CN110407854B - new tetracyclic compounds - Google Patents

Abstract

The present invention relates to novel tetracyclic compounds, wherein the tetracyclic compounds have the structure shown in formula (III), which are useful as bromodomain and extra-terminal (BET) inhibitors, their synthesis and their use in the treatment of diseases. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of preparing these compounds, and methods of treating diseases and conditions where inhibition of one or more BET bromodomains provides a benefit.

Description

Translated fromChinese

新的四环化合物new tetracyclic compounds

技术领域technical field

本发明涉及式I所示的作为溴域和额外终端(BET)抑制剂的一些新的四环化合物(式I)，它们的合成及治疗疾病的应用。更具体地，本发明涉及用作BET抑制剂的稠合的杂环衍生物，制备这些化合物的方法和抑制一种或多种BET溴域提供益处的治疗疾病和病症的方法。The present invention relates to some novel tetracyclic compounds (formula I) represented by formula I as bromodomain and extra terminal (BET) inhibitors, their synthesis and their use in the treatment of diseases. More particularly, the present invention relates to fused heterocyclic derivatives useful as BET inhibitors, methods of making these compounds and methods of treating diseases and disorders in which inhibition of one or more BET bromodomains provides benefit.

背景技术Background technique

几种生理过程可能有助于表观遗传调控，包括DNA甲基化，非编码RNA介导的支架(scaff醇ding)和复合物形成，以及组蛋白修饰。组蛋白修饰是与组蛋白的翻译后共价修饰相关的过程，组蛋白显著影响相关DNA被转录的能力。赖胺酸乙酰化是一种翻译后修饰，与细胞讯号传导和疾病生物学有广泛的相关性。调节组蛋白中赖胺酸乙酰化的酶被称为“撰写者”或组蛋白乙酰转移酶(HATs)，并且调节组蛋白中的赖胺酸脱乙酰的酶被称为“橡皮擦”或组蛋白脱乙酰酶(HDAC)。溴结构域(溴domains，BRDs)，表观遗传标记的“读者”，特别地识别组蛋白尾巴上的ε-N-乙酰基赖胺酸(Kac)残基。Several physiological processes may contribute to epigenetic regulation, including DNA methylation, noncoding RNA-mediated scaffolding and complex formation, and histone modifications. Histone modifications are processes associated with the post-translational covalent modification of histones, which significantly influence the ability of the associated DNA to be transcribed. Lysine acetylation is a post-translational modification with broad relevance to cell signaling and disease biology. Enzymes that regulate lysine acetylation in histones are called "writers" or histone acetyltransferases (HATs), and enzymes that regulate lysine deacetylation in histones are called "erasers" or histones. protein deacetylase (HDAC). Bromodomains (BRDs), "readers" of epigenetic marks, specifically recognize ε-N-acetyllysine (Kac) residues on histone tails.

BRD是由四个α-螺旋(αZ、αA、αB和αC)组成的保守的110胺基酸结构域，其包含左手束(bundle)(S.Mujtaba,L.Zeng,MMZhou,Oncogene,2007(26),5521-5527)。α-螺旋通过两个环区域(ZA和BC)连接在一起并形成与核小体组蛋白中的乙酰化赖胺酸相互作用的表面(C.Dhalluin,J.E.Carlson,L.Zengetal,Nature,1999(399),491-496)。基于结构/序列相似性，存在来自人的46种已知的含溴结构域的蛋白质，其跨越8个家族。其中，溴结构域和额外末端结构域(BET)识别组蛋白H3和H4中的乙酰化赖胺酸残基。BET家族，包含BRD2、BRD3、BRD4和BRDT四个成员，共享两个N-末端溴结构域和额外的C-末端结构域(ET)，表现出高度的序列保守性。据报导，沿着活跃转录的基因，BRD2和BRD3与组蛋白结合，并且可能参与促进转录延伸(Leroyetal.,M醇.Cell,200830(1),51-60)。BRD4似乎参与了正转录延伸因子复合物(pTEF-I3)的募集，其在RNA聚合酶调节转录和增加转录输出中起重要作用(Hargreavesetal.,Cell,2009138(1):1294145)。与普遍表现的其他三种BET蛋白不同，BRDT表现通常是睪丸特异性的(M.H.J酮setal,Genomics,1997(45),529-534)，BRDT对于精子发生是必须的(E.Shangetal,Development,2007(134),3507-3515)。BET蛋白与乙酰化组蛋白的结合导致将BET蛋白募集到基因的增强子和启动子区域以进行活性转录。由此，它们与共活化因子、抑制因子、转录因子和转录机制相互作用以形成蛋白质复合物并影响靶基因转录(A.Deyetal,Proc.Natl.Acad.Sci,U.S.A.,2003(100),8758-8763)。BET蛋白虽然具有相似的结构并且通常增强转录，但是基于它们的结合配体调节不同的过程，这通常是组织特异性的。BRD is a conserved 110-amino acid domain consisting of four α-helices (αZ, αA, αB, and αC) that contains a left-handed bundle (S. Mujtaba, L. Zeng, MM Zhou, Oncogene, 2007 ( 26), 5521-5527). Alpha-helices are linked together by two loop regions (ZA and BC) and form a surface that interacts with acetylated lysines in nucleosomal histones (C. Dhalluin, J.E. Carlson, L. Zengetal, Nature, 1999 (399), 491-496). Based on structural/sequence similarity, there are 46 known bromodomain-containing proteins from humans that span 8 families. Among them, the bromodomain and extra terminal domain (BET) recognize acetylated lysine residues in histones H3 and H4. The BET family, comprising four members BRD2, BRD3, BRD4 and BRDT, shares two N-terminal bromodomains and an additional C-terminal domain (ET), showing a high degree of sequence conservation. Along actively transcribed genes, BRD2 and BRD3 have been reported to bind to histones and may be involved in promoting transcription elongation (Leroy et al., M. Alcohol. Cell, 2008 30(1), 51-60). BRD4 appears to be involved in the recruitment of the positive transcription elongation factor complex (pTEF-I3), which plays an important role in RNA polymerase regulation of transcription and increased transcriptional output (Hargreaves et al., Cell, 2009138(1):1294145). Unlike the other three BET proteins that are commonly expressed, BRDT expression is usually testicular-specific (M.H.J Ketones et al, Genomics, 1997(45), 529-534), and BRDT is necessary for spermatogenesis (E. Shang et al, Development, 2007(134), 3507-3515). Binding of BET proteins to acetylated histones results in the recruitment of BET proteins to enhancer and promoter regions of genes for active transcription. As such, they interact with co-activators, repressors, transcription factors and transcription machinery to form protein complexes and affect target gene transcription (A. Deyetal, Proc. Natl. Acad. Sci, U.S.A., 2003(100), 8758- 8763). Although BET proteins have similar structures and generally enhance transcription, they regulate different processes based on their binding ligands, which are often tissue-specific.

据认为，BET蛋白主要大体上是通过定位于病理相关基因的超级增强子(SEs)并驱动它们的表现来介导它们在疾病发病机制和进展中的作用(M.A.Daws酮tal,Nature,2011(478),529-533；B.Chapuyetal,CancerCell,2013(24),777-790)。在癌症中，SEs富集于癌基因如MYC、RUNX1、FOSL2、CCND1、MCL1和BCL2L1(B.Chapuyetal.,CancerCell,2013(24),777-790；J.Loven,Cell,2013(153),320-334；W.A.Whyteetal.,Cell,2013(153),307-319；D.Hniszetal.,Cell,2013(155),934-947)。抑制BET蛋白已经成为治疗人类疾病的有希望的靶标，这些疾病包括病毒学、心衰、炎症、中枢神经系统(CNS)疾病和多种癌症(J.M.Sahnietal.,Pharmac醇.Res.,2017,1-21；P.An和etal.,Cell,2013(154),569-582；C.-Y.Wangetal.,TrendsBiochem.Sci,2015(40),468-479；A.Stathisetal.,CancerDiscovery,2017,8(1),1-13)。在临床开发中报导的小分子BET抑制剂包括RVX-208、GSK-525762A、GSK2820151、OTX-015、CPI-0610、TEN-010/RO6870810、ABBV-075/ABBV-744、BI894999、BMS-986158、INCB054329/INCB057643、ZEN-3694、GS-5829、AZD5153以及Celgene的抑制剂。需要产生比现有BET抑制剂具有改进性质的其他BET抑制剂，例如，改善活性、安全性、药代动力学和/或药物动力学。It is believed that BET proteins mediate their role in disease pathogenesis and progression primarily by localizing to super-enhancers (SEs) of pathologically-related genes and driving their expression (M.A. Daws et al., Nature, 2011 ( 478), 529-533; B. Chapuy et al, Cancer Cell, 2013(24), 777-790). In cancer, SEs are enriched in oncogenes such as MYC, RUNX1, FOSL2, CCND1, MCL1 and BCL2L1 (B. Chapuy et al., Cancer Cell, 2013(24), 777-790; J. Loven, Cell, 2013(153), 320-334; W.A. Whyte et al., Cell, 2013(153), 307-319; D. Hnisze et al., Cell, 2013(155), 934-947). Inhibition of BET proteins has emerged as a promising target for the treatment of human diseases including virology, heart failure, inflammation, central nervous system (CNS) diseases and various cancers (J.M.Sahnietal., Pharmac. Res., 2017, 1 -21; P. An and et al., Cell, 2013(154), 569-582; C.-Y. Wang et al., TrendsBiochem. Sci, 2015(40), 468-479; A. Stathistal., CancerDiscovery, 2017 , 8(1), 1-13). Small molecule BET inhibitors reported in clinical development include RVX-208, GSK-525762A, GSK2820151, OTX-015, CPI-0610, TEN-010/RO6870810, ABBV-075/ABBV-744, BI894999, BMS-986158, Inhibitors of INCB054329/INCB057643, ZEN-3694, GS-5829, AZD5153 and Celgene. There is a need to create other BET inhibitors with improved properties over existing BET inhibitors, eg, improved activity, safety, pharmacokinetics and/or pharmacokinetics.

发明内容SUMMARY OF THE INVENTION

一方面，提供式I的化合物、其药学上可接受的盐或其立体异构体：In one aspect, there is provided a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

X选自NR₅、O或S；X is selected from NR₅ , O or S;

环A是含1、2或3个选自N、O或S的杂原子的5元杂芳香环或5元酰胺环；Ring A is a 5-membered heteroaromatic or 5-membered amide ring containing 1, 2 or 3 heteroatoms selected from N, O or S;

可连接在相同原子或不同原子的每个R₁、R₂和R₃在每次出现时独立地选自不存在；氢；氘；卤素；-CN；-OH；羧基；-NO₂；-C_1-6烷基；-C_2-6烯基；-C_2-6炔基；-C_1-6烷氧基；

-NH₂；-NH(C_1-6烷基)；-N(C_1-6烷基)₂；-SC_1-6烷基；-SOC_1-6烷基；-SO₂C_1-6烷基；-SO₂NH₂；-SO₂NHC_1-6烷基；-SO₂N(C_1-6烷基)₂；-COC_1-6烷基；-CONH₂；-CONHC_1-6烷基；-CON(C_1-6烷基)₂；-P(O)H₂；-P(O)HC_1-6烷基；-P(O)(C_1-6烷基)₂；3-8元碳环；含1、2或3个选自N、O或S的杂原子的3-8元杂环；6-10元芳基；或含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；或Each of R₁ , R₂ and R₃ , which may be attached to the same atom or to a different atom, is independently at each occurrence selected from absent; hydrogen; deuterium; halogen; -CN; -OH; carboxyl; -NO₂ ;- -C_1-6 alkyl; -C_2-6 alkenyl; -C_2-6 alkynyl; -C_1-6 alkoxy;

-NH₂ ; -NH(C_1-6 alkyl); -N(C_1-6 alkyl)₂ ; -SC_1-6 alkyl; -SOC_1-6 alkyl; -SO₂ C_1-6 -SO₂ NH₂ ; -SO₂ NHC_1-6 alkyl; -SO₂ N(C_1-6 alkyl)₂ ; -COC_1-6 alkyl; -CONH₂ ; -CONHC_1-6 Alkyl; -CON(C_1-6 alkyl)_{2 ;} -P(O)H_{2 ;} -P(O)HC_1-6 alkyl; -P(O)(C_1-6 alkyl)₂ ; 3-8 membered carbocycle; 3-8 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 membered aryl; or 1, 2 or 3 membered N 5-10 membered heteroaryl of a heteroatom of , O or S; and each occurrence of R₁ , R₂ and R₃ is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents Substituted or unsubstituted, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 , carboxy,_-NO2 ,_-C1-6 alkyl or -C_1-6 alkoxy; or

R₁和R₂、R₁和R₃或R₂和R₃，与它们分别或共同连接的原子一起形成3-8元碳环，或含1、2或3个选自N、O或S的杂原子的3-8元杂环；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；R₁ and R₂ , R₁ and R₃ or R₂ and R₃ , together with the atoms to which they are attached individually or together, form a 3-8 membered carbocyclic ring, or contain 1, 2 or 3 atoms selected from N, O or S and each such ring system is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, and the Each substituent of is independently selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 , carboxy,_-NO2 ,_-C1-6alkyl , or_-C1-6alkoxy ;

每个R_a、和R_b在每次出现时独立地选自氢、氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；每个R_a、和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each R_a , and R_b at each occurrence is independently selected from hydrogen, deuterium, halogen, -OH, -CN,_-NH2 , carboxy,_-NO2 ,_-C1-6 alkyl, or_{-C1 -6} alkoxy; each of R_a , and R_b is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, and each of said groups are independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0、1、2、3、4、5或6；m is selected from 0, 1, 2, 3, 4, 5 or 6;

R₄选自

R₄ is selected from

每个R_4a和R_4b在每次出现时独立地选自氢；氘；卤素；-CN；-OH；羧基；-NO₂；-C_1-6烷基；-C_2-6烯基；-C_2-6炔基；-C_1-6烷氧基；-NH₂；-NH(C_1-6烷基)；-N(C_1-6烷基)₂；-SC_1-6烷基；-SOC_1-6烷基；-SO₂C_1-6烷基；-SO₂NH₂；-SO₂NHC_1-6烷基；-SO₂N(C_1-6烷基)₂；-COC_1-6烷基；-CONH₂；-CONHC_1-6烷基；-CON(C_1-6烷基)₂；-P(O)H₂；-P(O)HC_1-6烷基；-P(O)(C_1-6烷基)₂；3-8元碳环；含1、2或3个选自N、O或S的杂原子的3-8元杂环；6-10元芳基；或含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；且每个R_4a和R_4b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-NH₂、-CN、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；Each R_4a and R_4b at each occurrence is independently selected from hydrogen; deuterium; halogen; -CN; -OH; carboxyl;_-NO2 ;_-C1-6 alkyl;_-C2-6 alkenyl; -C_2-6 alkynyl; -C_1-6 alkoxy; -NH₂ ; -NH(C_1-6 alkyl); -N(C_1-6 alkyl)₂ ; -SC_1-6 alkane -SOC_1-6 alkyl; -SO₂ C_1-6 alkyl; -SO₂ NH₂ ; -SO₂ NHC_1-6 alkyl; -SO₂ N(C_1-6 alkyl)₂ ; -COC_1-6 alkyl; -CONH₂ ; -CONHC_1-6 alkyl; -CON(C_1-6 alkyl)_{2 ;} -P(O)H_{2 ;} -P(O)HC_1-6 alkane -P(O)(C_1-6 alkyl)₂ ; 3-8 membered carbocycle; 3-8 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; 6 -10 membered aryl; or 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; and each_{R4a and R4bat} each occurrence is optionally 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH,_-NH2 , -CN , carboxyl, -NO₂ , -C_1-6 alkyl or -C_1-6 alkoxy;

R₅在每次出现时独立地选自氢；氘；卤素；-CN；-OH；羧基；-NO₂；-C_1-6烷基；-C_2-6烯基；-C_2-6炔基；-C_1-6烷氧基；

-NH₂；-NH(C_1-6烷基)；-N(C_1-6烷基)₂；-SC_1-6烷基；-SOC_1-6烷基；-SO₂C_1-6烷基；-SO₂NH₂；-SO₂NHC_1-6烷基；-SO₂N(C_1-6烷基)₂；-COC_1-6烷基；-CONH₂；-CONHC_1-6烷基；-CON(C_1-6烷基)₂；-P(O)H₂；-P(O)HC_1-6烷基；-P(O)(C_1-6烷基)₂；3-8元碳环；含1、2或3个选自N、O或S的杂原子的3-8元杂环；6-10元芳基；或含1、2或3个选自N、O或S的杂原子的5-10元杂芳基；每个R₅在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；R₅ is independently selected at each occurrence from hydrogen; deuterium; halogen; -CN; -OH; carboxy; -NO₂ ; -C_1-6 alkyl; -C_2-6 alkenyl; -C_2-6 Alkynyl; -C_1-6 alkoxy;

-NH₂ ; -NH(C_1-6 alkyl); -N(C_1-6 alkyl)₂ ; -SC_1-6 alkyl; -SOC_1-6 alkyl; -SO₂ C_1-6 -SO₂ NH₂ ; -SO₂ NHC_1-6 alkyl; -SO₂ N(C_1-6 alkyl)₂ ; -COC_1-6 alkyl; -CONH₂ ; -CONHC_1-6 Alkyl; -CON(C_1-6 alkyl)_{2 ;} -P(O)H_{2 ;} -P(O)HC_1-6 alkyl; -P(O)(C_1-6 alkyl)₂ ; 3-8 membered carbocycle; 3-8 membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 membered aryl; or 1, 2 or 3 membered N 5-10 membered heteroaryl of a heteroatom of , O or S; each R is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4,₅ or 6 substituents, and Each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, -CN,_-NH2 , carboxyl,_-NO2 ,_-C1-6alkyl or_-C1-6alkane Oxygen;

每个R_5a和R_5b在每次出现时独立地选自氢、氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；每个R_5a和R_5b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each R_5a and R_5b is independently selected at each occurrence from hydrogen, deuterium, halogen, -OH, -CN, -NH₂ , carboxy, -NO₂ , -C_1-6 alkyl or -C_{1- 6} alkoxy; each R_5a and R_5b at each occurrence is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is Each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl;

n选自0、1、2、3、4、5或6；n is selected from 0, 1, 2, 3, 4, 5 or 6;

W₁选自氢；氘；卤素；-NH₂；-CN；-OH；羧基；-NO₂；-C_1-6烷基；-C_1-6烷氧基；-C_1-6亚烷基-C_1-6烷氧基；6-10元芳基；含1、2、3或4个选自N、O、S、SO或SO₂的杂原子的5-10元杂芳基；含1、2、3或4个选自N、O、S、SO或SO₂的杂原子的3-8元杂环；或3-8元碳环；且每个W₁在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；W₁ is selected from hydrogen; deuterium; halogen; -NH₂ ; -CN; -OH; carboxyl; -NO₂ ; -C_1-6 alkyl; -C_1-6 alkoxy; -C_1-6 alkylene base-C_1-6 alkoxy; 6-10 membered aryl; 5-10 membered heteroaryl containing 1,₂ , 3 or 4 heteroatoms selected from N, O, S, SO or SO2; 3-8 membered heterocycle containing₁ ,₂ , 3 or 4 heteroatoms selected from N, O, S, SO or SO2; or 3-8 membered carbocycle; and each W1 in each occurrence optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, -CN , -NH₂ , carboxyl, -NO₂ , -C_1-6 alkyl or -C_1-6 alkoxy;

W₂选自氢；氘；卤素；-NH₂；-CN；-OH；羧基；-NO₂；-C_1-6烷基；-C_1-6烷氧基；6-10元芳基；含1、2、3或4个选自N、O、S、SO或SO₂的杂原子的5-10元杂芳基；含1、2、3或4个选自N、O、S、SO或SO₂的杂原子的3-8元杂环；或3-8元碳环，且每个W₂在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；W₂ is selected from hydrogen; deuterium; halogen; -NH₂ ; -CN; -OH; carboxyl; -NO₂ ; -C_1-6 alkyl; -C_1-6 alkoxy; 5-10-membered heteroaryl group containing 1,₂ , 3 or 4 heteroatoms selected from N, O, S, SO or SO2; containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, A 3-8 membered heterocycle of a heteroatom of SO or SO; or a 3-8 membered carbocycle, and each W is optionally substituted at each occurrence with₁ ,₂ , 3, 4, 5, or 6 substituted or unsubstituted, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 , carboxy,_-NO2 ,_-C1-6alkane or -C_1-6 alkoxy;

Z选自氢、氘、卤素、-NH₂、-CN、-OH、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基。Z is selected from hydrogen, deuterium, halogen, -NH₂ , -CN, -OH, carboxyl, -NO₂ , -C_1-6 alkyl or -C_1-6 alkoxy.

在式I的一些实施方式中，其中所述的化合物为式II：In some embodiments of Formula I, wherein the compound is of Formula II:

在式I的一些实施方式中，其中所述的化合物为式III：In some embodiments of Formula I, wherein the compound is of Formula III:

在式I、式II或式III的一些实施方式中，其中可连接在相同原子或不同原子的每个R₁、R₂和R₃在每次出现时独立地选自不存在、氢、氘、卤素、-CN、-OH、-C_1-6烷基、-C_1-6烷氧基、

-NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-SO₂C_1-6烷基、-SO₂NH₂、-SO₂NHC_1-6烷基、-SO₂N(C_1-6烷基)₂、-COC_1-6烷基、-CONH₂、-CONHC_1-6烷基、-CON(C_1-6烷基)₂、-P(O)H₂、-P(O)HC_1-6烷基或-P(O)(C_1-6烷基)₂；且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；或In some embodiments of Formula I, Formula II, or Formula III, wherein each R₁ , R₂ , and R₃ , which may be attached to the same atom or to a different atom, are independently at each occurrence selected from absence, hydrogen, deuterium , halogen, -CN, -OH, -C_1-6 alkyl, -C_1-6 alkoxy,

-NH₂ , -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂ , -SO₂ C_1-6 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-6 Alkyl, -SO₂ N(C_1-6 alkyl)₂ , -COC_1-6 alkyl, -CONH₂ , -CONHC_1-6 alkyl, -CON(C_1-6 alkyl)₂ , - P(O)H₂ , -P(O)HC_1-6 alkyl or -P(O)(C_1-6 alkyl)₂ ; and each R₁ , R₂ and R₃ at each occurrence optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, -CN , -NH₂ , carboxyl, -NO₂ , -C_1-6 alkyl or -C_1-6 alkoxy; or

R₁和R₂、R₁和R₃或R₂和R₃，与它们分别或共同连接的原子一起形成3-6元碳环，或含1、2或3个选自N、O或S的杂原子的3-6元杂环；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、羧基、-NO₂、-C_1-6烷基或-C_1-6烷氧基；R₁ and R₂ , R₁ and R₃ or R₂ and R₃ , together with the atoms to which they are attached individually or together, form a 3-6 membered carbocyclic ring, or contain 1, 2 or 3 atoms selected from N, O or S and each such ring system is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, and the Each substituent of is independently selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 , carboxy,_-NO2 ,_-C1-6alkyl , or_-C1-6alkoxy ;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, -F, -Cl, -Br or_-C1-6 alkyl;

m选自0、1、2、3、4、5或6。m is selected from 0, 1, 2, 3, 4, 5 or 6.

在式I、式II或式III的一些实施方式中，其中可连接在相同原子或不同原子的每个R₁、R₂和R₃在每次出现时独立地选自不存在、氢、氘、-F、-Cl、-Br、-CN、-OH、-C_1-3烷基、-C_1-3烷氧基、

-NH₂、-NH(C_1-3烷基)、-N(C_1-3烷基)₂、-SO₂C_1-3烷基、-SO₂NH₂、-SO₂NHC_1-3烷基、-SO₂N(C_1-3烷基)₂、-COC_1-3烷基、-CONH₂、-CONHC_1-3烷基、-CON(C_1-3烷基)₂、-P(O)H₂、-P(O)HC_1-3烷基或-P(O)(C_1-3烷基)₂；且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、-C_1-3烷基或-C_1-3烷氧基；或In some embodiments of Formula I, Formula II, or Formula III, wherein each R₁ , R₂ , and R₃ , which may be attached to the same atom or to a different atom, are independently at each occurrence selected from absence, hydrogen, deuterium , -F, -Cl, -Br, -CN, -OH, -C_1-3 alkyl, -C_1-3 alkoxy,

-NH₂ , -NH(C_1-3 alkyl), -N(C_1-3 alkyl)₂ , -SO₂ C_1-3 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-3 Alkyl, -SO₂ N(C_1-3 alkyl)₂ , -COC_1-3 alkyl, -CONH₂ , -CONHC_1-3 alkyl, -CON(C_1-3 alkyl)₂ , - P(O)H₂ , -P(O)HC_1-3 alkyl or -P(O)(C_1-3 alkyl)₂ ; and each R₁ , R₂ and R₃ at each occurrence optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen, -OH, -CN , -NH₂ , -C_1-3 alkyl or -C_1-3 alkoxy; or

R₁和R₂、R₁和R₃或R₂和R₃，与它们分别或共同连接的原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，且每个所述杂环在每次出现时含有1或2个选自N或O的杂原子的；每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、-C_1-3烷基或-C_1-3烷氧基；R₁ and R₂ , R₁ and R₃ or R₂ and R₃ , taken together with the atoms to which they are attached separately or together, form a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered carbocycle Heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle, and each such heterocycle contains, in each occurrence, 1 or 2 heteroatoms selected from N or O; each such ring are optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen , -OH, -CN, -NH₂ , -C_1-3 alkyl or -C_1-3 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-3烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-3 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II或式III的一些实施方式中，其中可连接在相同原子或不同原子的每个R₁、R₂和R₃在每次出现时独立地选自不存在、氢、氘、-F、-Cl、-Br、-CN、-OH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、

-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂或-P(O)(CH₃)(CH₂CH₃)；每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基；或In some embodiments of Formula I, Formula II, or Formula III, wherein each R₁ , R₂ , and R₃ , which may be attached to the same atom or to a different atom, are independently at each occurrence selected from absence, hydrogen, deuterium , -F, -Cl, -Br, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,

_-NH2 ,_-NHCH3 , -NHCH2CH3, -NHCH2CH2CH3, -NHCH(_CH3)2 , -N(_CH3)2 , -N_{(CH3)(CH2CH3)} , -SO₂ CH₃ , -SO₂ CH₂ CH₃ , -SO₂ CH₂ CH₂ CH₃ , -SO₂ CH(CH₃ )₂ , -SO₂ NH₂ , -SO₂ NHCH₃ , -SO₂ NHCH₂ CH₃ , -SO₂ NHCH₂ CH₂ CH₃ , -SO₂ NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CH₃ )(CH₂ CH₃ ), -COCH₃ , -COCH₂ CH₃ , -COCH₂ CH₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CONHCH₂ CH₃ , -CONHCH₂ CH₂ CH₃ , -CONHCH (CH₃ )₂ , -CON(CH₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P(O)HCH₂ CH₂ CH₃ , -P(O)HCH(CH₃ )₂ , -P(O)(CH₃ )₂ or -P(O)(CH₃ )(CH₂ CH₃ ); each R₁ , R₂ and R₃ is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, and each of said The radicals at each occurrence are independently selected from deuterium, -F, -Cl, -Br, -OH, -CN,_-NH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , propoxy or isopropoxy; or

R₁和R₂、R₁和R₃或R₂和R₃，与它们分别或共同连接的原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，且每个所述杂环在每次出现时包含1个选自N或O的杂原子；每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。R₁ and R₂ , R₁ and R₃ or R₂ and R₃ , taken together with the atoms to which they are attached separately or together, form a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered carbocycle Heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle, and each of said heterocycles contains at each occurrence 1 heteroatom selected from N or O; is optionally substituted or unsubstituted at the first occurrence with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, -F, - Cl, -Br, -OH, -CN,_-NH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II或式III的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时可连接在相同原子或不同原子的独立地选自不存在、氢、氘、-F、-Cl、-Br、-CN、-OH、-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂、甲氧基、乙氧基、丙氧基、异丙氧基、

-NH₂、-NHCH₃、-NHCD₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CD₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂、-P(O)(CH₃)(CH₂CH₃)；或In some embodiments of Formula I, Formula II, or Formula III, wherein each R₁ , R₂ , and R₃ may be attached to the same atom or a different atom at each occurrence, independently selected from absence, hydrogen, deuterium , -F, -Cl,_-Br , -CN,_-OH ,_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_-CH2CD3 ,_{-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ , -CH(CD₃ )₂ , methoxy, ethoxy, propoxy, isopropoxy,

-NH₂ , -NHCH₃ , -NHCD₃ , -NHCH₂ CH₃ , -NHCH₂ CH₂ CH₃ , -NHCH(CH₃ )₂ , -N(CH₃ )₂ , -N(CD₃ )₂ ,_{-N(CH3)(CH2CH3)} ,_-SO2CH3 ,_-SO2CD3 ,_{-SO2CH2CH3,-SO2CH2CH2CH3,-SO2CH(CH3} )₂ , -SO₂ NH₂ , -SO₂ NHCH₃ , -SO₂ NHCH₂ CH₃ , -SO₂ NHCH₂ CH₂ CH₃ , -SO₂ NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CD₃ )₂ , -SO₂ N(CH₃ )(CH₂ CH₃ ), -COCH₃ , -COCD₃ , -COCH₂ CH₃ , -COCH₂ CH₂ CH₃ , -COCH(CH₃ )₂ , -CONH₂ , -CONHCH₃ , -CONHCD₃ , -CONHCH₂ CH₃ , -CONHCH₂ CH₂ CH₃ , -CONHCH(CH₃ )₂ , -CON(CH₃ )₂ , -CON(CD₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P( O)HCH₂ CH₂ CH₃ , -P(O)HCH(CH₃ )₂ , -P(O)(CH₃ )₂ , -P(O)(CD₃ )₂ , -P(O)(CH₃ ) (CH₂ CH₃ ); or

R₁和R₂、R₁和R₃或R₂和R₃，与它们分别或共同连接的原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，且每个所述杂环在每次出现时包含1个选自N或O的杂原子。R₁ and R₂ , R₁ and R₃ or R₂ and R₃ , taken together with the atoms to which they are attached separately or together, form a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered carbocycle heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle, and each of said heterocycles contains 1 heteroatom selected from N or O at each occurrence.

在式I、式II或式III的一些实施方式中，其中所述的化合物为式IV：In some embodiments of Formula I, Formula II, or Formula III, wherein the compound is of Formula IV:

在式I、式II、式III或IV的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时独立地选自氢、氘、-C_1-6烷基或

且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-C_1-6烷基或-C_1-6烷氧基；In some embodiments of Formula I, Formula II, Formula III, or IV, wherein each R₁ , R₂ and R₃ is independently selected at each occurrence from hydrogen, deuterium, -C_1-6 alkyl or

and each of R₁ , R₂ and R₃ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, halogen, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或IV的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；In some embodiments of Formula I, Formula II, Formula III, or IV, wherein R₁ at each occurrence is independently selected from -C_1-6 alkyl, optionally, said -C_1-6 alkyl substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen or_-C1-6 alkyl;

每个R₂和R₃选自氢、氘、-C_1-6烷基或

Each R and_R is selected from_hydrogen , deuterium, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或IV的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of Formula I, Formula II, Formula III, or IV, wherein R₁ at each occurrence is independently selected from -C_1-6 alkyl, optionally, said -C_1-6 alkyl is substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is at each occurrence independently selected from deuterium or -F;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

m选自0或1；m is selected from 0 or 1;

R₃选自氢、氘或-C_1-6烷基。R₃ is selected from hydrogen, deuterium or -C_1-6 alkyl.

在式I、式II、式III或IV的一些实施方式中，其中R₁选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of formula I, formula II, formula III or IV, wherein R₁ is selected from -C_1-3 alkyl, said -C_1-3 alkyl optionally 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

R₂为

_R2 is

每个R_a和R_b在每次出现时独立地选自-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from -C_1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F;

m选自0或1；m is selected from 0 or 1;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或IV的一些实施方式中，其中R₁选自甲基；乙基；丙基；异丙基；甲基氘或-F取代的；乙基氘或-F取代的；丙基氘或-F取代的；或异丙基氘或-F取代的；In some embodiments of Formula I, Formula II, Formula III, or IV, wherein R₁ is selected from methyl; ethyl; propyl; isopropyl; methyl deuterium or -F substituted; ethyl deuterium or -F substituted; propyldeuterium or -F substituted; or isopropyldeuterium or -F substituted;

R₂is

R₂ is

每个R_a和R_b在每次出现时独立地选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基；Each_Ra and_Rb at each occurrence is independently selected from methyl; ethyl; propyl; isopropyl; deuterium or -F substituted methyl; deuterium or -F substituted ethyl; deuterium or -F F substituted propyl; or deuterium or -F substituted isopropyl;

m选自0或1；m is selected from 0 or 1;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或式IV的一些实施方式中，其中R₁选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；In some embodiments of Formula I, Formula_II , Formula_III , or Formula IV, wherein R1 is selected from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 , -CH₂ CD₃ , -CH₂ CH₂ F, -CH₂ CHF₂ , -CH₂ CF₃ , -CH₂ CH₂ CH₃ , -CH₂ CH₂ CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ;

R₂为

_R2 is

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ ;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或IV的一些实施方式中，其中R₁为-CH₃；In some embodiments of Formula I, Formula II, Formula III, or IV, wherein R₁ is -CH₃ ;

R₂为

_R2 is

R₃为氢。R₃ is hydrogen.

在式I、式II或式III的一些实施方式中，其中所述的化合物为式V：In some embodiments of Formula I, Formula II, or Formula III, wherein the compound is of Formula V:

在式I、式II、式III或式V的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时独立地选自氢、氘、-C_1-6烷基或

且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-C_1-6烷基或-C_1-6烷氧基；In some embodiments of Formula I, Formula II, Formula III, or Formula V, wherein each R₁ , R₂ , and R₃ are at each occurrence independently selected from hydrogen, deuterium, -C_1-6 alkyl or

and each of R₁ , R₂ and R₃ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, halogen, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘、-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium, -C_1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或式V的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of Formula I, Formula II, Formula III, or Formula V, wherein R₁ at each occurrence is independently selected from -C_1-6alkyl , optionally is substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently selected at each occurrence from deuterium or -F;

每个R₂和R₃选自氢、氘、-C_1-6烷基或

Each R and_R is selected from_hydrogen , deuterium, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式V的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；In some embodiments of Formula I, Formula II, Formula III, or Formula V, wherein R₁ at each occurrence is independently selected from -C_1-6alkyl , optionally is substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is independently at each occurrence selected from deuterium, halogen or_-C1-6alkyl ;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自氢、氘、-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium, -C_1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

m选自0或1；m is selected from 0 or 1;

R₃选自氢、氘或-C_1-6烷基。R₃ is selected from hydrogen, deuterium or -C_1-6 alkyl.

在式I、式II、式III或式V的一些实施方式中，其中R₁选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of Formula I, Formula II, Formula III, or Formula V, wherein R₁ is selected from -C_1-3 alkyl, optionally by₁ , 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

R₂为

_R2 is

每个R_a和R_b在每次出现时独立地选自-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from -C_1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F;

m选自0或1；m is selected from 0 or 1;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或式V的一些实施方式中，其中R₁选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基；In some embodiments of Formula_I , Formula II, Formula III, or Formula V, wherein R1 is selected from methyl; ethyl; propyl; isopropyl; deuterium or -F substituted methyl; deuterium or -F substituted ethyl; propyl substituted with deuterium or -F; or isopropyl substituted with deuterium or -F;

R₂为

_R2 is

每个R_a和R_b在每次出现时独立地选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基；Each_Ra and_Rb at each occurrence is independently selected from methyl; ethyl; propyl; isopropyl; deuterium or -F substituted methyl; deuterium or -F substituted ethyl; deuterium or -F F substituted propyl; or deuterium or -F substituted isopropyl;

m选自0或1；m is selected from 0 or 1;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或式V的一些实施方式中，其中R₁选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；In some embodiments of Formula I, Formula_II , Formula_III , or Formula V, wherein R1 is selected from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 , -CH₂ CD₃ , -CH₂ CH₂ F, -CH₂ CHF₂ , -CH₂ CF₃ , -CH₂ CH₂ CH₃ , -CH₂ CH₂ CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ;

R₂为

_R2 is

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ ;

R₃选自氢或氘。_R3 is selected from hydrogen or deuterium.

在式I、式II、式III或式V的一些实施方式中，其中R₁为-CH₃；In some embodiments of Formula I, Formula II, Formula III, or Formula V, wherein R₁ is -CH₃ ;

R₂为

_R2 is

R₃为氢。R₃ is hydrogen.

在式I、式II或III的一些实施方式中，其中所述的化合物为式VI：In some embodiments of Formula I, Formula II or III, wherein the compound is of Formula VI:

在式I、式II、式III或式VI的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自氢、氘、-C_1-6烷基或

且每个R₁和R₂在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-C_1-6烷基或-C_1-6烷氧基；In some embodiments of Formula I, Formula II, Formula III, or Formula VI, wherein each R₁ and R₂ are at each occurrence independently selected from hydrogen, deuterium, -C_1-6 alkyl or

and each R1 and R2 is optionally substituted or unsubstituted with₁ ,₂ , 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is at each occurrence independently selected from deuterium, halogen, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘、-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium, -C_1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或VI的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；In some embodiments of Formula I, Formula II, Formula III, or VI, wherein R₁ at each occurrence is independently selected from -C_1-6 alkyl, said C_1-6 alkyl optionally being 1, 2, 3, 4, 5, or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen, or_-C1-6 alkyl;

R₂选自氢、氘、-C_1-6烷基或

R₂ is selected from hydrogen, deuterium, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或VI的一些实施方式中，其中R₁在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of Formula I, Formula II, Formula III, or VI, wherein R₁ at each occurrence is independently selected from -C_1-6 alkyl, optionally, said -C_1-6 alkyl is substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is at each occurrence independently selected from deuterium or -F;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自氢、氘、-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium, -C_1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或VI的一些实施方式中，其中R₁选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；In some embodiments of formula I, formula II, formula III or VI, wherein R₁ is selected from -C_1-3 alkyl, said -C_1-3 alkyl optionally 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or -F;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；Each_Ra and_Rb at each occurrence is independently selected from -C_1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或VI的一些实施方式中，其中R₁选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基；In some embodiments of formula I, formula II, formula III or VI, wherein R₁ is selected from methyl; ethyl; propyl; isopropyl; deuterium or -F substituted methyl; deuterium or -F substituted methyl ethyl; propyl substituted with deuterium or -F; or isopropyl substituted with deuterium or -F;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基；Each_Ra and_Rb at each occurrence is independently selected from methyl; ethyl; propyl; isopropyl; deuterium or -F substituted methyl; deuterium or -F substituted ethyl; deuterium or -F F substituted propyl; or deuterium or -F substituted isopropyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或VI的一些实施方式中，其中R₁选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；In some embodiments of Formula I, Formula II, Formula III, or VI, wherein R₁ is selected from -CH₃ , -CD₃ , -CH₂ F, -CF₂ H, -CF₃ , -CH₂ CH₃ ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-__} CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ;

R₂选自

R₂ is selected from

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂。Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ .

在式I、式II、式III或VI的一些实施方式中，其中R₁选自甲基；In some embodiments of Formula I, Formula II, Formula III, or VI, wherein R₁ is selected from methyl;

R₂选自

R₂ is selected from

在式I、式II或式III的一些实施方式中，其中所述的化合物为式VII：In some embodiments of Formula I, Formula II, or Formula III, wherein the compound is of Formula VII:

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时独立地选自氢、氘、-OH、-C_1-6烷基、-C_1-6烷氧基或

且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VII, wherein each R₁ , R₂ and R₃ is independently selected at each occurrence from hydrogen, deuterium, -OH, -C_1-6 Alkyl, -C_1-6 alkoxy or

and each of R₁ , R₂ and R₃ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy; or

R₁和R₂与它们都连接的碳原子一起形成3-6元碳环；或含有1或2个选自N或O的杂原子的3-6元杂环；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；R1 and R2 together with the carbon atoms to which they are attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing₁ or₂ heteroatoms selected from N or O; and each of said ring systems Each occurrence is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘,卤素,-OH,或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VII, wherein each R₁ and R₂ are at each occurrence independently selected from -C_1-6 alkyl, said -C_{1- 6} alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH , or -C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH或-C_1-6烷基；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH or -C_1-6 alkyl;

R₃选自氢、氘、-OH、-C_1-6烷基或

_R is selected from hydrogen, deuterium, -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VII, wherein each R₁ and R₂ are at each occurrence independently selected from -C_1-6 alkyl, said -C_{1- 6} Alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl;

R₃选自-OH、-C_1-6烷基或

R₃ is selected from -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or halogen;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；或In some embodiments of Formula I, Formula II, Formula III, or Formula VII, wherein each R₁ and R₂ are at each occurrence independently selected from -C_1-3 alkyl, said -C_{1- 3} alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium or -F; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or halogen;

R₃选自-OH、-C_1-3烷基、

R₃ is selected from -OH, -C_1-3 alkyl,

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F。Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F.

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；或In some embodiments of Formula I, Formula II, Formula III, or Formula VII, wherein each R₁ and R₂ are independently at each occurrence selected from -CH₃ , -CD₃ , -CH₂ F, -CF_2H ,_{-CF3,-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2} CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 together with the carbon atoms to which they are_both attached form a₃ -membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；R₃ is selected from -OH,

_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_{-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3} ,_-CH2CH2CH3 ,_-CH2CH2CF3 ,_-CH2CH2CD3 , -CH_(CH3)2 , -CH_(CF3)2 or -CH_(CD3)2 ;

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂。Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ .

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁和R₂独立地选自-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂；或In some embodiments_of Formula_I , Formula_II , Formula_III , or Formula VII, wherein each R1 and R2 is independently selected from_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 , or_-CH (CH₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂。R₃ is selected from -OH,

_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 or_-CH(CH3)2 .

在式I、式II、式III或式VII的一些实施方式中，其中R₁选自-CH₃；R₂选自-CH₃；和In some embodiments of Formula_I , Formula_II , Formula III, or Formula VII, wherein R1 is selected from_-CH3 ; R2 is selected from_-CH3 ; and

R₃选自-OH、

-CH₃或-CH₂CH₃。R₃ is selected from -OH,

_-CH3 or_-CH2CH3.

在式I、式II、式III或式VII的一些实施方式中，其中每个R₁选自-CH₃；R₂选自-CH₃；和R₃选自-CH₃。In some embodiments of Formula_I , Formula_II , Formula III, or Formula VII, wherein each R1 is selected from_-CH3 ; R2 is selected from_-CH3 ; and_R3 is selected from_-CH3 .

在式I、式II或式III的一些实施方式中，其中所述的化合物为式VIII：In some embodiments of Formula I, Formula II, or Formula III, wherein the compound is of Formula VIII:

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时独立地选自氢、氘、-OH、-C_1-6烷基、-C_1-6烷氧基或

且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ , R₂ and R₃ at each occurrence is independently selected from hydrogen, deuterium, -OH, -C_1-6 Alkyl, -C_1-6 alkoxy or

and each of R₁ , R₂ and R₃ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy; or

R₁和R₂与它们都连接的碳原子一起形成3-6元碳环；或含有1或2个选自N或O的杂原子的3-6元杂环；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；R1 and R2 together with the carbon atoms to which they are attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing₁ or₂ heteroatoms selected from N or O; and each of said ring systems Each occurrence is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ and R₂ at each occurrence is independently selected from -C_1-6 alkyl, said -C_{1- 6} Alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents is at each occurrence independently selected from deuterium, halogen, -OH or -C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH或-C_1-6烷基；R1 and R2 together with the carbon atoms to which they are_both attached form a₃ -membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, or 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH or -C_1-6 alkyl;

R₃选自氢、氘、-OH、-C_1-6烷基或

_R is selected from hydrogen, deuterium, -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘,卤素,或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ and R₂ at each occurrence is independently selected from -C_1-6 alkyl, said -C_{1- 6} alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, or - C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子，且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each said heterocycle containing 1 or 2 heteroatoms selected from N or O, and each said ring system is optionally 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl;

R₃选自-OH、-C_1-6烷基或

R₃ is selected from -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or halogen;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；或In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ and R₂ are independently selected at each occurrence from -C_1-3 alkyl, said -C_{1- 3} alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium or -F; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or halogen;

R₃选自-OH、-C_1-3烷基、

R₃ is selected from -OH, -C_1-3 alkyl,

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F。Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F.

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；或In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ and R₂ are independently at each occurrence selected from -CH₃ , -CD₃ , -CH₂ F, -CF_2H ,_{-CF3,-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2} CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 together with the carbon atoms to which they are_both attached form a₃ -membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；R₃ is selected from -OH,

_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_{-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3} ,_-CH2CH2CH3 ,_-CH2CH2CF3 ,_-CH2CH2CD3 , -CH_(CH3)2 , -CH_(CF3)2 or -CH_(CD3)2 ;

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂。Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ .

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁和R₂独立地选自-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂；或In some embodiments_of Formula_I , Formula_II , Formula_III , or Formula VIII, wherein each R1 and R2 is independently selected from_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 , or_-CH (CH₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂。R₃ is selected from -OH,

_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 or_-CH(CH3)2 .

在式I、式II、式III或式VIII的一些实施方式中，其中R₁选自-CH₃；R₂选自-CH₃；和R₃选自-OH、

-CH₃或-CH₂CH₃。In some embodiments of Formula_I , Formula II, Formula III, or Formula VIII, wherein R1 is selected from_-CH3 ; R2 is selected from_-CH3 ; and_R3 is selected from_-OH ,

_-CH3 or_-CH2CH3.

在式I、式II、式III或式VIII的一些实施方式中，其中每个R₁选自-CH₃；R₂选自-CH₃；和R₃选自-CH₃.In some embodiments of Formula I, Formula II, Formula III, or Formula VIII, wherein each R₁ is selected from -CH₃ ; R₂ is selected from -CH₃ ; and R₃ is selected from -CH₃ .

在式I、式II或式III的一些实施方式中，其中所述的化合物为式IX：In some embodiments of Formula I, Formula II, or Formula III, wherein the compound is of Formula IX:

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁、R₂和R₃在每次出现时独立地选自氢、氘、-OH、-C_1-6烷基、-C_1-6烷氧基或

且每个R₁、R₂和R₃在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；或In some embodiments of Formula I, Formula II, Formula III, or Formula IX, wherein each R₁ , R₂ and R₃ is independently selected at each occurrence from hydrogen, deuterium, -OH, -C_1-6 Alkyl, -C_1-6 alkoxy or

and each of R₁ , R₂ and R₃ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy; or

R₁和R₂与它们都连接的碳原子一起形成3-6元碳环；或含有1或2个选自N或O的杂原子的3-6元杂环，且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-C_1-6烷基或-C_1-6烷氧基；R1 and R2 together with the carbon atoms to which they are_both attached form a 3-6 membered carbocyclic ring; or a 3-6 membered heterocyclic ring containing₁ or 2 heteroatoms selected from N or O, and each of said ring systems Each occurrence is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula IX, wherein each R₁ and R₂ at each occurrence is independently selected from -C_1-6 alkyl, said -C_{1- 6} Alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH or -C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子；且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH或-C_1-6烷基；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing 1 or 2 heteroatoms selected from N or O; and each of said ring systems optionally at each occurrence by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen, -OH or -C_1-6 alkyl;

R₃选自氢、氘、-OH、-C_1-6烷基或

_R is selected from hydrogen, deuterium, -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium, halogen or -C_1-6 alkyl;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-6烷基，所述的-C_1-6烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；或In some embodiments of Formula I, Formula II, Formula III, or Formula IX, wherein each R₁ and R₂ at each occurrence is independently selected from -C_1-6 alkyl, said -C_{1- 6} Alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子，且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each said heterocycle containing 1 or 2 heteroatoms selected from N or O, and each said ring system is optionally 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-6 alkyl;

R₃选自-OH、-C_1-6烷基或

R₃ is selected from -OH, -C_1-6 alkyl or

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-6烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-6 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents is independently selected at each occurrence from deuterium or halogen;

m选自0或1。m is selected from 0 or 1.

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-C_1-3烷基，所述的-C_1-3烷基任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F；或In some embodiments of Formula I, Formula II, Formula III, or Formula IX, wherein each R₁ and R₂ are at each occurrence independently selected from -C_1-3 alkyl, said -C_{1- 3} alkyl is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is independently selected from deuterium or -F; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环含有1或2个选自N或O的杂原子，且每个所述环系在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或卤素；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each said heterocycle containing 1 or 2 heteroatoms selected from N or O, and each said ring system is optionally 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or halogen;

R₃选自-OH、-C_1-3烷基、

R₃ is selected from -OH, -C_1-3 alkyl,

每个R_a和R_b在每次出现时独立地选自氢、氘或-C_1-3烷基；且每个R_a和R_b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘或-F。Each_Ra and_Rb at each occurrence is independently selected from hydrogen, deuterium or_-C1-3 alkyl; and each_Ra and_Rb at each occurrence is optionally replaced by 1, 2, 3 , 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium or -F.

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁和R₂在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；或In some embodiments of Formula I, Formula_II , Formula III, or Formula IX, wherein each R1 and R2 is independently selected at each occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_{-CF3,-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2} CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ or -CH(CD₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环、6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 together with the carbon atoms to which they are_both attached form a₃ -membered carbocycle, 4-membered carbocycle, 5-membered carbocycle, 6-membered carbocycle, 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂；R₃ is selected from -OH,

_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_{-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3} ,_-CH2CH2CH3 ,_-CH2CH2CF3 ,_-CH2CH2CD3 , -CH_(CH3)2 , -CH_(CF3)2 or -CH_(CD3)2 ;

每个R_a和R_b在每次出现时独立地选自-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂或-CH(CD₃)₂。Each_Ra and_Rb is independently selected at each_occurrence from_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,-CH2CH2CD3,-CH(CH3)2} , -CH(CF₃ )₂ or -CH(CD₃ )₂ .

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁和R₂独立地选自-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂；或In some embodiments_of Formula_I , Formula_II , Formula_III , or Formula IX, wherein each R1 and R2 is independently selected from_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 , or_-CH (CH₃ )₂ ; or

R₁和R₂与它们都连接的碳原子一起形成3元碳环、4元碳环、5元碳环、6元碳环、3元杂环、4元杂环、5元杂环或6元杂环，每个所述杂环在每次出现时包含1个选自N或O的杂原子；R1 and R2 are taken together with the carbon atoms to which they are both attached to form_a3 -membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 6-membered carbocycle, a 3-membered heterocycle, a 4-membered heterocycle, a 5-membered heterocycle, or a 6-membered heterocycle membered heterocycles, each of said heterocycles containing at each occurrence 1 heteroatom selected from N or O;

R₃选自-OH、

-CH₃、-CH₂CH₃、-CH₂CH₂CH₃或-CH(CH₃)₂。R₃ is selected from -OH,

_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 or_-CH(CH3)2 .

在式I、式II、式III或式IX的一些实施方式中，其中R₁选自-CH₃；R₂选自-CH₃；和R₃选自-OH、

-CH₃或-CH₂CH₃。In some embodiments of Formula I, Formula II, Formula III, or Formula IX, wherein R₁ is selected from -CH₃ ; R₂ is selected from -CH₃ ; and R₃ is selected from -OH,

_-CH3 or_-CH2CH3.

在式I、式II、式III或式IX的一些实施方式中，其中每个R₁选自-CH₃；R₂选自-CH₃；和R₃选自-CH₃。In some embodiments of Formula_I , Formula_II , Formula III, or Formula IX, wherein each R1 is selected from_-CH3 ; R2 is selected from_-CH3 ; and_R3 is selected from_-CH3 .

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自氢、氘、-CN、-OH、-C_1-6烷基、-C_1-6烷氧基、-NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-SO₂C_1-6烷基、-SO₂NH₂、-SO₂NHC_1-6烷基、-SO₂N(C_1-6烷基)₂、-COC_1-6烷基、-CONH₂、-CONHC_1-6烷基、-CON(C_1-6烷基)₂、-P(O)H₂、-P(O)HC_1-6烷基或-P(O)(C_1-6烷基)₂；且每个R_4a和R_4b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、-C_1-6烷基或-C_1-6烷氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from Hydrogen, deuterium, -CN, -OH, -C_1-6 alkyl, -C_1-6 alkoxy, -NH₂ , -NH(C_1-6 alkyl), -N(C_1-6 alkane base)₂ , -SO₂ C_1-6 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-6 alkyl, -SO₂ N(C_1-6 alkyl)₂ , -COC_1-6 alkyl base, -CONH₂ , -CONHC_1-6 alkyl, -CON(C_1-6 alkyl)₂ , -P(O)H₂ , -P(O)HC_1-6 alkyl or -P(O )(C_1-6 alkyl)₂ ; and each of R_4a and R_4b is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, and all Each substituent recited is independently at each occurrence selected from deuterium, halogen, -OH, -CN,_-NH2 ,_-C1-6alkyl , or_-C1-6alkoxy .

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自氢、氘、卤素、-CN、-OH、-C_1-3烷基、-C_1-3烷氧基、-NH₂、-NH(C_1-3烷基)、-N(C_1-3烷基)₂、-SO₂C_1-3烷基、-SO₂NH₂、-SO₂NHC_1-3烷基、-SO₂N(C_1-3烷基)₂、-COC_1-3烷基、-CONH₂、-CONHC_1-3烷基、-CON(C_1-3烷基)₂、-P(O)H₂、-P(O)HC_1-3烷基或-P(O)(C_1-3烷基)₂；且每个R_4a和R_4b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、-C_1-3烷基或-C_1-3烷氧基.In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from Hydrogen, deuterium, halogen, -CN, -OH, -C_1-3 alkyl, -C_1-3 alkoxy, -NH₂ , -NH(C_1-3 alkyl), -N(C_{1- 3} alkyl)₂ , -SO₂ C_1-3 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-3 alkyl, -SO₂ N(C_1-3 alkyl)₂ , -COC_{1- 3} alkyl, -CONH₂ , -CONHC_1-3 alkyl, -CON(C_1-3 alkyl)₂ , -P(O)H₂ , -P(O)HC_1-3 alkyl or -P (O)(C_1-3 alkyl)₂ ; and each of R_4a and R_4b is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5, or 6 substituents, And each said substituent is independently selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 ,_-C1-3 alkyl or_-C1-3 alkoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自氢、氘、-F、-Cl、-Br、-CN、-OH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、-NH₂、-NHCH₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂或-P(O)(CH₃)(CH₂CH₃)；每个R_4a和R_4b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from Hydrogen, Deuterium, -F, -Cl, -Br, -CN, -OH, Methyl, Ethyl, Propyl, Isopropyl, Methoxy, Ethoxy, Propoxy, Isopropoxy, - NH₂ , -NHCH₃ , -NHCH₂ CH₃ , -NHCH₂ CH₂ CH₃ , -NHCH(CH₃ )₂ , -N(CH₃ )₂ , -N(CH₃ )(CH₂ CH₃ ), -SO₂ CH₃ , -SO₂ CH₂ CH₃ , -SO₂ CH₂ CH₂ CH₃ , -SO₂ CH(CH₃ )₂ , -SO₂ NH₂ , -SO₂ NHCH₃ , -SO₂ NHCH₂ CH₃ , -SO₂ NHCH₂ CH₂ CH₃ , -SO₂ NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CH₃ )(CH₂ CH₃ ), -_COCH3 ,_-COCH2CH3 ,_-COCH2CH2CH3 ,_-COCH(CH3)2 ,_-CONH2 ,_-CONHCH3 ,_-CONHCH2CH3 ,_{-CONHCH2CH2CH3,-CONHCH(} CH₃ )₂ , -CON(CH₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P(O)HCH₂ CH₂ CH₃ , -P(O)HCH(CH₃ )₂ , -P(O)(CH₃ )₂ or -P(O)(CH₃ )(CH₂ CH₃ ); each R_4a and R_4b is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is substituted at each occurrence When present, independently selected from deuterium, -F, -Cl, -Br, -OH, -CN,_-NH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy radical or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自氢、氘、-F、-Cl、-Br、-CN、-OH、-CH₃、-CD₃、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CD₃、-CH₂CH₂CF₃、-CH(CH₃)₂、-CH(CD₃)₂、-CH(CF₃)₂、甲氧基、乙氧基、丙氧基、异丙氧基、-NH₂、-NHCH₃、-NHCD₃、-NHCH₂CH₃、-NHCH₂CH₂CH₃、-NHCH(CH₃)₂、-N(CH₃)₂、-N(CD₃)₂、-N(CH₃)(CH₂CH₃)、-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂或-P(O)(CH₃)(CH₂CH₃)。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from Hydrogen, Deuterium, -F, -Cl,_-Br , -CN,_-OH ,_-CH3 ,_-CD3 ,_-CF3 ,_-CH2CH3 ,_-CH2CD3 ,_-CH2CF3 ,_- CH₂ CH₂ CH₃ , -CH₂ CH₂ CD₃ , -CH₂ CH₂ CF₃ , -CH(CH₃ )₂ , -CH(CD₃ )₂ , -CH(CF₃ )₂ , methoxy , ethoxy, propoxy, isopropoxy, -NH₂ , -NHCH₃ , -NHCD₃ , -NHCH₂ CH₃ , -NHCH₂ CH₂ CH₃ , -NHCH(CH₃ )₂ , -N (CH₃ )₂ , -N(CD₃ )₂ , -N(CH₃ )(CH₂ CH₃ ), -SO₂ CH₃ , -SO₂ CD₃ , -SO₂ CH₂ CH₃ , -SO_{2CH2CH2CH3,-SO2CH(CH3)2,-SO2NH2,-SO2NHCH3,-SO2NHCH2CH3,-SO2NHCH2CH2CH3,-SO2_} NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CD₃ )₂ , -SO₂ N(CH₃ )(CH₂ CH₃ ), -COCH_{3 , -COCD 3,-COCH2CH3} ,_-COCH2CH2CH3 ,_-COCH(CH3)2 ,_-CONH2 ,_-CONHCH3 ,_-CONHCD3 ,_{-CONHCH2CH3,-CONHCH2CH2CH3,-CONHCH} (CH₃ )₂ , -CON(CH₃ )₂ , -CON(CD₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P(O)HCH₂ CH₂ CH₃ , -P(O)HCH(CH₃ )₂ , -P(O)(CH₃ )₂ , -P(O )(CD₃ )₂ or -P(O)(CH₃ )(CH₂ CH₃ ).

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自-C_1-6烷基；或氘或-F取代的-C_1-6烷基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from -C_1-6 alkyl; or -C_1-6 alkyl substituted with deuterium or -F.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自-C_1-3烷基；或氘或-F取代的-C_1-3烷基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from -C_1-3 alkyl; or -C_1-3 alkyl substituted with deuterium or -F.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自甲基；乙基；丙基；异丙基；氘或-F取代的甲基；氘或-F取代的乙基；氘或-F取代的丙基；或氘或-F取代的异丙基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from methyl; ethyl; propyl; isopropyl; methyl substituted with deuterium or -F; ethyl substituted with deuterium or -F; propyl substituted with deuterium or -F; or isopropyl substituted with deuterium or -F .

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中每个R_4a和R_4b在每次出现时独立地选自甲基或氘取代的甲基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein each_{R4a and R4bat} each occurrence is independently selected from Methyl or deuterium substituted methyl.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中R₄选自：In some embodiments of Formula I, Formula II, Formula III, Formula_IV , Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein R is selected from:

在式I的一些实施方式中，其中R₅在每次出现时独立地选自氢、氘、-CN、-OH、-C_1-6烷基、-C_1-6烷氧基、

-SO₂C_1-6烷基、-SO₂NH₂、-SO₂NHC_1-6烷基、-SO₂N(C_1-6烷基)₂、-COC_1-6烷基、-CONH₂、-CONHC_1-6烷基、-CON(C_1-6烷基)₂、-P(O)H₂、-P(O)HC_1-6烷基或-P(O)(C_1-6烷基)₂；每个R₅在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素、-OH、-CN、-NH₂、-C_1-6烷基或-C_1-6烷氧基；_In some embodiments of Formula I, wherein R at each occurrence is independently selected from hydrogen, deuterium, -CN, -OH, -C_1-6 alkyl, -C_1-6 alkoxy,

-SO₂ C_1-6 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-6 alkyl, -SO₂ N(C_1-6 alkyl)₂ , -COC_1-6 alkyl, -CONH₂ , -CONHC_1-6 alkyl, -CON(C_1-6 alkyl)₂ , -P(O)H₂ , -P(O)HC_1-6 alkyl or -P(O)(C_{1 -6} alkyl)₂ ; each R₅ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is at each occurrence independently selected at the next occurrence from deuterium, halogen, -OH, -CN, -NH₂ , -C_1-6 alkyl or -C_1-6 alkoxy;

每个R_5a和R_5b在每次出现时独立地选自氢、氘或-C_1-6烷基；每个R_5a和R_5b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-6烷基；Each R_5a and R_5b at each occurrence is independently selected from hydrogen, deuterium or -C_1-6 alkyl; each R_5a and R_5b at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or_-C1-6 alkyl;

n选自0、1、2、3、4、5或6。n is selected from 0, 1, 2, 3, 4, 5 or 6.

在式I的一些实施方式中，其中R₅在每次出现时独立地选自氢、氘、-CN、-OH、-C_1-3烷基、-C_1-3烷氧基、

-SO₂C_1-3烷基、-SO₂NH₂、-SO₂NHC_1-3烷基、-SO₂N(C_1-3烷基)₂、-COC_1-3烷基、-CONH₂、-CONHC_1-3烷基、-CON(C_1-3烷基)₂、-P(O)H₂、-P(O)HC_1-3烷基或-P(O)(C_1-3烷基)₂；每个R₅在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br、-OH、-CN、-NH₂、-C_1-3烷基或-C_1-3烷氧基；_In some embodiments of Formula I, wherein R at each occurrence is independently selected from hydrogen, deuterium, -CN, -OH, -C_1-3 alkyl, -C_1-3 alkoxy,

-SO₂ C_1-3 alkyl, -SO₂ NH₂ , -SO₂ NHC_1-3 alkyl, -SO₂ N(C_1-3 alkyl)₂ , -COC_1-3 alkyl, -CONH₂ , -CONHC_1-3 alkyl, -CON(C_1-3 alkyl)₂ , -P(O)H₂ , -P(O)HC_1-3 alkyl or -P(O)(C_{1 -3} alkyl)₂ ; each R₅ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently selected at the next occurrence from deuterium, -F, -Cl, -Br, -OH, -CN,_-NH2 ,_-C1-3alkyl , or_-C1-3alkoxy ;

每个R_5a和R_5b在每次出现时独立地选自氢、氘或-C_1-3烷基；每个R_5a和R_5b在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、卤素或-C_1-3烷基；Each R_5a and R_5b at each occurrence is independently selected from hydrogen, deuterium or -C_1-3 alkyl; each R_5a and R_5b at each occurrence is optionally replaced by 1, 2, 3, 4, 5 or 6 substituents are substituted or unsubstituted, and each of said substituents at each occurrence is independently selected from deuterium, halogen or -C_1-3 alkyl;

n选自0、1、2、3或4。n is selected from 0, 1, 2, 3 or 4.

在式I的一些实施方式中，其中R₅在每次出现时独立地选自氢、氘、-CN、-OH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、

-SO₂CH₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂或-P(O)(CH₃)(CH₂CH₃)；每个R₅在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时独立地选自氘、-F、-Cl、-Br、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of Formula I, wherein R₅ is independently at each occurrence selected from hydrogen, deuterium, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy base, propoxy, isopropoxy,

-SO₂ CH₃ , -SO₂ CH₂ CH₃ , -SO₂ CH₂ CH₂ CH₃ , -SO₂ CH(CH₃ )₂ , -SO₂ NH₂ , -SO₂ NHCH₃ , -SO₂ NHCH₂ CH₃ , -SO₂ NHCH₂ CH₂ CH₃ , -SO₂ NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CH₃ )(CH₂ CH₃ ), -_COCH3 ,_-COCH2CH3 ,_-COCH2CH2CH3 ,_-COCH(CH3)2 ,_-CONH2 ,_-CONHCH3 ,_-CONHCH2CH3 ,_{-CONHCH2CH2CH3,-CONHCH(} CH₃ )₂ , -CON(CH₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P(O)HCH₂ CH₂ CH₃ , -P(O)HCH(CH₃ )₂ , -P(O)(CH₃ )₂ or -P(O)(CH₃ )(CH₂ CH₃ ); each R₅ is optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents at each occurrence, and each of said substituents is independently at each occurrence is selected from deuterium, -F, -Cl, -Br, -OH, -CN,_-NH2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropyl propoxy.

在式I的一些实施方式中，其中R₅在每次出现时独立地选自氢、氘、-CN、-OH、-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂、甲氧基、乙氧基、丙氧基、异丙氧基、

-SO₂CH₃、-SO₂CD₃、-SO₂CH₂CH₃、-SO₂CH₂CH₂CH₃、-SO₂CH(CH₃)₂、-SO₂NH₂、-SO₂NHCH₃、-SO₂NHCH₂CH₃、-SO₂NHCH₂CH₂CH₃、-SO₂NHCH(CH₃)₂、-SO₂N(CH₃)₂、-SO₂N(CD₃)₂、-SO₂N(CH₃)(CH₂CH₃)、-COCH₃、-COCD₃、-COCH₂CH₃、-COCH₂CH₂CH₃、-COCH(CH₃)₂、-CONH₂、-CONHCH₃、-CONHCD₃、-CONHCH₂CH₃、-CONHCH₂CH₂CH₃、-CONHCH(CH₃)₂、-CON(CH₃)₂、-CON(CD₃)₂、-CON(CH₃)(CH₂CH₃)、-P(O)H₂、-P(O)HCH₃、-P(O)HCH₂CH₃、-P(O)HCH₂CH₂CH₃、-P(O)HCH(CH₃)₂、-P(O)(CH₃)₂、-P(O)(CD₃)₂或-P(O)(CH₃)(CH₂CH₃)。_In some embodiments of Formula I, wherein R5 is independently at each occurrence selected from hydrogen, deuterium, -CN, -OH,_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H , -_{CF3,-CH2CH3,-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2CH2CH3,-CH2CH2CF3,_} -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ , -CH(CD₃ )₂ , methoxy, ethoxy, propoxy, isopropoxy,

-SO₂ CH₃ , -SO₂ CD₃ , -SO₂ CH₂ CH₃ , -SO₂ CH₂ CH₂ CH₃ , -SO₂ CH(CH₃ )₂ , -SO₂ NH₂ , -SO₂ NHCH₃ , -SO₂ NHCH₂ CH₃ , -SO₂ NHCH₂ CH₂ CH₃ , -SO₂ NHCH(CH₃ )₂ , -SO₂ N(CH₃ )₂ , -SO₂ N(CD₃ )₂ ,_-SO2N (_CH3) (_CH2CH3) , -COCH3,_-COCD3 ,_-COCH2CH3 ,_-COCH2CH2CH3 , -COCH_(CH3)2 ,_-CONH2 ,_- CONHCH₃ , -CONHCD₃ , -CONHCH₂ CH₃ , -CONHCH₂ CH₂ CH₃ , -CONHCH(CH₃ )₂ , -CON(CH₃ )₂ , -CON(CD₃ )₂ , -CON(CH₃ )(CH₂ CH₃ ), -P(O)H₂ , -P(O)HCH₃ , -P(O)HCH₂ CH₃ , -P(O)HCH₂ CH₂ CH₃ , -P(O )HCH(_CH3 )₂ , -P(O)(_CH3 )₂ , -P(O)(_CD3 )₂ or -P(O)(_CH3 )(_CH2CH3) .

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自氢；氘；-F；-Cl；-NH₂；-CN；-OH；羧基；-C_1-6烷基；-C_1-6烷氧基；-C_1-3亚烷基-C_1-3烷氧基；苯基；含1、2或3个选自N或O的杂原子的5元杂芳基；含1、2或3个选自N或O的杂原子的6元杂芳基；含1、2或3个选自N或O的杂原子的3元杂环；含1、2或3个选自N或O的杂原子的4元杂环；含1、2或3个选自N或O的杂原子的5元杂环；含1、2或3个选自N或O的杂原子的6元杂环；3元碳环；4元碳环；5元碳环；或6元碳环；且每个W₁在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时选自氘、卤素-OH、-CN、-NH₂、-C_1-3烷基或-C_1-3烷氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from hydrogen_; deuterium; -F; -Cl; -NH₂ ; -CN; -OH; carboxyl; -C_1-6 alkyl; -C_1-6 alkoxy; -C_1-3 alkylene-C_1-3 alkoxy; phenyl; containing 1, 5-membered heteroaryl with 2 or 3 heteroatoms selected from N or O; 6-membered heteroaryl with 1, 2 or 3 heteroatoms selected from N or O; 1, 2 or 3 heteroatoms selected from 3-membered heterocycle containing heteroatoms of N or O; 4-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N or O; 5-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N or O A membered heterocycle; a 6-membered heterocycle containing 1, 2, or 3 heteroatoms selected from N or O; a 3-membered carbocycle; a 4-membered carbocycle; a 5-membered carbocycle; or a 6-membered carbocycle; and each W₁ is optionally substituted or unsubstituted at each occurrence with 1, 2, 3, 4, 5 or 6 substituents, and each of said substituents at each occurrence is selected from deuterium, halo-OH , -CN, -NH₂ , -C_1-3 alkyl or -C_1-3 alkoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自氢；氘；-F；-Cl；-NH₂；-CN；-OH；甲基；乙基；丙基；异丙基；

甲氧基；乙氧基；丙氧基；异丙氧基；

-CH₂OCH₃；-CH₂CH₂OCH₃；-CH₂CH₂OCH₂CH₃；苯基；5元杂芳基含有1或2个选自N或O的杂原子的；6元杂芳基含有1或2个选自N或O的杂原子的；5元杂环含有1或2个选自N或O的杂原子的；6元杂环含有1或2个选自N或O的杂原子的；5元碳环；或6元碳环；且每个W₁在每次出现时任选地被1、2、3、4、5或6个取代基取代或不被取代，且所述的每个取代基在每次出现时选自氘、-F、-Cl、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from hydrogen_; deuterium; -F; -Cl; -NH₂ ;-CN;-OH;methyl;ethyl;propyl;isopropyl;

Methoxy; Ethoxy; Propoxy; Isopropoxy;

_{-CH2OCH3;-CH2CH2OCH3;-CH2CH2OCH2CH3;} phenyl;_5- membered heteroaryl containing 1 or₂ heteroatoms selected from N or O; 6-membered heteroaryl Aryl contains 1 or 2 heteroatoms selected from N or O; 5-membered heterocycle contains 1 or 2 heteroatoms selected from N or O; 6-membered heterocycle contains 1 or 2 heteroatoms selected from N or O 5-membered carbocycle; or 6-membered carbocycle; and each W is optionally substituted or unsubstituted at each occurrence with₁ , 2, 3, 4, 5, or 6 substituents, and each said substituent is selected at each occurrence from deuterium, -F, -Cl, -OH, -CN,_-NH2 , methyl, ethyl, propyl, isopropyl, methoxy, Ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自氢；氘；-F；甲基；乙基；丙基；异丙基；

甲氧基；-CH₂OCH₃；-CH₂CH₂OCH₃；6元杂芳基含有1或2个选自N或O的杂原子的；5元杂环含有1或2个选自N或O的杂原子的；6元杂环含有1或2个选自N或O的杂原子的；5元碳环；或6元碳环；且每个W₁在每次出现时任选地被取代或不被取代氘或-F。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from hydrogen_; deuterium; -F; methyl; ethyl ; Propyl; Isopropyl;

Methoxy; -CH₂ OCH₃ ; -CH₂ CH₂ OCH₃ ; 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O; 5-membered heterocycle containing 1 or 2 heteroatoms selected from N or a heteroatom of O; a 6-membered heterocycle containing 1 or 2 heteroatoms selected from N or O; a 5-membered carbocycle; or a₆ -membered carbocycle; and each W at each occurrence is optionally Substituted or unsubstituted deuterium or -F.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自氢、氘、-F、-CH₃、-CD₃、-CH₂F、-CF₂H、-CF₃、-CH₂CH₃、-CH₂CD₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CH₂CH₂CH₃、-CH₂CH₂CF₃、-CH₂CH₂CD₃、-CH(CH₃)₂、-CH(CF₃)₂、-CH(CD₃)₂、

甲氧基、-CH₂OCH₃、-CH₂CH₂OCH₃、

In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W1 is selected from hydrogen, deuterium, -F,_-CH3 ,_-CD3 ,_-CH2F ,_-CF2H ,_-CF3 ,_-CH2CH3 ,_{-CH2CD3,-CH2CH2F,-CH2CHF2,-CH2CF3,-CH2} CH₂ CH₃ , -CH₂ CH₂ CF₃ , -CH₂ CH₂ CD₃ , -CH(CH₃ )₂ , -CH(CF₃ )₂ , -CH(CD₃ )₂ ,

Methoxy, -CH₂ OCH₃ , -CH₂ CH₂ OCH₃ ,

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自-F取代的-C_1-6烷基或含有1个选自O的杂原子的6元杂环。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from -F substituted -C_1-6alkyl or A 6-membered heterocycle containing 1 heteroatom selected from O.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自-F取代的-C_1-6烷基、

In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W₁ is selected from -F substituted -C_1-6 alkyl,

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₁选自-CH₂CH₂CF₃或

In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W₁ is selected from -CH₂ CH₂ CF₃ or

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₂选自氢；氘；-F；-Cl；-NH₂；-CN；-OH；羧基；-C_1-3烷基；-C_1-3烷氧基；苯基；萘基；含1、2或3个选自N、O或S的杂原子的5元杂芳基；含1、2或3个选自N、O或S的杂原子的6元杂芳基；含1、2或3个选自N、O或S的杂原子7元杂芳基；含1、2或3个选自N、O或S的杂原子的8元杂芳基；含1、2或3个选自N、O或S的杂原子的9元杂芳基；含1、2或3个选自N或O的杂原子的10元杂芳基或S；含1、2或3个选自N、O或S的杂原子的3元杂环；含1、2或3个选自N、O或S的杂原子的4元杂环；含1、2或3个选自N、O或S的杂原子的5元杂环；含1、2或3个选自N、O或S的杂原子的6元杂环；3元碳环；4元碳环；5元碳环；或6元碳环；且每个W₂在每次出现时任选地被取代或不被取代1、2、3、4或5取代基，且所述的每个取代基在每次出现时选自氘、卤素、-OH、-CN、-NH₂、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基.In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from_hydrogen ; deuterium; -F; -Cl; -NH₂ ; -CN; -OH; carboxyl; -C_1-3 alkyl; -C_1-3 alkoxy; phenyl; naphthyl; containing 1, 2 or 3 heteroatoms selected from N, O or S 5-membered heteroaryl group; 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S Heteroaryl; 8-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; 9-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S 10-membered heteroaryl or S containing 1, 2 or 3 heteroatoms selected from N or O; 3-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; containing 4-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; 5-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O or S; 1, 2 or 6-membered heterocycle of 3 heteroatoms selected from N, O, or S;₃ -membered carbocycle; 4-membered carbocycle; 5-membered carbocycle; or 6-membered carbocycle; optionally substituted or unsubstituted 1, 2, 3, 4 or 5 substituents, and each said substituent is selected at each occurrence from deuterium, halogen, -OH, -CN,_-NH2 , methyl radical, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₂选自氢；氘；苯基；含有1或2个选自N、O或S的杂原子的5元杂芳基；或含有1或2个选自N、O或S的杂原子的6元杂芳基；且每个W₂在每次出现时任选地被取代或不被取代1、2、3、4或5取代基，且所述的每个取代基在每次出现时选自氘、-F、-Cl、-Br、-NH₂、-CN、-OH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from hydrogen; deuterium; phenyl; containing 1 or₂ a 5-membered heteroaryl group containing a heteroatom selected from N, O, or S; or a 6-membered heteroaryl group containing 1 or₂ heteroatoms selected from N, O, or S; and each W in each occurrence optionally substituted or unsubstituted 1, 2, 3, 4 or 5 substituents, and each of said substituents at each occurrence is selected from deuterium, -F, -Cl, -Br,_-NH2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₂选自苯基；含有1或2个选自N、O或S的杂原子的5元杂芳基；或含有1或2个选自N、O或S的杂原子的6元杂芳基；且每个W₂在每次出现时任选地被取代或不被取代1、2或3取代基，且所述的每个取代基在每次出现时选自-F、-Cl、-Br、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII or formula IX, wherein W₂ is selected from phenyl; contains 1 or 2 selected from N, A 5-membered heteroaryl group containing a heteroatom of O or S; or a 6-membered heteroaryl group containing 1 or₂ heteroatoms selected from N, O, or S; and each W at each occurrence is optionally substituted or unsubstituted 1, 2 or 3 substituents, and each of said substituents is selected at each occurrence from -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₂选自

且每个W₂在每次出现时任选地被取代或不被取代1、2或3取代基，且所述的每个取代基在每次出现时选自-F、-Cl、甲基或甲氧基。In some embodiments of Formula I, Formula_II , Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is selected from

and each W is optionally substituted or unsubstituted 1,₂ or 3 substituents at each occurrence, and each of said substituents is selected from -F, -Cl, methyl at each occurrence or methoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中W₂独立地选自：In some embodiments of Formula I, Formula_II , Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein W is independently selected from:

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中Z选自氢、氘、-F、-Cl、-OH、-C_1-3烷基或-C_1-3烷氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein Z is selected from hydrogen, deuterium, -F, -Cl, -OH, -C_1-3 alkyl or -C_1-3 alkoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中Z选自氢、氘、-F、-Cl、-OH、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein Z is selected from hydrogen, deuterium, -F, -Cl, -OH, Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中Z选自氢或氘。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein Z is selected from hydrogen or deuterium.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中Z选自氢。In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein Z is selected from hydrogen.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中所述的

选自：In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein the

Selected from:

且每个

在每次出现时任选地被取代或不被取代1、2或3取代基，且所述的每个取代基在每次出现时选自-F、-Cl、-Br、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基或异丙氧基。

and each

1, 2 or 3 substituents are optionally substituted or unsubstituted at each occurrence, and each said substituent is selected at each occurrence from -F, -Cl, -Br, methyl, ethyl radical, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

在式I、式II、式III、式IV、式V、式VI、式VII、式VIII或式IX的一些实施方式中，其中所述的

选自：In some embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX, wherein the

Selected from:

且每个

在每次出现时任选地被取代或不被取代1、2或3取代基，且所述的每个取代基在每次出现时选自-F、-Cl、甲基或甲氧基。and each

1, 2 or 3 substituents are optionally substituted or unsubstituted at each occurrence, and each said substituent is selected at each occurrence from -F, -Cl, methyl or methoxy.

在式I的一些实施方式中，其中所述化合物选自：In some embodiments of Formula I, wherein the compound is selected from:

另一方面，提供一种药物组合物，其包含至少一种本发明式I的化合物、其药学上可接受的盐或其立体异构体，及至少一种药学上可接受的赋形剂。In another aspect, there is provided a pharmaceutical composition comprising at least one compound of formula I of the present invention, a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

在一些所述药物组合物的实施方式中，其中所述化合物与所述赋形剂的重量比的范围为约0.0001至约10。In some embodiments of the pharmaceutical composition, wherein the weight ratio of the compound to the excipient ranges from about 0.0001 to about 10.

另一方面，本发明提供所述的式I的化合物、其药学上可接受的盐或其立体异构体；所述的药物组合物，在制备治疗与溴结构域蛋白相关的疾病或病症的药物中的应用。In another aspect, the present invention provides the compound of formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof; the pharmaceutical composition is prepared for the treatment of diseases or conditions associated with bromodomain proteins. application in medicine.

在较佳的实施方式中，所述的与溴结构域蛋白相关的疾病或病症选自实体瘤(solid tumor)和/或血液瘤(blood tumor)。In a preferred embodiment, the diseases or conditions associated with bromodomain proteins are selected from solid tumors and/or blood tumors.

在较佳的实施方式中，所述实体瘤选自肺癌(lung cancer)、消化道肿瘤(gastrointestinal cancer)、结肠癌(colon cancer)、直肠癌(rectal cancer)、结直肠癌(colorectal cancer)和/或卵巢癌(ovarian cancer)；所述血液瘤(blood tumor)选自骨髓瘤(myeloma)和/或白血病(leukemia)。In a preferred embodiment, the solid tumor is selected from the group consisting of lung cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal cancer and /or ovarian cancer; the blood tumor is selected from myeloma and/or leukemia.

在较佳的实施方式中，所述肺癌包括非小细胞肺癌(non-small cell lungcancer)和/或小细胞肺癌(small cell lung cancer)；所述消化道肿瘤(gastrointestinal cancer)包括食管癌(esophageal cancer)；所述白血病(leukemia)包括急性髓性白血病(acute myeloid leukemia(AML))和/或急性淋巴细胞白血病(acutelymphocytic leukemia(ALL))；所述骨髓瘤(myeloma)包括多发性骨髓瘤(multiplemyeloma)。In a preferred embodiment, the lung cancer includes non-small cell lung cancer and/or small cell lung cancer; the gastrointestinal cancer includes esophageal cancer cancer); the leukemia includes acute myeloid leukemia (AML) and/or acute lymphocytic leukemia (ALL); the myeloma includes multiple myeloma ( multiple myeloma).

定义definition

除非另有说明，本文所用的术语“卤素”是指氟、氯、溴或碘。优选的卤素基团包括F、Cl和Br。The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, unless otherwise specified. Preferred halogen groups include F, Cl and Br.

除非另有说明，本文所用的术语“烷基”包括具有直链或支链的饱和一价烷基。例如，烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似地，C_1-6烷基中的C_1-6被定义为直链或支链排列中该基团具有1、2、3、4、5或6个碳原子。Unless otherwise specified, the term "alkyl" as used herein includes saturated monovalent alkyl groups having straight or branched chains. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 - methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C1-6 in_C1-6alkyl is defined as having 1, 2, 3, 4, 5 or 6 carbon atoms in the group in a straight or branched chain arrangement.

术语“亚烷基”是指通过从如上定义的烷基除去氢原子而获得的双官能团。例如，亚甲基(即-CH₂-)、亚乙基(即-CH₂-CH₂-或-CH(CH₃)-)和亚丙基(即-CH₂-CH₂-CH₂-、-CH(-CH₂-CH₃))-或-CH₂-CH(CH₃)-)。The term "alkylene" refers to a bifunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (ie_-CH2- ), ethylene (ie_-CH2 -CH2- or -CH(_CH3) -) and propylene (ie_-CH2 -_CH2 -CH2-₎ , -CH(-CH₂ -CH₃ ))- or -CH₂ -CH(CH₃ )-).

术语“烯基”是指含有一个或多个双键且通常长度为2至20个碳原子的直链或支链烃基。例如，“C_2-6链烯基”含有2至6个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、2-甲基-2-丁烯-1-基、庚烯基、辛烯基等。The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and usually 2 to 20 carbon atoms in length. For example, "C_2-6 alkenyl" contains 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

术语“炔基”含有一个或多个三键并且通常长度为2至20个碳原子的直链或支链烃基。例如，“C_2-6炔基”含有2至6个碳原子。代表性的炔基包括但不限于，例如，乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。The term "alkynyl" contains one or more triple bonds and is usually a straight or branched chain hydrocarbon group of 2 to 20 carbon atoms in length. For example, "_C2-6alkynyl " contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

术语“烷氧基”基团是由前述烷基形成的氧醚。The term "alkoxy" group is an oxygen ether formed from the aforementioned alkyl groups.

除非另有说明，本文所用的术语“芳基”是指含有碳环原子的未取代或取代的单环或多环芳环系统。优选的芳基是单环或双环6-10元芳环系。苯基和萘基是优选的芳基。最优选的芳基是苯基。Unless otherwise indicated, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

除非另有说明，本文所用的术语“杂环”是指含有一个或多个杂原子的未取代和取代的单环或多环非芳族环系。优选的杂原子包括N、O和S，包括N-氧化物、硫氧化物和二氧化物。优选地，该环是三至八元并且是完全饱和的或具有一个或多个不饱和度。本定义包括多个取代度，优选一个、两个或三个取代度。这种杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、氧代氮杂环庚基、氮杂环庚基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻吩基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜和恶二唑。The term "heterocycle" as used herein, unless otherwise specified, refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably, the ring is three to eight membered and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably one, two or three degrees of substitution. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepanyl, Azacycloheptyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothienyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpho phosphonium sulfoxides, thiomorpholinyl sulfones and oxadiazoles.

除非另有说明，本文所用的术语“杂芳基”表示含有碳和至少一个杂原子的芳环系统。杂芳基可以是单环的或多环的，取代的或未取代的。单环杂芳基在环中可具有1至4个杂原子，而多环杂芳基可包含1至10个杂原子。多环杂芳基环可含有稠合、螺环或桥环结合，例如，双环杂芳基是多环杂芳基。双环杂芳基环可含有8至12个成员原子。单环杂芳基环可含有5至8个成员原子(碳原子和杂原子)。杂芳基的实例包括，但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻吩基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并恶唑基、苯并吡唑基、苯并噻吩基、苯并噻二唑基、苯并三唑基腺嘌呤基、喹啉基或异喹啉基。Unless otherwise indicated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain fused, spiro or bridged ring linkages, eg, a bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thienyl, thiadiazolyl, triazolyl, pyridyl, Pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazole group, benzothienyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

术语“碳环”是指取代或未取代的单环、双环或多环非芳族饱和环，其任选地包括亚烷基连接基，环烷基可通过该亚烷基连接基连接。示例性的“环烷基”基团包括但不限于环丙基、环丁基、环戊基、环己基等。The term "carbocycle" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, optionally including an alkylene linker through which a cycloalkyl group can be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

术语“氧代”是指氧与所连接的碳原子一起形成

基团。The term "oxo" means that oxygen is formed with the carbon atom to which it is attached

group.

术语“羧基”是指基团C(O)OH。The term "carboxy" refers to the group C(O)OH.

术语“P(O)”是指基团P＝O。The term "P(O)" refers to the group P=O.

术语“取代”指至少一个氢原子被非氢基团替代，只要保持正常的化学键并且取代的结果位稳定的化合物。The term "substituted" refers to compounds in which at least one hydrogen atom is replaced by a non-hydrogen group, so long as normal chemical bonds are maintained and the result of the substitution is stable.

如本文所用，术语“组合物”旨在涵盖包含特定量的特定成分的产品，以及直接或间接由特定量的特定成分的组合产生的任何产品。因此，含有本发明化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以作为多晶型存在，并且因此这些旨在包括在本发明中。另外，一些化合物可与水形成溶剂化物(即水合物)或常见的有机溶剂，这些溶剂化物也包括在本发明的范围内。As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and these are therefore intended to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention.

本发明化合物也可以药学上可接受的盐的形式存在。对于在医药中使用，本发明化合物的盐是指无毒的“药学上可接受的盐”。药学上可接受的盐形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐。药学上可接受的酸性/阴离子盐通常采用其中碱性氮用无机酸或有机酸质子化的形式。代表性的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、双羟萘酸、2-萘磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、糖精或三氟乙酸。药学上可接受的碱性/阳离子盐包括但不限于铝、钙、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、锂、镁、钾、钠和锌盐。The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anionic or basic/cationic salts. Pharmaceutically acceptable acid/anionic salts typically take the form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, apple acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid , salicylic acid, saccharin or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc salts.

本发明在其范围内包括本发明化合物的前药。通常，这种前药是化合物的功能性衍生物，其易于在体内转化为所需化合物。因此，在本发明的治疗方法中，术语“给药”应包括用特定公开的化合物，或用可能未具体公开的化合物，但给予受试者后在体内转化为特定化合物的化合物治疗描述的各种病症。用于选择和制备合适的前药衍生物的常规方法描述于例如“前药设计”(“Design of Prodrugs”,ed.H.Bundgaard,Elsevier,1985.)。The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of compounds that are readily converted to the desired compound in vivo. Thus, in the methods of treatment of the present invention, the term "administration" shall include treatment of each of the described compounds with a specifically disclosed compound, or with a compound that may not be specifically disclosed, but which upon administration to a subject converts to the specified compound in vivo disease. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs" ("Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.).

分子中特定位置的任何取代基或变量的定义旨在独立于该分子中其他位置的取代基或变量的定义。应当理解，本领域普通技术人员可以选择本发明化合物上的取代基和取代模式，以提供化学稳定的化合物，并且可以通过本领域已知的技术以及本文阐明的方法容易地合成。The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definition of substituents or variables at other positions in that molecule. It will be appreciated that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide chemically stable compounds that can be readily synthesized by techniques known in the art and by the methods set forth herein.

本发明包括所述化合物可含有一个或多个不对称中心，因此可产生对映异构体、非对映异构体和光学异构体。本发明包括所有这些可能的对映异构体、非对映异构体及其外消旋混合物、它们基本上纯的拆分的对映异构体、所有可能的几何异构体、及其药学上可接受的盐。The present invention includes that the compounds may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers and optical isomers. The present invention includes all such possible enantiomers, diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and Pharmaceutically acceptable salts.

本发明包括化合物的所有立体异构体及其药学上可接受的盐。此外，还包括立体异构体的混合物以及分离的特定立体异构体。在用于制备这些化合物的合成方法的过程中，或在使用本领域技术人员已知的外消旋化或差向异构化方法的过程中，这些方法的产物可以是立体异构体的混合物。The present invention includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic methods used to prepare these compounds, or during the use of racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers .

本发明旨在包括本发明化合物中存在的所有原子同位素。同位素是具有相同原子序数但质量数不同的原子。作为一般实例而非限制，氢的同位素包括氘和氚。氢的同位素可表示为¹H(氢)，²H(氘)和³H(氚)。它们通常也表示为D(氘)和T(氚)。在本申请中，CD₃表示甲基，其中所有氢原子都是氘。碳的同位素包括¹³C和¹⁴C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述类似的方法制备，使用适当的同位素标记的试剂代替非标记试剂。The present invention is intended to include all atomic isotopes present in the compounds of the present invention. Isotopes are atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented as¹ H (hydrogen),² H (deuterium) and³ H (tritium). They are also commonly denoted D (deuterium) and T (tritium). In this application, CD₃ represents a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon^{include13Cand14C} . Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using the appropriate isotopically-labeled reagent in place of the non-labeled reagent.

除非另有说明，当式I化合物的互变异构体存在时，本发明包括任何可能的互变异构体及其药学上可接受的盐，以及它们的混合物。Unless otherwise indicated, when tautomers of compounds of formula I exist, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof.

当式I化合物及其药学上可接受的盐以溶剂化物或多晶型形式存在时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂的类型没有特别限制，只要溶剂是药理学上可接受的即可。例如，可以使用水、乙醇、丙醇、丙酮等。When the compounds of formula I and pharmaceutically acceptable salts thereof exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and the like can be used.

术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸制备的盐。当本发明化合物是酸性时，其相应的盐可以方便地由药学上可接受的无毒碱制备，包括无机碱和有机碱。当本发明的化合物是碱性时，其相应的盐可以方便地由药学上可接受的无毒酸制备，包括无机酸和有机酸。由于式I化合物用于药物用途，它们优选以基本上纯的形式提供，例如至少60％纯，更合适地至少75％纯，特别是至少98％纯(％是以重量计的重量％))。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present invention are acidic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. As compounds of formula I are for pharmaceutical use, they are preferably provided in substantially pure form, eg at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight by weight)) .

本发明的药物组合物包含式I代表的化合物(或其药学上可接受的盐)作为活性成分，药学上可接受的载体和任选的其它治疗成分或佐剂。尽管在任何给定情况下最合适的途径将取决于特定的宿主，以及为病症(为治疗该病症而正在施用该活性成分)的性质和严重程度，但该组合物包括适于口服、直肠、局部和肠胃外(包括皮下、肌肉内和静脉内)给药的组合物。药物组合物可以方便地以单位剂型存在，并通过药学领域熟知的任何方法制备。The pharmaceutical composition of the present invention comprises a compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Although the most appropriate route in any given situation will depend on the particular host, as well as the nature and severity of the condition for which the active ingredient is being administered, the compositions include oral, rectal, Compositions for topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

在实践中，根据常规药物配制技术，本发明的式I代表的化合物或其前药或代谢物或其药学上可接受的盐可以作为活性成分与药物载体组合成紧密混合物。载体可以采取多种形式，这取决于给药途径所需的制剂形式，例如口服或肠胃外(包括静脉内)给药途径。因此，本发明的药物组合物可以作为适于口服给药的离散单位存在，例如每个含有预定量的活性成分的胶囊、扁囊剂(cachets)或片剂。此外，组合物可以粉末形式、颗粒形式、溶液形式、水性液体中的悬浮液、非水液体、水包油乳液或油包水乳液形式存在。除了上述常见剂型外，式I代表的化合物或其药学上可接受的盐还可以通过控释装置和/或递送装置给药。该组合物可以通过任何药学方法制备。通常，这些方法包括使活性成分与构成一种或多种必需成分的载体结合的步骤。通常，通过将活性成分与液体载体或细碎的固体载体或两者均匀且紧密地混合来制备组合物。然后可以方便地将产品成形为所需的样式。In practice, the compounds represented by formula I of the present invention, or prodrugs or metabolites thereof, or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a variety of forms, depending on the desired form of formulation for the route of administration, eg, oral or parenteral (including intravenous) routes of administration. Thus, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration, such as capsules, cachets or tablets each containing a predetermined quantity of the active ingredient. In addition, the compositions may exist in powder form, granular form, solution form, suspension in aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms described above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered by controlled release devices and/or delivery devices. The composition can be prepared by any method of pharmacy. Generally, these methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both. The product can then be conveniently shaped into the desired style.

因此，本发明的药物组合物可包括药学上可接受的载体和式I的化合物或药学上可接受的盐。式I的化合物或其药学上可接受的盐也可以与一种或多种其他治疗活性化合物一起包含在药物组合物中。Accordingly, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt. A compound of formula I, or a pharmaceutically acceptable salt thereof, may also be included in a pharmaceutical composition together with one or more other therapeutically active compounds.

所用的药物载体可以例如是固体、液体或气体。固体载体的实例包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁和硬脂酸。液体载体的实例是糖浆、花生油、橄榄油和水。气态载体的实例包括二氧化碳和氮气。在制备用于口服剂型的组合物中，可以使用任何方便的药物介质。例如，水、乙二醇、油、醇、调味剂、防腐剂、着色剂等可被用于形成例如悬浮液、酏剂和溶液的口服液体制剂；而淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等载体可被用于形成如粉末、胶囊和片剂的口服固体制剂。由于易于给药，片剂和胶囊是优选的口服剂量单位，其中使用固体药物载体。任选地，片剂可以通过标准水性或非水性技术包衣。The pharmaceutical carrier used can be, for example, solid, liquid or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while starch, sugar, microcrystalline cellulose, dilute Carriers such as agents, granulating agents, lubricants, binders, disintegrating agents, etc., can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units in which solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

含有本发明组合物的片剂可以通过压制或模塑制备，任选地含有一种或多种辅助成分或佐剂。压缩片剂可以通过在合适的机器中压制如粉末或颗粒自由流动形式的活性成分，任选地与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合来制备。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末化合物的混合物来制备。每片优选含有约0.05mg至约5g活性成分，每个扁囊剂或胶囊优选含有约0.05mg至约5g活性成分。例如，用于人口服给药的制剂可含有与适当和方便量的载体物质混合的约0.5mg至约5g活性剂，载体物质可占总组合物的约0.05％至约95％。单位剂型通常含有约0.01mg至约2g活性成分，通常0.01mg、0.02mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。Tablets containing the compositions of the present invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, formulations for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent in admixture with a suitable and convenient amount of carrier material, which may comprise from about 0.05% to about 95% of the total composition. A unit dosage form typically contains from about 0.01 mg to about 2 g of active ingredient, usually 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

适合肠胃外给药的本发明药物组合物可以制备成活性化合物在水中的溶液或悬浮液。可以包括合适的表面活性剂，例如羟丙基纤维素。分散体也可以在甘油、液体聚乙二醇及其在油中的混合物中制备。此外，可以包含防腐剂以防止微生物的有害生长。Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives may be included to prevent harmful growth of microorganisms.

适用于注射用途的本发明药物组合物包括无菌水溶液或分散液。此外，组合物可以是用于临时制备这种无菌可注射溶液或分散体的无菌粉末的形式。在所有情况下，最终的可注射形式必须是无菌的并且必须是有效流动的以便于注射。药物组合物在制造和储存条件下必须是稳定的；因此，优选应该防止如细菌和真菌的微生物的污染下保藏。载体可以是例如含有水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、植物油及其合适的混合物的溶剂或分散介质。Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Additionally, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be fluid for easy injection. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, they should preferably be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

本发明的药物组合物可以是适于局部使用的形式，例如气溶胶、乳膏、软膏、洗剂、撒粉等。此外，组合物可以是适用于透皮装置的形式。利用本发明的式I化合物或其药学上可接受的盐，这些制剂可以通过常规加工方法来制备。例如，通过将亲水性材料和水与约0.05wt％至约10wt％的化合物混合以产生具有所需稠度的乳膏或软膏来制备乳膏或软膏。The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, and the like. Furthermore, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared by conventional processing methods utilizing a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water with about 0.05% to about 10% by weight of the compound to produce a cream or ointment of the desired consistency.

本发明的药物组合物可以是适于直肠给药的形式，其中载体是固体。优选混合物形成单位剂量栓剂。合适的载体包括可可脂和本领域常用的其他材料。栓剂可以通过首先将组合物与软化或熔化的载体混合，然后在模具中冷却和成型来方便地形成。The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or molten carrier, then cooling and shaping in a mold.

除了上述载体成分之外，上述药物制剂可以适当地包括一种或多种另外的载体成分，例如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等等。此外，可以包括其他佐剂以使制剂与预期接受者的血液等渗。含有式I所示化合物或其药学上可接受的盐的组合物也可以制备成粉末或液体浓缩物形式。In addition to the aforementioned carrier ingredients, the aforementioned pharmaceutical formulations may suitably include one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surfactants, thickening agents, lubricants, preservatives agents (including antioxidants), etc. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, can also be prepared in the form of powders or liquid concentrates.

通常，每天约0.001mg/kg至约150mg/kg体重的剂量水平可用于治疗上述病症，或者每位患者每天约0.05mg至约7g。例如，炎症、癌症、牛皮癣、过敏/哮喘、免疫系统的疾病和病症、中枢神经系统(CNS)的疾病和病症，可以通过每天施用每公斤体重约0.001至50mg的化合物，或者每位患者每天约0.05mg至约3.5g来有效地治疗。Typically, dosage levels of about 0.001 mg/kg to about 150 mg/kg of body weight per day can be used to treat the above-mentioned conditions, or about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the central nervous system (CNS), can be achieved by administering about 0.001 to 50 mg of the compound per kilogram of body weight per day, or about 0.001 to 50 mg per day per patient. 0.05 mg to about 3.5 g to effectively treat.

然而，应理解，任何特定患者的具体剂量水平将取决于包括年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄率、药物组合以及接受治疗的特定疾病的严重程度的多种因素。It is to be understood, however, that the specific dosage level for any particular patient will depend on factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated. of various factors.

从以下对本发明的书面描述中，这些和其他方面将变得显而易见。These and other aspects will become apparent from the following written description of the invention.

缩写abbreviation

AIBN 2,2'-偶氮二异丁腈 LC-MS 液相色谱-质谱AIBN 2,2'-azobisisobutyronitrile LC-MS Liquid chromatography-mass spectrometry

aq 水的 LDA 二异丙基氨基锂LDA Lithium Diisopropylamide in aq Water

Bn 苄基 LiHMDS 双(三甲基甲硅烷基)氨基锂Bn benzyl LiHMDS lithium bis(trimethylsilyl)amide

Boc 叔丁氧基羰 Me 甲烷Boc tert-butoxycarbonyl Me methane

Boc₂O 二碳酸二叔丁酯 MeI 碘甲烷Boc₂ O Di-tert-butyl dicarbonate MeI Iodomethane

CuI 碘化亚铜 MeCN 乙腈CuI Cuprous iodide MeCN Acetonitrile

DCM 二氯甲烷 MeOH 甲醇DCM Dichloromethane MeOH Methanol

DIAD 偶氮二甲酸二异丙酯 min 分钟DIAD Diisopropyl azodicarboxylate min min

DIEA 二异丙基胺 mL 毫升DIEA Diisopropylamine mL mL

DMAP 4-二甲基氨基吡啶 mmol 毫摩尔DMAP 4-Dimethylaminopyridine mmol mmol

DMF 二甲基甲酰胺 MTBE 甲基叔丁基醚DMF Dimethylformamide MTBE Methyl tert-butyl ether

DMSO 二甲基亚砜 NaHCO₃ 碳酸氢钠DMSO Dimethyl Sulfoxide NaHCO₃ Sodium Bicarbonate

DPPE 1,2-双(二苯基膦基)乙烷 NaHMDS 双(三甲基甲硅烷基)氨基钠DPPE 1,2-bis(diphenylphosphino)ethane NaHMDS sodium bis(trimethylsilyl)amide

dtbpy 碘(4,4-二叔丁基-2,2-联吡啶)甲基钯(II) NBS N-溴琥珀酰亚胺dtbpy Iodo(4,4-di-tert-butyl-2,2-bipyridyl)methylpalladium(II) NBS N-bromosuccinimide

equiv. 当量 n-BuLi 正丁基锂equiv. Equiv. n-BuLi n-butyllithium

Et₃N 三乙胺 NH₄OAc 醋酸铵Et₃ N Triethylamine NH₄ OAc Ammonium acetate

Et₂O 乙醚 Pd(OAc)2 醋酸钯Et₂ O Diethyl ether Pd(OAc)2 Palladium acetate

EtOAc 乙酸乙酯 Pd(dppf)Cl₂ [1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)EtOAc Ethyl acetate Pd(dppf)Cl₂ [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

EtOH 乙醇 Prep-TLC 制备薄层色谱EtOH Ethanol Prep-TLC Preparative Thin Layer Chromatography

g 克 SEM 三甲硅基乙氧基甲基g Gram SEM Trimethylsilylethoxymethyl

h or hr 小时 SEM-Cl 2-(三甲基甲硅烷基)乙氧基甲基氯h or hr hours SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride

HBPin 频哪醇硼烷 RT 保留时间HBPin pinacol borane RT retention time

HPLC 高压液相色谱 r.t. 室温HPLC High pressure liquid chromatography r.t. room temperature

iPrOH 异丙醇 TEA 三乙胺iPrOH Isopropanol TEA Triethylamine

KOtBu 叔丁醇钾 THF 四氢呋喃KOtBu Potassium tert-butoxide THF Tetrahydrofuran

制备方法Preparation

有机合成领域的技术人员可采用如下描述的若干方法及有机合成化学领域熟知的合成方法或该领域技术人员知悉的上述方法的变化很好的合成本发明所述的化合物。优选的方法不限于如下描述的方法。本文引用的文献以引用的方式整体并入。Those skilled in the art of organic synthesis can well synthesize the compounds of the present invention using several of the methods described below and synthetic methods well known in the art of synthetic organic chemistry or variations of the above methods known to those skilled in the art. The preferred method is not limited to the method described below. The documents cited herein are incorporated by reference in their entirety.

下文描述的合成方法意图说明本发明，而非限制其主题和这些实施例中声称的化合物范围。在制备的起始化合物没有被描述时，它们是商业上可获得的或者可以与已知化合物或此处描述的方法类似地制备。文献中描述的物质可根据公开的合成方法制备。The synthetic methods described below are intended to illustrate the invention, but not to limit its subject matter and the scope of the compounds claimed in these examples. Where the starting compounds prepared are not described, they are either commercially available or can be prepared analogously to known compounds or methods described herein. Materials described in the literature can be prepared according to published synthetic methods.

式I的化合物可参考如下方案说明的方法制备。如此处所示，目标化合物是具有与式I描述的相同的结构式的产品。应当理解，任何式I化合物可以通过选择具有适当取代的试剂来制备。本领域技术人员可以容易地选择溶剂、温度、压力和其他反应条件。根据有机合成的标准方法(T.W.Green和P.G.M.Wuts(1999)Protective Groups in OrganicSynthesis，第3版，John Wiley&Sons)操作保护基团。使用本领域技术人员显而易见的方法在化合物合成的某些阶段去除这些基团。Compounds of formula I can be prepared by reference to the methods illustrated in the schemes below. As shown here, the target compound is a product having the same structural formula as described in Formula I. It will be appreciated that any compound of formula I can be prepared by selection of reagents with appropriate substitutions. Solvents, temperatures, pressures and other reaction conditions can be readily selected by those skilled in the art. Protecting groups were manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at certain stages of compound synthesis using methods apparent to those skilled in the art.

方案1plan 1

在方案1中描述了本发明所示化合物的一般合成路径，其中所述的R₁、R₂、R₃、R₄、W₁和W₂取代基是在之前的文本中被描述的或者是能够转化为需要的最终取代基的官能团。L是如卤素的离去基团。M是合适的偶合配体，例如硼酸、硼酸酯或锡烃。如方案1所示，在所述中间体(其合成在方案2至方案5中阐述)与卤素取代的吡啶(如但不限于2,5-二溴-3-硝基吡啶(1))之间的Suzuki反应可获得官能团化的吡啶(2)。于高的温度(如但不限于的150℃)，在膦试剂(如但不限于1,2-双(二苯基膦基)乙烷(DPPE))和溶剂(如但不限于1,2-二氯苯)的存在下，(2)的Cadogan还原环化可以得到官能团化的式(3)的四环化合物。使用试剂(如但不限于三苯基膦和偶氮二甲酸二异丙酯(DIAD))的(3)与烷基化剂(4)的Mitsunobu偶联反应提供(5)。使用Suzuku或Stille反应条件，(5)与(6)的合适偶联(此外M是合适的偶联配体，如硼酸、硼酯或锡烷)能产生化合物(7)，该化合物(7)具有通式(I)所示的相同结构，或能进一步转化为最终的通式式(I)的化合物。如果化合物(7)具有官能团(如但不限于乙基酯)，使用试剂(如但不限于MeMgBr)能提供通式式(I)的化合物。如果化合物(7)具有保护基团(如但不限于SEM)，其能被脱保护，然后进一步官能团化以提供通式式(I)的化合物。_A general synthetic route to_compounds of the present invention is depicted in Scheme₁ , wherein the R1, R2,_R3 , R4,_W1 and_W2 substituents are described in previous texts or are A functional group that can be converted to the desired final substituent. L is a leaving group such as halogen. M is a suitable coupling ligand such as boronic acid, boronic ester or tin hydrocarbon. As shown in Scheme 1, between the intermediate (whose synthesis is described in Schemes 2 to 5) and a halogen-substituted pyridine such as, but not limited to, 2,5-dibromo-3-nitropyridine (1) The Suzuki reaction between can obtain functionalized pyridine (2). At high temperature (such as but not limited to 150 ℃), in phosphine reagent (such as but not limited to 1,2-bis(diphenylphosphino)ethane (DPPE)) and solvent (such as but not limited to 1,2 In the presence of dichlorobenzene), the Cadogan reductive cyclization of (2) can obtain a functionalized tetracyclic compound of formula (3). Mitsunobu coupling reaction of (3) with an alkylating agent (4) using reagents such as but not limited to triphenylphosphine and diisopropyl azodicarboxylate (DIAD) provides (5). Using Suzuku or Stille reaction conditions, suitable coupling of (5) with (6) (in addition M is a suitable coupling ligand such as boronic acid, boronic ester or stannane) can yield compound (7), which is (7) It has the same structure shown in general formula (I), or can be further transformed into the final compound of general formula (I). If compound (7) has a functional group (such as but not limited to ethyl esters), the use of reagents (such as but not limited to MeMgBr) can provide compounds of general formula (I). If compound (7) has a protecting group (such as but not limited to SEM), it can be deprotected and then further functionalized to provide compounds of general formula (I).

如方案2所示，一种通式中间体能被获取。As shown in Scheme 2, an intermediate of the general formula can be obtained.

方案2Scenario 2

在溶剂(如但不限于EtOH)中，使用NaOEt，化合物(8)和2-叠氮基乙酸乙酯的反应提供式(9)的化合物。于升高的温度(如在约110℃)下，在溶剂(如但不限于无水甲苯)中，式(9)的化合物转化为式(10)的化合物。在碱(如但不限于NaH)存在下，于溶剂(如但不限于DMF)中，(10)与卤烷R₁-hal(如但不限于MeI)或保护试剂(SEM-Cl)的N烷基化提供式(11)的化合物。于升高的温度(如70℃)，在溶剂中(如但不限于THF)，在双(1,5-环辛二烯)二甲氧基二铱和4,4'-二叔丁基-2,2'-联吡啶的存在下，使用HBPin处理(11)提供所述中间体。The reaction of compound (8) with ethyl 2-azidoacetate using NaOEt in a solvent such as but not limited to EtOH provides a compound of formula (9). Compounds of formula (9) are converted to compounds of formula (10) in a solvent such as, but not limited to, anhydrous toluene at elevated temperature (eg, at about 110°C). In the presence of a base (such as but not limited to NaH), in a solvent (such as but not limited to DMF), (10) N with a haloalkane R₁ -hal (such as but not limited to MeI) or a protecting reagent (SEM-Cl) Alkylation provides compounds of formula (11). At elevated temperature (eg, 70°C), in a solvent (eg, but not limited to THF), in bis(1,5-cyclooctadiene)dimethoxydiiridium and 4,4'-di-tert-butyl Treatment of (11) with HBPin in the presence of -2,2'-bipyridine provides the intermediate.

另外地，如方案3所示，一种通式中间体能被合成。Alternatively, as shown in Scheme 3, an intermediate of the general formula can be synthesized.

方案3Scenario 3

在溶剂(如但不限于EtOH)中，使用NaOEt，化合物(12)和2-叠氮基乙酸乙酯的反应提供式(13)的化合物。于升高的温度(如在约110℃)下，在溶剂(如但不限于无水甲苯)中，式(13)的化合物转化为式(14)的化合物。在碱(如但不限于NaH)存在下，于溶剂(如但不限于DMF)中，(14)与卤烷R₁-hal(如但不限于MeI)或保护试剂(SEM-Cl)的N烷基化提供式(15)的化合物。于升高的温度(如70℃)，在溶剂中(如但不限于THF)，在双(1,5-环辛二烯)二甲氧基二铱和4,4'-二叔丁基-2,2'-联吡啶的存在下，使用HBPin处理(15)提供所述中间体。The reaction of compound (12) and ethyl 2-azidoacetate in a solvent such as but not limited to EtOH using NaOEt provides compounds of formula (13). Compounds of formula (13) are converted to compounds of formula (14) in a solvent such as, but not limited to, anhydrous toluene at elevated temperature (eg, at about 110°C). In the presence of a base (such as but not limited to NaH), in a solvent (such as but not limited to DMF), (14) with a haloalkane R₁ -hal (such as but not limited to MeI) or N of a protecting reagent (SEM-Cl) Alkylation provides compounds of formula (15). At elevated temperature (eg, 70°C), in a solvent (eg, but not limited to THF), in bis(1,5-cyclooctadiene)dimethoxydiiridium and 4,4'-di-tert-butyl Treatment of (15) with HBPin in the presence of -2,2'-bipyridine provides the intermediate.

另外地，如方案4所示，一种通式中间体能被合成：Alternatively, as shown in Scheme 4, an intermediate of the general formula can be synthesized:

方案4Scenario 4

于升高的温度(如但不限于85℃)，N₂下，在NBS和AIBN存在下，在溶剂(如但不限于乙腈)中，处理3-甲基噻吩-2-羧酸甲酯(16)提供(17)。于升高的温度(如但不限于80℃)下，在碱(如但不限于K₂CO₃)存在下，在溶剂(如但不限于MeOH)中，使用试剂NH₂R₃(18)处理，(17)转化为式(19)的化合物。在DMF的溶剂中，在碱(如但不限于NaH)存在下处理(19)及随后添加烷基卤R₁-hal或R₂-hal(如MeI)能提供式(20)的化合物。在-78℃，在溶剂(如但不限于THF)中，使用强碱(如但不限于LDA)，(20)的反应及随后使用硼酸三异丙酯能提供所述的通式中间体。Methyl 3-methylthiophene-₂ -carboxylate ( 16) Provide (17). At elevated temperature (such as but not limited to 80°C) in the presence of a base (such as but not limited to K2CO3₎ in a solvent (such as but not limited to MeOH) using the reagent_NH2R3(18 ) Upon treatment, (17) is converted to compounds of formula (19). Treatment of (19) in the presence of a base such as but not limited to NaH followed by addition of an alkyl halide R1_- hal or R2_- hal (eg MeI) in a solvent of DMF can provide compounds of formula (20). The reaction of (20) followed by triisopropyl borate using a strong base (such as but not limited to LDA) in a solvent (such as but not limited to THF) at -78°C can provide the intermediate of the general formula.

另外地，如方案5所示，一种通式中间体能被合成。Alternatively, as shown in Scheme 5, an intermediate of the general formula can be synthesized.

方案5Scenario 5

在-60℃至室温，在溶剂(如但不限于THF)中，使用碱(如但不限于t-BuONa)，在2-硝基噻吩(21)和2-氯乙酸乙酯(22)之间的偶联反应能提供化合物(23)。在升高的温度(如110℃)，在二氧六环和H₂O(5:1,v:v)的组合溶剂中，在铁粉和FeSO₄.7H₂O存在下，化合物(23)的NO₂官能团的还原能提供化合物(24)。在-80℃至室温之间，在溶剂(如但不限于THF)中，(24)和AlMe₃的反应能提供化合物(25)。在溶剂(如但不限于DMF)中，在碱(如但不限于NaH)存在下，与烷基卤R₃-hal(如但不限于MeI)的(25)的N烷基化，或与作为保护基(PG)的如但不限于SEM-Cl的(25)的N烷基化能提供式(26)的化合物。于0℃，在溶剂(如但不限于THF)中，使用强碱(如但不限于NaH)处理(26)，接着添加烷基卤R₁-hal或R₂-hal(如但不限于碘甲烷和碘乙烷)能提供式(27)的化合物。在-20℃至室温之间，在溶剂(如但不限于DCM)中，在[Ir(COD)(OMe)]₂和dtbpy存在下，HBPin与化合物(27)的反应能提供所述中间体。Between 2-nitrothiophene (21) and 2-chloroethyl acetate (22) at -60°C to room temperature in a solvent such as but not limited to THF using a base such as but not limited to t-BuONa A coupling reaction between can provide compound (23). Compound (23) in the presence of iron powder and FeSO₄ .7H₂ O in a combined solvent of dioxane and H₂ O (5:1, v:v) at elevated temperature (eg 110°C) Reduction of the NO₂ functionality of ) affords compound (24). The reaction of (24) with AlMe₃ in a solvent such as but not limited to THF between -80°C and room temperature can provide compound (25). N alkylation of (25) with an alkyl halide_R3 -hal (such as but not limited to MeI) in a solvent (such as but not limited to DMF) in the presence of a base (such as but not limited to NaH), or with N alkylation of (25) as a protecting group (PG) such as but not limited to SEM-Cl can provide compounds of formula (26). Treatment (26) with a strong base such as but not limited to NaH in a solvent such as but not limited to THF at 0°C followed by addition of an alkyl halide R₁ -hal or R₂ -hal (such as but not limited to iodine) methane and iodoethane) can provide compounds of formula (27). The reaction of HBPin with compound (27) in the presence of [Ir(COD)(OMe)]₂ and dtbpy in a solvent such as but not limited to DCM between -20°C and room temperature can provide the intermediate .

实施例1Example 1

(S)-2-(7-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-基)丙烷-2-醇(“化合物1”)(S)-2-(7-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-9-(phenyl(tetrahydro-2H -pyran-4-yl)methyl)-1,9-dihydropyrrole[2",3":4',5']thiophene[2',3':4,5]pyrrole[3,2- b] Pyridin-2-yl)propan-2-ol ("Compound 1")

步骤1:(Z)-2-叠氮基-3-(噻吩-2-基)丙烯酸乙酯Step 1: Ethyl (Z)-2-azido-3-(thiophen-2-yl)acrylate

在N₂，向噻吩-2-甲醛(29.7g,0.16mol)的EtOH(220mL)溶液中加入2-叠氮基乙酸乙酯(40.32g,0.31mol)。在-10℃至-5℃，向该混合物中滴加新鲜的NaOEt溶液(在0℃，由Na(8.90g,0.39mol)和无水乙醇(350mL)制备)。所得到的悬浮液在-5℃至0℃之间搅拌2小时。采用冷的饱和氯化铵溶液淬灭所述反应混合物，以调节其pH至约8。过滤沉淀的固体，使用冷水(50mL)洗涤且在真空下干燥以产生3.56g粗产品。通过硅胶色谱纯化该粗产品，以0-5％EtOAc的己烷溶液洗脱获得标题化合物(5.67g,12％产率)。To a solution of thiophene-₂ -carbaldehyde (29.7 g, 0.16 mol) in EtOH (220 mL) under N2 was added ethyl 2-azidoacetate (40.32 g, 0.31 mol). To this mixture was added dropwise a fresh solution of NaOEt (prepared from Na (8.90 g, 0.39 mol) and absolute ethanol (350 mL) at 0 °C) at -10°C to -5°C. The resulting suspension was stirred between -5°C and 0°C for 2 hours. The reaction mixture was quenched with cold saturated ammonium chloride solution to adjust its pH to about 8. The precipitated solid was filtered, washed with cold water (50 mL) and dried under vacuum to yield 3.56 g of crude product. The crude product was purified by silica gel chromatography, eluting with 0-5% EtOAc in hexanes to give the title compound (5.67 g, 12% yield).

步骤2:4H-噻吩[3,2-b]吡咯-5-羧酸乙酯Step 2: Ethyl 4H-thiophene[3,2-b]pyrrole-5-carboxylate

将(Z)-2-叠氮基-3-(噻吩-2-基)丙烯酸乙酯(5.62g,25.2mmol)溶解在无水甲苯(60mL)中。该混合物在110℃搅拌1h。然后，将该反应混合物倒入水中并用EtOAc(2×)萃取。合并的萃取物用盐水(2×)洗涤，无水硫酸钠干燥，过滤并在减压下浓缩。残余物通过硅胶色谱纯化，以0-10％EtOAc的己烷溶液洗脱获得标题化合物(4.34g,22.2mmol,88％产率)。LC-MS[M+H]⁺＝196。(Z)-ethyl 2-azido-3-(thiophen-2-yl)acrylate (5.62 g, 25.2 mmol) was dissolved in dry toluene (60 mL). The mixture was stirred at 110 °C for 1 h. Then, the reaction mixture was poured into water and extracted with EtOAc (2x). The combined extracts were washed with brine (2x), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexanes to give the title compound (4.34 g, 22.2 mmol, 88% yield). LC-MS [M+H]⁺ =196.

步骤3:4-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯Step 3: 4-Methyl-4H-thiophene[3,2-b]pyrrole-5-carboxylate ethyl ester

在室温下，向4H-噻吩[3,2-b]吡咯-5-羧酸乙酯(4.24g,21.7mmol)的DMF(20mL)溶液中加入K₂CO₃(7.82g,56.6mmol)，接着滴加碘甲烷(2.52g,17.8mmol)。该混合物在室温下搅拌2h。使用水淬灭该反应并用EtOAc(3×)萃取。用盐水洗涤合并的有机相，无水硫酸钠干燥，过滤并在减压下浓缩。残余物通过硅胶色谱纯化，以0-10％EtOAc的己烷溶液洗脱获得所述标题化合物(3.96g,18.9mmol,87％产率)。LC-MS[M+H]⁺＝210。To a solution of ethyl 4H-thiophene[3,2-b]pyrrole-5-carboxylate (4.24 g, 21.7 mmol) in DMF (₂₀ mL) was added K2CO3 (7.82_g , 56.6 mmol) at room temperature, Next, iodomethane (2.52 g, 17.8 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-10% EtOAc in hexanes to give the title compound (3.96 g, 18.9 mmol, 87% yield). LC-MS [M+H]⁺ =210.

步骤4:4-甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯Step 4: 4-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4H-thiophene[3,2-b]pyrrole -5-Carboxylic acid ethyl ester

在N₂下，向4-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯(720mg,3.44mmol)的THF(15mL)溶液中加入双(1,5-环辛二烯)二甲氧基二铱(126mg,0.19mmol)和4,4'-二叔丁基-2,2'-联吡啶(285mg,1.06mmol)。然后，在-10℃至-5℃之间加入HBPin(2.25g,17.6mmol)。将该混合物脱气，充N₂，并重复该过程3次。所获得的混合物在75℃搅拌2h。在减压下浓缩该反应混合物得到黑油，其未经纯化直接用于下一步的反应。LC-MS[M+H]⁺＝336。To a solution of ethyl 4-methyl-4H-thiophene[3,2-b]pyrrole-5-carboxylate (720 mg, 3.44 mmol) in THF (15 mL) under_N2 was added bis(1,5-cyclic Octadienyl)dimethoxydiiridium (126 mg, 0.19 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (285 mg, 1.06 mmol). Then, HBPin (2.25 g, 17.6 mmol) was added between -10°C and -5°C. The mixture was degassed, flushed with_N2 , and the process repeated 3 times. The obtained mixture was stirred at 75 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a black oil, which was used in the next reaction without purification. LC-MS [M+H]⁺ =336.

步骤5:2-(5-溴-3-硝基吡啶-2-基)-4-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯Step 5: Ethyl 2-(5-Bromo-3-nitropyridin-2-yl)-4-methyl-4H-thiophene[3,2-b]pyrrole-5-carboxylate

向上述粗化合物4-甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯的水(7mL)和THF(21mL)溶液中加入2,5-二溴-3-硝基吡啶(1.18g,4.19mmol)和K₃PO₄(2.21g,10.41mmol)。使用N₂流将该混合物脱气和接着在N₂下滴加Pd(PPh₃)₄(410mg,0.35mmol)。该反应混合物回流过夜。使用EtOAc(2×100mL)萃取该反应混合物。使用盐水洗涤合并的有机相，无水硫酸钠干燥，过滤并在减压条件下浓缩。残余物通过硅胶色谱纯化，以0-10％EtOAc的己烷溶液洗脱获得标题化合物(820mg,58％产率)。LC-MS[M+H]⁺＝410。To the above crude compound 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4H-thiophene[3,2-b] To a solution of ethyl pyrrole-5-carboxylate in water (7 mL) and THF (21 mL) was added 2,5-dibromo-3-nitropyridine (1.18 g, 4.19 mmol) and K₃ PO₄ (2.21 g, 10.41 g) mmol). The mixture was degassed using a stream of N₂ and then Pd(PPh₃ )₄ (410 mg, 0.35 mmol) was added dropwise under N₂ . The reaction mixture was refluxed overnight. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in hexanes to give the title compound (820 mg, 58% yield). LC-MS [M+H]⁺ =410.

步骤6:7-溴-1-甲基-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 6: 7-Bromo-1-methyl-1,9-dihydropyrrole[2",3":4',5']thiophene[2',3':4,5]pyrrole[3,2- b]Ethyl pyridine-2-carboxylate

在N₂下，将在1,2-二氯苯(20mL)中的2-(5-溴-3-硝基吡啶-2-基)-4-甲基-4H-噻吩[3,2-b]吡咯-5-羧酸乙酯(770mg,1.88mmol)和DPPE(1.89g,4.74mmol)的混合物加热至150℃并搅拌2h。然后，将该反应混合物冷却至室温。在旋转蒸发仪上除去大部分溶剂。残余物通过硅胶色谱纯化，以0-10％EtOAc的DCM溶液洗脱获得标题化合物(280mg,39％产率)。LC-MS[M+H]⁺＝378。_2- (5-Bromo-3-nitropyridin-2-yl)-4-methyl-4H-thiophene[3,2- b] A mixture of ethyl pyrrole-5-carboxylate (770 mg, 1.88 mmol) and DPPE (1.89 g, 4.74 mmol) was heated to 150 °C and stirred for 2 h. Then, the reaction mixture was cooled to room temperature. Most of the solvent was removed on a rotary evaporator. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc in DCM to afford the title compound (280 mg, 39% yield). LC-MS [M+H]⁺ =378.

步骤7:(S)-7-溴-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 7: (S)-7-Bromo-1-methyl-9-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,9-dihydropyrrole[2",3 ":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylate ethyl ester

室温下，向7-溴-1-甲基-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(250mg,0.66mmol)、(R)-苯基(四氢-2H-吡喃-4-基)甲醇(260mg,1.37mmol)和三苯基膦(526mg,2.00mmol)的干燥甲苯(10mL)溶液中滴加二异丙基偶氮二甲酸酯(412mg,2.04mmol)。所得溶液回流2h。冷却至室温后，用水(20mL)淬灭该反应并用EtOAc(3×30mL)萃取。以盐水洗涤合并的有机相，无水硫酸钠干燥，收集滤液并减压浓缩。残余物通过硅胶色谱纯化，使用梯度的0-30％EtOAc的己烷溶液洗脱获得标题化合物(110mg,30％产率)。LC-MS:[M+H]⁺＝552。7-Bromo-1-methyl-1,9-dihydropyrrole[2",3":4',5']thiophene[2',3':4,5]pyrrole[3,2 -b] ethyl pyridine-2-carboxylate (250 mg, 0.66 mmol), (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (260 mg, 1.37 mmol) and triphenylphosphine ( To a solution of 526 mg, 2.00 mmol) in dry toluene (10 mL) was added diisopropylazodicarboxylate (412 mg, 2.04 mmol) dropwise. The resulting solution was refluxed for 2h. After cooling to room temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in hexanes to give the title compound (110 mg, 30% yield). LC-MS: [M+H]⁺ =552.

步骤8:(S)-7-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 8: (S)-7-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-9-(phenyl(tetrahydro-2H -pyran-4-yl)methyl)-1,9-dihydropyrrole[2",3":4',5']thiophene[2',3':4,5]pyrrole[3,2- b]Ethyl pyridine-2-carboxylate

N₂下，向(S)-7-溴-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(110mg,0.20mmol)的1,4-二氧六环(5mL)的溶液中添加1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(289mg,0.75mmol)、PdCl₂(PPh₃)₂(21mg,0.030mmol)和DIEA(85mg,0.66mmol)。使用N₂流将反应混合物脱气，密封并在125℃搅拌过夜。将反应混合物冷却至室温，倒入水(10mL)中并用EtOAc(3×15mL)萃取。采用盐水(20mL)洗涤合并的有机相，无水硫酸钠干燥，收集滤液并减压浓缩。粗产品通过制备HPLC纯化，以梯度的0％至5％MeOH的EtOAc溶液洗脱获得标题化合物(80mg,70％产率)。LC-MS[M+H]⁺＝569。To (S)-7-bromo-1-methyl-9-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,9-dihydropyrrole[₂ " under N ,3":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylate ethyl ester (110 mg, 0.20 mmol) in 1,4-dicarboxylate To the solution of oxane (5 mL) was added 1,4-dimethyl-5-(tributyltin)-1H-1,2,3-triazole (289 mg, 0.75 mmol), PdCl₂ (PPh₃ )₂ (21 mg, 0.030 mmol) and DIEA (85 mg, 0.66 mmol). The reaction mixture was degassed using a stream of_N2 , sealed and stirred at 125 °C overnight. The reaction mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by preparative HPLC eluting with a gradient of 0% to 5% MeOH in EtOAc to afford the title compound (80 mg, 70% yield). LC-MS [M+H]⁺ =569.

步骤9:(S)-2-(7-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-基)丙烷-2-醇Step 9: (S)-2-(7-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-9-(phenyl(tetrazolium) Hydrogen-2H-pyran-4-yl)methyl)-1,9-dihydropyrrole[2",3":4',5']thiophene[2',3':4,5]pyrrole[3 ,2-b]pyridin-2-yl)propan-2-ol

N₂下，在-10℃至-5℃之间，向(S)-7-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-9-(苯基(四氢-2H-吡喃-4-基)甲基)-1,9-二氢吡咯[2”,3”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(60mg,0.10mmol)的THF(5mL)溶液中滴加甲基溴化镁(2.5mL)。将该混合物温至室温并搅拌2h。使用饱和的氯化铵水溶液淬灭该反应并用EtOAc(3×30mL)萃取。采用盐水(2×)洗涤合并的有机层，无水硫酸钠干燥，过滤并减压浓缩。粗产品通过制备HPLC纯化，以梯度的0％至5％MeOH的DCM溶液洗脱获得标题化合物(29mg,52％产率)。LC-MS[M+H]⁺＝555.¹H-NMR(400MHz,DMSO-d₆)δ8.34(s,1H),8.02(s,1H),7.65(d,J＝8.0Hz,2H),7.33(m,3H),6.53(s,1H),5.91(d,J＝12.0Hz,1H),4.48(s,3H),3.89(d,J＝4.0Hz,1H),3.85(s,3H),3.77(d,J＝8.0Hz,1H),3.51-3.48(m,2H),3.29-3.21(m,1H),2.18(s,3H),1.88(d,J＝12.0Hz,1H),1.65(s,6H),1.51-1.49(m,1H),1.43–1.33(m,1H),0.99(d,J＝12.0Hz,1H)。To (S)-7-(1,4-dimethyl_- 1H-1,2,3-triazol-5-yl)-1- Methyl-9-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,9-dihydropyrrole[2",3":4',5']thiophene[2', To a solution of ethyl 3':4,5]pyrrole[3,2-b]pyridine-2-carboxylate (60 mg, 0.10 mmol) in THF (5 mL) was added methylmagnesium bromide (2.5 mL) dropwise. The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2x), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC eluting with a gradient of 0% to 5% MeOH in DCM to afford the title compound (29 mg, 52% yield). LC-MS [M+H]⁺ =555.¹ H-NMR (400MHz, DMSO-d₆ ) δ 8.34(s, 1H), 8.02(s, 1H), 7.65(d, J=8.0Hz, 2H ), 7.33(m, 3H), 6.53(s, 1H), 5.91(d, J=12.0Hz, 1H), 4.48(s, 3H), 3.89(d, J=4.0Hz, 1H), 3.85(s ,3H),3.77(d,J=8.0Hz,1H),3.51-3.48(m,2H),3.29-3.21(m,1H),2.18(s,3H),1.88(d,J=12.0Hz, 1H), 1.65 (s, 6H), 1.51-1.49 (m, 1H), 1.43-1.33 (m, 1H), 0.99 (d, J=12.0Hz, 1H).

实施例2Example 2

(S)-2-(6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-基)丙烷-2-醇(“化合物2”)(S)-2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H -pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2- b] Pyridin-2-yl)propan-2-ol ("Compound 2")

步骤1:(Z)-2-叠氮基-3-(噻吩-3-基)丙烯酸乙酯Step 1: (Z)-ethyl 2-azido-3-(thiophen-3-yl)acrylate

N₂下，在-10℃至-5℃之间，向噻吩-3-甲醛(4.95g,44.14mol)和2-叠氮基乙酸乙酯(8.61g,66.68mol)的EtOH(50mL)溶液中滴加新鲜制备的NaOEt溶液(0℃下，将Na(2.41g,104.78mol)悬浮在无水乙醇(50mL中)。所得悬浮液在-5℃至0℃之间搅拌2h。使用冷的饱和氯化铵水溶液淬灭该反应混合物，并且其pH被调节到约8。使用EtOAc(3×300mL)萃取该混合物。使用盐水(100mL)洗涤合并的有机相，无水硫酸钠干燥，过滤并减压浓缩。残余物使用己烷通过硅胶色谱纯化获得标题化合物(4.69g,48％产率)。To a solution of thiophene-3-carbaldehyde (4.95 g, 44.14 mol) and ethyl 2-azidoacetate (8.61 g, 66.68 mol) in EtOH (50 mL) between -10 °C and -5 °C under_N2 A freshly prepared NaOEt solution was added dropwise (Na (2.41 g, 104.78 mol) was suspended in absolute ethanol (50 mL) at 0 °C. The resulting suspension was stirred between -5 °C and 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride, and its pH was adjusted to about 8. The mixture was extracted with EtOAc (3 x 300 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and Concentrate under reduced pressure. The residue was purified by silica gel chromatography using hexane to give the title compound (4.69 g, 48% yield).

步骤2:6H-噻吩[2,3-b]吡咯-5-羧酸乙酯Step 2: Ethyl 6H-thiophene[2,3-b]pyrrole-5-carboxylate

将(Z)-2-叠氮基-3-(噻吩-3-基)丙烯酸乙酯(4.16g,18.63mmol)溶解在无水对二甲苯(10mL)中。将该混合物在145℃搅拌3h。残余物通过硅胶色谱纯化，使用梯度的0-10％EtOAc的己烷溶液洗脱获得标题化合物(1.77g,48％产率)。LC-MS[M+H]⁺＝196。¹H-NMR(400MHz,DMSO-d₆)δ12.2(s,1H),7.11(d,J＝8.0Hz,1H),7.01(d,J＝4.0Hz,1H),6.99(d,J＝2.0Hz,1H),4.28-4.24(m,2H),1.30(t,J＝7.1Hz,3H)。(Z)-ethyl 2-azido-3-(thiophen-3-yl)acrylate (4.16 g, 18.63 mmol) was dissolved in dry p-xylene (10 mL). The mixture was stirred at 145 °C for 3 h. The residue was purified by silica gel chromatography, eluting with a gradient of 0-10% EtOAc in hexanes to give the title compound (1.77 g, 48% yield). LC-MS [M+H]⁺ =196.¹ H-NMR (400MHz, DMSO-d₆ )δ12.2(s, 1H), 7.11(d, J=8.0Hz, 1H), 7.01(d, J=4.0Hz, 1H), 6.99(d, J = 2.0 Hz, 1H), 4.28-4.24 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).

步骤3:6-甲基-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯Step 3: Ethyl 6-Methyl-6H-thiophene[2,3-b]pyrrole-5-carboxylate

室温下，向6H-噻吩[2,3-b]吡咯-5-羧酸乙酯(1.77g,9.06mmol)的DMF(15mL)的溶液中添加K₂CO₃(3.81g,27.6mmol)，接着滴加碘甲烷(1.65g,11.6mmol)。将该混合物在室温下搅拌3h。用水(30ml)淬灭该反应并用EtOAc(3×50mL)萃取。用盐水(4×50ml)洗涤合并的有机相，无水硫酸钠干燥，过滤并减压浓缩。残余物通过硅胶色谱纯化，使用梯度的0-5％EtOAc的己烷溶液获取标题化合物(1.83g,96％产率)。LC-MS[M+H]⁺＝210。To a solution of ethyl 6H-thiophene[2,3-b]pyrrole-5-carboxylate (1.77 g, 9.06 mmol) in DMF (15 mL) was added K2CO3 (_3.81g , 27.6 mmol) at room temperature, Next, iodomethane (1.65 g, 11.6 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (4 x 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-5% EtOAc in hexanes to obtain the title compound (1.83 g, 96% yield). LC-MS [M+H]⁺ =210.

步骤4:6-甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯Step 4: 6-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6H-thiophene[2,3-b]pyrrole -5-Carboxylic acid ethyl ester

按照实施例1步骤4中描述的类似的步骤，将6-甲基-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯(1.42g,6.78mmol)转化为标题粗化合物，其直接用于下一步。LC-MS[M+H]⁺＝336。Following procedures analogous to those described in Example 1, Step 4, ethyl 6-methyl-6H-thiophene[2,3-b]pyrrole-5-carboxylate (1.42 g, 6.78 mmol) was converted to the title crude compound, It was used directly in the next step. LC-MS [M+H]⁺ =336.

步骤5:2-(5-溴-3-硝基吡啶-2-基)-6-甲基-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯Step 5: 2-(5-Bromo-3-nitropyridin-2-yl)-6-methyl-6H-thiophene[2,3-b]pyrrole-5-carboxylate ethyl ester

向2,5-二溴-3-硝基吡啶(2.31g,8.19mmol)的水(10mL)和THF(50mL)的溶液中加入6-甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯(4.61g,6.78mmol)和K₃PO₄(4.38g,20.64mmol)。用N₂将所得混合物脱气及，接着，在N₂下添加Pd(dppf)Cl₂(568mg,0.70mmol)。将该反应混合物在50℃搅拌过夜。用EtOAc(3×150mL)萃取该反应混合物。用盐水(200mL)洗涤合并的有机相，无水硫酸钠干燥，收集滤液并减压浓缩。残余物通过硅胶色谱纯化，使用梯度的0-10％EtOAc的己烷溶液洗脱获得标题化合物(1.18g,42％产率)。LC-MS[M+H]⁺＝410。To a solution of 2,5-dibromo-3-nitropyridine (2.31 g, 8.19 mmol) in water (10 mL) and THF (50 mL) was added 6-methyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaboran-2-yl)-6H-thiophene[2,3-b]pyrrole-5-carboxylate (4.61 g, 6.78 mmol) and K₃ PO₄ (4.38 g, 20.64 mmol). The resulting mixture was degassed with_N2 and then Pd(dppf)Cl2 (568_mg , 0.70 mmol) was added under_N2 . The reaction mixture was stirred at 50°C overnight. The reaction mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexanes to give the title compound (1.18 g, 42% yield). LC-MS [M+H]⁺ =410.

步骤6:6-溴-1-甲基-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 6: 6-Bromo-1-methyl-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2- b]Ethyl pyridine-2-carboxylate

按照实施例1步骤6中所描述的类似步骤，将2-(5-溴-3-硝基吡啶-2-基)-6-甲基-6H-噻吩[2,3-b]吡咯-5-羧酸乙酯(1.18g,2.88mmol)转化为标题化合物(320mg,29％产率)。LC-MS[M+H]⁺＝378。Following procedures similar to those described in Example 1, Step 6, 2-(5-bromo-3-nitropyridin-2-yl)-6-methyl-6H-thiophene[2,3-b]pyrrole-5 - Ethyl carboxylate (1.18 g, 2.88 mmol) was converted to the title compound (320 mg, 29% yield). LC-MS [M+H]⁺ =378.

步骤7:(S)-6-溴-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 7: (S)-6-Bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2 ":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylate ethyl ester

按照实施例1步骤7中所描述的类似步骤，将6-溴-1-甲基-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(300mg,0.79mmol)和(R)-苯基(四氢-2H-吡喃-4-基)甲醇(320mg,1.68mmol)转化为标题化合物(810mg粗品)。使用梯度的0％至2％的甲醇乙酸乙酯溶液通过制备HPLC对该产品纯化得到产物(160mg,37％产率)。LC-MS[M+H]⁺＝552。Following a procedure similar to that described in Example 1, Step 7, 6-bromo-1-methyl-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3' : 4,5]Ethyl pyrrole[3,2-b]pyridine-2-carboxylate (300mg, 0.79mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (320mg , 1.68 mmol) was converted to the title compound (810 mg crude). The product was purified by preparative HPLC using a gradient of 0% to 2% methanol in ethyl acetate to give the product (160 mg, 37% yield). LC-MS [M+H]⁺ =552.

步骤8:(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯Step 8: (S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2- b]Ethyl pyridine-2-carboxylate

按照实施例1步骤8中类似的步骤，将(S)-6-溴-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(160mg,0.29mmol)和1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(466mg,1.21mmol)转化为粗的标题化合物，其通过制备HPLC纯化，使用0％至2％MeOH的EtOAc溶液洗脱获得化合物(79mg,48％产率)。LC-MS[M+H]⁺＝569。Following procedures analogous to Example 1, Step 8, (S)-6-bromo-1-methyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4 - Dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2-carboxylate (160 mg, 0.29 mmol ) and 1,4-dimethyl-5-(tributyltin)-1H-1,2,3-triazole (466 mg, 1.21 mmol) were converted to the crude title compound, which was purified by preparative HPLC using 0% Elution to 2% MeOH in EtOAc gave the compound (79 mg, 48% yield). LC-MS [M+H]⁺ =569.

步骤9:(S)-2-(6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-基)丙烷-2-醇Step 9: (S)-2-(6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl-4-(phenyl(tetrazolium) Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3 ,2-b]pyridin-2-yl)propan-2-ol

按照实施例1的步骤9中类似的步骤，将(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1-甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2-羧酸乙酯(60mg,0.10mmol)转化为粗的标题化合物，其通过制备HPLC纯化，使用0％至5％MeOH的DCM溶液洗脱获得标题化合物(35mg,63％产率)。LC-MS[M+H]⁺＝555。¹H-NMR(400MHz,DMSO-d₆)δ8.32(s,1H),8.28(s,1H),7.62(d,J＝8.0Hz,2H),7.28(m,3H),6.79(s,1H),5.65(d,J＝12.0Hz,1H),5.31(s,1H),3.95(s,3H),3.94(s,3H),3.89(d,J＝8.0Hz,1H),3.77(d,J＝12.0Hz,1H),3.50-3.37(m,1H),3.30-3.16(m,2H),2.25(s,3H),1.65(s,3H),1.64(s,3H),1.55(s,2H),1.39-1.19(m,2H)。Following procedures analogous to step 9 of Example 1, (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-methyl- 4-(Phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3': 4,5] Ethyl pyrrole[3,2-b]pyridine-2-carboxylate (60 mg, 0.10 mmol) was converted to the crude title compound, which was purified by preparative HPLC using 0% to 5% MeOH in DCM Removal afforded the title compound (35 mg, 63% yield). LC-MS [M+H]⁺ =555.¹ H-NMR (400MHz, DMSO-d₆ )δ8.32(s, 1H), 8.28(s, 1H), 7.62(d, J=8.0Hz, 2H), 7.28(m, 3H), 6.79(s ,1H),5.65(d,J＝12.0Hz,1H),5.31(s,1H),3.95(s,3H),3.94(s,3H),3.89(d,J＝8.0Hz,1H),3.77 (d, J=12.0Hz, 1H), 3.50-3.37(m, 1H), 3.30-3.16(m, 2H), 2.25(s, 3H), 1.65(s, 3H), 1.64(s, 3H), 1.55(s, 2H), 1.39-1.19(m, 2H).

实施例3Example 3

(S)-3-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-6,6,7-三甲基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(“化合物3”)(S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,6,7-trimethyl-5-(phenyl(tetrahydro -2H-pyran-4-yl)methyl)-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole[3, 2-b]pyridin-8(5H)-one ("Compound 3")

步骤1:3-(溴甲基)噻吩-2-羧酸甲酯Step 1: Methyl 3-(bromomethyl)thiophene-2-carboxylate

N₂下，向3-甲基噻吩-2-羧酸甲酯(2.99g，19.2mmol)的乙腈(38mL)溶液中加入NBS(3.98g,22.4mmol)和AIBN(1.01g,6.20mmol)，将该混合物在85℃搅拌15h。将该反应体系冷却至室温，减压浓缩。残余物添加水(50mL)并用EtOAc(100mL)萃取。用盐水洗涤有机相，无水硫酸钠干燥，过滤并减压浓缩获得粗的3-(溴甲基)噻吩-2-羧酸甲酯(5.57g),其未经纯化直接用于下一步。LC-MS[M+H]⁺＝236。To a solution of methyl 3-methylthiophene-₂ -carboxylate (2.99 g, 19.2 mmol) in acetonitrile (38 mL) under N2 was added NBS (3.98 g, 22.4 mmol) and AIBN (1.01 g, 6.20 mmol), The mixture was stirred at 85°C for 15h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The residue was added with water (50 mL) and extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude methyl 3-(bromomethyl)thiophene-2-carboxylate (5.57 g), which was used directly in the next step without purification. LC-MS [M+H]⁺ =236.

步骤2:3-(氨甲基)噻吩-2-羧酸甲酯Step 2: Methyl 3-(aminomethyl)thiophene-2-carboxylate

向3-(溴甲基)噻吩-2-羧酸甲酯(5.57g,粗品)的甲醇(30mL)溶液中加入NH₃的甲醇溶液(7N,40mL)。所得混合物在25℃搅拌3h。将反应体系减压浓缩并向残余物中加入EtOAc(25mL)。将该混合物搅拌30min，通过过滤收集所得固体并用EtOAc(2mL)洗涤得所述标题化合物(2.17g，12.6mmol,两步66％收率)。LC-MS[M+H]⁺＝172。To a solution of methyl 3-(bromomethyl)thiophene-2-carboxylate (5.57 g, crude) in methanol (30 mL) was added_NH3 in methanol (7N, 40 mL). The resulting mixture was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure and EtOAc (25 mL) was added to the residue. The mixture was stirred for 30 min and the resulting solid was collected by filtration and washed with EtOAc (2 mL) to give the title compound (2.17 g, 12.6 mmol, 66% yield for two steps). LC-MS [M+H]⁺ =172.

步骤3:4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮Step 3: 4,5-Dihydro-6H-thiophene[2,3-c]pyrrol-6-one

向3-(氨甲基)噻吩-2-羧酸甲酯(2.27g,14.5mmol)的甲醇(20mL)溶液中加入K₂CO₃(5.27g,38.1mmol)。将所得混合物在80℃搅拌10h。将反应体系冷却至室温，减压浓缩。向该残余物中添加水(100mL)并用EtOAc(500mL)萃取。用盐水洗涤有机相，无水硫酸钠干燥，过滤并减压浓缩。该残余物通过硅胶色谱，使用25％EtOAc的己烷溶液获得标题化合物(0.61g,31％产率)。LC-MS:[M+H]⁺＝140。¹H-NMR(400MHz,DMSO-d₆)δ8.38(s,1H),7.94(d,J＝4.0Hz,1H),7.19(d,J＝4.0Hz,1H),4.29(s,2H)。To a solution of methyl 3-(aminomethyl)thiophene-2-carboxylate (2.27 g, 14.5 mmol) in methanol (₂₀ mL) was added K2CO3 (5.27_g , 38.1 mmol). The resulting mixture was stirred at 80 °C for 10 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (100 mL) and extracted with EtOAc (500 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel using 25% EtOAc in hexanes to give the title compound (0.61 g, 31% yield). LC-MS: [M+H]⁺ =140.¹ H-NMR (400MHz, DMSO-d₆ )δ8.38(s, 1H), 7.94(d, J=4.0Hz, 1H), 7.19(d, J=4.0Hz, 1H), 4.29(s, 2H) ).

步骤4:4,4,5-三甲基-4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮Step 4: 4,4,5-Trimethyl-4,5-dihydro-6H-thiophene[2,3-c]pyrrol-6-one

在0℃，在10min内，向4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮(2.02g,14.5mmol)的DMF(20mL)溶液中分批加入NaH(60％,2.98g,72.7mmol)，然后将该混合物升至室温并搅拌30min。将反应体系冷却至0℃，接着加入CH₃I(10.8g,73.0mmol)，缓慢升至室温并在N₂下搅拌1.5h。在0℃，用水(20mL)淬灭该反应并用EtOAc(100mL)萃取。用盐水洗涤该有机相，无水硫酸钠干燥，收集滤液并减压浓缩。残余物通过硅胶色谱纯化，使用梯度的5-10％EtOAc的溶液洗脱获取标题化合物(1.75g,70％产率)。LC-MS[M+H]⁺＝182。¹H-NMR(400MHz,CDCl₃)δ7.59(d,J＝4.0Hz,1H),7.00(d,J＝4.0Hz,1H),2.98(s,3H),1.44(s,6H)。To a solution of 4,5-dihydro-6H-thiophene[2,3-c]pyrrol-6-one (2.02 g, 14.5 mmol) in DMF (20 mL) was added portionwise NaH ( 60%, 2.98 g, 72.7 mmol), then the mixture was warmed to room temperature and stirred for 30 min. The reaction was cooled to 0 °C, then_CH3I (10.8 g, 73.0 mmol) was added, slowly warmed to room temperature and stirred under_N2 for 1.5 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL) at 0 °C. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-10% EtOAc to afford the title compound (1.75 g, 70% yield). LC-MS [M+H]⁺ =182.¹ H-NMR (400 MHz, CDCl₃ ) δ 7.59 (d, J=4.0 Hz, 1H), 7.00 (d, J=4.0 Hz, 1H), 2.98 (s, 3H), 1.44 (s, 6H).

步骤5:(4,4,5-三甲基-6-氧代-5,6-二氢-4H-噻吩[2,3-c]吡咯-2-基)硼酸Step 5: (4,4,5-Trimethyl-6-oxo-5,6-dihydro-4H-thiophene[2,3-c]pyrrol-2-yl)boronic acid

在-78℃，N₂下，30min内，向4,4,5-三甲基-4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮(2.72g,15.0mmol)的THF(60mL)溶液中滴加LDA(2N,14mL,28.5mmol)并将所得混合物在-78℃搅拌1h。然后，30min内，在-78℃滴加硼酸三异丙酯。所得反应混合物搅拌另外的1h，并且在0℃至10℃之间通过2N HCl(25mL)淬灭，达到pH5-6。向该混合物中加入盐水50mL，并且然后用EtOAc(150mL)萃取。用盐水洗涤有机相，无水硫酸钠干燥，过滤并减压浓缩。所得残余物用EtOAc(20mL)搅拌。通过过滤收集该固体并在空气中干燥获得标题化合物(2.18g,70％产率)。LC-MS[M+H]⁺＝226。To 4,4,5_- trimethyl-4,5-dihydro-6H-thiophene[2,3-c]pyrrol-6-one (2.72 g, 15.0 mmol) in THF (60 mL) was added dropwise LDA (2N, 14 mL, 28.5 mmol) and the resulting mixture was stirred at -78 °C for 1 h. Then, within 30 min, triisopropyl borate was added dropwise at -78°C. The resulting reaction mixture was stirred for an additional 1 h and quenched by 2N HCl (25 mL) between 0°C and 10°C to pH 5-6. To the mixture was added brine 50 mL, and then extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was stirred with EtOAc (20 mL). The solid was collected by filtration and dried in air to give the title compound (2.18 g, 70% yield). LC-MS [M+H]⁺ =226.

步骤6:2-(5-溴-3-硝基吡啶-2-基)-4,4,5-三甲基-4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮Step 6: 2-(5-Bromo-3-nitropyridin-2-yl)-4,4,5-trimethyl-4,5-dihydro-6H-thiophene[2,3-c]pyrrole- 6-keto

向(4,4,5-三甲基-6-氧代-5,6-二氢-4H-噻吩[2,3-c]吡咯-2-基)硼酸(2.16g,9.62mmol)的THF(100mL)和水(25mL)的溶液中加入2,5-二溴-3-硝基吡啶(2.98g,10.6mmol)、Pd(dppf)Cl₂(0.69g,0.67mmol)和K₃PO₄(6.02g,28.4mmol)，该混合物充N₂2min。所得混合物在35℃搅拌2.5h，接着加入水(50mL)，并用EtOAc(100mL)萃取。用盐水洗涤所得有机相，无水硫酸钠干燥，并且通过过滤收集滤液。在旋转蒸发仪上去除溶剂，所得残余物通过硅胶色谱纯化，使用梯度的10-20％EtOAc的己烷溶液洗脱获得标题化合物(2.32g,65％产率)。LC-MS[M+H]⁺＝382。To (4,4,5-trimethyl-6-oxo-5,6-dihydro-4H-thiophene[2,3-c]pyrrol-2-yl)boronic acid (2.16 g, 9.62 mmol) in THF To a solution of (100 mL) and water (25 mL) was added 2,5-dibromo-3-nitropyridine (2.98 g, 10.6 mmol), Pd(dppf)Cl₂ (0.69 g, 0.67 mmol) and K₃ PO₄ (6.02 g, 28.4 mmol), the mixture was charged with N2 for₂ min. The resulting mixture was stirred at 35 °C for 2.5 h, then water (50 mL) was added and extracted with EtOAc (100 mL). The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, and the filtrate was collected by filtration. The solvent was removed on a rotary evaporator and the resulting residue was purified by silica gel chromatography using a gradient of 10-20% EtOAc in hexanes to give the title compound (2.32 g, 65% yield). LC-MS [M+H]⁺ =382.

步骤7:3-溴-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮Step 7: 3-Bromo-6,6,7-trimethyl-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole [3,2-b]pyridin-8(5H)-one

向2-(5-溴-3-硝基吡啶-2-基)-4,4,5-三甲基-4,5-二氢-6H-噻吩[2,3-c]吡咯-6-酮(1.61g,4.21mmol)的二甲基苯溶液中加入磷酸三乙酯(4.55g,27.4mmol)并且充N₂1min。所得混合物在130o C搅拌3h。将该反应混合物冷却至室温。固体从该溶剂中出来并通过过滤收集，己烷洗涤得到标题化合物(0.67g,43％产率)。LC-MS[M+H]⁺＝350。To 2-(5-bromo-3-nitropyridin-2-yl)-4,4,5-trimethyl-4,5-dihydro-6H-thiophene[2,3-c]pyrrole-6- To a solution of ketone (1.61 g, 4.21 mmol) in dimethylbenzene was added triethyl phosphate (4.55 g, 27.4 mmol) and flushed with N2 for₁ min. The resulting mixture was stirred at 130°C for 3h. The reaction mixture was cooled to room temperature. The solid came out of the solvent and was collected by filtration and washed with hexanes to give the title compound (0.67 g, 43% yield). LC-MS [M+H]⁺ =350.

步骤8:(S)-3-溴-6,6,7-三甲基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮Step 8: (S)-3-Bromo-6,6,7-trimethyl-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-6,7-dihydropyrrole [3",4":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-8(5H)-one

按照实施例2的步骤7中描述的类似的步骤，将3-溴-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(1.05g,3mmol)和(R)-苯基(四氢-2H-吡喃-4-基)甲醇(0.98g,5.16mmol)转化为标题化合物(0.45g,30％产率)，并通过使用梯度的0-20％EtOAc己烷溶液的硅胶色谱纯化。LC-MS[M+H]⁺＝524。Following a procedure similar to that described in Step 7 of Example 2, 3-bromo-6,6,7-trimethyl-6,7-dihydropyrrole[3",4":4',5']thiophene was [2',3':4,5]pyrro[3,2-b]pyridin-8(5H)-one (1.05 g, 3 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4 -yl)methanol (0.98 g, 5.16 mmol) was converted to the title compound (0.45 g, 30% yield) and purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexanes. LC-MS [M+H]⁺ =524.

步骤9:(S)-3-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-6,6,7-三甲基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮Step 9: (S)-3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-6,6,7-trimethyl-5-(phenyl (Tetrahydro-2H-pyran-4-yl)methyl)-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole [3,2-b]pyridin-8(5H)-one

按照实施例2步骤8中类似的步骤，将(S)-3-溴-6,6,7-三甲基-5-(苯基(四氢-2H-吡喃-4-基)甲基)-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(0.45g,0.85mmol)和1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(0.59g,1.50mmol)转化为标题化合物(170mg,53％产率)，并通过使用梯度的0-50％EtOAc的DCM溶液的硅胶色谱纯化。LC-MS[M+H]⁺＝541。¹H-NMR(400MHz,DMSO-d₆)δ8.59(s,1H),8.07(s,1H),7.71(d,J＝8.0Hz,2H),7.49-7.40(m,3H),5.53(d,J＝8.0Hz,1H),3.99(m,1H),3.90(s,3H),3.63-3.57(m,3H),3.33(m,1H),3.11(s,3H),2.21(s,3H),2.11-2.07(m,1H),1.89(s,3H),1.84(s,3H),1.68-1.64(m,1H),1.23-1.41(m,2H)。Following procedures analogous to Example 2, Step 8, (S)-3-bromo-6,6,7-trimethyl-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl )-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-8(5H)-one (0.45 g, 0.85 mmol) and 1,4-dimethyl-5-(tributyltin)-1H-1,2,3-triazole (0.59 g, 1.50 mmol) were converted to the title compound (170 mg, 53%) yield) and purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM. LC-MS [M+H]⁺ =541.¹ H-NMR (400MHz, DMSO-d₆ )δ8.59(s, 1H), 8.07(s, 1H), 7.71(d, J=8.0Hz, 2H), 7.49-7.40(m, 3H), 5.53 (d, J=8.0Hz, 1H), 3.99(m, 1H), 3.90(s, 3H), 3.63-3.57(m, 3H), 3.33(m, 1H), 3.11(s, 3H), 2.21( s,3H), 2.11-2.07(m,1H), 1.89(s,3H), 1.84(s,3H), 1.68-1.64(m,1H), 1.23-1.41(m,2H).

实施例4Example 4

3-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(“化合物4”)3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran- 4-yl)methyl)-6,6,7-trimethyl-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5] Pyrro[3,2-b]pyridin-8(5H)-one ("Compound 4")

步骤1:(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇Step 1: (3-Fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol

在N₂下，向镁(24.3g,1.00mol)的THF(500mL)悬浮液中加入三颗碘晶体，接着滴加纯净的4-溴四氢-2H-吡喃(100g,607mmoL)，滴加过程中，控制内部温度低于45℃。在环境温度下，将该反应混合物继续搅拌2h。将该反应混合物冷却至-30℃，接着滴加3-氟吡啶甲醛(50.3g,402mmoL)的THF(300mL)溶液，在滴加过程中内部温度保持在-20℃至-30℃。1h后，将反应混合物通过薄薄的硅藻土垫过滤。向滤液中加入饱和的NH₄Cl(100mL)水溶液，分离成两层。无水Na₂SO₄干燥有机相并收集滤液。滤液在旋转蒸发仪上浓缩。粗化合物使用反相色谱纯化，以40-50％MeCN的H₂O溶液洗脱，获得外消旋化合物(52g,61％产率),其通过手性制备SFC分离获得对映异构体A(25.1g,29.6％产率)和对映异构体B(25.3g,29.7％产率)。To a suspension of magnesium (24.3 g, 1.00 mol) in THF (500 mL) under_N2 was added three iodine crystals, followed by dropwise addition of neat 4-bromotetrahydro-2H-pyran (100 g, 607 mmol), dropwise During the addition, the internal temperature was controlled to be lower than 45°C. The reaction mixture was stirred for an additional 2 h at ambient temperature. The reaction mixture was cooled to -30°C, followed by the dropwise addition of 3-fluoropyridinecarbaldehyde (50.3 g, 402 mmoL) in THF (300 mL), maintaining the internal temperature at -20°C to -30°C during the addition. After 1 h, the reaction mixture was filtered through a thin pad of celite. To the filtrate was added saturated aqueous_NH4Cl (100 mL), and the two layers were separated._The organic phase was dried over anhydrous_Na2SO4 and the filtrate was collected. The filtrate was concentrated on a rotary evaporator. The crude compound was purified using reverse phase chromatography eluting with 40-50% MeCN in_H2O to give the racemic compound (52 g, 61% yield) which was separated by chiral preparative SFC to give enantiomer A (25.1 g, 29.6% yield) and Enantiomer B (25.3 g, 29.7% yield).

对映异构体A:LC-MS[M+H]⁺＝212。手性色谱报告:RT＝12.25min(柱:ChiralpakAY-H(ADH0CE-VC001 0.46×25cm；流动相:90/10/0.1己烷/EtOH/DEA；流速:1.0mL/min).¹HNMR(400MHz,DMSO-d₆)δ8.42(dd,J＝3.20,1.32Hz,1H),7.66(ddd,J＝9.8,8.36,1.12Hz,1H),7.42-7.35(m,1H),5.23(d,J＝6.52Hz,1H),4.52(dd,J＝7.32,7.28Hz,1H),3.88(dd,J＝11.4,2.92Hz,1H),3.75(dd,J＝11.2,3.02Hz,1H),3.26(dt,J＝12.0,2.04Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.12-2.01(m,1H),1.82(dd,J＝13.3,1.52Hz,1H),1.38-1.24(m,1H),1.24-1.12(m,1H),1.00(dd,J＝12.9,1.34,1H)。Enantiomer A: LC-MS [M+H]⁺ =212. Chiral chromatography report: RT=12.25min (column: ChiralpakAY-H (ADH0CE-VC001 0.46×25cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0mL/min).¹ HNMR (400MHz) ,DMSO-d₆ )δ8.42(dd,J=3.20,1.32Hz,1H),7.66(ddd,J=9.8,8.36,1.12Hz,1H),7.42-7.35(m,1H),5.23(d , J=6.52Hz, 1H), 4.52 (dd, J=7.32, 7.28Hz, 1H), 3.88 (dd, J=11.4, 2.92Hz, 1H), 3.75 (dd, J=11.2, 3.02Hz, 1H) ,3.26(dt,J＝12.0,2.04Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.12-2.01(m,1H),1.82(dd,J＝13.3,1.52Hz,1H) ), 1.38-1.24 (m, 1H), 1.24-1.12 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

对映异构体B:LC-MS[M+H]⁺＝212。手性色谱报告:RT＝13.57min(柱:ChiralpakAY-H(ADH0CE-VC001 0.46×25cm；流动相:90/10/0.1己烷/EtOH/DEA；流速:1.0mL/min)。¹HNMR(400MHz,DMSO-d₆)δ8.42(dd,J＝3.2,1.35Hz,1H),7.66(ddd,J＝1.12,8.4,9.8Hz,1H),7.42-7.35(m,1H),5.23(d,J＝6.48Hz,1H),4.52(dd,J＝7.32,7.24Hz,1H),3.88(dd,J＝11.3,2.96,1H),3.75(dd,J＝2.96,11.2Hz,1H),3.26(dt,J＝12.0,2.0Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.01-2.12(m,1H),1.82(dd,J＝13.3,1.52Hz,1H),1.24-1.38(m,1H),1.24–1.12(m,1H),1.00(dd,J＝12.9,1.34,1H)。Enantiomer B: LC-MS [M+H]⁺ =212. Chiral chromatography report: RT=13.57 min (column: ChiralpakAY-H (ADHOCE-VC001 0.46×25 cm; mobile phase: 90/10/0.1 hexane/EtOH/DEA; flow rate: 1.0 mL/min).¹ HNMR (400 MHz) ,DMSO-d₆ )δ8.42(dd,J=3.2,1.35Hz,1H),7.66(ddd,J=1.12,8.4,9.8Hz,1H),7.42-7.35(m,1H),5.23(d , J=6.48Hz, 1H), 4.52 (dd, J=7.32, 7.24Hz, 1H), 3.88 (dd, J=11.3, 2.96, 1H), 3.75 (dd, J=2.96, 11.2Hz, 1H), 3.26(dt,J＝12.0,2.0Hz,1H),3.17(dt,J＝11.8,2.24Hz,1H),2.01-2.12(m,1H),1.82(dd,J＝13.3,1.52Hz,1H) , 1.24-1.38 (m, 1H), 1.24-1.12 (m, 1H), 1.00 (dd, J=12.9, 1.34, 1H).

步骤2:3-溴-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮Step 2: 3-Bromo-5-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6,6,7-trimethyl-6,7 -Dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-8(5H)-one

按照实施例2步骤7中类似的步骤，在干燥的甲苯(15mL)中，将3-溴-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(200mg,0.57mmol)和(3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲醇(来自于步骤1的对映异构体A，150mg,0.69mmol)、三苯基膦(387mg,1.47mmol)转化为标题化合物(73mg,25％产率)，通过硅胶色谱使用梯度的10-20％EtOAc的己烷溶液纯化。LC-MS[M+H]⁺＝543。Following a procedure similar to Example 2, Step 7, in dry toluene (15 mL), 3-bromo-6,6,7-trimethyl-6,7-dihydropyrrole[3",4":4 ',5']thiophene[2',3':4,5]pyrro[3,2-b]pyridin-8(5H)-one (200 mg, 0.57 mmol) and (3-fluoropyridin-2-yl) (Tetrahydro-2H-pyran-4-yl)methanol (Enantiomer A from Step 1, 150 mg, 0.69 mmol), triphenylphosphine (387 mg, 1.47 mmol) were converted to the title compound (73 mg, 25% yield), purified by silica gel chromatography using a gradient of 10-20% EtOAc in hexanes. LC-MS [M+H]⁺ =543.

步骤3:3-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮Step 3: 3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-((3-fluoropyridin-2-yl)(tetrahydro-2H- Pyran-4-yl)methyl)-6,6,7-trimethyl-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4 ,5]pyrro[3,2-b]pyridin-8(5H)-one

按照实施例2步骤8中类似的合成步骤，将3-溴-5-((3-氟吡啶-2-基)(四氢-2H-吡喃-4-基)甲基)-6,6,7-三甲基-6,7-二氢吡咯[3”,4”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-8(5H)-酮(73mg,0.13mmol)和1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(91mg,0.24mmol)转化为标题化合物(42mg,56％产率)，其通过硅胶色谱使用梯度的0-50％EtOAc的DCM溶液纯化。LC-MS[M+H]⁺＝560。¹H NMR(400MHz,DMSO-d₆)δ8.59(d,J＝4.52Hz,1H),8.56(d,J＝1.76Hz,1H),8.26(d,J＝1.80Hz,1H),7.85-7.79(m,1H),7.59-7.55(m,1H),5.80(d,J＝10.48Hz,1H),3.95(s,3H),3.86(d,J＝8.0Hz,1H),3.66(d,J＝12.0Hz,1H),3.43-3.34(m,2H),3.15-3.12(m,1H),3.02(s,3H),2.21(s,3H),1.85(s,3H),1.72-1.69(m,1H),1.66(s,3H),1.57-1.47(m,1H),1.26-1.21(m,1H),0.51(m,1H)。Following a similar synthetic procedure in Example 2, Step 8, 3-bromo-5-((3-fluoropyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methyl)-6,6 ,7-Trimethyl-6,7-dihydropyrrole[3",4":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-8 (5H)-one (73 mg, 0.13 mmol) and 1,4-dimethyl-5-(tributyltin)-1H-1,2,3-triazole (91 mg, 0.24 mmol) were converted to the title compound (42 mg) , 56% yield), which was purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM. LC-MS [M+H]⁺ =560.¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.59 (d, J=4.52 Hz, 1H), 8.56 (d, J=1.76 Hz, 1H), 8.26 (d, J=1.80 Hz, 1H), 7.85 -7.79(m,1H),7.59-7.55(m,1H),5.80(d,J=10.48Hz,1H),3.95(s,3H),3.86(d,J=8.0Hz,1H),3.66( d, J=12.0Hz, 1H), 3.43-3.34(m, 2H), 3.15-3.12(m, 1H), 3.02(s, 3H), 2.21(s, 3H), 1.85(s, 3H), 1.72 -1.69(m, 1H), 1.66(s, 3H), 1.57-1.47(m, 1H), 1.26-1.21(m, 1H), 0.51(m, 1H).

实施例5Example 5

(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1,3,3-三甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(“化合物5”)(S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1,3,3-trimethyl-4-(phenyl(tetrahydro -2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3, 2-b]pyridin-2(3H)-one ("Compound 5")

步骤1:2-(2-硝基噻吩-3-基)乙酸乙酯Step 1: Ethyl 2-(2-nitrothiophen-3-yl)acetate

在-60℃，向2-硝基噻吩(24.9g,0.19mol)的THF(800mL)溶液中滴加t-BuONa(54.33g,0.57mol)的THF(100mL)溶液。将该混合物在-60℃搅拌1h。在-60℃，加入2-氯乙酸乙酯(23.7g,0.19mol)并在-60℃搅拌1h。将该混合物温至室温并且在室温搅拌1h。向该混合物中加入饱和的NH₄Cl(15mL)水溶液并且在室温下搅拌10min。在该混合物中加入Na₂SO₄(30g)并将该混合物过滤且滤液减压浓缩。残余物通过硅胶色谱使用0-50％EtOAc的己烷溶液纯化获得标题化合物。(19.6g,48％产率)。LC-MS[M+H]⁺＝216；¹H NMR(400MHz,DMSO-d₆)δ7.97(d,J＝5.2Hz,1H),7.22(d,J＝5.2Hz,1H),4.13-4.07(m,4H),1.18(t,J＝7.2Hz,3H)。To a solution of 2-nitrothiophene (24.9 g, 0.19 mol) in THF (800 mL) was added dropwise a solution of t-BuONa (54.33 g, 0.57 mol) in THF (100 mL) at -60°C. The mixture was stirred at -60°C for 1 h. At -60°C, ethyl 2-chloroacetate (23.7 g, 0.19 mol) was added and stirred at -60°C for 1 h. The mixture was warmed to room temperature and stirred at room temperature for 1 h. To the mixture was added saturated aqueous_NH4Cl (15 mL) and stirred at room temperature for 10 min. To the mixture was added_Na2SO4( 30 g) and the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-50% EtOAc in hexanes to give the title compound. (19.6 g, 48% yield). LC-MS [M+H]⁺ =216;¹ H NMR (400 MHz, DMSO-d₆ ) δ 7.97 (d, J=5.2 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 4.13 -4.07(m, 4H), 1.18(t, J=7.2Hz, 3H).

步骤2:2-(2-氨基噻吩-3-基)乙酸乙酯Step 2: Ethyl 2-(2-Aminothiophen-3-yl)acetate

N₂下，向2-(2-硝基噻吩-3-基)乙酸乙酯(19.6g,91.0mmol)的二氧六环(400mL)和H₂O(80mL)的溶液中加入铁粉(18.3g,328mmol)、FeSO₄.7H₂O(5.26g,18.9mmol)。将该混合物抽真空，回填N₂，且该过程重复三次，并在110℃搅拌16h。将该反应混合物冷却至室温，在该混合物中加入Na₂SO₄(120g)，并将该混合物过滤，将滤液减压浓缩获得2-(2-氨基噻吩-3-基)乙酸乙酯粗品(19.5g)。LC-MS[M+H]⁺＝186。To a solution of ethyl 2-(2-nitrothiophen-3-yl)acetate (19.6 g, 91.0 mmol) in dioxane (400 mL) and H₂ O (80 mL) under N₂ was added iron powder ( 18.3 g, 328 mmol),_FeSO4.7H2O (5.26_g , 18.9 mmol). The mixture was evacuated, backfilled with_N2 , and the process was repeated three times and stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, Na₂ SO₄ (120 g) was added to the mixture, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude ethyl 2-(2-aminothiophen-3-yl)acetate ( 19.5g). LC-MS [M+H]⁺ =186.

步骤3:4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 3: 4,6-Dihydro-5H-thiophene[2,3-b]pyrrol-5-one

在N₂下，于-80℃，向2-(2-氨基噻吩-3-基)乙酸乙酯(19.5g,91.0mmol)粗品的THF(400mL)溶液中滴加AlMe₃的己烷溶液(2M,50mL)。将该混合物在-80℃搅拌1h，升至室温并继续搅拌16h。滴加4M HCl水溶液(80mL)并在室温下搅拌20min。向该混合物中加入Na₂SO₄(140g)并将该混合物过滤。滤液减压浓缩并且残余物通过硅胶色谱使用梯度的0-30％EtOAc的己烷溶液纯化获得标题化合物(6.96g,两步41％收率)。LC-MS[M+H]⁺＝140；¹H NMR(400MHz,DMSO-d₆)δ10.47(br s,1H),6.91(d,J＝5.2Hz,1H),6.83(d,J＝5.2Hz,1H),3.39(s,2H)。To a solution of crude 2-(₂ -aminothiophen-3-yl)acetate (19.5 g, 91.0 mmol) in THF (400 mL) was added dropwise a solution_of AlMe in hexane ( 2M, 50 mL). The mixture was stirred at -80°C for 1 h, warmed to room temperature and stirring continued for 16 h. Aqueous 4M HCl (80 mL) was added dropwise and stirred at room temperature for 20 min. To the mixture was added_Na2SO4( 140 g) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using a gradient of 0-30% EtOAc in hexanes to afford the title compound (6.96 g, 41% yield over two steps). LC-MS [M+H]⁺ =140;¹ H NMR (400 MHz, DMSO-d₆ ) δ 10.47 (br s, 1H), 6.91 (d, J=5.2 Hz, 1H), 6.83 (d, J = 5.2Hz, 1H), 3.39 (s, 2H).

步骤4:4,4,6-三甲基-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 4: 4,4,6-Trimethyl-4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one

在0℃，向4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(3.93g,28.2mmol)的THF(80mL)溶液中缓慢加入NaH(60％在矿物油中,4.54g,113.50mmol)。添加之后，将该混合物在0℃搅拌30min并且接着滴加碘甲烷(16.2g,114mmol)。将该混合物温至室温并搅拌3h。将该混合物倒入水中(100mL)，用EtOAc(3×100mL)萃取，盐酸洗涤，无水硫酸钠干燥，过滤及滤液减压浓缩。残余物通过硅胶色谱使用梯度的0-50％EtOAc的己烷溶液纯化获得标题化合物(2.71g,53％产率)。LC-MS[M+H]⁺＝182。¹H NMR(400MHz,DMSO-d₆)δ7.01(d,J＝4.8Hz,1H),6.98(d,J＝5.2Hz,1H),3.14(s,3H),1.24(s,6H)。To a solution of 4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one (3.93 g, 28.2 mmol) in THF (80 mL) at 0 °C was slowly added NaH (60% in mineral oil) in, 4.54 g, 113.50 mmol). After addition, the mixture was stirred at 0 °C for 30 min and then iodomethane (16.2 g, 114 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into water (100 mL), extracted with EtOAc (3 x 100 mL), washed with hydrochloric acid, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to give the title compound (2.71 g, 53% yield). LC-MS [M+H]⁺ =182.¹ H NMR (400MHz, DMSO-d₆ ) δ 7.01 (d, J=4.8 Hz, 1H), 6.98 (d, J=5.2 Hz, 1H), 3.14 (s, 3H), 1.24 (s, 6H) .

步骤5:4,4,6-三甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 5: 4,4,6-Trimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4,6-dihydro -5H-thiophene[2,3-b]pyrrol-5-one

在-20℃，N₂下，向[Ir(COD)(OMe)]₂(0.97g,0.29mmol)、4,4,6-三甲基-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(1.02g,5.63mmol)和dtbpy(459mg,1.71mmol)的DCM(20mL)溶液中加入HBPin(3.61g,28.21mmol)的DCM(5mL)溶液。将该反应混合物在室温下搅拌4h。减压除去大部分溶剂以获得标题化合物(2.62g)。LC-MS[M+H]⁺＝308。To [Ir(COD)(OMe)]₂₍ 0.97 g, 0.29 mmol), 4,4,6-trimethyl-4,6-dihydro-5H-thiophene[2 ,3-b]pyrrol-5-one (1.02 g, 5.63 mmol) and dtbpy (459 mg, 1.71 mmol) in DCM (20 mL) was added HBPin (3.61 g, 28.21 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 4 h. Most of the solvent was removed under reduced pressure to obtain the title compound (2.62 g). LC-MS [M+H]⁺ =308.

步骤6:2-(5-溴-3-硝基吡啶-2-基)-4,4,6-三甲基-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 6: 2-(5-Bromo-3-nitropyridin-2-yl)-4,4,6-trimethyl-4,6-dihydro-5H-thiophene[2,3-b]pyrrole- 5-keto

N₂下，向4,4,6-三甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮粗品(2.62g,5.63mmol)的二氧六环(50mL)和水(10mL)的溶液中加入2,5-二溴-3-硝基吡啶(1.57g,5.57mmol)、Pd(PPh₃)₄(654mg,0.57mmol)和Na₂CO₃(1.83g,17.27mmol)。将该混合物抽真空，回填N₂，并且该过程重复3次并在75℃搅拌16h。将该反应混合物冷却至室温，倒入水(50mL)中，并且用EtOAc(3×50mL)萃取。用盐水洗涤合并的有机相，无水硫酸钠干燥，及减压浓缩。残余物通过硅胶色谱使用0-10％EtOAc的己烷溶液纯化获得标题化合物(424mg,两步20％产率)。LC-MS:[M+H]⁺＝383。¹H NMR(400MHz,DMSO-d₆)δ8.83(d,J＝2.4Hz,1H),8.64(d,J＝2.0Hz,1H),7.26(s,1H),3.21(s,3H),1.27(s,6H)。under_N2 , to 4,4,6-trimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4,6- 2,5-Dibromo-2,5-dibromo- 3-Nitropyridine (1.57 g, 5.57 mmol), Pd(_PPh3 )₄ (654 mg, 0.57 mmol) and_Na2CO3 (1.83_g , 17.27 mmol). The mixture was evacuated, backfilled with_N2 , and this process was repeated 3 times and stirred at 75°C for 16h. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-10% EtOAc in hexanes to give the title compound (424 mg, 20% yield for two steps). LC-MS: [M+H]⁺ =383.¹ H NMR (400MHz, DMSO-d₆ ) δ 8.83(d, J=2.4Hz, 1H), 8.64(d, J=2.0Hz, 1H), 7.26(s, 1H), 3.21(s, 3H) , 1.27(s, 6H).

步骤7:6-溴-1,3,3-三甲基-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 7: 6-Bromo-1,3,3-trimethyl-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole [3,2-b]pyridin-2(3H)-one

向2-(5-溴-3-硝基吡啶-2-基)-4,4,6-三甲基-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(292mg,0.76mmol)的1,2-二氯苯(6mL)的溶液中加入DPPE(397mg,1.00mmol)。将该混合物抽真空，回填N₂，并且该过程重复3次及在N₂下于160℃搅拌5h。将该反应冷却至室温，并通过硅胶色谱使用梯度的0-20％EtOAc的己烷溶液纯化获得标题化合物(86mg,33％产率)。LC-MS[M+H]⁺＝350。To 2-(5-bromo-3-nitropyridin-2-yl)-4,4,6-trimethyl-4,6-dihydro-5H-thiophene[2,3-b]pyrrole-5- To a solution of the ketone (292 mg, 0.76 mmol) in 1,2-dichlorobenzene (6 mL) was added DPPE (397 mg, 1.00 mmol). The mixture was evacuated, backfilled with_N2 , and the process was repeated 3 times and stirred at 160 °C for 5 h under_N2 . The reaction was cooled to room temperature and purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexanes to afford the title compound (86 mg, 33% yield). LC-MS [M+H]⁺ =350.

步骤8:(S)-6-溴-1,3,3-三甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 8: (S)-6-Bromo-1,3,3-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole [3",2":4',5']thiophene[2',3':4,5]pyrro[3,2-b]pyridin-2(3H)-one

向6-溴-1,3,3-三甲基-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(86mg,0.25mmol)的甲苯(2mL)溶液中加入三苯基膦(135mg,0.51mmol)和(R)-苯基(四氢-2H-吡喃-4-基)甲醇(61mg,0.32mmol)。将该混合物抽真空，回填N₂，且该过程回填3次。在N₂，室温下加入DIAD(107mg,0.53mmol)。将该混合物在110℃搅拌16h。将该反应混合物冷却至室温，倒入水(10mL)中并用EtOAc(3×10mL)萃取。用盐水洗涤合并的有机相，无水硫酸钠干燥，过滤且减压浓缩滤液。残余物通过硅胶色谱使用梯度的0-50％EtOAc的己烷溶液洗脱获得标题化合物(86mg,64％产率)。LC-MS:[M+H]⁺＝524。To 6-bromo-1,3,3-trimethyl-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3 ,2-b]pyridin-2(3H)-one (86 mg, 0.25 mmol) in toluene (2 mL) was added triphenylphosphine (135 mg, 0.51 mmol) and (R)-phenyl(tetrahydro-2H- Pyran-4-yl)methanol (61 mg, 0.32 mmol). The mixture was evacuated, backfilled with_N2 , and the process was backfilled 3 times. DIAD (107 mg, 0.53 mmol) was added at room temperature under_N2 . The mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient of 0-50% EtOAc in hexanes to give the title compound (86 mg, 64% yield). LC-MS: [M+H]⁺ =524.

步骤9:(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-1,3,3-三甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 9: (S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-1,3,3-trimethyl-4-(phenyl (Tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole [3,2-b]pyridin-2(3H)-one

按照实施例1步骤8中描述的类似步骤，将(S)-6-溴-1,3,3-三甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(46mg,0.088mmol)和1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(112mg,0.29mmol)转化为标题化合物(14mg,30％yield)并通过硅胶色谱梯度的1-10％MeOH的DCM溶液纯化。LC-MS:[M+H]⁺＝541；¹H NMR(400MHz,DMSO-d₆)δ8.31(s,1H),7.85(s,1H),7.68-7.57(m,2H),7.44-7.25(m,3H),5.26(d,J＝10.4Hz,1H),3.95-3.82(m,1H),3.81(s,3H),3.80-3.70(m,1H),3.56-3.41(m,2H),3.28(s,3H),2.14(s,3H),2.01-1.91(m,1H),1.64(s,3H),1.62(s,3H),1.53-1.43(m,1H),1.39-1.26(m,2H),0.92-0.75(m,1H)。Following procedures similar to those described in Example 1, Step 8, (S)-6-bromo-1,3,3-trimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methan base)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridine-2(3H)- Ketone (46 mg, 0.088 mmol) and 1,4-dimethyl-5-(tributyltin)-1H-1,2,3-triazole (112 mg, 0.29 mmol) were converted to the title compound (14 mg, 30% yield) ) and purified by silica gel chromatography gradient 1-10% MeOH in DCM. LC-MS: [M+H]⁺ =541;¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.31 (s, 1H), 7.85 (s, 1H), 7.68-7.57 (m, 2H), 7.44 -7.25(m, 3H), 5.26(d, J=10.4Hz, 1H), 3.95-3.82(m, 1H), 3.81(s, 3H), 3.80-3.70(m, 1H), 3.56-3.41(m ,2H),3.28(s,3H),2.14(s,3H),2.01-1.91(m,1H),1.64(s,3H),1.62(s,3H),1.53-1.43(m,1H), 1.39-1.26 (m, 2H), 0.92-0.75 (m, 1H).

实施例6Example 6

(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(“化合物6”)(S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3,3-dimethyl-4-(phenyl(tetrahydro-2H) -pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2- b] Pyridin-2(3H)-one ("Compound 6")

步骤1:6-((2-(三甲基硅烷基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 1: 6-((2-(Trimethylsilyl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one

在-10℃，10min内，向4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(3.51g,25.25mmol)的THF(50mL)溶液中加入NaH(60％在矿物油中,1.12g,28.0mmol)，并且在-10℃搅拌30min。在-10℃，滴加SEMCl(5.19g,31.1mmol)，并在室温下搅拌2h。将该混合物倒入水(50mL)中并用EtOAc(3×100mL)萃取。用盐水洗涤合并的有机层，无水硫酸钠干燥，及减压浓缩。残余物通过硅胶色谱使用梯度的0-10％EtOAc的己烷溶液洗脱获得标题化合物(4.17g,61％产率)。LC-MS[M+H]⁺＝270；¹HNMR(400MHz,DMSO-d₆)δ7.05(d,J＝5.2Hz,1H),6.92(s,d,J＝5.2Hz,1H),4.98(s,2H),3.58(s,2H),3.53-3.49(m,2H),0.89-0.81(m,2H),-0.04(s,9H)。To a solution of 4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one (3.51 g, 25.25 mmol) in THF (50 mL) was added NaH (60%) at -10 °C over 10 min in mineral oil, 1.12 g, 28.0 mmol) and stirred at -10 °C for 30 min. At -10 °C, SEMCl (5.19 g, 31.1 mmol) was added dropwise and stirred at room temperature for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel using a gradient of 0-10% EtOAc in hexanes to give the title compound (4.17 g, 61% yield). LC-MS [M+H]⁺ =270;¹ HNMR (400MHz, DMSO-d₆ )δ7.05(d,J=5.2Hz,1H),6.92(s,d,J=5.2Hz,1H), 4.98(s, 2H), 3.58(s, 2H), 3.53-3.49(m, 2H), 0.89-0.81(m, 2H), -0.04(s, 9H).

步骤2:4,4-二甲基-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 2: 4,4-Dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3-b]pyrrole -5-keto

按照实施例5步骤4中描述的类似的步骤，将6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(4.14g,15.37mmol)转化为标题化合物(2.20g,48％产率)，并通过硅胶色谱使用梯度的0-10％EtOAc的己烷溶剂洗脱纯化。LC-MS[M+H]⁺＝298。¹H NMR(400MHz,DMSO-d₆)δ7.04(d,J＝4.8Hz,1H),6.97(d,J＝5.2Hz,1H),5.00(s,2H),3.50-3.47(m,2H),1.27(s,6H),0.86-0.82(m,2H),-0.07(s,9H)。Following a procedure similar to that described in Example 5, Step 4, 6-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3- b] Pyrrol-5-one (4.14 g, 15.37 mmol) was converted to the title compound (2.20 g, 48% yield) and purified by silica gel chromatography eluting with a gradient of 0-10% EtOAc in hexanes. LC-MS [M+H]⁺ =298.¹ H NMR (400MHz, DMSO-d₆ )δ7.04(d, J=4.8Hz, 1H), 6.97(d, J=5.2Hz, 1H), 5.00(s, 2H), 3.50-3.47(m, 2H), 1.27(s, 6H), 0.86-0.82(m, 2H), -0.07(s, 9H).

步骤3:4,4-二甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 3: 4,4-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6-((2-(tri Methylsilyl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one

按照实施例5步骤5中描述的类似步骤，将4,4-二甲基-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(1.05g,3.53mmol)转化为粗的标题化合物(1.36g)，其未经纯化直接用于下一步LC-MS[M+H]⁺＝424。Following procedures similar to those described in Example 5, Step 5, 4,4-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-5H -Thiophene[2,3-b]pyrrol-5-one (1.05 g, 3.53 mmol) was converted to the crude title compound (1.36 g), which was used directly in the next step LC-MS [M+H]⁺ without purification =424.

步骤4:2-(5-溴-3-硝基吡啶-2-基)-4,4-二甲基-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮Step 4: 2-(5-Bromo-3-nitropyridin-2-yl)-4,4-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)- 4,6-Dihydro-5H-thiophene[2,3-b]pyrrol-5-one

按照实施例5步骤6中描述的类似的步骤，将粗的4,4-二甲基-2-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(1.36g,3.53mmol)和2,5-二溴-3-硝基吡啶(1.05g,3.58mmol)转化为标题化合物(0.61g,两步35％收率)，并通过硅胶色谱使用梯度的0-10％EtOAc的己烷溶液洗脱纯化。LC-MS[M+H]⁺＝498。¹H NMR(400MHz,DMSO-d₆)δ8.84(d,J＝2.0Hz,1H),8.66(d,J＝2.0Hz,1H),7.28(s,1H),5.07(s,2H),3.51(t,J＝8.0Hz,2H),1.30(s,6H),0.86(t,J＝8.0Hz,2H),-0.06(s,9H)。Following a procedure similar to that described in Example 5, Step 6, crude 4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one (1.36 g, 3.53 mmol) and 2,5-dibromo-3-nitropyridine (1.05 g, 3.58 mmol) were converted to the title compound (0.61 g, 35% yield over two steps) and chromatographed on silica using a gradient of 0- Purified by eluting with 10% EtOAc in hexanes. LC-MS [M+H]⁺ =498.¹ H NMR (400MHz, DMSO-d₆ ) δ 8.84(d, J=2.0Hz, 1H), 8.66(d, J=2.0Hz, 1H), 7.28(s, 1H), 5.07(s, 2H) , 3.51(t, J=8.0Hz, 2H), 1.30(s, 6H), 0.86(t, J=8.0Hz, 2H), -0.06(s, 9H).

步骤5:6-溴-3,3-二甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 5: 6-Bromo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrole[3",2": 4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-2(3H)-one

按照实施例5步骤7中描述的类似步骤，将2-(5-溴-3-硝基吡啶-2-基)-4,4-二甲基-6-((2-(三甲基硅基)乙氧基)甲基)-4,6-二氢-5H-噻吩[2,3-b]吡咯-5-酮(593mg,1.19mmol)转化为标题化合物(236mg,43％yield)，并通过硅胶色谱使用梯度的0-20％EtOAc的己烷溶液洗脱纯化。LC-MS[M+H]⁺＝466。¹H NMR(400MHz,DMSO-d₆)δ8.38(d,J＝1.6Hz,1H),8.11(d,J＝1.6Hz,1H),5.08(s,2H),3.54(t,J＝8.0Hz,2H),1.46(s,6H),0.87(t,J＝8.0Hz,2H),-0.06(s,9H)。Following a procedure similar to that described in Example 5, Step 7, 2-(5-bromo-3-nitropyridin-2-yl)-4,4-dimethyl-6-((2-(trimethylsilyl) yl)ethoxy)methyl)-4,6-dihydro-5H-thiophene[2,3-b]pyrrol-5-one (593 mg, 1.19 mmol) was converted to the title compound (236 mg, 43% yield), and purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in hexanes. LC-MS [M+H]⁺ =466.¹ H NMR (400MHz, DMSO-d₆ ) δ 8.38 (d, J=1.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 5.08 (s, 2H), 3.54 (t, J= 8.0Hz, 2H), 1.46(s, 6H), 0.87(t, J=8.0Hz, 2H), -0.06(s, 9H).

步骤6:(S)-6-溴-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 6: (S)-6-Bromo-3,3-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2- b]pyridin-2(3H)-one

按照实施例5步骤8中描述的类似的步骤，将6-溴-3,3-二甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(236mg,0.51mmol)和(R)-苯基(四氢-2H-吡喃-4-基)甲醇(121mg,0.63mmol)转化为标题化合物(323mg)，并通过硅胶色谱使用梯度的0-15％EtOAc的己烷溶液洗脱纯化。LC-MS[M+H]⁺＝640。Following procedures similar to those described in Example 5, Step 8, 6-bromo-3,3-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4 -Dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-2(3H)-one (236 mg, 0.51 mmol ) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (121 mg, 0.63 mmol) were converted to the title compound (323 mg) and chromatographed on silica using a gradient of 0-15% EtOAc in hexanes Alkane solution elution purification. LC-MS [M+H]⁺ =640.

步骤7:(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 7: (S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3,3-dimethyl-4-(phenyl(tetrazolium) Hydrogen-2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrole[3",2": 4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-2(3H)-one

按照实施例5步骤9中描述的类似步骤，将粗的(S)-6-溴-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(323mg,0.51mmol)和1,4-二甲基-5-(三丁基锡)-1H-1,2,3-三氮唑(589mg,1.51mmol)转化为标题化合物(63mg,两步20％收率)，并通过硅胶色谱使用梯度的50-100％EtOAc的己烷溶液洗脱纯化。LC-MS[M+H]⁺＝657。Following procedures analogous to those described in Example 5, Step 9, crude (S)-6-bromo-3,3-dimethyl-4-(phenyl(tetrahydro-2H-pyran-4-yl)methan was base)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3 ':4,5]pyrro[3,2-b]pyridin-2(3H)-one (323 mg, 0.51 mmol) and 1,4-dimethyl-5-(tributyltin)-1H-1,2, 3-Triazole (589 mg, 1.51 mmol) was converted to the title compound (63 mg, 20% yield for two steps) and purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc in hexanes. LC-MS [M+H]⁺ =657.

步骤8:(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮Step 8: (S)-6-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-3,3-dimethyl-4-(phenyl(tetrazolium) Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3 ,2-b]pyridin-2(3H)-one

向(S)-6-(1,4-二甲基-1H-1,2,3-三氮唑-5-基)-3,3-二甲基-4-(苯基(四氢-2H-吡喃-4-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,4-二氢吡咯[3”,2”:4',5']噻吩[2',3':4,5]吡咯[3,2-b]吡啶-2(3H)-酮(51mg,0.078mmol)的EtOH(4mL)溶液中加入6N的HCl(4mL)水溶液。将该混合物在75℃搅拌48h。将反应混合物冷却至室温，倒入饱和的NaHCO₃(10mL)水溶液中，并用EtOAc(3×50mL)萃取。用盐水洗涤合并的有机层，无水硫酸钠干燥，及浓缩。残余物通过硅胶色谱使用梯度的0-10％MeOH的DCM溶液洗脱纯化，然后使用制备HPLC获得标题化合物(5mg,12％产率)LC-MS[M+H]⁺＝527；¹H NMR(400MHz,DMSO-d₆)δ8.28(s,1H),7.82(s,1H),7.64-7.59(m,2H),7.42-7.33(m,2H),7.31-7.25(m,1H),5.24(d,J＝10.8Hz,1H),3.98-3.80(m,1H),3.80(s,3H),3.80-3.74(m,1H),3.49-3.24(m,2H),2.12(s,3H),1.99-1.91(m,1H),1.61(s,3H),1.59(s,3H),1.51-1.38(m,1H),1.33-1.16(m,2H),0.91-0.74(m,1H)。To (S)-6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,3-dimethyl-4-(phenyl(tetrahydro- 2H-pyran-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyrrole[3",2":4',5']thiophene[2',3':4,5]pyrrole[3,2-b]pyridin-2(3H)-one (51 mg, 0.078 mmol) in EtOH (4 mL) was added 6N HCl ( 4 mL) aqueous solution. The mixture was stirred at 75°C for 48h. The reaction mixture was cooled to room temperature, poured into saturated aqueous_NaHCO3 (10 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM followed by preparative HPLC to give the title compound (5 mg, 12% yield) LC-MS [M+H]⁺ = 527;¹ H NMR (400MHz,DMSO-d₆ )δ8.28(s,1H),7.82(s,1H),7.64-7.59(m,2H),7.42-7.33(m,2H),7.31-7.25(m,1H) ,5.24(d,J＝10.8Hz,1H),3.98-3.80(m,1H),3.80(s,3H),3.80-3.74(m,1H),3.49-3.24(m,2H),2.12(s ,3H),1.99-1.91(m,1H),1.61(s,3H),1.59(s,3H),1.51-1.38(m,1H),1.33-1.16(m,2H),0.91-0.74(m , 1H).

参照实施例1～实施例6类似的步骤，本发明合成得到如下化合物：Referring to the similar steps of Example 1 to Example 6, the present invention synthesized the following compounds:

药理学测试Pharmacological testing

1.BRD4(BD1)亲和力测试1. BRD4 (BD1) affinity test

使用HTRF技术在384孔白板(OptiPlate-384，PerkinElmer)中进行BRD4(BD1)生化结合测试。BRD4 (BD1 ) biochemical binding assays were performed in 384-well white plates (OptiPlate-384, PerkinElmer) using HTRF technology.

通过

550液体处理器(Labcyte，USA)将20nL化合物转移至384孔板，然后将5μL BRD4(BD1)(ReactionBiologyCompany，RD-11-157)溶液或测定缓冲液加至每个孔中。在室温下孵育15分钟后，向每个孔中加入5μL生物素化的H4衍生的乙酰化肽(由GL Biochem(Shanghai)Ltd合成)和10μL的检测溶液(Cisbio Assay)。在室温下孵育1小时后，使用EnVision Multilabel PlateReader(PerkinElmer，USA)在615nm和665nm处测量HTRF信号。用双波长信号比分析结果：强度(665nm)/强度(615nm)。根据下式计算化合物的抑制率：抑制率＝(Max-Signal)/(Max-Min)×100％。使用GrphaPadPrismV5.0软件(San Diego,CA)中的数据拟合IC₅₀值，使用方程式进行非线性回归分析，Y＝底部+(顶部-底部)/(1+10^((LogIC₅₀-X)×斜率)，其中Y代表抑制率，X代表化合物浓度。测得化合物3对BRD4(BD1)的IC₅₀为0.28nM。pass

A 550 liquid handler (Labcyte, USA) transferred 20 nL of compound to a 384-well plate, and then 5 μL of BRD4 (BD1) (Reaction Biology Company, RD-11-157) solution or assay buffer was added to each well. After 15 min incubation at room temperature, 5 μL of biotinylated H4-derived acetylated peptide (synthesized by GL Biochem (Shanghai) Ltd) and 10 μL of detection solution (Cisbio Assay) were added to each well. After 1 hour incubation at room temperature, HTRF signals were measured at 615 nm and 665 nm using an EnVision Multilabel PlateReader (PerkinElmer, USA). The results were analyzed with a dual wavelength signal ratio: intensity (665 nm)/intensity (615 nm). The inhibition rate of the compound was calculated according to the following formula: Inhibition Rate=(Max-Signal)/(Max-Min)×100%._IC50 values were fitted to the data using GrphaPad Prism V5.0 software (San Diego, CA) and nonlinear regression analysis was performed using the equation, Y=bottom+(top-bottom)/(1+10^((_LogIC50 -X) × slope), where Y represents inhibition rate and X represents compound concentration. The_IC50 of compound 3 for BRD4 (BD1) was determined to be 0.28 nM.

2.细胞增殖测试2. Cell Proliferation Test

MTS测定方案：MTS assay protocol:

通过MTS(3-(4,5-二甲基噻吩-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑，内盐)方法检测化合物对MV-4-11细胞增殖的影响。简而言之，在温度为37℃，5％CO₂和95％湿度下，将MV-4-11细胞用10％(v/v)FBS(胎牛血清)的IMDM(Iscove's ModifiedDubecco's Medium)培养基培养。在对数生长期收集细胞并用细胞计数仪(hemocytometer)计数。通过台盼蓝染色法(trypanblue exclusion)测定细胞活率，细胞存活率超过90％。用完全培养基将MV-4-11细胞浓度调节至1.2×10⁵个细胞/mL。向96孔板中加入100μL细胞悬浮液(每个浓度设置三个复孔)，最终细胞密度为1.2×10⁴个细胞/孔。第二天，用DMSO溶解测试化合物作为储备溶液。将5μL储备溶液加入到1mL培养基中，并将25μL药物培养基加入96孔板中。在用培养基连续稀释后，化合物的最终浓度为0、0.03、0.1、0.3、1、3、10、30、100nM。药物孵育3天，然后通过MTS法检测。将PMS(phenaziniummethosulfate)溶液加入到MTS溶液(1:20)中。再将20μL MTS/PMS混合溶液加到96孔板的每个孔中。将96孔板在培养箱中孵育1-4小时。使用微孔板分光光度计(Envision^R，PeikinElmer)测定490nm处的吸光度。使用GraphPad5.0拟合数据并获取IC₅₀值。Via MTS (3-(4,5-Dimethylthiophen-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazole, internal Salt) method to detect the effect of compounds on the proliferation of MV-4-11 cells. Briefly, MV-4-11 cells were cultured with 10% (v/v) FBS (fetal bovine serum) in IMDM (Iscove's Modified Dubecco's Medium) at 37°C, 5%_CO and 95% humidity. base culture. Cells were harvested in logarithmic growth phase and counted with a hemocytometer. Cell viability was determined by trypan blue exclusion, and the cell viability was over 90%. The MV^- 4-11 cell concentration was adjusted to 1.2 x 105 cells/mL with complete medium. 100 μL of cell suspension was added to a 96-well plate (three replicate wells were set for each concentration), and the final cell density was 1.2×10⁴ cells/well. The next day, test compounds were dissolved in DMSO as stock solutions. Add 5 μL of the stock solution to 1 mL of medium and 25 μL of drug medium into a 96-well plate. The final concentrations of the compounds were 0, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 nM after serial dilution with medium. Drugs were incubated for 3 days and then detected by MTS assay. The PMS (phenaziniummethosulfate) solution was added to the MTS solution (1:20). Another 20 μL of the MTS/PMS mixed solution was added to each well of the 96-well plate. Incubate the 96-well plate in the incubator for 1-4 hours. Absorbance at 490 nm was measured using a microplate spectrophotometer (Envision^R , PeikinElmer). Data were fitted using GraphPad 5.0 and_IC50 values were obtained.

结果：result:

细胞增殖活性测试的结果如下表1所示：The results of the cell proliferation activity test are shown in Table 1 below:

表1.细胞增殖活性测试的结果Table 1. Results of Cell Proliferation Activity Test

从表1中可以看出本发明化合物对白血病细胞MV-4-11具有优良的抑制作用。It can be seen from Table 1 that the compounds of the present invention have excellent inhibitory effect on leukemia cell MV-4-11.

Claims (9)

1. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

wherein:

ring A is selected from a 5-membered heteroaromatic ring containing 1 heteroatom selected from N or a 5-membered amide ring;

each R which may be attached to the same atom or different atoms₁、R₂And R₃Independently at each occurrence, selected from hydrogen, deuterium, -CH₃、-CD₃Ethyl, propyl, isopropyl,

R₄Selected from:

W₁is selected from

W₂Selected from:

2. the compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is of formula IV or V:

wherein:

R₁is selected from-CH₃；

R₂Is selected from

R₃Selected from hydrogen.

3. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is of formula VII, VIII or IX:

wherein:

each R₁Is selected from-CH₃；R₂Is selected from-CH₃(ii) a And R₃Is selected from-CH₃。

4. A compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1, wherein the compound is selected from:

5. a pharmaceutical composition comprising at least one compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as claimed in any one of claims 1-4, and at least one pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5, wherein the weight ratio of the compound to the excipient ranges from 0.0001 to 10.

7. Use of a compound of formula III, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as claimed in any one of claims 1 to 4, or a pharmaceutical composition as claimed in claim 5, in the manufacture of a medicament for the treatment of solid and/or hematological tumours associated with bromodomain proteins.

8. Use according to claim 7, wherein the solid tumor is selected from lung cancer, tumors of the digestive tract, colon cancer, rectal cancer, colorectal cancer and/or ovarian cancer; the hematological neoplasm is selected from myeloma and/or leukemia.

9. The use of claim 8, wherein the lung cancer is non-small cell lung cancer and/or small cell lung cancer; the tumor of the digestive tract is esophageal cancer; the leukemia is acute myelogenous leukemia and/or acute lymphocytic leukemia; the myeloma is multiple myeloma.