基)噁唑烷-2-酮；3-((1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-2-yl)methyl)oxazolidin-2-one;8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-2,8-二甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-2,8-dimethyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-7-(8-氰基萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-8-甲腈；1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-7-(8-cyanonaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinoline-8-carbonitrile;8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;3-(7-(苯并[b]噻吩-3-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(7-(Benzo[b]thiophen-3-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(((S)-1-(二甲基氨基)丙烷-2-基)氧基)-6-氟-7-(7-氟萘-1-基)-2-((2-氧代吡咯烷-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(((S)-1-(dimethylamino)propan-2-yl)oxy)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((2-oxopyrrolidin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;8-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-6-氟-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-6-fluoro-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-4-((3-氟-1-甲基氮杂环丁烷-3-基)甲氧基)-7-(3-羟基萘-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基丙酰胺；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-4-((3-fluoro-1-methylazetidin-3-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpropanamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-2-甲基-4-(5-甲基吡嗪-2-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-methyl-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-甲基-2-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-methyl-2-((4-methyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯-5-羟基苯基)-4-乙氧基-6-氟-2-((4-异丙基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichloro-5-hydroxyphenyl)-4-ethoxy-6-fluoro-2-((4-isopropyl-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-(3-(二甲基氨基)-3-甲基氮杂环丁烷-1-基)-6-氟-7-(7-氟萘-1-基)-2-((3-氧代-N-吗啉基)甲基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((3-oxo-N-morpholinyl)methyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-4-乙氧基-6-氟-7-(3-羟基萘-1-基)-2-(1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-(1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((内)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(3-羟基萘-1-基)-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-2-(吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((endo)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-2-(pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(7,8-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(7,8-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(2-(3-(氮杂环丁烷-1-基)-3-氧代丙基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(6,7-二氟萘-1-基)-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(2-(3-(azetidin-1-yl)-3-oxopropyl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(6,7-difluoronaphthalen-1-yl)-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;1-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)异喹啉-8-甲腈；1-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)isoquinoline-8-carbonitrile;8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1-naphthocarbonitrile;8-(1-((2S,4S)-1-乙酰基-2-(氰基甲基)哌啶-4-基)-8-氯-6-氟-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡唑并[4,3-c]喹啉-7-基)-1-萘甲腈；8-(1-((2S,4S)-1-acetyl-2-(cyanomethyl)piperidin-4-yl)-8-chloro-6-fluoro-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrazolo[4,3-c]quinolin-7-yl)-1-naphthocarbonitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟-3-羟基萘-1-基)-2-甲基-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-2-甲基-4-((S)-1-((S)-1-甲基吡咯烷-2-基)乙氧基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.38.如权利要求1所述的化合物，其中所述式I化合物选自：38. The compound of claim 1, wherein the compound of formula I is selected from:(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)-N,N-二甲基吡咯烷-1-甲酰胺；以及(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-N,N-dimethylpyrrolidine-1-carboxamide; and(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-甲基苯基)-8-(2-氰基乙基)-6-氟-4-(1H-1,2,4-三唑-1-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-4-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.39.如权利要求1所述的化合物，其中所述式I化合物选自：39. The compound of claim 1, wherein the compound of formula I is selected from:(1S,3R,5S)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯；(1S,3R,5S)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-(5-oxo-1,2,3,5-tetrahydroindolizin-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2-氯-3-氟苯基)-2-((R)-1-(环丙烷羰基)吡咯烷-2-基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2-chloro-3-fluorophenyl)-2-((R)-1-(cyclopropanecarbonyl)pyrrolidin-2-yl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;8-(2-((R)-1-乙酰基吡咯烷-2-基)-1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-8-甲基-4-(2-甲基吡啶-4-基)-1H-吡咯并[3,2-c]喹啉-7-基)-1,2,3,4-四氢萘-1-甲腈；8-(2-((R)-1-acetylpyrrolidin-2-yl)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-8-methyl-4-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]quinolin-7-yl)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile;5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-8-(2-氰基乙基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺；5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-8-(2-cyanoethyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪-2-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(5-氟-6-(甲基氨甲酰基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸乙酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid ethyl ester;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-4-(甲基-d3)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-4-(methyl-d3)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-2-((R)-1-(3,3-二氟氮杂环丁烷-1-羰基)吡咯烷-2-基)-6-氟-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-2-((R)-1-(3,3-difluoroazetidine-1-carbonyl)pyrrolidin-2-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-6-氟-4-(5-甲基吡嗪-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-6-fluoro-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-6-氟-7-(7-氟萘-1-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-N-甲基吡啶甲酰胺；5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N-methylpicolinamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-6-氟-7-(7-氟萘-1-基)-4-(5-甲基吡嗪-2-基)-2-((R)-1-(3-氧代-N-吗啉基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(5-methylpyrazin-2-yl)-2-((R)-1-(3-oxo-N-morpholinyl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;(1R,3R,5R)-3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(6-(二甲基氨甲酰基)吡啶-3-基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)-2-氮杂双环[3.1.0]己烷-2-甲酸甲酯；(1R,3R,5R)-3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(6-(dimethylcarbamoyl)pyridin-3-yl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-2-((1R,3R,5R)-2-(环丙烷羰基)-2-氮杂双环[3.1.0]己烷-3-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；以及3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile; and3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.40.如权利要求1所述的化合物，其中所述式I化合物选自：40. The compound of claim 1, wherein the compound of formula I is selected from:(2R,4S)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-4-氟吡咯烷-1-甲酸甲酯；(2R,4S)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-4-fluoropyrrolidine-1-carboxylic acid methyl ester;(2R,5R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)-5-甲基吡咯烷-1-甲酸甲酯；(2R,5R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)-5-methylpyrrolidine-1-carboxylic acid methyl ester;(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-3-氯-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(6-(2-羟基丙烷-2-基)吡啶-3-基)-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-3-chloro-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;4-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(2-氧代吡嗪-1(2H)-基)乙基)-1H-吡咯并[3,2-c]喹啉-4-基)-2-氟-N-甲基苯甲酰胺；4-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(2-oxopyrazin-1(2H)-yl)ethyl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-2-fluoro-N-methylbenzamide;((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)氨基甲酸甲酯；N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-2,2-二氟乙酰胺；Methyl ((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)carbamate; N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-2,2-二氟乙酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-2,2-difluoroacetamide;(2S)-N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)四氢呋喃-2-甲酰胺；(2S)-N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)tetrahydrofuran-2-carboxamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)环丙烷磺酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)cyclopropanesulfonamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)噻唑-4-甲酰胺；以及N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)thiazole-4-carboxamide; andN-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-N-甲基环丙烷甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-N-methylcyclopropanecarboxamide;或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.41.如权利要求1所述的化合物，其中所述式I化合物选自41. The compound of claim 1, wherein the compound of formula I is selected fromN-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-甲基环丙烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-methylcyclopropane-1-carboxamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-2-((1R,3R,5R)-2-(1-甲基环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-2-((1R,3R,5R)-2-(1-methylcyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-2-((1R,3R,5R)-2-(1-氟环丙烷-1-羰基)-2-氮杂双环[3.1.0]己烷-3-基)-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((1R,3R,5R)-2-(1-fluorocyclopropane-1-carbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丙烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclopropane-1-carboxamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-(1-羟基乙基)-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-1-氟环丁烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-(1-hydroxyethyl)-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-1-fluorocyclobutane-1-carboxamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(3-氯-2-甲基苯基)-2-(1-(2,6-二甲基-3-氧代-2,3-二氢哒嗪-4-基)乙基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(3-chloro-2-methylphenyl)-2-(1-(2,6-dimethyl-3-oxo-2,3-dihydropyridazin-4-yl)ethyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)嘧啶-4-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyrimidine-4-carboxamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)哒嗪-3-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)pyridazine-3-carboxamide;N-((1R)-1-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-4-甲基-1H-吡咯并[3,2-c]喹啉-2-基)乙基)-3,3-二氟氮杂环丁烷-1-甲酰胺；N-((1R)-1-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-2-yl)ethyl)-3,3-difluoroazetidine-1-carboxamide;3-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-7-(2,3-二氯苯基)-6-氟-4-甲基-2-((R)-1-((1-甲基-1H-吡唑-4-基)氨基)乙基)-1H-吡咯并[3,2-c]喹啉-8-基)丙腈；3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-2-((R)-1-((1-methyl-1H-pyrazol-4-yl)amino)ethyl)-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile;5-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-6-氟-2-((R)-1-(1-氟环丙烷-1-羰基)吡咯烷-2-基)-1H-吡咯并[3,2-c]喹啉-4-基)-N,N-二甲基吡啶甲酰胺；以及5-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-6-fluoro-2-((R)-1-(1-fluorocyclopropane-1-carbonyl)pyrrolidin-2-yl)-1H-pyrrolo[3,2-c]quinolin-4-yl)-N,N-dimethylpicolinamide; and(2R)-2-(1-((1R,4R,5S)-2-氮杂双环[2.1.1]己烷-5-基)-8-(2-氰基乙基)-7-(2,3-二氯苯基)-4-(4-((二甲基氨基)甲基)-2,3-二氟苯基)-6-氟-1H-吡咯并[3,2-c]喹啉-2-基)吡咯烷-1-甲酸甲酯；(2R)-2-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-8-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-4-(4-((dimethylamino)methyl)-2,3-difluorophenyl)-6-fluoro-1H-pyrrolo[3,2-c]quinolin-2-yl)pyrrolidine-1-carboxylic acid methyl ester;或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.42.一种药物组合物，其包含如权利要求1至41中任一项所述的化合物或其药学上可接受的盐和至少一种药学上可接受的载剂或赋形剂。42. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.43.一种抑制KRAS活性的方法，所述方法包括使如权利要求1至41中任一项所述的化合物或其药学上可接受的盐或如权利要求42所述的组合物与KRAS接触。43. A method of inhibiting KRAS activity, the method comprising contacting the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or the composition of claim 42, with KRAS.44.如权利要求43所述的方法，其中所述接触包括向患者施用所述化合物。44. The method of claim 43, wherein said contacting comprises administering said compound to a patient.45.一种治疗与抑制KRAS相互作用相关的疾病或病症的方法，所述方法包括向有需要的患者施用治疗有效量的如权利要求1至41中任一项所述的化合物或其药学上可接受的盐，或如权利要求42所述的组合物。45. A method of treating a disease or condition associated with inhibition of KRAS interaction, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 41, or a composition as described in claim 42.46.一种治疗与抑制含有G12D突变的KRAS蛋白相关的疾病或病症的方法，所述方法包括向有需要的患者施用治疗有效量的如权利要求1至41中任一项所述的化合物或其药学上可接受的盐，或如权利要求42所述的组合物。46. A method for treating a disease or condition associated with inhibition of a KRAS protein containing a G12D mutation, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 41, or a composition as described in claim 42.47.一种用于治疗患者的癌症的方法，所述方法包括向所述患者施用治疗有效量的如权利要求1至41中任一项所述的化合物或其药学上可接受的盐，或如权利要求42所述的组合物。47. A method for treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, or a composition as claimed in claim 42.48.如权利要求47所述的方法，其中所述癌症选自癌瘤、血液癌、肉瘤和神经胶质母细胞瘤。48. The method of claim 47, wherein the cancer is selected from the group consisting of carcinoma, hematological cancer, sarcoma, and glioblastoma.49.如权利要求48所述的方法，其中所述血液癌选自骨髓增生性赘瘤、骨髓发育不良综合征、慢性和幼年型粒单核细胞白血病、急性骨髓白血病、急性淋巴细胞性白血病和多发性骨髓瘤。49. The method of claim 48, wherein the blood cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemias, acute myeloid leukemias, acute lymphocytic leukemias, and multiple myeloma.50.如权利要求48所述的方法，其中所述癌瘤选自胰腺、结肠直肠、肺、膀胱、胃、食道、乳房、头颈部、宫颈、皮肤和甲状腺。50. The method of claim 48, wherein the carcinoma is selected from the group consisting of pancreatic, colorectal, lung, bladder, stomach, esophagus, breast, head and neck, cervix, skin, and thyroid.51.如权利要求46所述的方法，其中所述疾病或病症为免疫或发炎病症。51. The method of claim 46, wherein the disease or disorder is an immune or inflammatory disorder.52.如权利要求51所述的方法，其中所述免疫或发炎病症是由KRAS体细胞突变引起的Ras相关淋巴增生性病症和幼年型粒单核细胞白血病。52. The method of claim 51, wherein the immune or inflammatory disorder is Ras-associated lymphoproliferative disorder and juvenile myelomonocytic leukemia caused by somatic mutations in KRAS.