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WO2020135878A1 - Imidazopyridine derivative as fgfr and vegfr dual inhibitor - Google Patents

Imidazopyridine derivative as fgfr and vegfr dual inhibitorDownload PDF

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WO2020135878A1
WO2020135878A1PCT/CN2019/130053CN2019130053WWO2020135878A1WO 2020135878 A1WO2020135878 A1WO 2020135878A1CN 2019130053 WCN2019130053 WCN 2019130053WWO 2020135878 A1WO2020135878 A1WO 2020135878A1
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compound
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pharmaceutically acceptable
acceptable salt
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戴美碧
张杨
陈正霞
陈曙辉
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Medshine Discovery Inc
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Abstract

An FGFR and VEGFR dual inhibitor, specifically the compound shown in formula (III) or a pharmaceutically acceptable salt.

Description

Translated fromChinese
作为FGFR和VEGFR双重抑制剂的咪唑并吡啶衍生物Imidazopyridine derivatives as dual inhibitors of FGFR and VEGFR

相关申请的引用Citation of related applications

本申请主张如下优先权：This application claims the following priority:

CN201811640177.2，申请日：2018-12-29；CN201811640177.2, application date: 2018-12-29;

CN201910313237.8，申请日：2019-04-18；CN201910313237.8, application date: 2019-04-18;

CN201910802391.1，申请日：2019-08-28；CN201910802391.1, application date: 2019-08-28;

CN201911310776.2，申请日：2019-12-18。CN201911310776.2, application date: 2019-12-18.

技术领域Technical field

本发明涉及一种FGFR和VEGFR双重抑制剂，具体涉及式(III)所示化合物或药学上可接受的盐。The present invention relates to a dual inhibitor of FGFR and VEGFR, in particular to a compound represented by formula (III) or a pharmaceutically acceptable salt.

背景技术Background technique

FGFR是一类具有传导生物信号、调节细胞生长、参与组织修复等功能的生物活性物质，近年来，已有多个FGFR家族成员被发现在肿瘤发生、发展过程中起重要作用。成纤维细胞生长因子受体(FGFR)是一类可与成纤维细胞生长因子(FGF)特异性结合的受体蛋白，FGFRs家族包括以下类型：FGFR1b、FGFR1c、FGFR2b、FGFR2c、FGFR3b、FGFR3c、FGFR4。不同亚型的FGFR与之结合的FGF不一样，FGFs与FGFRs结合后导致胞内多个酪氨酸残基的自身磷酸化，磷酸化的FGFRs激活下游的信号通路包括MEK/MAPK、PLCy/PKC、PI3K/AKT、STATS等。在肿瘤中，如在肝癌，膀胱癌，肺癌，乳腺癌，子宫内膜癌，脑胶质瘤，前列腺癌等，FGFR激活突变或者配体/受体过表达导致其持续组成型激活，不仅与肿瘤的发生、发展、不良预后等密切相关，并且在肿瘤新生血管生成、肿瘤的侵袭与转移等过程中也发挥重要作用。因此，FGFR被认为是抗肿瘤重要靶点。FGFR is a type of biologically active substance that has the functions of conducting biological signals, regulating cell growth, and participating in tissue repair. In recent years, several FGFR family members have been found to play an important role in tumorigenesis and development. Fibroblast growth factor receptor (FGFR) is a type of receptor protein that can specifically bind to fibroblast growth factor (FGF). The FGFRs family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4 . Different subtypes of FGFR are different from the FGF to which they bind. The combination of FGFs and FGFRs results in the autophosphorylation of multiple tyrosine residues in the cell. Phosphorylated FGFRs activate downstream signaling pathways including MEK/MAPK, PLCy/PKC , PI3K/AKT, STATS, etc. In tumors, such as liver cancer, bladder cancer, lung cancer, breast cancer, endometrial cancer, glioma, prostate cancer, etc., FGFR activation mutations or ligand/receptor overexpression lead to its continuous constitutive activation, not only with The occurrence, development, and poor prognosis of tumors are closely related, and also play an important role in tumor neovascularization, tumor invasion and metastasis. Therefore, FGFR is considered an important anti-tumor target.

血管生成和淋巴管生产是肿瘤形成和转移中的重要环节，血管内皮细胞生长因子(VEGF)和VEGF受体(VEGFR)家族在上述两个环节中起着主要作用。VEGFR家族包括VEGFR-1、VEGFR-2(KDR)和VEGFR-3三种特异的酪氨酸激酶受体。VEGFR-2是VEGF信号传导引起内皮细胞增殖，增加血管通透性效应和促进血管生成的重要调节因子，而且VEGFR-2和VEGF的亲和力要大于VEGFR-1。研究表明，内皮细胞中只表达VEGFR-2，激活VEGFR-2后能高效的刺激血管生成。因此VEGFR-2是抗新生血管生成药物研发的主要靶点。Angiogenesis and lymphatic vessel production are important links in tumor formation and metastasis, and the vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) families play a major role in the above two links. The VEGFR family includes three specific tyrosine kinase receptors, VEGFR-1, VEGFR-2 (KDR) and VEGFR-3. VEGFR-2 is an important regulator of endothelial cell proliferation caused by VEGF signaling, increasing vascular permeability and promoting angiogenesis, and the affinity of VEGFR-2 and VEGF is greater than that of VEGFR-1. Studies have shown that only VEGFR-2 is expressed in endothelial cells, and activation of VEGFR-2 can effectively stimulate angiogenesis. Therefore, VEGFR-2 is the main target for the development of anti-angiogenic drugs.

在特定的实验条件下，VEGF需要FGF的存在才能发挥其促血管生成作用，VEGFR和FGFR通路共同完成血管生成中内皮细胞的激活和生成。FGFR和VEGFR能够直接抑制肿瘤细胞的生长，存活、增殖和迁移；还具有肿瘤生血管的抑制作用，改善微环境。FGFR和VEGFR通路协同作用还可以抑制肿瘤免疫逃逸作用提高肿瘤抑制效果。Under certain experimental conditions, VEGF needs the presence of FGF to play its role in promoting angiogenesis, and the VEGFR and FGFR pathways jointly complete the activation and generation of endothelial cells in angiogenesis. FGFR and VEGFR can directly inhibit the growth, survival, proliferation and migration of tumor cells; they also have the inhibitory effect of tumor angiogenesis and improve the microenvironment. The synergistic effect of FGFR and VEGFR pathway can also suppress tumor immune escape and improve tumor suppression effect.

发明内容Summary of the invention

本发明提供了式(III)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

Figure PCTCN2019130053-appb-000001
Figure PCTCN2019130053-appb-000001

其中，among them,

R1选自H、-S(＝O)2CH3、C1-6烷基、C1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基，所述C1-6烷基、C1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个Ra取代；R1 is selected from H, —S(═O)2 CH3 , C1-6 alkyl, C1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, said C1-6 alkyl group, C1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with one, two or three Ra;

R2和R3分别独立地选自H、F、Cl、Br、I、OH、NH2、CH3和OCH3；R2 and R3 are independently selected from H, F, Cl, Br, I, OH, NH2 , CH3 and OCH3 ;

R4选自H、NH2、C1-6烷基、C1-3烷氧基、C3-5环烷基和

Figure PCTCN2019130053-appb-000002
所述C1-6烷基、C1-3烷氧基、C3-5环烷基和
Figure PCTCN2019130053-appb-000003
任选被1、2或3个Rb取代；R4 is selected from H, NH2 , C1-6 alkyl, C1-3 alkoxy, C3-5 cycloalkyl and
Figure PCTCN2019130053-appb-000002
The C1-6 alkyl, C1-3 alkoxy, C3-5 cycloalkyl and
Figure PCTCN2019130053-appb-000003
Optionally substituted by 1, 2 or 3 Rb ;

m选自1和2；m is selected from 1 and 2;

L选自-N(R5)C(＝O)-、-N(R5)S(＝O)2-、-N(R5)C(＝O)N(R5)-、N(R5)S(＝O)2N(R5)-和-N(R5)-；L is selected from -N(R5 )C(=O)-, -N(R5 )S(=O)2 -, -N(R5 )C(=O)N(R5 )-, N( R5 )S(=O)2 N(R5 )- and -N(R5 )-;

环A选自苯基、吡咯基、嘧啶基和吡啶基；Ring A is selected from phenyl, pyrrolyl, pyrimidinyl and pyridyl;

环B不存在；Ring B does not exist;

或者，环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基；Alternatively, ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3,6-dihydro-2H-pyranyl;

R5分别独立地选自H和C1-3烷基；R5 is independently selected from H and C1-3 alkyl;

Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基任选被1、2或3个R取代；Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, —S(═O)2 CH3 , C1-3 alkyl, C1-3 alkoxy Group and C1-3 alkylamino, the -S(=O)2 CH3 , C1-3 alkyl, C1-3 alkoxy and C1-3 alkylamino are optionally substituted by 1, 2 or 3 R substitutions;

R选自H、F、Cl、Br、I、OH和NH2。R is selected from H, F, Cl, Br, I, OH and NH2 .

本发明的一些方案中，上述Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2，所述-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2任选被1、2或3个R取代，其他变量如本发明所定义。Some aspects of the present invention, the above Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, -S (= O) 2 CH 3, CH 3, -OCH3 , -N(CH3 )2 and -NHCH(CH3 )2 , the -S(=O)2 CH3 , CH3 , -OCH3 , -N(CH3 )2 and -NHCH(CH3 )2 is optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.

本发明的一些方案中，上述Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3、CH2OH、-OCH3、-S(＝O)2CH3、-N(CH3)2和-NHCH(CH3)2，其他变量如本发明所定义。Some aspects of the present invention, the above Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, CH 3, CH 2 OH, -OCH 3, -S (= O)2 CH3 , -N(CH3 )2 and -NHCH(CH3 )2 , other variables are as defined in the present invention.

本发明的一些方案中，上述R1选自H、-S(＝O)2CH3、CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、OCH2CH3、四氢吡喃基、四氢呋喃基和哌啶基，所述CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、OCH2CH3、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个Ra取代，其他变量如本发明所定义。In some aspects of the present invention, the above R1 is selected from H, —S(═O)2 CH3 , CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2 CH(CH3 )2 , OCH2 CH3 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, the CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2 CH(CH3 )2 , OCH2 CH3 , tetrahydropyridine tetrahydrothiopyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with 1,2 or 3 substituents Ra, the other variables are as defined in the present invention.

本发明的一些方案中，上述R1选自H、-S(＝O)2CH3、CH3、CH2OH、CH2CH3、CH2CH2OH、OCH2CH3、

Figure PCTCN2019130053-appb-000004
Figure PCTCN2019130053-appb-000005
其他变量如本发明所定义。In some aspects of the present invention, the above R1 is selected from H, —S(═O)2 CH3 , CH3 , CH2 OH, CH2 CH3 , CH2 CH2 OH, OCH2 CH3 ,
Figure PCTCN2019130053-appb-000004
Figure PCTCN2019130053-appb-000005
Other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、OCH3、OCH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、OCH3、OCH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the present invention, the above R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , OCH3 , OCH2 CH3 , cyclopropane, azetidine and pyrrolidinium, the CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , OCH3. OCH2 CH3 , cyclopropane, azetidine and pyrrolidinyl are optionally substituted with 1, 2 or 3 Rb , and other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、CH2CH2N(CH3)2、OCH3、

Figure PCTCN2019130053-appb-000006
Figure PCTCN2019130053-appb-000007
其他变量如本发明所定义。In some aspects of the present invention, the above R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , CH2 CH2 N(CH3 )2 , OCH3 ,
Figure PCTCN2019130053-appb-000006
Figure PCTCN2019130053-appb-000007
Other variables are as defined in the present invention.

本发明的一些方案中，上述R5分别独立地选自H、CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R5 is independently selected from H, CH3 and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O)2-、-NHS(＝O)2NH-和-NH-，其他变量如本发明所定义。In some aspects of the present invention, the above L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2 -, -NHS(=O)2 NH- and -NH- , Other variables are as defined in the present invention.

本发明的一些方案中，上述-L-R4选自

Figure PCTCN2019130053-appb-000008
Figure PCTCN2019130053-appb-000009
Figure PCTCN2019130053-appb-000010
其他变量如本发明所定义。In some aspects of the invention, the above-LR4 is selected from
Figure PCTCN2019130053-appb-000008
Figure PCTCN2019130053-appb-000009
Figure PCTCN2019130053-appb-000010
Other variables are as defined in the present invention.

本发明的一些方案中，上述环A选自

Figure PCTCN2019130053-appb-000011
其他变量如本发明所定义。In some embodiments of the present invention, the aforementioned ring A is selected from
Figure PCTCN2019130053-appb-000011
Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000012
选自
Figure PCTCN2019130053-appb-000013
Figure PCTCN2019130053-appb-000014
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000012
Select from
Figure PCTCN2019130053-appb-000013
Figure PCTCN2019130053-appb-000014
Other variables are as defined in the present invention.

本发明的一些方案中，上述环B选自

Figure PCTCN2019130053-appb-000015
其他变量如本发明所定义。In some embodiments of the present invention, the aforementioned ring B is selected from
Figure PCTCN2019130053-appb-000015
Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000016
选自
Figure PCTCN2019130053-appb-000017
Figure PCTCN2019130053-appb-000018
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000016
Select from
Figure PCTCN2019130053-appb-000017
Figure PCTCN2019130053-appb-000018
Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000019
选自OCH2CH3、
Figure PCTCN2019130053-appb-000020
Figure PCTCN2019130053-appb-000021
Figure PCTCN2019130053-appb-000022
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000019
Selected from OCH2 CH3 ,
Figure PCTCN2019130053-appb-000020
Figure PCTCN2019130053-appb-000021
Figure PCTCN2019130053-appb-000022
Other variables are as defined in the present invention.

本发明提供了式(III)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

Figure PCTCN2019130053-appb-000023
Figure PCTCN2019130053-appb-000023

其中，among them,

R1选自H、C1-6烷基和4-6元杂环烷基，所述C1-6烷基和4-6元杂环烷基任选被1、2或3个Ra取代；R1 is selected from H, C1-6 alkyl and 4-6 membered heterocycloalkyl, the C1-6 alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 Ra replace;

R2和R3分别独立地选自H、F、Cl、Br、I、OH、NH2、CH3和OCH3；R2 and R3 are independently selected from H, F, Cl, Br, I, OH, NH2 , CH3 and OCH3 ;

R4选自H、NH2、C1-6烷基、C3-5环烷基和4-6元杂环烷基，所述C1-6烷基、C3-5环烷基和4-6元杂环烷基任选被1、2或3个Rb取代；R4 is selected from H, NH2 , C1-6 alkyl, C3-5 cycloalkyl and 4-6 membered heterocycloalkyl, the C1-6 alkyl, C3-5 cycloalkyl and 4-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 Rb ;

L选自-N(R5)C(＝O)-、-N(R5)S(＝O)2-、-N(R5)C(＝O)N(R5)-、和-N(R5)-；L is selected from -N(R5 )C(=O)-, -N(R5 )S(=O)2 -, -N(R5 )C(=O)N(R5 )-, and- N(R5 )-;

环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;

环B选自5-6元杂芳基、5-6元杂环烷基和5-6元杂环烯基；Ring B is selected from 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;

R5分别独立地选自H和C1-3烷基；R5 is independently selected from H and C1-3 alkyl;

Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基任选被1、2或3个R取代；Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, —S(═O)2 CH3 , C1-3 alkyl, C1-3 alkoxy Group and C1-3 alkylamino, the -S(=O)2 CH3 , C1-3 alkyl, C1-3 alkoxy and C1-3 alkylamino are optionally substituted by 1, 2 or 3 R substitutions;

R选自H、F、Cl、Br、I、OH和NH2；R is selected from H, F, Cl, Br, I, OH, and NH2 ;

所述5-6元杂芳基、4-6元杂环烷基、5-6元杂环烷基和5-6元杂环烯基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 5-6 membered heteroaryl group, 4-6 membered heterocycloalkyl group, 5-6 membered heterocycloalkyl group and 5-6 membered heterocycloalkenyl group respectively comprise 1, 2, 3 or 4 independently selected from- Heteroatoms or heteroatom groups of NH-, -O-, -S- and N.

本发明的一些方案中，上述Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2，所述-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2任选被1、2或3个R取代，其他变量如本发明所定义。Some aspects of the present invention, the above Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, -S (= O) 2 CH 3, CH 3, -OCH3 , -N(CH3 )2 and -NHCH(CH3 )2 , the -S(=O)2 CH3 , CH3 , -OCH3 , -N(CH3 )2 and -NHCH(CH3 )2 is optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.

本发明的一些方案中，上述Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3、CH2OH、-OCH3、-S(＝O)2CH3、-N(CH3)2和-NHCH(CH3)2，其他变量如本发明所定义。Some aspects of the present invention, the above Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH 2, CN, CH 3, CH 2 OH, -OCH 3, -S (= O)2 CH3 , -N(CH3 )2 and -NHCH(CH3 )2 , other variables are as defined in the present invention.

本发明的一些方案中，上述R1选自H、CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、四氢吡喃基、四氢呋喃基和哌啶基，所述CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个Ra取代，其他变量如本发明所定义。In some embodiments of the present invention, the above R1 is selected from H, CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2 CH(CH3 )2 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl , The CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2 CH(CH3 )2 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl are optionally substituted by 1, 2 or 3 Ra Instead, other variables are as defined in the present invention.

本发明的一些方案中，上述R1选自H、CH3、CH2OH、CH2CH3、CH2CH2OH、

Figure PCTCN2019130053-appb-000024
Figure PCTCN2019130053-appb-000025
其他变量如本发明所定义。In some aspects of the present invention, the above R1 is selected from H, CH3 , CH2 OH, CH2 CH3 , CH2 CH2 OH,
Figure PCTCN2019130053-appb-000024
Figure PCTCN2019130053-appb-000025
Other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the present invention, the above R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , cyclopropanyl, Azetidine and pyrrolidinium, the CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , cyclopropane, azetidine And pyrrolidinyl is optionally substituted with 1, 2, or 3 Rb , and other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、CH2CH2N(CH3)2、

Figure PCTCN2019130053-appb-000026
其他变量如本发明所定义。In some aspects of the present invention, the above R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , CH2 CH2 N(CH3 )2 ,
Figure PCTCN2019130053-appb-000026
Other variables are as defined in the present invention.

本发明的一些方案中，上述R5分别独立地选自H、CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R5 is independently selected from H, CH3 and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O)2-和-NH-，其他变量如本发明所定义。In some aspects of the invention, the aforementioned L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2 -, and -NH-, and other variables are as defined in the invention.

本发明的一些方案中，上述-L-R4选自

Figure PCTCN2019130053-appb-000027
Figure PCTCN2019130053-appb-000028
Figure PCTCN2019130053-appb-000029
其他变量如本发明所定义。In some aspects of the invention, the above-LR4 is selected from
Figure PCTCN2019130053-appb-000027
Figure PCTCN2019130053-appb-000028
Figure PCTCN2019130053-appb-000029
Other variables are as defined in the present invention.

本发明的一些方案中，上述环A选自苯基、吡咯基、嘧啶基和吡啶基，其他变量如本发明所定义。In some embodiments of the present invention, the aforementioned ring A is selected from phenyl, pyrrolyl, pyrimidinyl, and pyridyl, and other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000030
选自
Figure PCTCN2019130053-appb-000031
Figure PCTCN2019130053-appb-000032
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000030
Select from
Figure PCTCN2019130053-appb-000031
Figure PCTCN2019130053-appb-000032
Other variables are as defined in the present invention.

本发明的一些方案中，上述环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基，其他变量如本发明所定义。In some embodiments of the present invention, the above ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl, and 3,6-dihydro-2H-pyranyl , Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000033
选自
Figure PCTCN2019130053-appb-000034
Figure PCTCN2019130053-appb-000035
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000033
Select from
Figure PCTCN2019130053-appb-000034
Figure PCTCN2019130053-appb-000035
Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000036
选自
Figure PCTCN2019130053-appb-000037
Figure PCTCN2019130053-appb-000038
Figure PCTCN2019130053-appb-000039
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000036
Select from
Figure PCTCN2019130053-appb-000037
Figure PCTCN2019130053-appb-000038
Figure PCTCN2019130053-appb-000039
Other variables are as defined in the present invention.

本发明提供了式(II)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

Figure PCTCN2019130053-appb-000040
Figure PCTCN2019130053-appb-000040

其中，among them,

R1选自H和任选被1、2或3个Ra取代的C1-3烷基；R1 is selected from H and optionally substituted with 1,2 or 3 substituents Ra is C1-3 alkyl;

R2和R3分别独立地选自H、F、Cl、Br、I、OH和NH2；R2 and R3 are independently selected from H, F, Cl, Br, I, OH and NH2 ;

R4选自H、C1-6烷基和C3-5环烷基，所述C1-6烷基和C3-5环烷基任选被1、2或3个Rb取代；R4 is selected from H, C1-6 alkyl and C3-5 cycloalkyl, and the C1-6 alkyl and C3-5 cycloalkyl are optionally substituted with 1, 2 or 3 Rb ;

L选自-N(R5)C(＝O)-、-N(R5)S(＝O)2-、-N(R5)C(＝O)N(R5)-和-N(R5)-；L is selected from -N(R5 )C(=O)-, -N(R5 )S(=O)2 -, -N(R5 )C(=O)N(R5 )- and -N (R5 )-;

R5分别独立地选自H和C1-3烷基；R5 is independently selected from H and C1-3 alkyl;

环B选自5-6元杂芳基和5-6元杂环烷基；Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN和CH3；Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN and CH3 ;

所述5-6元杂芳基和5-6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。The 5-6 membered heteroaryl group and 5-6 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N .

本发明的一些方案中，上述R1选自H、CH3和CH2CH3，所述CH3和CH2CH3任选被1、2或3个Ra取代，其他变量如本发明所定义。Some aspects of the present invention, of R1 is selected from H, CH3 and CH2 CH3, and the CH3 CH2 CH3 optionally substituted by 1, 2 or 3 Ra, according to the present invention as other variables definition.

本发明的一些方案中，上述R1选自H、CH3、CH2OH、CH2CH2OH和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R1 is selected from H, CH3 , CH2 OH, CH2 CH2 OH, and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、环丙烷基、CH3、CH2CH3、CH(CH3)2、C(CH3)3和CH2CH2CH3，所述环丙烷基、CH3、CH2CH3、CH(CH3)2、C(CH3)3和CH2CH2CH3任选被1、2或3个Rb取代，其他变量如本发明所定义。In some embodiments of the present invention, the above R4 is selected from H, cyclopropanyl, CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 and CH2 CH2 CH3 , the ring Propyl, CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 and CH2 CH2 CH3 are optionally substituted with 1, 2 or 3 Rb , other variables are as described in this invention definition.

本发明的一些方案中，上述R4选自H、

Figure PCTCN2019130053-appb-000041
CH3、CH2CH3、CH(CH3)2、C(CH3)3和CH2CH2CH3，其他变量如本发明所定义。In some aspects of the invention, the above R4 is selected from H,
Figure PCTCN2019130053-appb-000041
CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 and CH2 CH2 CH3 , other variables are as defined in the present invention.

本发明的一些方案中，上述R5分别独立地选自H、CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R5 is independently selected from H, CH3 and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O)2-和-NH-，其他变量如本发明所定义。In some aspects of the invention, the aforementioned L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2 -, and -NH-, and other variables are as defined in the invention.

本发明的一些方案中，上述-L-R4选自

Figure PCTCN2019130053-appb-000042
Figure PCTCN2019130053-appb-000043
其他变量如本发明所定义。In some aspects of the invention, the above-LR4 is selected from
Figure PCTCN2019130053-appb-000042
Figure PCTCN2019130053-appb-000043
Other variables are as defined in the present invention.

本发明的一些方案中，上述环B选自咪唑基、吡唑基、哌啶基、吗啉基和四氢吡喃基，其他变量如本发明所定义。In some embodiments of the present invention, the aforementioned ring B is selected from imidazolyl, pyrazolyl, piperidinyl, morpholinyl, and tetrahydropyranyl, and other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000044
选自
Figure PCTCN2019130053-appb-000045
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000044
Select from
Figure PCTCN2019130053-appb-000045
Other variables are as defined in the present invention.

本发明的一些方案中，上述结构单元

Figure PCTCN2019130053-appb-000046
选自
Figure PCTCN2019130053-appb-000047
其他变量如本发明所定义。In some solutions of the present invention, the above structural unit
Figure PCTCN2019130053-appb-000046
Select from
Figure PCTCN2019130053-appb-000047
Other variables are as defined in the present invention.

本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

Figure PCTCN2019130053-appb-000048
Figure PCTCN2019130053-appb-000048

其中，among them,

R1选自H和任选被1、2或3个Ra取代的C1-3烷基；R1 is selected from H and optionally substituted with 1,2 or 3 substituents Ra is C1-3 alkyl;

R2和R3分别独立地选自H、F、Cl、Br、I、OH和NH2；R2 and R3 are independently selected from H, F, Cl, Br, I, OH and NH2 ;

R4选自H、环丙烷基和任选被1、2或3个Rb取代的C1-3烷基；R4 is selected from H, cyclopropanyl and C1-3 alkyl optionally substituted with 1, 2 or 3 Rb ;

L选自-N(R5)C(＝O)-、-N(R5)S(＝O)2-和-NH-；L is selected from -N(R5 )C(=O)-, -N(R5 )S(=O)2 -and -NH-;

R5分别独立地选自H和C1-3烷基；R5 is independently selected from H and C1-3 alkyl;

Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN和CH3。Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, and CH3 .

本发明的一些方案中，上述R1选自H、CH3和CH2CH3，所述CH3和CH2CH3任选被1、2或3个Ra取代，其他变量如本发明所定义。Some aspects of the present invention, of R1 is selected from H, CH3 and CH2 CH3, and the CH3 CH2 CH3 optionally substituted by 1, 2 or 3 Ra, according to the present invention as other variables definition.

本发明的一些方案中，上述R1选自H、CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R1 is selected from H, CH3 and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述R4选自H、环丙烷基、CH3和CH2CH3，所述CH3和CH2CH3任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the present invention, the above R4 is selected from H, cyclopropanyl, CH3 and CH2 CH3 , the CH3 and CH2 CH3 are optionally substituted with 1, 2 or 3 Rb , other variables As defined in the present invention.

本发明的一些方案中，上述R4选自H、

Figure PCTCN2019130053-appb-000049
CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the invention, the above R4 is selected from H,
Figure PCTCN2019130053-appb-000049
CH3 and CH2 CH3 , other variables are as defined in the present invention.

本发明的一些方案中，上述R5分别独立地选自H、CH3和CH2CH3，其他变量如本发明所定义。In some aspects of the present invention, the above R5 is independently selected from H, CH3 and CH2 CH3 , and other variables are as defined in the present invention.

本发明的一些方案中，上述L选自-NHC(＝O)-、-NHS(＝O)2-和-NH-，其他变量如本发明所定义。In some aspects of the invention, the aforementioned L is selected from -NHC(=O)-, -NHS(=O)2 -, and -NH-, and other variables are as defined in the invention.

本发明的一些方案中，上述-L-R4选自

Figure PCTCN2019130053-appb-000050
其他变量如本发明所定义。In some aspects of the invention, the above-LR4 is selected from
Figure PCTCN2019130053-appb-000050
Other variables are as defined in the present invention.

本发明还有一些方案由上述变量任意组合而来。There are still some solutions of the present invention derived from any combination of the above variables.

本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from

Figure PCTCN2019130053-appb-000051
Figure PCTCN2019130053-appb-000051

其中，among them,

R1、R2、R3、L、T1和R4如本发明所定义。R1 , R2 , R3 , L, T1 and R4 are as defined in the present invention.

本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from

Figure PCTCN2019130053-appb-000052
Figure PCTCN2019130053-appb-000052

Figure PCTCN2019130053-appb-000053
Figure PCTCN2019130053-appb-000053

其中，among them,

R1、R2、R3、T1和R4如本发明所定义。R1 , R2 , R3 , T1 and R4 are as defined in the present invention.

本发明还提供了下式所示化合物或其药学上可接受的盐，The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,

Figure PCTCN2019130053-appb-000054
Figure PCTCN2019130053-appb-000054

Figure PCTCN2019130053-appb-000055
Figure PCTCN2019130053-appb-000055

Figure PCTCN2019130053-appb-000056
Figure PCTCN2019130053-appb-000056

本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备FGFR和VEGFR双重抑制剂相关药物上的应用。The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of drugs related to dual inhibitors of FGFR and VEGFR.

本发明的一些方案中，上述的应用，其中所述FGFR和VEGFR双重抑制剂相关药物是用于实体瘤的药物。In some aspects of the present invention, in the above application, the drug associated with the dual inhibitor of FGFR and VEGFR is a drug used for solid tumors.

定义和说明Definition and description

除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定 义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear unless it is specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding trade product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any base or acid addition salt.

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.

本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物 有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate). The compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium (3 H), iodine-125 (125 I) or C-14 (14 C). For another example, the hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have lower toxicity and increase drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages. The conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.

术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The term "optional" or "optionally" means that the subsequently described event or condition may, but need not necessarily occur, and that the description includes situations where the event or condition occurs and circumstances where the event or condition does not occur .

术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of. When the substituent is oxygen (ie = O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with at most two Rs, and R in each case has independent options. Furthermore, combinations of substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.

当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR)0 -, it means that the linking group is a single bond.

当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，

Figure PCTCN2019130053-appb-000057
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019130053-appb-000058
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019130053-appb-000059
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When a substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in AX, it means that the structure is actually A. When the substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group. When the listed linking group does not indicate the connection direction, the connection direction is arbitrary, for example,
Figure PCTCN2019130053-appb-000057
The linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2019130053-appb-000058
It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
Figure PCTCN2019130053-appb-000059
Combinations of the linking group, substituents, and/or variants thereof are only allowed if such a combination will produce a stable compound.

除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。Unless otherwise specified, the term "C1-6 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C1-6 alkyl group includes C1-5 , C1-4 , C1-3 , C1-2 , C2-6 , C2-4 , C6 and C5 alkyl groups; etc.; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.

除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述 C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C1-3 alkyl group includes C1-2 and C2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) . Example C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.

除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom. The C1-3 alkoxy group includes C1-2 , C2-3 , C3 and C2 alkoxy groups and the like. Examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-2、C3和C2烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。Unless otherwise specified, the term "C1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. The C1-3 alkylamino group includes C1-2 , C3 and C2 alkylamino groups and the like. Examples of C1-3 alkylamino include but are not limited to -NHCH3 , -N(CH3 )2 , -NHCH2 CH3 , -N(CH3 )CH2 CH3 , -NHCH2 CH2 CH3 ,- NHCH2 (CH3 )2 etc.

除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O)p , p Is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro ring, parallel ring and bridge ring. In addition, as for the "4-6 membered heterocycloalkyl group", the hetero atom may occupy the connection position of the heterocycloalkyl group to the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiatanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl Pyridyl and so on.

除非另有规定，“C3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C3-5环烷基包括C3-4和C4-5环烷基等；其可以是一价、二价或者多价。C3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。Unless otherwise specified, "C3-5 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic system, and the C3-5 cycloalkyl includes C3 -4 and C4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O)p , p Is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro ring, parallel ring and bridge ring. In addition, as far as the "5-6 membered heterocycloalkyl group" is concerned, the hetero atom may occupy the connection position of the heterocyclic alkyl group to the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -Piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示 由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl group" of the present invention can be used interchangeably. The term "5-6 membered heteroaryl group" means from 5 to 6 ring atoms The monocyclic group composed of a conjugated π electron system has 1, 2, 3, or 4 ring atoms as heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O)p , p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -Pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidyl and 4-pyrimidyl, etc.).

除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于

Figure PCTCN2019130053-appb-000060
Figure PCTCN2019130053-appb-000061
Unless otherwise specified, the term "5-6 membered heterocyclenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond , 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S(O)p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro ring, parallel ring and bridge ring, any ring of this system is non-aromatic. In addition, as far as the "5-6 membered heterocyclic alkenyl group" is concerned, the hetero atom may occupy the connection position of the heterocyclic alkenyl group with the rest of the molecule. The 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups and the like. Examples of 5-6 membered heterocyclic alkenyl groups include, but are not limited to
Figure PCTCN2019130053-appb-000060
Figure PCTCN2019130053-appb-000061

术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, etc.

术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes but is not limited to "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl groups. Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.

本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方 式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.

本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表PE；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮N-氯代丁二酰亚胺；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH4代表四氢铝锂；Pd(dba)2代表三(二亚苄基丙酮)二钯；mCPBA代表间氯过氧苯甲酸；pd(dppf)Cl2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DBU代表1,8-二氮杂双环[5.4.0]十一碳-7-烯；NIS代表N-碘代丁二酰亚胺；Pd2(dba)3代表三(二亚苄基丙酮)二钯；BINAP代表(±)-2,2-双(二苯膦基)-11-联萘；K3PO4代表磷酸钾。The solvent used in the present invention is commercially available. This invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyldiimidazole; DCM for methylene chloride; PE for PE; DIAD for diisopropyl azodicarboxylate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate ; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, which is an amine protecting group; BOC stands for tert-butoxycarbonyl, which is an amine protecting group; HOAc stands for acetic acid; NaCNBH3 stands for sodium cyanoborohydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl2 represents sulfoxide chloride; CS2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione N-chlorosuccinyl Imine; n-Bu4 NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; LiHMDS stands for lithium hexamethyldisilazide; Xantphos Represents 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; LiAlH4 represents lithium tetrahydrogen aluminum; Pd(dba)2 represents tris(dibenzylideneacetone) dipalladium; mCPBA represents the Chloroperoxybenzoic acid; pd(dppf)Cl2 represents [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride; DBU represents 1,8-diazabicyclo[5.4.0 ]Undec-7-ene; NIS stands for N-iodosuccinimide; Pd2 (dba)3 stands for tris(dibenzylideneacetone) dipalladium; BINAP stands for (±)-2,2-bis (Diphenylphosphino)-11-binaphthalene; K3 PO4 represents potassium phosphate.

化合物依据本领域常规命名原则或者使用

Figure PCTCN2019130053-appb-000062
软件命名，市售化合物采用供应商目录名称。Compounds are used according to conventional naming principles in the art or used
Figure PCTCN2019130053-appb-000062
The software is named, and the commercially available compounds adopt the supplier catalog name.

技术效果Technical effect

与专利WO2013053983中Example 5(本专利中对照例1)相比，本发明咪唑并吡啶母核多个化合物在FGFR1或者FGFR2激酶上提高了近4-10倍，FGFR4上提高了近3-10倍和VEGFR2激酶活性上提高了近3-20倍，细胞活性提高了近3-6倍，极有可能在临床上能够更低的剂量下展示更优异的治疗效果。在临床前动物模型中在较低的剂量下展示了优异的肿瘤治疗效果，对于FGFR异常的肿瘤抑制效果要明显优于FGFR单靶点选择性抑制剂，有望提高临床FGFR异常的患者治疗效果。Compared with Example 5 in Patent WO2013053983 (Comparative Example 1 in this patent), multiple compounds of the imidazopyridine parent nucleus of the present invention have increased by nearly 4-10 times on FGFR1 or FGFR2 kinase, and nearly 3-10 times on FGFR4 And VEGFR2 kinase activity increased by nearly 3-20 times, cell activity increased by nearly 3-6 times, it is very likely to be able to show a more excellent therapeutic effect at a lower dose clinically. In the preclinical animal model, it shows excellent tumor treatment effect at a lower dose. The tumor suppression effect for FGFR abnormality is significantly better than that of FGFR single-target selective inhibitors, and it is expected to improve the therapeutic effect of clinical FGFR abnormal patients.

附图说明BRIEF DESCRIPTION

图1为肿瘤生长抑制曲线；Figure 1 is the tumor growth inhibition curve;

图2为给药期间小鼠体重曲线。Figure 2 shows the body weight curve of mice during the administration period.

具体实施方式detailed description

下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any disadvantageous limitation of the present invention. The present invention has been described in detail herein, and the specific embodiments thereof are also disclosed. For those skilled in the art, various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention Will be obvious.

对照例1Comparative Example 1

Figure PCTCN2019130053-appb-000063
Figure PCTCN2019130053-appb-000063

步骤一step one

将3,5-二硝基溴苯(10g,40.49mmol)和(2,4-二氟)苯硼酸(6.39g,40.49mmol)溶于水(2mL)和乙腈(120mL)中，加入醋酸钯(454.46mg,2.02mmol)和三乙胺(12.29g,121.46mmol,16.91mL)，85℃下搅拌反应16小时，将反应液直接旋干，得固体粗品，将粗品以PE:EA＝5:1进行过柱纯化得到化合物a。Dissolve 3,5-dinitrobromobenzene (10g, 40.49mmol) and (2,4-difluoro)benzeneboronic acid (6.39g, 40.49mmol) in water (2mL) and acetonitrile (120mL), add palladium acetate (454.46mg, 2.02mmol) and triethylamine (12.29g, 121.46mmol, 16.91mL), the reaction was stirred at 85 ℃ for 16 hours, the reaction solution was directly spin-dried to give a solid crude product, the crude product with PE: EA = 5: 1 Perform column purification to obtain compound a.

1H NMR(400MHz,CDCl3)δ9.06(t,J＝2.00Hz,1H),8.72(dd,J＝1.92,1.10Hz,2H),7.54(td,J＝8.74,6.32Hz,1H),7.00-7.15(m,2H).1 H NMR (400 MHz, CDCl3 ) δ 9.06 (t, J = 2.00 Hz, 1H), 8.72 (dd, J = 1.92, 1.10 Hz, 2H), 7.54 (td, J = 8.74, 6.32 Hz, 1H) , 7.00-7.15(m, 2H).

步骤二Step two

将化合物a(6.5g,23.20mmol)溶于EtOAc(65mL)的氢化瓶中，加入Pd/C(1g,23.20mmol,10％纯度)，于50Psi压力的氢气瓶(46.77mg,23.20mmol,1eq)中，45℃下搅拌反应16小时。反应液过滤，滤液旋干，得化合物b。Compound a (6.5g, 23.20mmol) was dissolved in a hydrogenation flask of EtOAc (65mL), Pd/C (1g, 23.20mmol, 10% purity) was added, and a hydrogen flask (46.77mg, 23.20mmol, 1eq) at a pressure of 50Psi ), the reaction was stirred at 45°C for 16 hours. The reaction solution was filtered and the filtrate was dried to give compound b.

LCMS(ESI)m/z:220.9[M+1]+LCMS(ESI)m/z:220.9[M+1]+

1H NMR(400MHz,DMSO-d6,):δ7.36-7.45(m,1H),7.20-7.30(m,1H),7.10(td,J＝8.52,2.44Hz,1H),5.92(d,J＝1.52Hz,2H),5.86(d,J＝1.82Hz,1H),4.84(s,4H).1 H NMR (400 MHz, DMSO-d6 ,): δ 7.36-7.45 (m, 1H), 7.20-7.30 (m, 1H), 7.10 (td, J=8.52, 2.44 Hz, 1H), 5.92 (d , J = 1.52 Hz, 2H), 5.86 (d, J = 1.82 Hz, 1H), 4.84 (s, 4H).

步骤三Step three

向化合物b(2.37g,10.76mmol)的DMSO(15mL)溶液中加入DIEA(417.28mg,3.23mmol,562.37μL)，乙氧基三甲基硅烷(2.29g,19.37mmol)，加入4-溴-1-氟-2-硝基-苯(2.37g,10.76mmol,1.32mL)，100℃搅拌16小时。反应液加入100mL水中搅拌，有大量固体析出，减压抽滤后收集滤饼，滤饼用20mL无水甲苯带水旋干得化合物c。To a solution of compound b (2.37 g, 10.76 mmol) in DMSO (15 mL) was added DIEA (417.28 mg, 3.23 mmol, 562.37 μL), ethoxytrimethylsilane (2.29 g, 19.37 mmol), and 4-bromo- 1-fluoro-2-nitro-benzene (2.37g, 10.76mmol, 1.32mL), stirred at 100°C for 16 hours. The reaction solution was added to 100 mL of water and stirred, and a large amount of solid precipitated. The filter cake was collected after suction filtration under reduced pressure, and the filter cake was spin-dried with 20 mL of anhydrous toluene with water to obtain compound c.

LCMS(ESI)m/z:419.9[M+3]+,421.9[M+3]+LCMS(ESI)m/z: 419.9[M+3]+ , 421.9[M+3]+

1H NMR(400MHz,CDCl3)δ9.40(s,1H),8.33(d,J＝2.26Hz,1H),7.33-7.46(m,2H),7.21-7.25(m,2H),7.11-7.19(m,1H),6.86-6.97(m,2H),6.76(d,J＝1.52Hz,1H),6.68(d,J＝1.76Hz,1H),6.56(t,J＝2.02Hz,1H),1 H NMR (400 MHz, CDCl3 ) δ 9.40 (s, 1H), 8.33 (d, J=2.26 Hz, 1H), 7.33-7.46 (m, 2H), 7.21-7.25 (m, 2H), 7.11 7.19 (m, 1H), 6.86-6.97 (m, 2H), 6.76 (d, J = 1.52 Hz, 1H), 6.68 (d, J = 1.76 Hz, 1H), 6.56 (t, J = 2.02 Hz, 1H) ),

步骤四Step four

氮气保护下，向化合物c(4.5g,10.71mmol)的吡啶(30mL)混悬液中加入环丙基磺酰氯(1.66g,11.78mmol)。20℃搅拌2小时。向反应液中加入醋酸(34.6mL)，再加入水(250mL)，加入乙酸乙酯(150mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得化合物d。Under nitrogen protection, cyclopropylsulfonyl chloride (1.66 g, 11.78 mmol) was added to the suspension of compound c (4.5 g, 10.71 mmol) in pyridine (30 mL). Stir at 20°C for 2 hours. Acetic acid (34.6 mL) was added to the reaction solution, water (250 mL) was added, ethyl acetate (150 mL*2) was added for extraction, the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound d.

LCMS(ESI)m/z:523.8[M+1]+,525.8[M+3]+LCMS(ESI)m/z: 523.8[M+1]+ , 525.8[M+3]+

步骤五Step five

向化合物d(5.6g,10.68mmol)，1-甲基-4-吡唑硼酸酯(2.78g,13.35mmol)的二甲基亚砜(110mL)/水(30mL)溶液中加入三苯基膦(1.40g,5.34mmol)，醋酸钯(359.67mg,1.60mmol)，碳酸钾(3.84g,27.77mmol)。氮气保护下100℃搅拌16小时。将反应液加入含搅拌的水(200mL)，有固体析出，减压抽滤收集滤饼，滤饼经二氯甲烷转移到单口瓶中，再减压浓缩得粗品。将粗品以石油醚/乙酸乙酯＝0/1进行过柱(快速硅胶柱层析)纯化得到化合物e。To a solution of compound d (5.6 g, 10.68 mmol), 1-methyl-4-pyrazole borate (2.78 g, 13.35 mmol) in dimethyl sulfoxide (110 mL)/water (30 mL) was added triphenyl Phosphine (1.40 g, 5.34 mmol), palladium acetate (359.67 mg, 1.60 mmol), potassium carbonate (3.84 g, 27.77 mmol). Stir at 100°C for 16 hours under nitrogen protection. The reaction solution was added with stirring water (200 mL), and a solid precipitated. The filter cake was collected by suction filtration under reduced pressure. The filter cake was transferred to a single-necked bottle via dichloromethane, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column (flash silica gel column chromatography) with petroleum ether/ethyl acetate=0/1 to obtain compound e.

LCMS(ESI)m/z:526.4[M+3]+LCMS (ESI) m/z: 526.4 [M+3]+

1H NMR(400MHz,CDCl3)δ9.45(s,1H),8.29(d,J＝2.02Hz,1H),7.73(s,1H),7.62(s,1H),7.53-7.58(m,1H),7.37-7.48(m,2H),7.16-7.24(m,3H),6.90-7.01(m,2H),6.71(s,1H),3.96(s,3H),2.52-2.65(m,1H),1.22-1.26(m,2H),0.98-1.11(m,2H).1 H NMR (400 MHz, CDCl3 ) δ 9.45 (s, 1H), 8.29 (d, J = 2.02 Hz, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.53-7.58 (m, 1H), 7.37-7.48(m, 2H), 7.16-7.24(m, 3H), 6.90-7.01(m, 2H), 6.71(s, 1H), 3.96(s, 3H), 2.52-2.65(m, 1H), 1.22-1.26(m, 2H), 0.98-1.11(m, 2H).

步骤六Step six

向化合物e(2.8g,5.33mmol,1eq)的甲酸(30mL)溶液中加入Pd/C(1g,5.33mmol,10％纯度)，30℃置于氢气球(15psi)氛围下搅拌16小时。反应完通过硅藻土过滤，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:YMC-Triart Prep C18 150*40mm*7μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:35％-50％,10min)得对照例1。To a solution of compound e (2.8 g, 5.33 mmol, 1 eq) in formic acid (30 mL) was added Pd/C (1 g, 5.33 mmol, 10% purity), and the mixture was stirred under a hydrogen balloon (15 psi) atmosphere at 30° C. for 16 hours. After the reaction was completed, it was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product is subjected to high performance liquid chromatography (chromatographic column: YMC-Triart Prep C18 150*40mm*7μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 35%-50%, 10min )得控制例1。 1 to get Comparative Example 1.

LCMS(ESI)m/z:506.0[M+1]+LCMS(ESI)m/z:506.0[M+1]+

1H NMR(400MHz,DMSO-d6)δ10.25(br s,1H),8.65(s,1H),8.19(s,1H),7.99(s,1H),7.94(s,1H),7.71-7.81 (m,1H),7.64-7.70(m,1H),7.55-7.63(m,3H),7.40-7.51(m,2H),7.27(br t,J＝7.53Hz,1H),3.88(s,3H),2.81-2.93(m,1H),0.98-1.08(m,4H).1 H NMR (400 MHz, DMSO-d6 ) δ 10.25 (br s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.71 -7.81 (m,1H),7.64-7.70(m,1H),7.55-7.63(m,3H),7.40-7.51(m,2H),7.27(br t,J=7.53Hz,1H),3.88( s, 3H), 2.81-2.93 (m, 1H), 0.98-1.08 (m, 4H).

对照例1的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到对照例1。The trifluoroacetic acid salt of Comparative Example 1 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Comparative Example 1.

实施例1Example 1

Figure PCTCN2019130053-appb-000064
Figure PCTCN2019130053-appb-000064

步骤一step one

将3,5-二硝基溴苯(20g,80.97mmol)溶于冰醋酸(120mL)中，升温至90℃，将还原铁粉(11.30g,202.43mmol)在30分钟内分批缓慢加到反应液中，加完即反应结束。向反应液中加入碎冰，有固体析出，过滤，水洗3次。收集滤饼，用甲苯带水得化合物1a。Dissolve 3,5-dinitrobromobenzene (20g, 80.97mmol) in glacial acetic acid (120mL), warm to 90°C, and slowly add the reduced iron powder (11.30g, 202.43mmol) to the batch in 30 minutes In the reaction solution, the reaction is completed when the addition is completed. Crushed ice was added to the reaction liquid, and a solid precipitated, which was filtered and washed 3 times with water. Collect the filter cake and bring water with toluene to obtain compound 1a.

1H NMR(400MHz,DMSO-d6)δ7.09-7.32(m,3H),6.13(br s,2H).1 H NMR (400 MHz, DMSO-d6 ) δ 7.09-7.32 (m, 3H), 6.13 (br s, 2H).

步骤二Step two

0℃将下将乙酸酐(16.02g,156.95mmol,14.7mL)加入到1a(14.7g,67.74mmol)中，在15℃继续搅拌30分钟。向反应液中加入碎冰140mL，有固体析出，过滤，用冰水洗两次，收集滤饼，旋干得化合物1b。1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.19(s,1H),8.02(s,1H),2.10(s,3H).Acetic anhydride (16.02g, 156.95mmol, 14.7mL) was added to la (14.7g, 67.74mmol) at 0°C, and stirring was continued at 15°C for 30 minutes. 140 mL of crushed ice was added to the reaction solution, and a solid precipitated, which was filtered, washed twice with ice water, and the filter cake was collected and spin-dried to obtain compound 1b.1 H NMR (400 MHz, DMSO-d6 ) δ 8.46 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 2.10 (s, 3H).

步骤三Step three

将化合物1b(16g,61.76mmol)和2,4-二氟苯硼酸(11.70g,74.12mmol)溶于乙二醇二甲醚(160mL)和 H2O(60mL)中，加入Pd(dppf)Cl2(4.52g,6.18mmol)和碳酸钠(19.64g,185.29mmol)，90℃下搅拌2小时。将反应液过滤，加入水(200mL)，二氯甲烷(300mL*2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得粗品。将粗品经快速硅胶柱(石油醚/乙酸乙酯＝1:1～0:1)纯化得到化合物1c。Compound 1b (16g, 61.76mmol) and 2,4-difluorophenylboronic acid (11.70g, 74.12mmol) were dissolved in ethylene glycol dimethyl ether (160mL) and H2 O (60mL), Pd (dppf) was added Cl2 (4.52 g, 6.18 mmol) and sodium carbonate (19.64 g, 185.29 mmol) were stirred at 90°C for 2 hours. The reaction solution was filtered, water (200 mL) was added, and dichloromethane (300 mL*2) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified through a flash silica gel column (petroleum ether/ethyl acetate = 1:1 ~ 0:1) to obtain compound 1c.

1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.09(s,1H),8.01(s,1H),7.60-7.70(m,1H),7.45-7.49(m,1H),2.12(s,3H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.63 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.60-7.70 (m, 1H), 7.45-7.49 (m, 1H) ), 2.12(s, 3H).

步骤四Step four

将化合物1c(4g,13.69mmol)溶于乙酸乙酯(25mL)和甲醇(50mL)中，加入干Pd/C(0.5g,13.69mmol，50％纯度)，氮气置换2次后，氢气置换2次，最后在30℃下，50psi搅拌反应8小时。反应液过滤，滤液旋干得产物1d。Compound 1c (4g, 13.69mmol) was dissolved in ethyl acetate (25mL) and methanol (50mL), dry Pd/C (0.5g, 13.69mmol, 50% purity) was added, after nitrogen was replaced twice, hydrogen was replaced by 2 At last, the reaction was stirred at 50 psi for 8 hours at 30°C. The reaction solution was filtered, and the filtrate was spin-dried to obtain the product 1d.

1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.14-7.48(m,3H),6.98(s,1H),6.85(s,1H),6.38(s,1H),5.31(s,2H),2.01(s,3H).1 H NMR (400 MHz, DMSO-d6 ) δ 9.75 (s, 1H), 7.14-7.48 (m, 3H), 6.98 (s, 1H), 6.85 (s, 1H), 6.38 (s, 1H), 5.31(s, 2H), 2.01(s, 3H).

步骤五Step five

0℃向化合物1d(1g,3.81mmol)的乙腈(30mL)溶液中加入亚硝酸叔丁酯(786.41mg,7.63mmol)，0℃搅拌30分钟，再加入溴化亚铜(1.09g,7.63mmol)，25℃搅拌30分钟，再于60℃下搅拌1小时。向反应液中加入水(50mL)，再加入乙酸乙酯(50mL*2)萃取，收集有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)分离得产物得化合物1e。To a solution of compound 1d (1g, 3.81mmol) in acetonitrile (30mL) was added tert-butyl nitrite (786.41mg, 7.63mmol) at 0°C, stirred at 0°C for 30 minutes, and then added copper bromide (1.09g, 7.63mmol) ), stirred at 25°C for 30 minutes, and then stirred at 60°C for 1 hour. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL*2), the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the product to obtain compound 1e.

步骤六Step six

向化合物1e(100mg,306.62μmol)，双联硼酸嚬哪醇酯(116.79mg,459.93μmol)的二氧六环(5mL)溶液中加入Pd(dppf)Cl2(22.44mg,30.66μmol)，醋酸钾(60.18mg,613.24μmol)。氮气保护下100℃搅拌3小时。过滤旋干得粗品化合物1f。Pd(dppf)Cl2 (22.44mg, 30.66μmol), acetic acid was added to a solution of compound 1e (100mg, 306.62μmol), dicandole borate (116.79mg, 459.93μmol) in dioxane (5mL) Potassium (60.18mg, 613.24μmol). Stir at 100°C for 3 hours under nitrogen protection. Filtration and spin-drying gave crude compound 1f.

LCMS(ESI)m/z:374.2[M+1]+LCMS(ESI)m/z: 374.2[M+1]+

Figure PCTCN2019130053-appb-000065
Figure PCTCN2019130053-appb-000065

步骤七Step 7

向4-溴-2-氨基吡啶(5g,28.90mmol)的EtOH(60mL)中滴加氯乙醛(8.51g,43.35mmol,6.97mL)，80℃搅拌16小时。反应液经减压旋干得粗品化合物1g。Chloroacetaldehyde (8.51 g, 43.35 mmol, 6.97 mL) was added dropwise to 4-bromo-2-aminopyridine (5 g, 28.90 mmol) in EtOH (60 mL), and stirred at 80° C. for 16 hours. The reaction solution was spin-dried under reduced pressure to obtain 1 g of crude compound.

1H NMR(400MHz,DMSO-d6)δ8.89-8.96(m,1H),8.40-8.45(m,1H),8.30(d,J＝1.52Hz,1H),8.19(d,J＝2.02Hz,1H),7.70(dd,J＝1.76,7.28Hz,1H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.89-8.96 (m, 1H), 8.40-8.45 (m, 1H), 8.30 (d, J = 1.52 Hz, 1H), 8.19 (d, J = 2.02 Hz, 1H), 7.70 (dd, J=1.76, 7.28Hz, 1H).

步骤八Step 8

将化合物1g(10g,50.75mmol)和1-甲基-4-吡唑硼酸酯(11.62g,55.83mmol)溶于二氧六环(155mL)和H2O(75mL)中，加入Pd(dppf)Cl2(3.71g,5.08mmol)和K3PO4(21.55g,101.51mmol)，100℃下搅拌反应16小时，反应液加水(150mL)，乙酸乙酯(150mL*2)进行萃取，有机相用无水硫酸钠干燥，过滤，滤液旋干得粗品。将粗品以石油醚/乙酸乙酯＝3/1进行过柱(快速硅胶柱层析)纯化得到化合物1h。LCMS(ESI)m/z:198.8[M+1]+Compound 1g (10g, 50.75mmol) and 1-methyl-4-pyrazole borate (11.62g, 55.83mmol) were dissolved in dioxane (155mL) and H2 O (75mL), Pd ( dppf) Cl2 (3.71 g, 5.08 mmol) and K3 PO4 (21.55 g, 101.51 mmol), the reaction was stirred at 100° C. for 16 hours, and the reaction solution was added with water (150 mL) and ethyl acetate (150 mL*2) for extraction, The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by column (flash silica gel column chromatography) with petroleum ether/ethyl acetate=3/1 to obtain compound 1h. LCMS(ESI)m/z:198.8[M+1]+

1H NMR(400MHz,CDCl3)δ8.11(br d,J＝7.04Hz,1H),7.79(s,1H),7.54-7.71(m,3H),7.37(br s,1H),6.90(d,J＝6.78Hz,1H),3.96(s,3H).1 H NMR (400 MHz, CDCl3 ) δ 8.11 (br d, J = 7.04 Hz, 1H), 7.79 (s, 1H), 7.54-7.71 (m, 3H), 7.37 (br s, 1H), 6.90 ( d, J = 6.78 Hz, 1H), 3.96 (s, 3H).

步骤九Step 9

向化合物1h(0.48g,2.42mmol)的乙腈(10mL)溶液中加入溴代丁二酰亚胺(517.19mg,2.91mmol)，30℃搅拌2小时。反应液经抽滤得滤液，滤液经减压浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1,Rf＝0.59)分离得化合物1i。To a solution of compound 1h (0.48 g, 2.42 mmol) in acetonitrile (10 mL) was added bromosuccinimide (517.19 mg, 2.91 mmol), and stirred at 30°C for 2 hours. The reaction solution was filtered by suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1, Rf = 0.59) to obtain compound 1i.

LCMS(ESI)m/z:276.7[M+1]+LCMS(ESI)m/z:276.7[M+1]+

步骤十Step ten

向1h(2.7g,13.62mmol)的二氯甲烷(27mL)溶液中加入NIS(3.68g,16.35mmol)，30℃搅拌16小 时。向反应液加水(100mL)，再加入二氯甲烷(100mL*3)萃取，合并有机相并减压浓缩。粗品经快速硅胶柱层析分离(DCM:MeOH＝10:1,Rf＝0.13)分离得得化合物1j。To a solution of 1h (2.7 g, 13.62 mmol) in dichloromethane (27 mL) was added NIS (3.68 g, 16.35 mmol), and stirred at 30°C for 16 hours. Water (100 mL) was added to the reaction solution, followed by extraction with dichloromethane (100 mL*3), and the organic phases were combined and concentrated under reduced pressure. The crude product was separated by flash silica gel column chromatography (DCM:MeOH=10:1, Rf=0.13) to obtain compound 1j.

LCMS(ESI)m/z:324.9[M+1]+LCMS(ESI)m/z:324.9[M+1]+

步骤十一Step eleven

向化合物1i(80mg,288.68μmol)，化合物1f(107.74mg,288.68μmol)的二氧六环(6mL)和H2O(3mL)混合溶液中加入K3PO4(122.56mg,577.37μmol)，Pd(dppf)Cl2(21.12mg,28.87μmol)。氮气保护下100℃反应2小时。反应液分层，有机相浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)得到粗品。粗品再经高效液相色谱(色谱柱:YMC-Actus Triart C18 100×30mm×5μm；流动相:[水(0.05％盐酸)-乙腈]；B(乙腈)％:25％-55％,10min)分离得化合物1的盐酸盐。To a mixed solution of compound 1i (80 mg, 288.68 μmol), compound 1f (107.74 mg, 288.68 μmol) in dioxane (6 mL) and H2 O (3 mL) was added K3 PO4 (122.56 mg, 577.37 μmol), Pd(dppf)Cl2 (21.12 mg, 28.87 μmol). The reaction was carried out at 100°C for 2 hours under nitrogen protection. The reaction solution was separated into layers, the organic phase was concentrated, and purified by silica gel column (DCM:MeOH=10:1) to obtain crude product. The crude product was then subjected to high performance liquid chromatography (chromatographic column: YMC-Actus Triart C18 100×30mm×5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 10min ) The hydrochloride salt ofcompound 1 was isolated.

LCMS(ESI)m/z:444.1[M+1]+LCMS(ESI)m/z:444.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.72(d,J＝7.28Hz,1H),8.41(s,1H),8.11-8.17(m,3H),8.07(s,1H),7.81(d,J＝1.52Hz,1H),7.75(dd,J＝1.52,7.28Hz,1H),7.59-7.67(m,1H),7.57(d,J＝1.00Hz,1H),7.07-7.14(m,2H),4.00(s,3H),2.20(s,3H).1 H NMR (400 MHz, CD3 OD) δ 8.72 (d, J = 7.28 Hz, 1H), 8.41 (s, 1H), 8.11-8.17 (m, 3H), 8.07 (s, 1H), 7.81 (d , J = 1.52 Hz, 1H), 7.75 (dd, J = 1.52, 7.28 Hz, 1H), 7.59-7.67 (m, 1H), 7.57 (d, J = 1.00 Hz, 1H), 7.07-7.14 (m, 2H), 4.00(s, 3H), 2.20(s, 3H).

化合物1的盐酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物1。The hydrochloride salt ofCompound 1 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtainCompound 1.

实施例2Example 2

Figure PCTCN2019130053-appb-000066
Figure PCTCN2019130053-appb-000066

步骤一step one

向化合物3-溴-5-硝基-苯酚(1g,4.59mmol)，2,4-二氟苯硼酸(869.21mg,5.50mmol)的THF(10mL)和H2O(5mL)溶液中加入Pd(dppf)Cl2(335.64mg,458.71μmol)，K3PO4(2.43g,11.47mmol)。氮气保护下90℃搅拌16小时。反应液中加水(50mL)，用乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(PE:EA＝5:1,Rf＝0.12)得化合物2a。Pd was added to a solution of compound 3-bromo-5-nitro-phenol (1 g, 4.59 mmol), 2,4-difluorophenylboronic acid (869.21 mg, 5.50 mmol) in THF (10 mL) and H2 O (5 mL) (dppf) Cl2 (335.64 mg, 458.71 μmol), K3 PO4 (2.43 g, 11.47 mmol). Stir at 90°C for 16 hours under nitrogen protection. Water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (PE:EA=5:1, Rf=0.12) to obtain compound 2a.

1H NMR(400MHz,DMSO-d6)δ10.69(br s,1H),7.77(d,J＝1.52Hz,1H),7.68(dt,J＝6.54,8.92Hz,1H),7.59(t,J＝2.14Hz,1H),7.38-7.47(m,1H),7.35(d,J＝1.76Hz,1H),7.23(dt,J＝2.14,8.48Hz,1H).1 H NMR (400 MHz, DMSO-d6 ) δ 10.69 (br s, 1H), 7.77 (d, J = 1.52 Hz, 1H), 7.68 (dt, J = 6.54, 8.92 Hz, 1H), 7.59 (t , J = 2.14 Hz, 1H), 7.38-7.47 (m, 1H), 7.35 (d, J = 1.76 Hz, 1H), 7.23 (dt, J = 2.14, 8.48 Hz, 1H).

步骤二Step two

向化合物2a(4g,15.92mmol)的DMF(50mL)溶液中加入DIEA(6.17g,47.77mmol,8.32mL)，N-苯基双(三氟甲烷磺酰)亚胺(8.53g,23.89mmol)，15℃搅拌16小时。反应液中加水50mL，用乙酸乙酯(50mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(PE:EA＝3:1,Rf＝0.76)得化合物2b。To a solution of compound 2a (4 g, 15.92 mmol) in DMF (50 mL) was added DIEA (6.17 g, 47.77 mmol, 8.32 mL), N-phenylbis(trifluoromethanesulfonyl)imide (8.53 g, 23.89 mmol) , Stir for 16 hours at 15 ℃. 50 mL of water was added to the reaction solution and extracted with ethyl acetate (50 mL*2). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (PE:EA=3:1, Rf=0.76) to obtain compound 2b.

1H NMR(400MHz,DMSO-d6)δ8.42-8.50(m,2H),8.25(s,1H),7.79(dt,J＝6.54,8.92Hz,1H),7.41-7.54(m,1H),7.22-7.36(m,1H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.42-8.50 (m, 2H), 8.25 (s, 1H), 7.79 (dt, J = 6.54, 8.92 Hz, 1H), 7.41-7.54 (m, 1H) ), 7.22-7.36 (m, 1H).

步骤三Step three

向化合物2b(6g,15.66mmol)的二氧六环(40mL)溶液中加入Pd(dppf)Cl2(1.15g,1.57mmol)，双联嚬哪醇硼酸酯(4.77g,18.79mmol)，醋酸钾(3.07g,31.31mmol)。氮气保护下90℃搅拌16小时。TLC显示有新点生成。经硅藻土过滤后浓缩得化合物2c。Solution of compound 2b (6g, 15.66mmol) in dioxane (40 mL) was added Pd(dppf) Cl 2 (1.15g, 1.57mmol), double knit the brows pinacolato boronate (4.77g, 18.79mmol), Potassium acetate (3.07g, 31.31mmol). Stir at 90°C for 16 hours under nitrogen protection. TLC shows that new points are generated. After filtering through celite and concentrating to obtain compound 2c.

步骤四Step four

向化合物2c(4.68g,12.96mmol)，1j(3.5g,10.80mmol)的二氧六环(30mL)和H2O(10mL)溶液中加入Pd(dppf)Cl2(790.13mg,1.08mmol)，K3PO4(4.58g,21.60mmol)。氮气保护下100℃搅拌3小时。反应液中加入水(200mL)，乙酸乙酯(200mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经快速硅胶柱层析纯化(DCM:MeOH＝10:1,Rf＝0.71)得化合物2d。To a solution of compound 2c (4.68 g, 12.96 mmol), 1j (3.5 g, 10.80 mmol) in dioxane (30 mL) and H2 O (10 mL) was added Pd(dppf)Cl2 (790.13 mg, 1.08 mmol) , K3 PO4 (4.58 g, 21.60 mmol). Stir at 100°C for 3 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and ethyl acetate (200 mL*2) was extracted. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1, Rf=0.71) to give compound 2d.

LCMS(ESI)m/z:432.0[M+1]+LCMS(ESI)m/z:432.0[M+1]+

步骤五Step five

向化合物2d(2.0g,4.64mmol)的MeOH(20mL)溶液中加入Pd/C(0.2g,10％纯度)，于氢气(15psi)球氛围下15℃搅拌5小时。反应液经硅藻土过滤，滤液减压浓缩。粗品经快速硅胶柱层析(DCM:MeOH＝10:1,Rf＝0.62)纯化得化合物2e。To a solution of compound 2d (2.0 g, 4.64 mmol) in MeOH (20 mL) was added Pd/C (0.2 g, 10% purity), and stirred at 15°C for 5 hours under a hydrogen (15 psi) ball atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1, Rf=0.62) to obtain compound 2e.

LCMS(ESI)m/z:402.2[M+1]+LCMS(ESI)m/z:402.2[M+1]+

步骤六Step six

向化合物2e(50.00mg,124.56μmol)的吡啶(2mL)溶液中加入乙基磺酰氯(38.44mg,298.95μmol, 28.26μL)，15℃搅拌2小时。反应液用醋酸(3mL)调pH至5，加入水(8mL)，加入乙酸乙酯(8mL*2)萃取，合并有机相减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物2的三氟乙酸盐。To a solution of compound 2e (50.00 mg, 124.56 μmol) in pyridine (2 mL) was added ethylsulfonyl chloride (38.44 mg, 298.95 μmol, 28.26 μL), and stirred at 15°C for 2 hours. The reaction solution was adjusted to pH 5 with acetic acid (3 mL), water (8 mL) was added, ethyl acetate (8 mL*2) was added for extraction, and the combined organic phase was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8min) The trifluoroacetate salt of compound 2 is obtained.

LCMS(ESI)m/z:494.0[M+1]+LCMS(ESI)m/z:494.0[M+1]+

1H NMR(400MHz,CD3OD)δ8.70(d,J＝6.78Hz,1H),8.38(s,1H),8.15(s,2H),8.05(d,J＝0.76Hz,1H),7.76(dd,J＝1.76,7.28Hz,1H),7.60-7.68(m,3H),7.55-7.59(m,1H),7.09-7.18(m,2H),4.00(s,3H),3.25(q,J＝7.36Hz,2H),1.37(t,J＝7.40Hz,3H).1 H NMR (400 MHz, CD3 OD) δ 8.70 (d, J=6.78 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 2H), 8.05 (d, J=0.76 Hz, 1H), 7.76(dd, J=1.76, 7.28Hz, 1H), 7.60-7.68(m, 3H), 7.55-7.59(m, 1H), 7.09-7.18(m, 2H), 4.00(s, 3H), 3.25( q, J = 7.36 Hz, 2H), 1.37 (t, J = 7.40 Hz, 3H).

化合物2的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物2。The trifluoroacetic acid salt of compound 2 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2.

表1中实施例化合物的制备可以参照前述制备实施例2的路线类似的步骤方法进行，不同之处在于在步骤六中使用的原料A代替乙基磺酰氯得到相应化合物的三氟乙酸盐，将得到的化合物的三氟乙酸盐分别加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到相应的化合物。The preparation of the compounds of the examples in Table 1 can be carried out by referring to the steps similar to those in the foregoing preparation example 2, except that the raw material A used in step 6 replaces ethylsulfonyl chloride to obtain the trifluoroacetate salt of the corresponding compound. The trifluoroacetic acid salt of the obtained compound was added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.

表1Table 1

Figure PCTCN2019130053-appb-000067
Figure PCTCN2019130053-appb-000067

Figure PCTCN2019130053-appb-000068
Figure PCTCN2019130053-appb-000068

实施例4Example 4

Figure PCTCN2019130053-appb-000069
Figure PCTCN2019130053-appb-000069

步骤一step one

向化合物2e(30mg,74.74μmol)，环丙基乙酸(9.65mg,112.10μmol,8.85μL)的DMF(2mL)溶液中加入HATU(42.63mg,112.10μmol)，DIEA(19.32mg,149.47μmol,26.04μL)。15℃搅拌16小时。反应液过滤。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:27％-57％,8min)纯化得到化合物4的三氟乙酸盐。To a solution of compound 2e (30 mg, 74.74 μmol), cyclopropylacetic acid (9.65 mg, 112.10 μmol, 8.85 μL) in DMF (2 mL) was added HATU (42.63 mg, 112.10 μmol), DIEA (19.32 mg, 149.47 μmol, 26.04 μL). Stir at 15°C for 16 hours. The reaction solution is filtered. The crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 27%-57%, 8min) The trifluoroacetate salt of compound 4 is obtained.

LCMS(ESI)m/z:470.1[M+1]+LCMS(ESI)m/z: 470.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.73(d,J＝7.54Hz,1H),8.36(s,1H),8.07-8.19(m,3H),8.02(s,1H),7.78(d,J＝1.52Hz,1H),7.71(dd,J＝1.64,7.16Hz,1H),7.59-7.67(m,1H),7.57(d,J＝1.26Hz,1H),7.06-7.18(m,2H),3.99(s,3H),1.74-1.89(m,1H),0.96-1.03(m,2H),0.88-0.96(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.73 (d, J = 7.54 Hz, 1H), 8.36 (s, 1H), 8.07-8.19 (m, 3H), 8.02 (s, 1H), 7.78 (d , J = 1.52 Hz, 1H), 7.71 (dd, J = 1.64, 7.16 Hz, 1H), 7.59-7.67 (m, 1H), 7.57 (d, J = 1.26 Hz, 1H), 7.06-7.18 (m, 2H), 3.99 (s, 3H), 1.74-1.89 (m, 1H), 0.96-1.03 (m, 2H), 0.88-0.96 (m, 2H).

化合物4的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物4。The trifluoroacetic acid salt of compound 4 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4.

实施例5Example 5

Figure PCTCN2019130053-appb-000070
Figure PCTCN2019130053-appb-000070

步骤一step one

向化合物2e(9.88mg,112.10μmol,10.40μL)，2-甲基丙酸(9.88mg,112.10μmol,10.40μL)的DMF(2mL)溶液中加入HATU(42.63mg,112.10μmol)，DIEA(19.32mg,149.47μmol,26.04μL)。15℃搅拌16小时。反应液直接过滤浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:28％-58％,8min)纯化得到化合物5的三氟乙酸盐。To a solution of compound 2e (9.88 mg, 112.10 μmol, 10.40 μL), 2-methylpropionic acid (9.88 mg, 112.10 μmol, 10.40 μL) in DMF (2 mL) was added HATU (42.63 mg, 112.10 μmol), DIEA (19.32 mg, 149.47 μmol, 26.04 μL). Stir at 15°C for 16 hours. The reaction solution was directly filtered and concentrated. The crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 28%-58%, 8min) The trifluoroacetate salt of compound 5 is obtained.

LCMS(ESI)m/z:472.1[M+1]+LCMS(ESI)m/z: 472.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.75(d,J＝7.28Hz,1H),8.38(s,1H),8.20(s,1H),8.15(d,J＝7.04Hz,2H),8.05(s,1H),7.80(s,1H),7.75(d,J＝7.28Hz,1H),7.57-7.68(m,2H),7.05-7.18(m,2H),4.00(s,3H),2.70(td,J＝6.88,13.62Hz,1H),1.24(d,J＝6.78Hz,6H).1 H NMR (400 MHz, CD3 OD) δ 8.75 (d, J = 7.28 Hz, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 7.04 Hz, 2H), 8.05(s, 1H), 7.80(s, 1H), 7.75(d, J=7.28Hz, 1H), 7.57-7.68(m, 2H), 7.05-7.18(m, 2H), 4.00(s, 3H) , 2.70 (td, J = 6.88, 13.62 Hz, 1H), 1.24 (d, J = 6.78 Hz, 6H).

化合物5的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物5。The trifluoroacetic acid salt of compound 5 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5.

实施例7Example 7

Figure PCTCN2019130053-appb-000071
Figure PCTCN2019130053-appb-000071

步骤一step one

向化合物2e(30mg,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol)，0℃下搅拌5分钟；同时环丙胺(4.27mg,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol)和三光气(11.09mg,37.37μmol)，0℃下搅拌5分钟；然后将含环丙胺的反应液加到化合物2e的反应液中，继续0℃搅拌5分钟。反应液直接旋干。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:23％-53％,10min)纯化得到化合物7的三氟乙酸盐。Compound 2e (30 mg, 74.74 μmol) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21 μmol) was added, and stirred at 0° C. for 5 minutes; meanwhile, cyclopropylamine (4.27 mg, 74.74 μmol) was dissolved in DCM (1 mL) In, add DIEA (28.98mg, 224.21μmol) and triphosgene (11.09mg, 37.37μmol) and stir at 0°C for 5 minutes; then add the reaction solution containing cyclopropylamine to the reaction solution of compound 2e and continue stirring at 0°C 5 minutes. The reaction solution was directly spun dry. The crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 23%-53%, 10min) The trifluoroacetate salt ofcompound 7 is obtained.

LCMS(ESI)m/z:485.2[M+1]+LCMS(ESI)m/z:485.2[M+1]+

1H NMR(400MHz,CD3OD)δ8.76(d,J＝7.54Hz,1H),8.16(s,1H),8.38(s,1H),8.10(s,1H),8.02(m,2H),7.72(d,J＝7.28Hz,1H),7.60-7.68(m,2H),7.49(s,1H),7.08-7.18(m,2H),4.02(s,2H),3.98-4.05(m,1H),2.64(dt,J＝7.04,3.52Hz,1H),0.76-0.84(m,2H),0.57(br s,2H).1 H NMR (400 MHz, CD3 OD) δ 8.76 (d, J = 7.54 Hz, 1H), 8.16 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 8.02 (m, 2H ), 7.72 (d, J = 7.28 Hz, 1H), 7.60-7.68 (m, 2H), 7.49 (s, 1H), 7.08-7.18 (m, 2H), 4.02 (s, 2H), 3.98-4.05 ( m, 1H), 2.64 (dt, J = 7.04, 3.52 Hz, 1H), 0.76-0.84 (m, 2H), 0.57 (br s, 2H).

化合物7的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物7。The trifluoroacetic acid salt ofcompound 7 was added to the sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 7.

实施例8Example 8

Figure PCTCN2019130053-appb-000072
Figure PCTCN2019130053-appb-000072

步骤一step one

向7-溴咪唑并[1,2-a]吡啶(10g,50.75mmol)，吗啡啉(6.63g,76.13mmol)的甲苯(100mL)溶液中加入三(二亚苄基丙酮)二钯(4.65g,5.08mmol)，(±)-2,2-双(二苯膦基)-11-联萘(6.32g,10.15mmol)，叔丁醇钠(9.76g,101.51mmol)。氮气保护下95℃搅拌3小时。LCMS表明有产物生成。反应液经抽滤得滤液，滤液经减压浓缩得粗品。粗品经硅胶柱层析分离(EA:MeOH＝10:1)纯化得到化合物8a。To a solution of 7-bromoimidazo[1,2-a]pyridine (10g, 50.75mmol), morpholine (6.63g, 76.13mmol) in toluene (100mL) was added tris(dibenzylideneacetone) dipalladium (4.65 g, 5.08 mmol), (±)-2,2-bis(diphenylphosphino)-11-binaphthalene (6.32 g, 10.15 mmol), sodium tert-butoxide (9.76 g, 101.51 mmol). Stir at 95°C for 3 hours under nitrogen protection. LCMS indicated product formation. The reaction solution was filtered with suction to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (EA:MeOH=10:1) to obtain compound 8a.

LCMS(ESI)m/z:204.1[M+1]+LCMS(ESI)m/z:204.1[M+1]+

步骤二Step two

向化合物8a(500mg,2.46mmol)的DCM(10mL)溶液中加入NIS(664.19mg,2.95mmol)，20℃搅拌16小时。向反应液中加水(10mL)，萃取分液，有机相用无水硫酸钠干燥减压浓缩得到化合物8b。To a solution of compound 8a (500 mg, 2.46 mmol) in DCM (10 mL) was added NIS (664.19 mg, 2.95 mmol), and stirred at 20°C for 16 hours. Water (10 mL) was added to the reaction liquid, the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 8b.

LCMS(ESI)m/z:329.9[M+1]+LCMS(ESI)m/z:329.9[M+1]+

步骤三Step three

向化合物8b(0.9g,2.73mmol)，2c(1.19g,3.28mmol)的二氧六环(9mL)和H2O(3mL)溶液中加入Pd(dppf)Cl2(200.08mg,273.44μmol)，K3PO4(1.16g,5.47mmol)，氮气保护下90℃搅拌16小时。反应液分层后，用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)过柱纯化得到化合物8c。To a solution of compound 8b (0.9 g, 2.73 mmol), 2c (1.19 g, 3.28 mmol) in dioxane (9 mL) and H2 O (3 mL) was added Pd(dppf)Cl2 (200.08 mg, 273.44 μmol) , K3 PO4 (1.16g, 5.47mmol), stirred at 90 °C for 16 hours under nitrogen protection. After the reaction solution was separated into layers, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 8c.

LCMS(ESI)m/z:437.1[M+1]+LCMS(ESI)m/z:437.1[M+1]+

步骤四Step four

将化合物8c(0.8g,1.83mmol)溶于MeOH(30mL)中，加入Pd/C(0.8g,10％纯度)，氮气置换2次后， 氢气置换2次，最后在30℃下，50psi搅拌反应16小时。反应液过滤，滤液旋干得化合物8d。Compound 8c (0.8g, 1.83mmol) was dissolved in MeOH (30mL), Pd/C (0.8g, 10% purity) was added, after nitrogen substitution twice, hydrogen substitution twice, and finally stirring at 30℃, 50psi React for 16 hours. The reaction solution was filtered, and the filtrate was spin-dried to obtain compound 8d.

LCMS(ESI)m/z:407.1[M+1]+LCMS(ESI)m/z:407.1[M+1]+

步骤五Step five

向化合物8d(0.16g,393.67μmol)的吡啶(2mL)溶液中加入环丙基磺酰氯(100mg,711.30μmol)。20℃搅拌3小时。反应液加入乙酸调pH至5，再加入水10mL，用乙酸乙酯(10mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:30％-60％,10min)纯化得到化合物8的三氟乙酸盐。To a solution of compound 8d (0.16 g, 393.67 μmol) in pyridine (2 mL) was added cyclopropylsulfonyl chloride (100 mg, 711.30 μmol). Stir at 20°C for 3 hours. Acetic acid was added to the reaction solution to adjust the pH to 5, then 10 mL of water was added, extracted with ethyl acetate (10 mL*2), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 30%-60%, 10min) The trifluoroacetate salt of compound 8 is obtained.

LCMS(ESI)m/z:511.2[M+1]+LCMS(ESI)m/z:511.2[M+1]+

1H NMR(400MHz,CD3OD)δ8.44(d,J＝7.78Hz,1H),7.86(s,1H),7.54-7.66(m,4H),7.28(dd,J＝2.26,8.04Hz,1H),7.07-7.17(m,2H),6.92(d,J＝2.02Hz,1H),3.80-3.91(m,4H),3.51-3.58(m,4H),2.66-2.75(m,1H),1.11(br d,J＝3.76Hz,2H),0.98-1.06(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.44 (d, J = 7.78 Hz, 1 H), 7.86 (s, 1 H), 7.54-7.66 (m, 4 H), 7.28 (dd, J = 2.26, 8.04 Hz , 1H), 7.07-7.17 (m, 2H), 6.92 (d, J = 2.02 Hz, 1H), 3.80-3.91 (m, 4H), 3.51-3.58 (m, 4H), 2.66-2.75 (m, 1H ), 1.11 (br d, J = 3.76 Hz, 2H), 0.98-1.06 (m, 2H).

化合物8的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物8。The trifluoroacetic acid salt of compound 8 was added to the sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8.

实施例9Example 9

Figure PCTCN2019130053-appb-000073
Figure PCTCN2019130053-appb-000073

Figure PCTCN2019130053-appb-000074
Figure PCTCN2019130053-appb-000074

步骤一step one

在0℃条件下，在溴乙醇中(500g,4.00mol,284.09mL)加入3,4-二氢2H-吡喃(500.00g,5.94mol,543.48mL)、浓盐酸(1.02g,10.35mmol,1.00mL)，19℃搅拌1小时。反应完成后，加入100g碳酸氢钠搅拌30分钟，过滤除去不溶物得粗品。减压蒸馏0.09MPa，收集80℃馏分，得到化合物9f。At 0°C, add 3,4-dihydro 2H-pyran (500.00g, 5.94mol, 543.48mL) and concentrated hydrochloric acid (1.02g, 10.35mmol, to bromoethanol (500g, 4.00mol, 284.09mL) 1.00 mL), stirred at 19°C for 1 hour. After the reaction was completed, 100 g of sodium bicarbonate was added and stirred for 30 minutes, and the insoluble matter was removed by filtration to obtain a crude product. 0.09 MPa was distilled under reduced pressure, and the 80°C fraction was collected to obtain compound 9f.

1H NMR(400MHz,CDCl3)δ4.66-4.60(m,1H),4.00-3.76(m,3H),3.50-3.47(m,1H),1.83-1.50(m,6H).1 H NMR (400 MHz, CDCl3 ) δ 4.66-4.60 (m, 1H), 4.00-3.76 (m, 3H), 3.50-3.47 (m, 1H), 1.83-1.50 (m, 6H).

步骤二Step two

将化合物9f(600.78g,2.87mol,435.35mL)、4-硼酸酯-1H-吡唑(280g,1.44mol)溶于DMF(1120mL)，加入碳酸钾(397.12g,2.87mol)，60℃搅拌48小时。过滤除去不溶物，用乙酸乙酯洗涤，合并滤液，旋除溶剂得粗品。粗品经硅胶柱层析(正庚烷：乙酸乙酯＝8:1)得化合物9g。Compound 9f (600.78g, 2.87mol, 435.35mL), 4-boronate-1H-pyrazole (280g, 1.44mol) was dissolved in DMF (1120mL), potassium carbonate (397.12g, 2.87mol) was added at 60°C Stir for 48 hours. The insoluble material was removed by filtration, washed with ethyl acetate, the filtrate was combined, and the solvent was removed by rotation to obtain a crude product. The crude product was subjected to silica gel column chromatography (n-heptane: ethyl acetate = 8: 1) to obtain compound 9g.

1H NMR(400MHz,CDCl3)δ7.84-7.78(m,1H),4.52-4.51(m,1H),4.35-4.32(m,2H),4.05-4.04(m,1H),3.79-3.45(m,3H),1.79-1.47(m,6H),1.32(s,12H).1 H NMR(400MHz,CDCl3 )δ7.84-7.78(m,1H),4.52-4.51(m,1H),4.35-4.32(m,2H),4.05-4.04(m,1H),3.79-3.45 (m,3H), 1.79-1.47(m,6H), 1.32(s,12H).

步骤三Step three

向7-溴咪唑并[1,2-a]吡啶(8g,40.60mmol)，化合物9g(15.70g,48.72mmol)的二氧六环(80mL)和H2O(40mL)溶液中加入Pd(dppf)Cl2(2.97g,4.06mmol)，K3PO4(17.24g,81.21mmol)。95℃搅拌16小时。反应液分层，收集有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(DCM:MeOH＝10:1)得到化合物9a。To a solution of 7-bromoimidazo[1,2-a]pyridine (8g, 40.60mmol), compound 9g (15.70g, 48.72mmol) in dioxane (80mL) and H2 O (40mL) was added Pd( dppf) Cl2 (2.97 g, 4.06 mmol), K3 PO4 (17.24 g, 81.21 mmol). Stir at 95°C for 16 hours. The reaction solution was separated into layers, the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 9a.

LCMS(ESI)m/z:313.0[M+1]+LCMS(ESI)m/z:313.0[M+1]+

步骤四Step four

向化合物9a(3.7g,11.85mmol)的DCM(30mL)溶液中加入NIS(3.20g,14.21mmol)，20℃搅拌16小时。向反应液中加水(100mL)，萃取分液，有机相用无水硫酸钠干燥减压浓缩得到化合物9b。To a solution of compound 9a (3.7 g, 11.85 mmol) in DCM (30 mL) was added NIS (3.20 g, 14.21 mmol), and stirred at 20°C for 16 hours. Water (100 mL) was added to the reaction liquid, the liquid was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 9b.

LCMS(ESI)m/z:439.0[M+1]+LCMS(ESI)m/z:439.0[M+1]+

步骤五Step five

向化合物9b(2.5g,5.70mmol)，2c(2.47g,6.85mmol)的二氧六环二氧六环(50mL)和H2O(15mL)溶液中加入Pd(dppf)Cl2(417.39mg,570.44μmol)，K3PO4(2.42g,11.41mmol)。氮气保护下90℃搅拌16小时。反应液分层后，有机相用无水硫酸钠干燥，减压浓缩。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)过柱纯化得到9c。To a solution of compound 9b (2.5 g, 5.70 mmol), 2c (2.47 g, 6.85 mmol) in dioxane dioxane (50 mL) and H2 O (15 mL) was added Pd(dppf)Cl2 (417.39 mg , 570.44 μmol), K3 PO4 (2.42 g, 11.41 mmol). Stir at 90°C for 16 hours under nitrogen protection. After the reaction solution was separated into layers, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=20:1) to obtain 9c.

LCMS(ESI)m/z:546.3[M+1]+LCMS(ESI)m/z:546.3[M+1]+

步骤六Step six

向化合物9c(0.2g,366.61μmol)的EtOH(10mL)和H2O(2mL)溶液中加入锌粉(239.73mg,3.67mmol)，氯化铵(196.11mg,3.67mmol)。20℃搅拌16小时。反应液直接过滤，滤液减压浓缩得到化合物9d。To a solution of compound 9c (0.2 g, 366.61 μmol) in EtOH (10 mL) and H2 O (2 mL) was added zinc powder (239.73 mg, 3.67 mmol), ammonium chloride (196.11 mg, 3.67 mmol). Stir at 20°C for 16 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9d.

LCMS(ESI)m/z:516.1[M+1]+LCMS(ESI)m/z:516.1[M+1]+

步骤七Step 7

向化合物9d(0.19g,368.54μmol)的吡啶(2mL)溶液中加入环丙基磺酰氯(62.17mg,442.24μmol)，20℃搅拌4小时。反应液中加入20mL冰水，再加入醋酸6mL调pH至5，加入乙酸乙酯(20mL*3)萃取，有机相减压浓缩得到化合物9e。To a solution of compound 9d (0.19 g, 368.54 μmol) in pyridine (2 mL) was added cyclopropylsulfonyl chloride (62.17 mg, 442.24 μmol), and stirred at 20° C. for 4 hours. 20 mL of ice water was added to the reaction solution, and then 6 mL of acetic acid was added to adjust the pH to 5, ethyl acetate (20 mL*3) was added for extraction, and the organic phase was concentrated under reduced pressure to obtain compound 9e.

LCMS(ESI)m/z:620.1[M+1]+LCMS(ESI)m/z:620.1[M+1]+

步骤八Step 8

向化合物9e(0.19g,306.61μmol)的单口瓶中加入氯化氢/乙酸乙酯(4M,28.50mL)，20℃搅拌16小时。反应液直接减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:28％-58％,10min)纯化得到化合物9的三氟乙酸盐。Hydrogen chloride/ethyl acetate (4M, 28.50 mL) was added to the single-necked flask of compound 9e (0.19 g, 306.61 μmol), and stirred at 20° C. for 16 hours. The reaction solution was directly concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 28%-58%, 10min) The trifluoroacetate salt of compound 9 is obtained.

LCMS(ESI)m/z:536.3[M+1]+LCMS(ESI)m/z:536.3[M+1]+

1H NMR(400MHz,CD3OD)δ8.67-8.74(m,1H),8.44(s,1H),8.18(d,J＝14.06Hz,2H),8.06(s,1H),7.79(dd,J＝1.64,7.16Hz,1H),7.55-7.72(m,4H),7.07-7.21(m,2H),4.33(t,J＝5.14Hz,2H),3.95(t,J＝5.14Hz,2H),2.65-2.81(m,1H),1.09-1.17(m,2H),0.98-1.07(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.67-8.74 (m, 1H), 8.44 (s, 1H), 8.18 (d, J = 14.06 Hz, 2H), 8.06 (s, 1H), 7.79 (dd , J = 1.64, 7.16 Hz, 1H), 7.55-7.72 (m, 4H), 7.07-7.21 (m, 2H), 4.33 (t, J = 5.14 Hz, 2H), 3.95 (t, J = 5.14 Hz, 2H), 2.65-2.81(m, 1H), 1.09-1.17(m, 2H), 0.98-1.07(m, 2H).

化合物9的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物9。The trifluoroacetate salt of compound 9 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 9.

实施例11Example 11

Figure PCTCN2019130053-appb-000075
Figure PCTCN2019130053-appb-000075

步骤一step one

向4-硼酸酯-1H-吡唑(0.13g,669.97μmol)和氧杂异丁烯(633.36mg,8.78mmol,780.00μL)混悬液中加入碳酸铯(32.74mg,100.50μmol)，120℃下于微波反应器中搅16小时。直接用于下一步，无需处理。得到化合物11a。To a suspension of 4-boronate-1H-pyrazole (0.13g, 669.97μmol) and oxaisobutene (633.36mg, 8.78mmol, 780.00μL) was added cesium carbonate (32.74mg, 100.50μmol) at 120°C Stir for 16 hours in a microwave reactor. Used directly in the next step without processing. Compound 11a is obtained.

LCMS(ESI)m/z:267.0[M+1]+LCMS(ESI)m/z:267.0[M+1]+

步骤二Step two

向化合物1g(0.11g,558.29μmol)，11a(178.30mg,669.94μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl2(40.85mg,55.83μmol)，K3PO4(237.01mg,1.12mmol)。氮气保护下90℃搅拌16小时。反应液分层，有机相浓缩旋干得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物11b。LCMS(ESI)m/z:256.9[M+1]+Solution of compound 1g (0.11g, 558.29μmol), 11a (178.30mg, 669.94μmol) in dioxane (3mL) and water (1mL) was addedPd (dppf) Cl 2 (40.85mg , 55.83μmol), K3 PO4 (237.01 mg, 1.12 mmol). Stir at 90°C for 16 hours under nitrogen protection. The reaction solution was separated into layers, and the organic phase was concentrated and dried to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 11b. LCMS(ESI)m/z: 256.9[M+1]+

步骤三Step three

向化合物11b(0.12g,468.20μmol)的DCM(3mL)溶液中加入NIS(126.40mg,561.84μmol)，25℃搅拌16小时。向反应液中水(20mL)，用二氯甲烷(15mL*3)萃取分液，有机相并用无水硫酸钠干燥减压浓缩得到化合物11c。To a solution of compound 11b (0.12 g, 468.20 μmol) in DCM (3 mL) was added NIS (126.40 mg, 561.84 μmol), and stirred at 25° C. for 16 hours. Water (20 mL) was added to the reaction liquid, and the liquid was separated with dichloromethane (15 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 11c.

LCMS(ESI)m/z:383.0[M+1]+LCMS(ESI)m/z:383.0[M+1]+

步骤四Step four

将化合物2b(17.71g,46.21mmol)溶于EtOH(150mL)和H2O(50mL)中，加入氯化铵(24.72g,462.10mmol)混合均匀，然后缓慢加入锌粉(15.11g,231.05mmol)。80℃下搅拌反应16小时。将反应液经硅藻土过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离(PE:EA＝10:1)得到化合物11d。Compound 2b (17.71g, 46.21mmol) was dissolved in EtOH (150mL) and H2 O (50mL), was added ammonium chloride (24.72g, 462.10mmol) mixed, then was slowly added zinc dust (15.11g, 231.05mmol ). The reaction was stirred at 80°C for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (PE:EA=10:1) to obtain compound 11d.

LCMS(ESI)m/z:353.9[M+1]+LCMS(ESI)m/z:353.9[M+1]+

1H NMR(400MHz,DMSO-d6)δ7.58-7.54(m,1H),7.38-7.35(m,1H),7.19-7.18(m,1H),6.79(s,1H),6.79-6.62(m,2H),5.87(s,2H).1 H NMR (400MHz, DMSO-d6 ) δ 7.58-7.54 (m, 1H), 7.38-7.35 (m, 1H), 7.19-7.18 (m, 1H), 6.79 (s, 1H), 6.79-6.62 (m, 2H), 5.87 (s, 2H).

步骤五Step five

向化合物11d(16.5g,46.71mmol)的吡啶(75mL)溶液中加入甲烷磺酰氯(8.03g,70.06mmol)，30℃搅拌3小时。反应完成后，反应液加水(100mL)，用乙酸乙酯萃取(80mL*3)萃取，合并有机相并用无水硫酸钠干燥，油泵减压浓缩得到化合物11e。To a solution of compound 11d (16.5 g, 46.71 mmol) in pyridine (75 mL), methanesulfonyl chloride (8.03 g, 70.06 mmol) was added, and the mixture was stirred at 30° C. for 3 hours. After the reaction was completed, the reaction solution was added with water (100 mL), and extracted with ethyl acetate (80 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and the oil pump was concentrated under reduced pressure to obtain compound 11e.

步骤六Step six

将化合物11e，双联嚬哪醇硼酸酯(8.12g,31.99mmol)溶于二氧六环(200mL)中，加入Pd(dppf)Cl2(1.95g,2.67mmol)，醋酸钾(5.23g,53.32mmol)100℃搅拌反应16小时。反应液经过硅藻土过滤收集滤液，滤液减压浓缩得粗品。粗品经硅胶柱层析分离(PE/EA＝5:1)得到化合物11f。Dissolve compound 11e, bis-carbazinol borate (8.12g, 31.99mmol) in dioxane (200mL), add Pd(dppf)Cl2 (1.95g, 2.67mmol), potassium acetate (5.23g , 53.32 mmol) was stirred at 100°C for 16 hours. The reaction solution was filtered through celite to collect the filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (PE/EA=5:1) to obtain compound 11f.

LCMS(ESI)m/z:409.13[M+1]+LCMS(ESI)m/z:409.13[M+1]+

1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.54-7.55(m,1H),7.50(s,2H),7.48-7.46(m,1H),7.33-7.42(m,1H),7.20(br d,J＝2.24Hz,1H),3.01(s,3H),1.26-1.35(m,12H).1 H NMR (400 MHz, DMSO-d6 ) δ 7.93 (s, 1H), 7.54-7.55 (m, 1H), 7.50 (s, 2H), 7.48-7.46 (m, 1H), 7.33-7.42 (m , 1H), 7.20 (br d, J = 2.24 Hz, 1H), 3.01 (s, 3H), 1.26-1.35 (m, 12H).

步骤七Step 7

向化合物11c(65mg,170.07μmol)，化合物11f(153.12mg,374.15μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl2(12.44mg,17.01μmol)，K3PO4(72.20mg,340.14μmol)，氮气保护下90℃搅拌16小时。反应液浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得化合物11的三氟乙酸盐。To a solution of compound 11c (65 mg, 170.07 μmol), compound 11f (153.12 mg, 374.15 μmol) in dioxane (3 mL) and water (1 mL) was added Pd(dppf)Cl2 (12.44 mg, 17.01 μmol), K3 PO4 (72.20mg, 340.14μmol), stirred at 90°C for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain a crude product. The crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min) The trifluoroacetate salt of compound 11 was obtained.

LCMS(ESI)m/z:538.1[M+1]+LCMS(ESI)m/z:538.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.71(br d,J＝7.03Hz,1H),8.40(s,1H),8.17(br d,J＝2.76Hz,2H),8.08(br s,1H),7.53-7.83(m,5H),7.13(br s,2H),4.20(s,2H),3.11(s,3H),1.23(s,6H).1 H NMR (400 MHz, CD3 OD) δ 8.71 (br d, J = 7.03 Hz, 1H), 8.40 (s, 1H), 8.17 (br d, J = 2.76 Hz, 2H), 8.08 (br s, 1H), 7.53-7.83 (m, 5H), 7.13 (br s, 2H), 4.20 (s, 2H), 3.11 (s, 3H), 1.23 (s, 6H).

化合物11的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物11。The trifluoroacetic acid salt of compound 11 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 11.

Figure PCTCN2019130053-appb-000076
Figure PCTCN2019130053-appb-000076

步骤一step one

将化合物11d(9g,25.48mmol)溶于吡啶(10mL)中，滴加乙烷磺酰氯(3.93g,30.57mmol,2.89mL)，30℃下搅拌反应4小时。反应液加水30mL和乙酸乙酯30mL萃取，有机相再用水30mL洗两次，旋干得化合物11g。Compound 11d (9g, 25.48mmol) was dissolved in pyridine (10mL), ethanesulfonyl chloride (3.93g, 30.57mmol, 2.89mL) was added dropwise, and the reaction was stirred at 30°C for 4 hours. The reaction solution was extracted with 30 mL of water and 30 mL of ethyl acetate, and the organic phase was washed twice with 30 mL of water and spin-dried to obtain 11 g of the compound.

1H NMR(400MHz,CDCl3):δ7.67(s,1H),7.27(d,J＝1.52Hz,1H),7.22(s,1H),7.11(s,1H),6.84-6.99(m,2H),3.06-3.22(m,2H),1.28-1.39(m,3H).1 H NMR (400 MHz, CDCl3 ): δ 7.67 (s, 1H), 7.27 (d, J = 1.52 Hz, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 6.84-6.99 (m , 2H), 3.06-3.22 (m, 2H), 1.28-1.39 (m, 3H).

步骤二Step two

将实施例11g(9g,20.21mmol)和双联嚬哪醇硼酸酯(6.16g,24.25mmol,1.2)溶于dioxane(90mL)中，加入Pd(dppf)Cl2(1.48g,2.02mmol)和KOAc(3.97g,40.41mmol)，氮气保护下90℃搅拌反应16小时。反应液直接过滤，乙酸乙酯洗，滤液旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化得到11h。Example 11g (9g, 20.21mmol) and the double knit the brows embodiment pinacolato boronate (6.16g, 24.25mmol, 1.2) was dissolved in dioxane (90mL) was addedPd (dppf) Cl 2 (1.48g , 2.02mmol) With KOAc (3.97g, 40.41mmol), the reaction was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was directly filtered, washed with ethyl acetate, and the filtrate was spin-dried to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1 to obtain 11 h.

1H NMR(400MHz,CDCl3):δ7.68-7.71(m,1H),7.56(d,J＝2.02Hz,1H),7.49-7.55(m,1H),7.41(td,J＝8.54,6.5Hz,1H),6.84-6.96(m,2H),3.15(q,J＝7.32Hz,2H),1.32-1.35(m,12H),1.24(br s,3H).1 H NMR (400 MHz, CDCl3 ): δ 7.68-7.71 (m, 1H), 7.56 (d, J=2.02 Hz, 1H), 7.49-7.55 (m, 1H), 7.41 (td, J=8.54, 6.5Hz, 1H), 6.84-6.96 (m, 2H), 3.15 (q, J = 7.32Hz, 2H), 1.32-1.35 (m, 12H), 1.24 (br s, 3H).

实施例12Example 12

Figure PCTCN2019130053-appb-000077
Figure PCTCN2019130053-appb-000077

Figure PCTCN2019130053-appb-000078
Figure PCTCN2019130053-appb-000078

步骤一step one

向化合物11d(6.9g,19.53mmol)的吡啶(67.62g,854.87mmol,69.00mL)溶液中加入环丙烷磺酰氯(3.30g,23.44mmol)，20℃搅拌16小时。反应液加入醋酸(80mL)，再加入水(250mL)，乙酸乙酯(200mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得到化合物12a。To a solution of compound 11d (6.9 g, 19.53 mmol) in pyridine (67.62 g, 854.87 mmol, 69.00 mL) was added cyclopropanesulfonyl chloride (3.30 g, 23.44 mmol), and stirred at 20° C. for 16 hours. Acetic acid (80 mL) was added to the reaction solution, followed by addition of water (250 mL) and extraction with ethyl acetate (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain compound 12a.

步骤二Step two

向化合物12a(8g,17.49mmol)，双联嚬哪醇硼酸酯(4.44g,17.49mmol)的二氧六环(80mL)溶液中加入Pd(dppf)Cl2(1.28g,1.75mmol)，醋酸钾(3.43g,34.98mmol)。氮气保护下90℃搅拌16小时。反应液经硅藻土抽滤，滤液减压浓缩得粗品。粗品经快速硅胶柱(PE:EA＝3:1)过柱纯化得到化合物12b。Pd(dppf)Cl2 (1.28g, 1.75mmol) was added to a solution of compound 12a (8g, 17.49mmol), bis-binazinol borate (4.44g, 17.49mmol) in dioxane (80mL), Potassium acetate (3.43g, 34.98mmol). Stir at 90°C for 16 hours under nitrogen protection. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column (PE:EA=3:1) to obtain compound 12b.

步骤三Step three

向化合物11c(65mg,176.55μmol)，化合物12b(153.70mg,353.10μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl2(12.92mg,17.65μmol)，K3PO4(74.95mg,353.10μmol)，氮气保护下90℃搅拌16小时。反应液浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得化合物12的三氟乙酸盐。To a solution of compound 11c (65 mg, 176.55 μmol), compound 12b (153.70 mg, 353.10 μmol) in dioxane (3 mL) and water (1 mL) was added Pd(dppf)Cl2 (12.92 mg, 17.65 μmol), K3 PO4 (74.95mg, 353.10μmol), stirred at 90°C for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain a crude product. The crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min) The trifluoroacetate salt of compound 12 was obtained.

LCMS(ESI)m/z:564.2[M+1]+LCMS(ESI)m/z:564.2[M+1]+

1H NMR(400MHz,CD3OD)δ8.70(d,J＝7.28Hz,1H),8.40(s,1H),8.17(d,J＝6.54Hz,2H),8.07(s,1H),7.79(dd,J＝1.64,7.16Hz,1H),7.59-7.72(m,4H),7.08-7.19(m,2H),4.20(s,2H),2.66-2.80(m,1H),1.14(s,6H),1.09-1.17(m,2H),0.99-1.07(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.70 (d, J = 7.28 Hz, 1H), 8.40 (s, 1H), 8.17 (d, J = 6.54 Hz, 2H), 8.07 (s, 1H), 7.79(dd, J=1.64, 7.16Hz, 1H), 7.59-7.72(m, 4H), 7.08-7.19(m, 2H), 4.20(s, 2H), 2.66-2.80(m, 1H), 1.14( s, 6H), 1.09-1.17(m, 2H), 0.99-1.07(m, 2H).

化合物12的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物12。The trifluoroacetate salt of compound 12 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 12.

实施例13Example 13

Figure PCTCN2019130053-appb-000079
Figure PCTCN2019130053-appb-000079

步骤一step one

向1g(10g,50.75mmol)，吗啡啉(6.63g,76.13mmol,6.70mL)的甲苯(100mL)溶液中加入Pd2(dba)3(4.65g,5.08mmol)，BINAP(6.32g,10.15mmol)，t-BuONa(9.76g,101.51mmol)。氮气保护下95℃搅拌3小时。反应液经抽滤收集滤液，滤液减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物13b。To a solution of 1 g (10 g, 50.75 mmol), morpholine (6.63 g, 76.13 mmol, 6.70 mL) in toluene (100 mL) was added Pd2 (dba)3 (4.65 g, 5.08 mmol), BINAP (6.32 g, 10.15 mmol) ), t-BuONa (9.76 g, 101.51 mmol). Stir at 95°C for 3 hours under nitrogen protection. The filtrate was collected by suction filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 13b.

LCMS(ESI)m/z:204.1[M+1]+LCMS(ESI)m/z:204.1[M+1]+

步骤二Step two

将化合物13b(5.8g,28.54mmol)溶DCM(110mL)中，加入NIS(7.70g,34.25mmol)，25℃搅拌反应16小时。反应液加水(100mL)，分液，收集有机相，有机相无水硫酸钠干燥，减压浓缩得到化合物13c。LCMS(ESI)m/z:329.8[M+1]+Compound 13b (5.8 g, 28.54 mmol) was dissolved in DCM (110 mL), NIS (7.70 g, 34.25 mmol) was added, and the reaction was stirred at 25° C. for 16 hours. Water (100 mL) was added to the reaction solution to separate the liquid, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 13c. LCMS(ESI)m/z:329.8[M+1]+

步骤三Step three

将化合物13c(50mg,151.91μmol)和化合物11f(93.26mg,227.87μmol)溶于THF(1.5mL)和H2O(0.7mL)中，加入Pd(dppf)Cl2(11.12mg,15.19μmol)和K3PO4(64.49mg,303.83μmol)，氮气保护下90℃搅拌反应16小时。反应液浓缩得粗品，粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:21％-51％,12min)纯化得到化合物13的三氟乙酸盐。Compound 13c (50 mg, 151.91 μmol) and compound 11f (93.26 mg, 227.87 μmol) were dissolved in THF (1.5 mL) and H2 O (0.7 mL), and Pd (dppf) Cl2 (11.12 mg, 15.19 μmol) was added With K3 PO4 (64.49 mg, 303.83 μmol), the reaction was stirred at 90° C. for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain a crude product, which was subjected to high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 21%- 51%, 12 min) purification to obtain the trifluoroacetate salt ofcompound 13.

LCMS(ESI)m/z:485.0[M+1]+LCMS(ESI)m/z:485.0[M+1]+

1H NMR(400MHz,CD3OD)δppm 8.46(d,J＝8.0Hz,1H),7.86(s,1H),7.53-7.67(m,4H),7.29(dd,J＝7.78,2.52Hz,1H),7.08-7.17(m,2H),6.95(d,J＝2.26Hz,1H),3.84-3.93(m,4H),3.51-3.61(m,4H),3.11(s,3H).1 H NMR (400 MHz, CD3 OD) δ ppm 8.46 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.53-7.67 (m, 4H), 7.29 (dd, J=7.78, 2.52 Hz, 1H), 7.08-7.17 (m, 2H), 6.95 (d, J = 2.26Hz, 1H), 3.84-3.93 (m, 4H), 3.51-3.61 (m, 4H), 3.11 (s, 3H).

化合物13的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得 到化合物13。The trifluoroacetic acid salt ofcompound 13 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 13.

实施例14Example 14

Figure PCTCN2019130053-appb-000080
Figure PCTCN2019130053-appb-000080

步骤一step one

将化合物9b(100mg,228.17μmol)和化合物11f(140.07mg,342.26μmol)溶于四氢呋喃(1.5mL)和水(0.7mL)中，加入Pd(dppf)Cl2(16.70mg,22.82μmol)和K3PO4(96.87mg,456.35μmol)，氮气保护下微波90℃搅拌反应0.5小时。向反应液中加水(3mL)，用乙酸乙酯(3mL*2)萃取，收集有机相，有机相浓缩旋干得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物14a。Compound 9b (100 mg, 228.17 μmol) and compound 11f (140.07 mg, 342.26 μmol) were dissolved in tetrahydrofuran (1.5 mL) and water (0.7 mL), and Pd (dppf) Cl2 (16.70 mg, 22.82 μmol) and K were added3 PO4 (96.87 mg, 456.35 μmol), microwave reaction at 90° C. under nitrogen protection for 0.5 hour with stirring. Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (3 mL*2), the organic phase was collected, and the organic phase was concentrated and spin-dried to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=20:1) to obtain compound 14a.

LCMS(ESI)m/z:594.1[M+1]+LCMS(ESI)m/z:594.1[M+1]+

步骤二Step two

将化合物14a(50mg,84.23μmol)溶于DCM(2mL)中，加入氯化氢/乙酸乙酯(4M,2mL)，25℃搅拌反应1小时。反应液直接旋干得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:15％-45％,12min)纯化得到化合物14的三氟乙酸盐。Compound 14a (50 mg, 84.23 μmol) was dissolved in DCM (2 mL), hydrogen chloride/ethyl acetate (4M, 2 mL) was added, and the reaction was stirred at 25° C. for 1 hour. The reaction solution was directly spin-dried to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 15%-45%, 12min) The trifluoroacetate salt of compound 14 is obtained.

LCMS(ESI)m/z:510.0[M+1]+LCMS(ESI)m/z:510.0[M+1]+

1H NMR(400MHz,CD3OD)δppm 8.72(s,1H),8.45(s,1H),8.21(s,1H),8.17(s,1H),8.08(s,1H),7.79(dd,J＝7.32,1.6Hz,1H),7.62-7.71(m,3H),7.59(d,J＝1.60Hz,1H),7.11-7.20(m,2H),4.35(t,J＝5.20Hz,2H),3.97(t,J＝5.20Hz,2H),3.13(s,3H).1 H NMR (400 MHz, CD3 OD) δ ppm 8.72 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.79 (dd, J = 7.32, 1.6 Hz, 1H), 7.62-7.71 (m, 3H), 7.59 (d, J = 1.60 Hz, 1H), 7.11-7.20 (m, 2H), 4.35 (t, J = 5.20 Hz, 2H) ), 3.97 (t, J = 5.20 Hz, 2H), 3.13 (s, 3H).

化合物14的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物14。The trifluoroacetic acid salt of compound 14 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 14.

实施例15Example 15

Figure PCTCN2019130053-appb-000081
Figure PCTCN2019130053-appb-000081

步骤一step one

向4-硼酸酯-1H-吡唑(5g,25.77mmol)的乙腈(50mL)溶液中入1-甲烷磺酰基乙烯(4.10g,38.65mmol,3.39mL)，DBU(1.96g,12.88mmol,1.94mL)。90℃搅拌16小时。反应液减压浓缩得到化合物15a。LCMS(ESI)m/z:300.9[M+1]+To a solution of 4-borate-1H-pyrazole (5g, 25.77mmol) in acetonitrile (50mL) was added 1-methanesulfonylethylene (4.10g, 38.65mmol, 3.39mL), DBU (1.96g, 12.88mmol, 1.94mL). Stir at 90°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 15a. LCMS(ESI)m/z:300.9[M+1]+

步骤二Step two

向化合物1g(549.98mg,558.29μmol)，15a(1.0g,3.333mmol)的二氧六环(10mL)和水(5m L)溶液中加入Pd(dppf)Cl2(203.13mg,277.61μmol)和K3PO4(1.18g,5.55mmol)，氮气保护下85℃搅拌反应16小时。向反应液中加水(10mL)，用乙酸乙酯(10mL*2)萃取，收集有机相，有机相浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物15b。Solution of compound 1g (549.98mg, 558.29μmol), 15a (1.0g, 3.333mmol) in dioxane (5m L) (10mL) and water was addedPd (dppf) Cl 2 (203.13mg , 277.61μmol) and K3 PO4 (1.18g, 5.55mmol), stirred at 85°C under nitrogen for 16 hours. Water (10 mL) was added to the reaction liquid, extracted with ethyl acetate (10 mL*2), the organic phase was collected, and the organic phase was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=20:1) to obtain compound 15b.

1HNMR(400MHz,CDCl3)δ8.08-8.15(m,1H),7.92(s,1H),7.89(s,1H),7.68(s,1H),7.56(br d,J＝13.30Hz,2H),6.93(dd,J＝1.00,7.04Hz,1H),4.66(t,J＝6.16Hz,2H),3.65-3.70(m,2H),2.62(s,3H).1 HNMR (400 MHz, CDCl3 ) δ 8.08-8.15 (m, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 7.56 (br d, J = 13.30 Hz, 2H), 6.93 (dd, J = 1.00, 7.04 Hz, 1H), 4.66 (t, J = 6.16 Hz, 2H), 3.65-3.70 (m, 2H), 2.62 (s, 3H).

步骤三Step three

向化合物15b(100mg,344.42μmol)溶于DCM(2mL)，加入NIS(92.99mg,413.31μmol)，30℃搅拌反应16小时。反应液加水(3mL)和二氯甲烷(3mL)进行萃取分液，有机相用无水硫酸钠干燥，减压浓缩得到化合物15c。Compound 15b (100 mg, 344.42 μmol) was dissolved in DCM (2 mL), NIS (92.99 mg, 413.31 μmol) was added, and the reaction was stirred at 30° C. for 16 hours. The reaction solution was added with water (3 mL) and dichloromethane (3 mL) for extraction and separation. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 15c.

LCMS(ESI)m/z:416.8[M+1]+LCMS(ESI)m/z:416.8[M+1]+

步骤四Step four

将化合物15c(80mg,192.20μmol)和化合物11f(94.39mg,230.64μmol)溶于四氢呋喃(2mL)和水(1mL)中，加入Pd(dppf)Cl2(14.06mg,19.22μmol)和K3PO4(81.59mg,384.40μmol)，氮气保护下微波90℃搅 拌反应0.5小时。反应液加水(4mL)和乙酸乙酯(4mL)萃取分液，有机相浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得到化合物15的三氟乙酸盐。Compound 15c (80 mg, 192.20 μmol) and compound 11f (94.39 mg, 230.64 μmol) were dissolved in tetrahydrofuran (2 mL) and water (1 mL), and Pd (dppf) Cl2 (14.06 mg, 19.22 μmol) and K3 PO were added4 (81.59mg, 384.40μmol), microwaved at 90°C for 0.5 hours under nitrogen protection. The reaction solution was added with water (4 mL) and ethyl acetate (4 mL) to extract and separate, and the organic phase was concentrated to obtain a crude product. The crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min) The trifluoroacetate salt of compound 15 is obtained.

LCMS(ESI)m/z:572.1[M+1]+LCMS(ESI)m/z:572.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.73(d,J＝7.28Hz,1H),8.52(s,1H),8.25(s,1H),8.18(s,1H),8.10(s,1H),7.79(dd,J＝1.60,7.28Hz,1H),7.62-7.71(m,3H),7.60(d,J＝1.76Hz,1H),7.10-7.19(m,2H),4.77(t,J＝6.40Hz,2H),3.81(t,J＝6.40Hz,2H),3.13(s,3H),2.91(s,3H).1 H NMR (400 MHz, CD3 OD) δ 8.73 (d, J = 7.28 Hz, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H ), 7.79 (dd, J = 1.60, 7.28 Hz, 1H), 7.62-7.71 (m, 3H), 7.60 (d, J = 1.76 Hz, 1H), 7.10-7.19 (m, 2H), 4.77 (t, J = 6.40 Hz, 2H), 3.81 (t, J = 6.40 Hz, 2H), 3.13 (s, 3H), 2.91 (s, 3H).

化合物15的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物15。The trifluoroacetic acid salt of compound 15 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15.

实施例16Example 16

Figure PCTCN2019130053-appb-000082
Figure PCTCN2019130053-appb-000082

步骤一step one

将1g(0.2g,1.02mmol)溶于DCM(4mL)中，25℃加入NIS(274.05mg,1.22mmol)，搅拌反应2小时。反应液加水(5mL)和二氯甲烷(5mL)萃取，收集有机相，浓缩得到化合物16a。1 g (0.2 g, 1.02 mmol) was dissolved in DCM (4 mL), NIS (274.05 mg, 1.22 mmol) was added at 25°C, and the reaction was stirred for 2 hours. The reaction solution was extracted with water (5 mL) and dichloromethane (5 mL), and the organic phase was collected and concentrated to obtain compound 16a.

1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝7.24Hz,1H),8.18(d,J＝1.24Hz,1H),8.14(s,1H),7.51(dd,J＝1.88,7.24Hz,1H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.51 (d, J = 7.24 Hz, 1H), 8.18 (d, J = 1.24 Hz, 1H), 8.14 (s, 1H), 7.51 (dd, J = 1.88, 7.24Hz, 1H).

步骤二Step two

将化合物16a(200mg,619.33μmol)和化合物11f(304.16mg,743.20μmol)溶于二氧六环(1mL)和水(0.25mL)中，加入碳酸钠(164.11mg,1.55mmol)和Pd(dppf)Cl2(45.32mg,61.93μmol)，氮气保护 下110℃微波搅拌20分钟。反应液加水(3mL)和乙酸乙酯(3mL*2)萃取，有机相浓缩得粗品。粗品经快速硅胶柱层析(PE/EA＝1/1～0/1)纯化得到化合物16b。Compound 16a (200 mg, 619.33 μmol) and compound 11f (304.16 mg, 743.20 μmol) were dissolved in dioxane (1 mL) and water (0.25 mL), and sodium carbonate (164.11 mg, 1.55 mmol) and Pd (dppf were added ) Cl2 (45.32 mg, 61.93 μmol), microwave stirring at 110° C. for 20 minutes under nitrogen protection. The reaction solution was extracted with water (3 mL) and ethyl acetate (3 mL*2), and the organic phase was concentrated to obtain a crude product. The crude product was purified by flash silica gel column chromatography (PE/EA=1/1～0/1) to obtain compound 16b.

LCMS(ESI)m/z:479.7[M+1]+LCMS(ESI)m/z: 479.7[M+1]+

步骤三Step three

将化合物16b(120mg,250.88μmol)和4-硼酸酯-1H-吡唑(58.42mg,301.06μmol)溶于二氧六环(2mL)和水(1mL)中，加入Pd(dppf)Cl2(18.36mg,25.09μmol)和K3PO4(106.51mg,501.77μmol)，氮气保护下微波90℃搅拌反应0.5小时。反应液加水(3mL)和乙酸乙酯(4mL)萃取分液，有机相减压浓缩得到化合物16c。Compound 16b (120 mg, 250.88 μmol) and 4-borate-1H-pyrazole (58.42 mg, 301.06 μmol) were dissolved in dioxane (2 mL) and water (1 mL), and Pd(dppf)Cl2 was added (18.36 mg, 25.09 μmol) and K3 PO4 (106.51 mg, 501.77 μmol), and microwaved at 90° C. under nitrogen for 0.5 hours. The reaction solution was added with water (3 mL) and ethyl acetate (4 mL) to extract and separate the layers, and the organic phase was concentrated under reduced pressure to obtain compound 16c.

LCMS(ESI)m/z:466.2[M+1]+LCMS(ESI)m/z:466.2[M+1]+

步骤四Step four

将化合物16c(100mg,214.83μmol)和四氢吡喃-4-基4-甲基苯磺酸(55.07mg,214.83μmol)溶于DMF(1mL)中，加入碳酸铯(209.99mg,644.50μmol)，90℃搅拌反应16小时。反应液过滤，滤液经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-45％,12min)纯化得到化合物16的三氟乙酸盐。Compound 16c (100 mg, 214.83 μmol) and tetrahydropyran-4-yl 4-methylbenzenesulfonic acid (55.07 mg, 214.83 μmol) were dissolved in DMF (1 mL), and cesium carbonate (209.99 mg, 644.50 μmol) was added At 90°C, the reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was subjected to high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-45% , 12 min) purification to obtain the trifluoroacetate salt ofcompound 16.

LCMS(ESI)m/z:550.1[M+1]+LCMS(ESI)m/z:550.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.70-8.76(m,1H),8.54(s,1H),8.21(s,1H),8.17(s,1H),8.09(s,1H),7.80(dd,J＝1.52,7.28Hz,1H),7.63-7.71(m,3H),7.60(s,1H),7.11-7.21(m,2H),4.49-4.62(m,1H),4.12(br d,J＝11.04Hz,2H),3.59-3.68(m,2H),3.13(s,3H),2.15(br d,J＝3.76Hz,2H),1.26-1.42(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.70-8.76 (m, 1H), 8.54 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.80 (dd, J = 1.52, 7.28 Hz, 1H), 7.63-7.71 (m, 3H), 7.60 (s, 1H), 7.11-7.21 (m, 2H), 4.49-4.62 (m, 1H), 4.12 (br d, J = 11.04 Hz, 2H), 3.59-3.68 (m, 2H), 3.13 (s, 3H), 2.15 (br d, J = 3.76 Hz, 2H), 1.26-1.42 (m, 2H).

化合物16的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物16。The trifluoroacetic acid salt ofcompound 16 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 16.

实施例17Example 17

Figure PCTCN2019130053-appb-000083
Figure PCTCN2019130053-appb-000083

Figure PCTCN2019130053-appb-000084
Figure PCTCN2019130053-appb-000084

步骤一step one

向3-溴5-硝基-苯酚(3g,13.76mmol)，双联嚬哪醇硼酸酯(4.19g,16.51mmol)的二氧六环(50mL)溶液中加入Pd(dppf)Cl2(1.01g,1.38mmol)，醋酸钾(2.70g,27.52mmol)。氮气保护下100℃搅拌16小时。反应液抽滤后滤液浓缩得到粗品化合物17a，未纯化直接用于下一步。To a solution of 3-bromo 5-nitro-phenol (3g, 13.76mmol), bis-carbamol borate (4.19g, 16.51mmol) in dioxane (50mL) was added Pd(dppf)Cl2 ( 1.01g, 1.38mmol), potassium acetate (2.70g, 27.52mmol). Stir at 100°C for 16 hours under nitrogen protection. After the reaction solution was filtered with suction, the filtrate was concentrated to obtain crude compound 17a, which was directly used in the next step without purification.

步骤二Step two

向化合物1j(3g,9.26mmol)，17a(3.65g,13.77mmol)的二氧六环(5mL)和H2O(1.5mL)溶液中加入Pd(dppf)Cl2(677.25mg,925.58μmol)，K3PO4(3.93g,18.51mmol)。氮气保护下100℃搅拌16小时。向反应液中加水(100mL)，用乙酸乙酯(100mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17b。To a solution of compound 1j (3 g, 9.26 mmol), 17a (3.65 g, 13.77 mmol) in dioxane (5 mL) and H2 O (1.5 mL) was added Pd(dppf)Cl2 (677.25 mg, 925.58 μmol) , K3 PO4 (3.93 g, 18.51 mmol). Stir at 100°C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 17b.

LCMS(ESI)m/z:335.9[M+1]+LCMS(ESI)m/z: 335.9[M+1]+

步骤三Step three

向化合物17b(0.8g,2.39mmol)的DMF(5mL)溶液中加入DIEA(925.05mg,7.16mmol,1.25mL)，N-苯基双(三氟甲烷磺酰)亚胺(1.28g,3.58mmol)。20℃搅拌16小时。反应液加水(50mL)，用乙酸乙酯(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17c。To a solution of compound 17b (0.8 g, 2.39 mmol) in DMF (5 mL) was added DIEA (925.05 mg, 7.16 mmol, 1.25 mL), N-phenylbis(trifluoromethanesulfonyl)imide (1.28 g, 3.58 mmol ). Stir at 20°C for 16 hours. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 17c.

LCMS(ESI)m/z:468.0[M+1]+LCMS(ESI)m/z: 468.0[M+1]+

步骤四Step four

向化合物17c(320mg,684.67μmol)的EtOH(10mL)和水(2mL)溶液中加入氯化铵(366.24mg,6.85mmol)，锌粉(447.71mg,6.85mmol)。25℃搅拌16小时，升至60℃搅拌3小时。反应液直接过滤，滤液减压浓缩得到化合物17d。To a solution of compound 17c (320 mg, 684.67 μmol) in EtOH (10 mL) and water (2 mL), ammonium chloride (366.24 mg, 6.85 mmol) and zinc powder (447.71 mg, 6.85 mmol) were added. Stir for 16 hours at 25°C, and stir at 60°C for 3 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17d.

LCMS(ESI)m/z:438.0[M+1]+LCMS(ESI)m/z:438.0[M+1]+

步骤五Step five

0℃向17d(1.4g,3.20mmol)的吡啶(15mL)溶液中加入甲烷磺酰氯(439.98mg,3.84mmol,297.29μL)，30℃搅拌3小时。0℃下加水(10mL)淬灭，加入乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩得粗品，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17e。LCMS(ESI)m/z:516.1[M+1]+To a solution of 17d (1.4g, 3.20mmol) in pyridine (15mL) was added methanesulfonyl chloride (439.98mg, 3.84mmol, 297.29μL) at 0°C, and stirred at 30°C for 3 hours. At 0°C, water (10 mL) was added to quench, ethyl acetate (20 mL*3) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 17e. LCMS(ESI)m/z:516.1[M+1]+

步骤六Step six

向17e(0.05g,97.00μmol)，(2-氟-4-甲氧基-苯基)硼酸(19.78mg,116.40μmol)的二氧六环(3mL)和水(1mL)溶液中加Pd(dppf)Cl2(7.10mg,9.70μmol)，K3PO4(41.18mg,194.00μmol)。氮气保护下于微波反应器中100℃搅拌0.5小时。反应液加入硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％氨水)-乙腈]；B(乙腈)％:20％-50％,8.5min)纯化得到化合物17。To a solution of 17e (0.05g, 97.00μmol), (2-fluoro-4-methoxy-phenyl)boronic acid (19.78mg, 116.40μmol) in dioxane (3mL) and water (1mL) was added Pd( dppf) Cl2 (7.10 mg, 9.70 μmol), K3 PO4 (41.18 mg, 194.00 μmol). Stir in a microwave reactor at 100°C for 0.5 hour under nitrogen protection. The reaction solution was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04% ammonia)-acetonitrile]; B (acetonitrile)%: 20%-50%, 8.5min) Compound 17.

LCMS(ESI)m/z:492.1[M+1]+LCMS(ESI)m/z:492.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.54(d,J＝7.04Hz,1H),8.16(s,1H),7.99(s,1H),7.75(s,1H),7.69(s,1H),7.39-7.56(m,4H),7.26(d,J＝7.28Hz,1H),6.71-6.92(m,2H),3.96(s,3H),3.85(s,3H),3.02(s,3H).1 H NMR (400 MHz, CD3 OD) δ 8.54 (d, J = 7.04 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.69 (s, 1H ), 7.39-7.56 (m, 4H), 7.26 (d, J = 7.28 Hz, 1H), 6.71-6.92 (m, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.02 (s, 3H).

实施例18Example 18

Figure PCTCN2019130053-appb-000085
Figure PCTCN2019130053-appb-000085

步骤一step one

向17e(100mg,193.99μmol)，双联嚬哪醇硼酸酯(54.19mg,213.39μmol)的二氧六环(2mL)溶液中加入Pd(dppf)Cl2(14.19mg,19.40μmol)，醋酸钾(38.08mg,387.98μmol)。氮气保护下于微波反应器中100℃搅拌1小时。反应液过滤，滤液减压浓缩得到化合物18a。Pd(dppf)Cl2 (14.19mg, 19.40μmol), acetic acid was added to a solution of 17e (100mg, 193.99μmol), bisbicarbanol borate (54.19mg, 213.39μmol) in dioxane (2mL) Potassium (38.08mg, 387.98μmol). Stir at 100°C for 1 hour in a microwave reactor under nitrogen. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 18a.

LCMS(ESI)m/z:494.2[M+1]+LCMS(ESI)m/z:494.2[M+1]+

步骤二Step two

向18a(45mg,91.21μmol)，2-溴吡嗪(14.50mg,91.21μmol)的二氧六环(2mL)和水(0.5mL)溶液中加入Pd(dppf)Cl2(6.67mg,9.12μmol)，K3PO4(38.72mg,182.41μmol)。氮气保护下于微波反应器中100℃搅 拌1小时。反应液抽滤得滤液，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:10％-40％,12min)纯化得到化合物18的三氟乙酸盐。To 18a (45mg, 91.21μmol), 2- bromo-pyrazine (14.50mg, 91.21μmol) in dioxane (2mL) and water(0.5mL) (dppf) Cl 2 (6.67mg added Pd, 9.12μmol ), K3 PO4 (38.72 mg, 182.41 μmol). Stir at 100°C for 1 hour in a microwave reactor under nitrogen. The reaction solution was filtered by suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 10%-40%, 12min) Trifluoroacetate salt of compound 18.

LCMS(ESI)m/z:445.9[M+1]+LCMS(ESI)m/z: 445.9[M+1]+

1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.34(s,1H),8.78(br s,1H),8.69(s,1H),8.58(s,1H),8.32(s,1H),8.21(br d,J＝12.05Hz,2H),8.14(s,1H),8.08(br s,1H),7.61-7.72(m,2H),7.10-7.27(m,1H),3.92(s,3H),3.33(br s,3H).1 H NMR (400 MHz, DMSO-d6 ) δ 10.37 (s, 1H), 9.34 (s, 1H), 8.78 (br s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 8.21 (br d, J = 12.05 Hz, 2H), 8.14 (s, 1H), 8.08 (br s, 1H), 7.61-7.72 (m, 2H), 7.10-7.27 (m, 1H ), 3.92 (s, 3H), 3.33 (br s, 3H).

化合物18的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物18。The trifluoroacetic acid salt of compound 18 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 18.

表2中实施例化合物的制备可以参照前述制备实施例18的路线类似的步骤方法进行，不同之处在于在步骤二中使用的原料A代替2-溴吡嗪得到相应化合物的三氟乙酸盐。The preparation of the compounds of the examples in Table 2 can be carried out by referring to the steps similar to the above route of Preparation Example 18, except that the raw material A used in step 2 replaces 2-bromopyrazine to obtain the trifluoroacetate of the corresponding compound .

表2Table 2

Figure PCTCN2019130053-appb-000086
Figure PCTCN2019130053-appb-000086

实施例21Example 21

Figure PCTCN2019130053-appb-000087
Figure PCTCN2019130053-appb-000087

步骤一step one

向水(30mL)中加入化合物2-氨基-4-甲氧基吡啶(1g,7.24mmol)和盐酸(12M,60.31μL)，在25℃下搅拌2.5小时，再升温到80℃搅拌1.5小时，冷却到25℃后加入碳酸氢钠(972.85mg,11.58mmol)和溴乙醛缩二乙醇(2.85g,14.48mmol)，反应置于25℃搅拌12小时。反应液用乙酸乙酯100毫升*3萃取，有机相用无水硫酸钠干燥，过滤，旋干。经过柱纯化(二氯甲烷:甲醇＝1:0到10：1)得到化合物21a。To water (30 mL) was added compound 2-amino-4-methoxypyridine (1 g, 7.24 mmol) and hydrochloric acid (12M, 60.31 μL), stirred at 25°C for 2.5 hours, and then heated to 80°C and stirred for 1.5 hours. After cooling to 25°C, sodium bicarbonate (972.85 mg, 11.58 mmol) and bromoacetaldehyde diethanol (2.85 g, 14.48 mmol) were added, and the reaction was stirred at 25°C for 12 hours. The reaction solution was extracted with 100 ml of ethyl acetate*3, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. After column purification (dichloromethane:methanol=1:0 to 10:1), compound 21a was obtained.

LCMS(ESI)m/z:163.2[M+1]+LCMS(ESI)m/z:163.2[M+1]+

1H NMR(399MHz,DMSO-d6)δ8.37-8.39(d,J＝7.2Hz,1H),7.74(s,1H),7.40(s,1H),6.89–6.90(d,J＝2.8Hz,1H),6.59–6.62(m,1H),4.05–4.11(m,2H),1.34–1.37(t,J＝7.0Hz,3H).1 H NMR (399 MHz, DMSO-d6 ) δ 8.37-8.39 (d, J=7.2 Hz, 1H), 7.74 (s, 1H), 7.40 (s, 1H), 6.89–6.90 (d, J=2.8 Hz, 1H), 6.59–6.62 (m, 1H), 4.05–4.11 (m, 2H), 1.34–1.37 (t, J=7.0Hz, 3H).

步骤二Step two

向无水二氯甲烷(5mL)中加入化合物21a(0.5g,3.08mmol)，N-碘代丁二酰亚胺(762.95mg,3.39mmol)，反应置于25℃反应12小时。，反应液用饱和碳酸氢钠水溶液100mL和二氯甲烷100mL*3萃取，有机相用无水硫酸钠干燥，旋干。经过柱纯化(石油醚:乙酸乙酯＝20:1到3:1)得到化合物21b。To anhydrous dichloromethane (5 mL), compound 21a (0.5 g, 3.08 mmol), N-iodosuccinimide (762.95 mg, 3.39 mmol) was added, and the reaction was left at 25°C for 12 hours. The reaction solution was extracted with 100 mL of saturated aqueous sodium bicarbonate solution and 100 mL of dichloromethane*3, and the organic phase was dried over anhydrous sodium sulfate and spin-dried. After column purification (petroleum ether: ethyl acetate = 20:1 to 3:1), compound 21b was obtained.

LCMS(ESI)m/z:289.0[M+1]+LCMS(ESI)m/z:289.0[M+1]+

1H NMR(400MHz,DMSO-d6)δ8.15–8.18(m,1H),7.55(s,1H),7.00(s,1H),6.73–6.75(d,J＝7.6Hz,1H),4.08–4.14(m,2H),1.35–1.38(t,J＝7.0Hz,3H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.15–8.18 (m, 1H), 7.55 (s, 1H), 7.00 (s, 1H), 6.73–6.75 (d, J=7.6Hz, 1H), 4.08–4.14 (m, 2H), 1.35–1.38 (t, J=7.0Hz, 3H).

步骤三Step three

在反应中加入二氧六环(5mL)和水(2mL)，21b(0.01g,34.71μmol)，11f(17.05mg)，无水磷酸钾(14.74mg,69.42μmol)，1,1-双(二苯基磷)二茂铁氯化钯(2.54mg)，反应用氮气置换，在65℃下反应3小时。反应液用水20毫升和二氯甲烷(20毫升*3)萃取，有机相用无水硫酸钠干燥后，过滤，旋干。得到粗品，经制备薄层色谱硅胶板纯化得化合物21。Add dioxane (5mL) and water (2mL), 21b (0.01g, 34.71μmol), 11f (17.05mg), anhydrous potassium phosphate (14.74mg, 69.42μmol), 1,1-bis( Diphenylphosphine)ferrocene palladium chloride (2.54 mg), the reaction was replaced with nitrogen, and the reaction was carried out at 65°C for 3 hours. The reaction solution was extracted with 20 ml of water and dichloromethane (20 ml*3). The organic phase was dried over anhydrous sodium sulfate, filtered and spin-dried. The crude product was obtained and purified by preparative thin layer chromatography silica gel plate to obtain compound 21.

LCMS(ESI)m/z:444.2[M+1]+LCMS(ESI)m/z: 444.2[M+1]+

1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.45–8.47(d,J＝7.6Hz,1H),7.46(s,2H),7.43–7.45(m,4H),7.04(s,1H),6.72(s,1H),4.12–4.17(m,2H),3.11(s,1H),1.38(s,3H).1 H NMR (400 MHz, DMSO-d6 ) δ 10.04 (s, 1H), 8.45–8.47 (d, J=7.6 Hz, 1H), 7.46 (s, 2H), 7.43–7.45 (m, 4H), 7.04(s, 1H), 6.72(s, 1H), 4.12–4.17(m, 2H), 3.11(s, 1H), 1.38(s, 3H).

实施例22Example 22

Figure PCTCN2019130053-appb-000088
Figure PCTCN2019130053-appb-000088

步骤一step one

0℃将2e(30mg,74.74μmol)的DCM(1mL)溶液中加入DIEA(28.98mg,224.22μmol,39.05μL)，再加入三光气(11.09mg,37.37μmol)，0℃搅拌10分钟，同时另外将3-甲氧基吡咯(7.56mg,54.94μmol,HCl)的DCM(1mL)溶液中加入DIEA(28.98mg,224.22μmol,39.05μL)搅拌10分钟，倒入到上述反应液中，0℃搅拌20分钟。0℃加水(5mL)淬灭反应，再加入DCM(5mL*4)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经制备高效液相色谱分离(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:23％-53％,8min)纯化得化合物22的三氟乙酸盐。DIEA (28.98mg, 224.22μmol, 39.05μL) was added to a solution of 2e (30mg, 74.74μmol) in DCM (1mL) at 0°C, and then triphosgene (11.09mg, 37.37μmol) was added, and the mixture was stirred at 0°C for 10 minutes while adding Add 3-methoxypyrrole (7.56 mg, 54.94 μmol, HCl) in DCM (1 mL) to DIEA (28.98 mg, 224.22 μmol, 39.05 μL) and stir for 10 minutes. Pour into the above reaction solution and stir at 0°C. 20 minutes. Water (5 mL) was added to quench the reaction at 0°C, and DCM (5 mL*4) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 23%-53%, 8min ) Purification to obtain trifluoroacetate salt ofcompound 22.

LCMS(ESI)m/z:529.1[M+1]+LCMS(ESI)m/z:529.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.77(d,J＝7.28Hz,1H),8.38(s,1H),8.15(s,1H),8.12(s,1H),8.05(d,J＝0.75Hz,1H),7.97(t,J＝1.76Hz,1H),7.71-7.78(m,2H),7.62(dt,J＝6.40,8.85Hz,1H),7.50(d,J＝1.51Hz,1H),7.05-7.17(m,2H),4.00(s,3H),3.49-3.68(m,5H),3.37(s,3H),1.98-2.22(m,2H).1 H NMR (400 MHz, CD3 OD) δ 8.77 (d, J = 7.28 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 0.75 Hz, 1H), 7.97 (t, J=1.76 Hz, 1H), 7.71-7.78 (m, 2H), 7.62 (dt, J=6.40, 8.85 Hz, 1H), 7.50 (d, J=1.51 Hz , 1H), 7.05-7.17 (m, 2H), 4.00 (s, 3H), 3.49-3.68 (m, 5H), 3.37 (s, 3H), 1.98-2.22 (m, 2H).

化合物22的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物22。The trifluoroacetate salt ofcompound 22 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 22.

实施例23Example 23

Figure PCTCN2019130053-appb-000089
Figure PCTCN2019130053-appb-000089

Figure PCTCN2019130053-appb-000090
Figure PCTCN2019130053-appb-000090

步骤一step one

将化合物2e(50.00mg,124.56μmol)溶于DCM(1mL)中，加入DIEA(48.29mg,373.68μmol,65.09μL,3eq)，加入三光气(55.44mg,186.84μmol)，0℃搅拌10min，同时将O-甲基羟胺盐酸盐(20.81mg,249.12μmol HCl)溶于DCM(1mL)中加入DIEA(48.29mg,373.68μmol,65.09μL)，0℃搅拌10分钟，再倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物23的三氟乙酸盐。Compound 2e (50.00 mg, 124.56 μmol) was dissolved in DCM (1 mL), DIEA (48.29 mg, 373.68 μmol, 65.09 μL, 3 eq) was added, triphosgene (55.44 mg, 186.84 μmol) was added, and stirred at 0°C for 10 min while Dissolve O-methylhydroxylamine hydrochloride (20.81 mg, 249.12 μmol HCl) in DCM (1 mL), add DIEA (48.29 mg, 373.68 μmol, 65.09 μL), stir at 0°C for 10 minutes, and then pour into the above reaction solution In, stirring at 0°C for 7-10 minutes. The reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. Purified by preparative high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8min) The trifluoroacetate salt of compound 23 is obtained.

LCMS(ESI)m/z:475.3[M+1]+LCMS(ESI)m/z: 475.3[M+1]+

1H NMR(400MHz,CD3OD)δ8.75(d,J＝7.00Hz,1H),8.37(s,1H),8.13(d,J＝12.02Hz,2H),8.06(t,J＝1.74Hz,1H),8.02(s,1H),7.84(d,J＝1.64Hz,1H),7.73(dd,J＝1.70,7.32Hz,1H),7.64(dt,J＝6.50,8.82Hz,1H),7.56(d,J＝1.50Hz,1H),7.04-7.18(m,2H),3.99(s,3H),3.77(s,3H).1 H NMR (400 MHz, CD3 OD) δ 8.75 (d, J = 7.00 Hz, 1H), 8.37 (s, 1H), 8.13 (d, J = 12.02 Hz, 2H), 8.06 (t, J = 1.74 Hz, 1H), 8.02 (s, 1H), 7.84 (d, J = 1.64 Hz, 1H), 7.73 (dd, J = 1.70, 7.32 Hz, 1H), 7.64 (dt, J = 6.50, 8.82 Hz, 1H) ), 7.56 (d, J = 1.50 Hz, 1H), 7.04-7.18 (m, 2H), 3.99 (s, 3H), 3.77 (s, 3H).

化合物23的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物23。The trifluoroacetate salt of compound 23 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 23.

实施例24Example 24

Figure PCTCN2019130053-appb-000091
Figure PCTCN2019130053-appb-000091

步骤一step one

将化合物2e(0.03g,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL)加入三光气(33.27mg,112.10μmol)，0℃搅拌10分钟，同时另外将2-(二甲氨基)乙醇(13.32mg,149.47μmol,15.00μL)溶于DCM(1mL)加入DIEA(28.98mg,224.21μmol,39.05μL)，0℃搅拌10分钟，倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物24的三氟乙酸盐。Compound 2e (0.03g, 74.74μmol) was dissolved in DCM (1mL), DIEA (28.98mg, 224.21μmol, 39.05μL) was added, and triphosgene (33.27mg, 112.10μmol) was added, and the mixture was stirred at 0°C for 10 minutes while additionally 2-(Dimethylamino)ethanol (13.32mg, 149.47μmol, 15.00μL) was dissolved in DCM (1mL) and DIEA (28.98mg, 224.21μmol, 39.05μL) was added, stirred at 0°C for 10 minutes, and poured into the above reaction solution , Stir at 0 ℃ for 7-10 minutes. The reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. Purified by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8min) The trifluoroacetate salt of compound 24 is obtained.

LCMS(ESI)m/z:517.3[M+1]+LCMS(ESI)m/z:517.3[M+1]+

1H NMR(400MHz,CD3OD)δ8.69(d,J＝7.54Hz,1H),8.34(s,1H),8.12(s,1H),8.05(d,J＝9.80Hz,2H),7.96(s,1H),7.79(s,1H),7.67(br d,J＝7.54Hz,1H),7.55(s,1H),7.35(d,J＝8.28Hz,1H),7.06-7.20(m,2H),4.50-4.61(m,2H),4.00(s,3H),3.50-3.59(m,2H),3.01(s,6H).1 H NMR (400 MHz, CD3 OD) δ 8.69 (d, J = 7.54 Hz, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 8.05 (d, J = 9.80 Hz, 2H), 7.96 (s, 1H), 7.79 (s, 1H), 7.67 (br d, J = 7.54 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.28 Hz, 1H), 7.06-7.20 ( m, 2H), 4.50-4.61(m, 2H), 4.00(s, 3H), 3.50-3.59(m, 2H), 3.01(s, 6H).

化合物24的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物24。The trifluoroacetate salt of compound 24 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24.

实施例25Example 25

Figure PCTCN2019130053-appb-000092
Figure PCTCN2019130053-appb-000092

步骤一step one

将化合物2e(0.04g,99.65μmol)溶于吡啶(3mL)中，缓慢加入用吡啶(3mL)稀释的2-甲氧基-1-乙基磺酰氯(79.02mg,498.24μmol)，25℃下搅拌反应2小时。反应液加水淬灭，加乙酸乙酯10mL*3萃取有机相，有机相减压旋蒸得粗品。粗品经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:26％-％,7min)纯化得到化合物25的三氟乙酸盐。Compound 2e (0.04 g, 99.65 μmol) was dissolved in pyridine (3 mL), and 2-methoxy-1-ethylsulfonyl chloride (79.02 mg, 498.24 μmol) diluted with pyridine (3 mL) was slowly added at 25°C The reaction was stirred for 2 hours. The reaction solution was quenched with water, ethyl acetate 10mL*3 was added to extract the organic phase, and the organic phase was evaporated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 26%-%, 7min) The trifluoroacetate salt ofcompound 25 is obtained.

LCMS(ESI)m/z:524.1[M+1]+LCMS(ESI)m/z:524.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.72(d,J＝7.28Hz,1H),8.39(s,1H),8.16(d,J＝2.52Hz,2H),8.07(s,1H),7.77(dd,J＝1.76,7.28Hz,1H),7.73-7.81(m,1H),7.58-7.71(m,4H),7.14(br d,J＝4.02Hz,2H),4.01(s,3H),3.78-3.90(m,2H),3.47(s,2H),3.31(br s,3H).1 H NMR (400 MHz, CD3 OD) δ 8.72 (d, J = 7.28 Hz, 1H), 8.39 (s, 1H), 8.16 (d, J = 2.52 Hz, 2H), 8.07 (s, 1H), 7.77(dd, J=1.76, 7.28Hz, 1H), 7.73-7.81(m, 1H), 7.58-7.71(m, 4H), 7.14(br d, J=4.02Hz, 2H), 4.01(s, 3H ), 3.78-3.90 (m, 2H), 3.47 (s, 2H), 3.31 (br s, 3H).

化合物25的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物25。The trifluoroacetic acid salt ofcompound 25 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 25.

实施例26Example 26

Figure PCTCN2019130053-appb-000093
Figure PCTCN2019130053-appb-000093

步骤一step one

将化合物2e(0.03g,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL)，三光气(11.09mg,37.37μmol)，0℃搅拌10分钟；同时另外将氮杂环丁烷(6.99mg,74.74μmol,8.26μL,HCl)溶 于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL,3eq)，0℃搅拌10分钟；倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。粗品经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:20％-60％,7min)纯化得到化合物26的三氟乙酸盐。Compound 2e (0.03g, 74.74μmol) was dissolved in DCM (1mL), DIEA (28.98mg, 224.21μmol, 39.05μL), triphosgene (11.09mg, 37.37μmol) were added and stirred at 0°C for 10 minutes; Azetidine (6.99 mg, 74.74 μmol, 8.26 μL, HCl) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21 μmol, 39.05 μL, 3eq) was added and stirred at 0°C for 10 minutes; pour into the above The reaction solution was stirred at 0°C for 7-10 minutes. The reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. The reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was prepared by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-60%, 7min) Purification afforded the trifluoroacetate salt of compound 26.

LCMS(ESI)m/z:485.3[M+1]+LCMS(ESI)m/z:485.3[M+1]+

1H NMR(400MHz,CD3OD)δ8.74(d,J＝7.04Hz,1H),8.36(s,1H),8.14(s,1H),8.08(s,1H),7.95-8.04(m,2H),7.68-7.78(m,2H),7.61(d,J＝6.54Hz,1H),7.47(d,J＝1.24Hz,1H),7.02-7.19(m,2H),4.14(t,J＝7.64Hz,4H),4.00(s,3H),2.34(s,2H).1 H NMR (400 MHz, CD3 OD) δ 8.74 (d, J = 7.04 Hz, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.95-8.04 (m , 2H), 7.68-7.78 (m, 2H), 7.61 (d, J = 6.54 Hz, 1H), 7.47 (d, J = 1.24 Hz, 1H), 7.02-7.19 (m, 2H), 4.14 (t, J = 7.64 Hz, 4H), 4.00 (s, 3H), 2.34 (s, 2H).

化合物26的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物26。The trifluoroacetate salt of compound 26 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 26.

表3中实施例化合物的制备可以参照前述制备实施例26的路线类似的步骤方法进行，不同之处在于在步骤六中使用的原料A代替环丁胺得到相应化合物的三氟乙酸盐。The preparation of the compounds of the examples in Table 3 can be carried out by referring to the steps similar to those of the aforementioned preparation example 26, except that the raw material A used in step 6 replaces cyclobutylamine to obtain the trifluoroacetate salt of the corresponding compound.

表3table 3

Figure PCTCN2019130053-appb-000094
Figure PCTCN2019130053-appb-000094

实施例28Example 28

Figure PCTCN2019130053-appb-000095
Figure PCTCN2019130053-appb-000095

Figure PCTCN2019130053-appb-000096
Figure PCTCN2019130053-appb-000096

步骤一step one

向1g(6g,30.45mmol)，4-吡唑硼酸嚬哪醇酯(8.86g,45.68mmol)的四氢呋喃(60mL)和水(30mL)溶液中加入Pd(dppf)Cl2(2.23g,3.05mmol)，磷酸钾(12.93g,60.90mmol)。氮气保护下80℃搅拌16小时。反应液分液，收集有机相，减压浓缩得粗品。将粗品以二氯甲烷/甲醇＝10/1进行过柱(快速硅胶柱层析)纯化得化合物28a。To a solution of 1 g (6 g, 30.45 mmol), 4-pyrazole boronic acid coronaol ester (8.86 g, 45.68 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was added Pd(dppf)Cl2 (2.23 g, 3.05 mmol ), potassium phosphate (12.93g, 60.90mmol). Under nitrogen, the mixture was stirred at 80°C for 16 hours. The reaction solution was separated, the organic phase was collected, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column (flash silica gel column chromatography) with dichloromethane/methanol=10/1 to obtain compound 28a.

LCMS(ESI)m/z:184.9[M+1]+LCMS(ESI)m/z:184.9[M+1]+

步骤二Step two

向化合物28a(2.5g,13.57mmol)的二氯甲烷(25mL)和DMF(25mL)溶液中加入NIS(3.66g,16.29mmol)，30℃搅拌16小时。向反应液中加入水(50mL)，再加入二氯甲烷(50mL*3)萃取，合并有机相并用油泵减压旋干得化合物28b。To a solution of compound 28a (2.5 g, 13.57 mmol) in methylene chloride (25 mL) and DMF (25 mL) was added NIS (3.66 g, 16.29 mmol), and stirred at 30°C for 16 hours. Water (50 mL) was added to the reaction solution, followed by extraction with dichloromethane (50 mL*3). The organic phases were combined and dried under reduced pressure with an oil pump to obtain compound 28b.

LCMS(ESI)m/z:310.7[M+1]+LCMS(ESI)m/z:310.7[M+1]+

步骤三Step three

0℃向化合物28b(2g,6.45mmol)的二氯甲烷(25mL)溶液中加入三乙胺(1.96g,19.35mmol,2.69mL)，MsCl(1.48g,12.90mmol,998.40μL)，30℃搅拌3小时。反应液加水(25mL)，二氯甲烷(25mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品，粗品经DCM:MeOH＝25:25打浆处理，抽滤得化合物28c。To a solution of compound 28b (2g, 6.45mmol) in methylene chloride (25mL) was added triethylamine (1.96g, 19.35mmol, 2.69mL), MsCl (1.48g, 12.90mmol, 998.40μL) at 0°C, and stirred at 30°C 3 hours. The reaction solution was added with water (25mL) and extracted with dichloromethane (25mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with DCM:MeOH=25:25 and filtered to obtain compound 28c. .

LCMS(ESI)m/z:388.8[M+1]+LCMS(ESI)m/z:388.8[M+1]+

步骤四Step four

向化合物28c(0.1g,257.61μmol)，11f(137.06mg,334.89μmol)的四氢呋喃(5mL)和水(2.5mL)溶液中加入Pd(dppf)Cl2(18.85mg,25.76μmol)，硫酸钾(109.36mg,515.22μmol)。氮气保护下90℃搅拌16小时。反应液分层后有机相浓缩得粗品。粗品经制备HPLC(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,7min)纯化得化合物28的三氟乙酸盐。To a solution of compound 28c (0.1 g, 257.61 μmol), 11f (137.06 mg, 334.89 μmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was added Pd(dppf)Cl2 (18.85 mg, 25.76 μmol), potassium sulfate ( 109.36mg, 515.22μmol). Stir at 90°C for 16 hours under nitrogen protection. After the reaction solution was separated into layers, the organic phase was concentrated to obtain a crude product. The crude product was purified by preparative HPLC (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 7min) to obtain the compound The trifluoroacetate of 28.

LCMS(ESI)m/z:544.1[M+1]+LCMS(ESI)m/z:544.1[M+1]+

1H NMR(400MHz,CD3OD)δ9.00(s,1H),8.77(d,J＝7.28Hz,1H),8.54(s,1H),8.26(s,1H),8.23(s,1H),7.86(dd,J＝1.25,7.28Hz,1H),7.56-7.70(m,4H),7.07-7.18(m,2H),3.47-3.59(m,3H),3.05-3.16(m,3H).1 H NMR (400 MHz, CD3 OD) δ 9.00 (s, 1H), 8.77 (d, J = 7.28 Hz, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H ), 7.86 (dd, J = 1.25, 7.28 Hz, 1H), 7.56-7.70 (m, 4H), 7.07-7.18 (m, 2H), 3.47-3.59 (m, 3H), 3.05-3.16 (m, 3H) ).

化合物28的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物28。The trifluoroacetic acid salt ofcompound 28 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtaincompound 28.

实施例29Example 29

Figure PCTCN2019130053-appb-000097
Figure PCTCN2019130053-appb-000097

步骤一step one

将化合物2e(0.15g,373.68μmol)溶于二氯甲烷(10mL)中，降温到0℃加入吡啶(88.67mg,1.12mmol,90.48μL)和甲胺磺酰氯(58.10mg,448.42μmol)，反应在0℃搅拌1小时。向反应液中加入水(100mL)和二氯甲烷(200mL)萃取分液，有机相干燥，过滤浓缩得到粗品。粗品经高效液相色谱纯化(色谱柱:Welch Xtimate C18 100*25mm*3μm；流动相:[水(10mM碳酸氢铵)-乙腈]；B(乙腈)％:27％-57％,10.5min)得到化合物29。Compound 2e (0.15g, 373.68μmol) was dissolved in dichloromethane (10mL), the temperature was lowered to 0°C and pyridine (88.67mg, 1.12mmol, 90.48μL) and mesyl chloride (58.10mg, 448.42μmol) were added to react Stir at 0°C for 1 hour. Water (100 mL) and dichloromethane (200 mL) were added to the reaction liquid to extract and separate the liquid. The organic phase was dried, filtered and concentrated to obtain a crude product. The crude product was purified by high-performance liquid chromatography (column:Welch Xtimate C18 100*25mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; B (acetonitrile)%: 27%-57%, 10.5min) Compound 29 is obtained.

LCMS(ESI)m/z:495.1[M+1]+LCMS(ESI)m/z:495.1[M+1]+

1H NMR(399MHz,DMSO-d6)δ8.53-8.56(m,1H)8.35(s,1H)8.08(s,1H)7.87(s,1H)7.79(s,1H)7.71-7.73(m,2H)7.51-7.56(m,2H)7.49(s,1H)7.41(s,1H)7.33(s,1H)7.23-7.28(m,2H)3.86-3.91(m,3H)3.28-3.32(m,3H).1 H NMR (399 MHz, DMSO-d6 ) δ 8.53-8.56 (m, 1H) 8.35 (s, 1H) 8.08 (s, 1H) 7.87 (s, 1H) 7.79 (s, 1H) 7.71-7.73 (m ,2H)7.51-7.56(m,2H)7.49(s,1H)7.41(s,1H)7.33(s,1H)7.23-7.28(m,2H)3.86-3.91(m,3H)3.28-3.32(m ,3H).

实施例30Example 30

Figure PCTCN2019130053-appb-000098
Figure PCTCN2019130053-appb-000098

Figure PCTCN2019130053-appb-000099
Figure PCTCN2019130053-appb-000099

步骤一step one

将3-溴-5-硝基-苯酚(20g,91.74mmol)和双联嚬哪醇硼酸酯(25.63g,100.92mmol)溶于二氧六环(200mL)中，加入KOAc(18.01g,183.48mmol)和Pd(dppf)Cl2(3.36g,4.59mmol)，氮气保护下90℃搅拌16小时。反应液直接垫硅藻土过滤，用乙酸乙酯洗两次，收集滤液旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化得到化合物30a。Dissolve 3-bromo-5-nitro-phenol (20g, 91.74mmol) and bis-carbamol borate (25.63g, 100.92mmol) in dioxane (200mL), add KOAc (18.01g, 183.48 mmol) and Pd(dppf)Cl2 (3.36 g, 4.59 mmol), stirred at 90° C. for 16 hours under nitrogen protection. The reaction solution was filtered through a pad of celite, washed twice with ethyl acetate, and the filtrate was collected by rotary drying to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1 to obtain compound 30a.

1H NMR(400MHz,CDCl3)δ8.17(d,J＝1.52Hz,1H),7.76(t,J＝2.26Hz,1H),7.57(d,J＝2.02Hz,1H),7.00(br s,1H),1.35(s,12H).1 H NMR (400 MHz, CDCl3 ) δ 8.17 (d, J = 1.52 Hz, 1H), 7.76 (t, J = 2.26 Hz, 1H), 7.57 (d, J = 2.02 Hz, 1H), 7.00 (br s, 1H), 1.35 (s, 12H).

步骤二Step two

向化合物30a(3g,11.32mmol)和二甲基叔丁基氯硅烷(2.05g,13.58mmol,1.66mL)溶于DMF(30mL)中，加入咪唑(1.93g,28.29mmol)和DMAP(138.27mg,1.13mmol)，室温下30℃搅拌反应16小时。反应液加水3mL萃取，收集有机相，无水硫酸钠干燥，旋干得粗品。不做纯化直接得到化合物30b。To compound 30a (3g, 11.32mmol) and dimethyl tert-butylchlorosilane (2.05g, 13.58mmol, 1.66mL) were dissolved in DMF (30mL), imidazole (1.93g, 28.29mmol) and DMAP (138.27mg) were added , 1.13 mmol), and the reaction was stirred at 30°C for 16 hours at room temperature. The reaction solution was extracted with 3 mL of water, and the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The compound 30b was obtained without purification.

1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝1.24Hz,1H),7.69(t,J＝2.12Hz,1H),7.45(d,J＝1.52Hz,1H),1.32(s,12H),0.98(s,9H),0.24(s,6H).1 H NMR (400 MHz, DMSO-d6 ) δ 8.01 (d, J = 1.24 Hz, 1H), 7.69 (t, J = 2.12 Hz, 1 H), 7.45 (d, J = 1.52 Hz, 1 H), 1.32 (s,12H), 0.98(s,9H), 0.24(s,6H).

步骤三Step three

将化合物30b(2.8g,7.38mmol)溶于乙醇(120mL)和水(20mL)中，加入氯化铵(3.95g,73.81mmol)和锌粉(4.83g,73.81mmol)，室温30℃下搅拌反应16小时。反应液直接过滤，用无水乙醇洗两次，滤液旋干得粗品。将粗品以PE/EA＝5/1进行过柱纯化得到化合物30c。Compound 30b (2.8g, 7.38mmol) was dissolved in ethanol (120mL) and water (20mL), ammonium chloride (3.95g, 73.81mmol) and zinc powder (4.83g, 73.81mmol) were added, and stirred at room temperature 30 ℃ React for 16 hours. The reaction solution was directly filtered, washed twice with absolute ethanol, and the filtrate was spin-dried to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1 to obtain compound 30c.

LCMS(ESI)m/z:350.0[M+1]+LCMS(ESI)m/z:350.0[M+1]+

步骤四Step four

将化合物30c(1.9g,5.44mmol)溶于吡啶(5mL)中，加入环丙磺酰氯(917.55mg,6.53mmol)，30℃下搅拌反应16小时。反应液加水10mL和乙酸乙酯15mL萃取，有机相再用水10mL洗两次，无水硫酸钠干燥，旋干得粗品。将粗品以PE/EA＝5/1～1/1进行过柱纯化得到化合物30d。Compound 30c (1.9 g, 5.44 mmol) was dissolved in pyridine (5 mL), cyclopropanesulfonyl chloride (917.55 mg, 6.53 mmol) was added, and the reaction was stirred at 30°C for 16 hours. The reaction solution was extracted with 10 mL of water and 15 mL of ethyl acetate, and the organic phase was washed twice with 10 mL of water, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1 to 1/1 to obtain compound 30d.

LCMS(ESI)m/z:454.1[M+1]+LCMS(ESI)m/z:454.1[M+1]+

步骤五Step five

向化合物30d(2.85g,6.28mmol)，化合物1j(1.36g,4.19mmol)的二氧六环(30mL)和H2O(10mL)的溶液中加入Pd(dppf)Cl2(306.58mg,418.99μmol)，硫酸钾(1.78g,8.38mmol)。氮气保护下100℃搅拌16小时。反应液加水(80mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物30e。To a solution of compound 30d (2.85 g, 6.28 mmol), compound 1j (1.36 g, 4.19 mmol) in dioxane (30 mL) and H2 O (10 mL) was added Pd(dppf)Cl2 (306.58 mg, 418.99 μmol), potassium sulfate (1.78 g, 8.38 mmol). Stir at 100°C for 16 hours under nitrogen protection. Water (80 mL) was added to the reaction solution, and ethyl acetate (50 mL*3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column purification with DCM/MeOH=20/1 to obtain compound 30e.

LCMS(ESI)m/z:410.1[M+1]+LCMS(ESI)m/z:410.1[M+1]+

步骤六Step six

向化合物30e(870mg,2.12mmol)的DMF(9mL)溶液中加入DIEA(823.83mg,6.37mmol)，N-苯基双(三氟甲烷磺酰)亚胺(1.14g,3.19mmol)，20℃搅拌16小时。反应液中加入水(20mL)，加入乙酸乙酯(20mL*3)萃取，合并有机相并用水洗(50mL*3)，有机相再用无水硫酸钠干燥，减压浓缩得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物30f。To a solution of compound 30e (870 mg, 2.12 mmol) in DMF (9 mL) was added DIEA (823.83 mg, 6.37 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (1.14 g, 3.19 mmol), 20°C Stir for 16 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (20 mL*3) was added for extraction. The organic phases were combined and washed with water (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column purification with DCM/MeOH=20/1 to obtain compound 30f.

LCMS(ESI)m/z:542.1[M+1]+LCMS(ESI)m/z:542.1[M+1]+

步骤七Step 7

向化合物30f(100mg,184.66μmol)，双联频哪醇硼酸酯(56.27mg,221.60μmol)的二氧六环(3mL)溶液中加入Pd(dppf)Cl2(13.51mg,18.47μmol)，KOAc(36.25mg,369.33μmol)。氮气保护下90℃搅拌16小时。反应液浓缩得化合物30g。Pd(dppf)Cl2 (13.51mg, 18.47μmol) was added to a solution of compound 30f (100mg, 184.66μmol), double pinacol borate (56.27mg, 221.60μmol) in dioxane (3mL), KOAc (36.25 mg, 369.33 μmol). Stir at 90°C for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain 30 g of compound.

LCMS(ESI)m/z:520.1[M+1]+LCMS(ESI)m/z:520.1[M+1]+

步骤八Step 8

向化合物30g(95mg,182.90μmol)，2-溴3,5-二氟吡啶(40mg,206.21μmol)的二氧六环(3mL)和H2O(1mL)溶液中加入Pd(dppf)Cl2(15.09mg,20.62μmol)，磷酸钾(87.54mg,412.42μmol,2eq)。氮气保护下100℃搅拌3小时。反应液直接干燥，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板分离(DCM:MeOH＝10:1)得粗品，粗品再经制备高效液相色谱纯化(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,7min)得化合物30的三氟乙酸盐。To a solution of compound 30g (95 mg, 182.90 μmol), 2-bromo 3,5-difluoropyridine (40 mg, 206.21 μmol) in dioxane (3 mL) and H2 O (1 mL) was added Pd(dppf)Cl2 (15.09mg, 20.62μmol), potassium phosphate (87.54mg, 412.42μmol, 2eq). Stir at 100°C for 3 hours under nitrogen protection. The reaction solution was directly dried, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative thin layer chromatography silica gel plate (DCM:MeOH=10:1) to obtain the crude product, and the crude product was purified by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075 % Trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 7 min) to obtain the trifluoroacetate salt of compound 30.

LCMS(ESI)m/z:507.1[M+1]+LCMS(ESI)m/z:507.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.73(d,J＝7.03Hz,1H),8.56(d,J＝2.26Hz,1H),8.39(s,1H),8.17(d,J＝5.52Hz,2H),7.99-8.09(m,3H),7.74-7.82(m,3H),4.00(s,3H),2.68-2.80(m,1H),1.09-1.19(m,2H),0.99-1.07(m,2H).化合物30的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得 到化合物30。1 H NMR (400 MHz, CD3 OD) δ 8.73 (d, J = 7.03 Hz, 1H), 8.56 (d, J = 2.26 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J = 5.52 Hz, 2H), 7.99-8.09 (m, 3H), 7.74-7.82 (m, 3H), 4.00 (s, 3H), 2.68-2.80 (m, 1H), 1.09-1.19 (m, 2H), 0.99- 1.07 (m, 2H). The trifluoroacetate salt of compound 30 was added to the sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 30.

实施例31Example 31

Figure PCTCN2019130053-appb-000100
Figure PCTCN2019130053-appb-000100

步骤一step one

将化合物33c(20g,57.25mmol,1eq)和乙磺酰氯(8.83g,68.70mmol)溶于吡啶(80mL)中，室温25℃搅拌反应16小时，反应液加水100mL和乙酸乙酯100mL*3萃取3次，有机相用无水硫酸钠干燥，旋干得粗品，将粗品以PE/EA＝5/1进行过柱纯化，所得粗品旋干后用石油醚25℃打浆2小时，得到化合31a。Compound 33c (20g, 57.25mmol, 1eq) and ethanesulfonyl chloride (8.83g, 68.70mmol) were dissolved in pyridine (80mL), and the reaction was stirred at room temperature at 25°C for 16 hours. The reaction solution was extracted with water 100mL and ethyl acetate 100mL*3 Three times, the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1. The crude product obtained was spin-dried and then beaten with petroleum ether at 25°C for 2 hours to obtain compound 31a.

LCMS(ESI)m/z:442.2[M+1]+LCMS(ESI)m/z:442.2[M+1]+

1H NMR(400MHz,DMSO-d6):δ9.68-9.78(m,1H),7.14(d,J＝1.52Hz,1H),6.94(t,J＝2.12Hz,1H),6.82(d,J＝1.86Hz,1H),3.05(q,J＝7.32Hz,2H),1.29(s,12H),1.17(t,J＝7.40Hz,3H),0.95(s,9H),0.16-0.20(m,6H).步骤二1 H NMR (400 MHz, DMSO-d6 ): δ 9.68-9.78 (m, 1H), 7.14 (d, J = 1.52 Hz, 1H), 6.94 (t, J = 2.12 Hz, 1H), 6.82 (d , J = 1.86 Hz, 1H), 3.05 (q, J = 7.32 Hz, 2H), 1.29 (s, 12H), 1.17 (t, J = 7.40 Hz, 3H), 0.95 (s, 9H), 0.16-0.20 (m,6H). Step two

将化合物31a(11g,24.92mmol)和化合物1j(6.73g,20.76mmol)溶于二氧六环(100mL)和H2O(50mL)中，加入Pd(dppf)Cl2(1.52g,2.08mmol)和硫酸钾(8.82g,41.53mmol)，氮气保护下90℃搅拌反应16小时，反应液加水100mL和乙酸乙酯100mL*2萃取，有机相用无水硫酸钠干燥，旋干得粗品，将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物31b。Compound 31a (11 g, 24.92 mmol) and compound 1j (6.73 g, 20.76 mmol) were dissolved in dioxane (100 mL) and H2 O (50 mL), and Pd (dppf) Cl2 (1.52 g, 2.08 mmol) was added ) And potassium sulfate (8.82g, 41.53mmol), stirred at 90°C for 16 hours under nitrogen protection, the reaction solution was extracted with water 100mL and ethyl acetate 100mL*2, the organic phase was dried over anhydrous sodium sulfate, spin-dried to obtain a crude product, The crude product was subjected to column purification with DCM/MeOH=20/1 to obtain compound 31b.

LCMS(ESI)m/z:398.0[M+1]+LCMS(ESI)m/z:398.0[M+1]+

步骤三Step three

将化合物31b(2.6g,6.54mmol)和N-苯基双(三氟甲烷磺酰)亚胺(3.51g,9.81mmol)溶于DMF(20mL)中，加入DIEA(3.38g,26.17mmol,4.56mL)，室温25℃下搅拌16小时。反应液中加入水(20mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用水洗(50mL*3)，有机相用无水硫酸钠干燥，旋干得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物31c。Compound 31b (2.6g, 6.54mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (3.51g, 9.81mmol) were dissolved in DMF (20mL), DIEA (3.38g, 26.17mmol, 4.56) was added mL) and stirred atroom temperature 25°C for 16 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate (50 mL*3) was added for extraction. The organic phases were combined and washed with water (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and vortexed to obtain a crude product. The crude product was subjected to column purification with DCM/MeOH=20/1 to obtain compound 31c.

LCMS(ESI)m/z:530.3[M+1]+LCMS(ESI)m/z:530.3[M+1]+

步骤四Step four

将化合物31c(2.6g,4.91mmol)和双联嚬哪醇硼酸酯(1.50g,5.89mmol)溶于二氧六环(1.5mL)中，加入Pd(dppf)Cl2(359.28mg,491.02μmol)和KOAc(963.79mg,9.82mmol)，氮气保护下90℃搅拌反应16小时。反应液直接用于下一步反应。最终得到化合物31d。Compound 31c (2.6g, 4.91mmol) and bis knit the brows pinacolato boronate (1.50g, 5.89mmol) was dissolved in dioxane (1.5mL) was addedPd (dppf) Cl 2 (359.28mg , 491.02 μmol) and KOAc (963.79 mg, 9.82 mmol), and the reaction was stirred at 90°C for 16 hours under nitrogen protection. The reaction solution is used directly in the next reaction. Finally, compound 31d is obtained.

LCMS(ESI)m/z:508.2[M+1]+LCMS(ESI)m/z:508.2[M+1]+

步骤五Step five

将化合物31d(2.2g,4.34mmol)和2-溴3,5-二氟吡啶(1.68g,8.67mmol)溶于二氧六环(1.5mL)和H2O(0.5mL)中，加入Pd(dppf)Cl2(317.25mg,433.57μmol)和硫酸钾(1.84g,8.67mmol)，氮气保护下100℃搅拌反应3小时。反应液加入无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品以DCM/MeOH＝20/1进行过柱纯化得粗产物，再经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:15％-45％,7min)纯化得化合物31的三氟乙酸盐。Compound 31d (2.2g, 4.34mmol) and 2-bromo 3,5-difluoropyridine (1.68g, 8.67mmol) were dissolved in dioxane (1.5mL) and H2 O (0.5mL), Pd was added (dppf) Cl2 (317.25 mg, 433.57 μmol) and potassium sulfate (1.84 g, 8.67 mmol), and the reaction was stirred at 100° C. for 3 hours under nitrogen protection. The reaction solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was subjected to column purification with DCM/MeOH=20/1 to obtain the crude product, which was then subjected to preparative high performance liquid chromatography (chromatographic column:Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (0.075% trifluoroacetic acid)- Acetonitrile]; B (acetonitrile)%: 15%-45%, 7 min) to obtain the trifluoroacetate salt of compound 31.

LCMS(ESI)m/z:495.0[M+1]+LCMS(ESI)m/z:495.0[M+1]+

1H NMR(400MHz,CD3OD):δ8.72(d,J＝7.34Hz,1H),8.52-8.59(m,1H),8.34-8.44(m,1H),8.17(d,J＝7.56Hz,2H),8.08(s,1H),7.98(s,2H),7.69-7.84(m,3H),4.01(s,3H),3.27(q,J＝7.38Hz,2H),1.39(t,J＝7.44Hz,3H).化合物31的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物31。1 H NMR (400 MHz, CD3 OD): δ 8.72 (d, J = 7.34 Hz, 1 H), 8.52-8.59 (m, 1 H), 8.34-8.44 (m, 1 H), 8.17 (d, J = 7.56 Hz, 2H), 8.08 (s, 1H), 7.98 (s, 2H), 7.69-7.84 (m, 3H), 4.01 (s, 3H), 3.27 (q, J = 7.38 Hz, 2H), 1.39 (t , J = 7.44 Hz, 3H). The trifluoroacetate salt of compound 31 was added to the sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 31.

实施例32Example 32

Figure PCTCN2019130053-appb-000101
Figure PCTCN2019130053-appb-000101

Figure PCTCN2019130053-appb-000102
Figure PCTCN2019130053-appb-000102

步骤一step one

向2-溴-3,5-二氟-吡啶(4g,20.62mmol)，30a(6.01g,22.68mmol)的二氧六环(40mL)和水(10mL)溶液中加入Pd(dppf)Cl2(1.51g,2.06mmol,0.1eq)，磷酸钾(8.75g,41.24mmol,2eq)。氮气保护下100℃搅拌16小时。反应液加水(100mL)，加乙酸乙酯(100mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。将粗品以PE/EA＝10/1进行过柱纯化得到化合物32a。To a solution of 2-bromo-3,5-difluoro-pyridine (4g, 20.62mmol), 30a (6.01g, 22.68mmol) in dioxane (40mL) and water (10mL) was added Pd(dppf)Cl2 (1.51g, 2.06mmol, 0.1eq), potassium phosphate (8.75g, 41.24mmol, 2eq). Stir at 100°C for 16 hours under nitrogen protection. The reaction solution was added with water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column purification with PE/EA=10/1 to obtain compound 32a.

LCMS(ESI)m/z:252.9[M+1]+LCMS(ESI)m/z:252.9[M+1]+

步骤二Step two

向化合物32a(3.85g,15.27mmol)的DMF(50mL)溶液中加入DIEA(5.92g,45.80mmol,7.98mL)，再加入N-苯基双(三氟甲烷磺酰)亚胺(8.18g,22.90mmol)，20℃搅拌16小时。反应液加水(200mL)，加入乙酸乙酯(200mL*3)萃取，合并有机相加水反洗(300mL*3)，饱和氯化钠水溶液洗(300mL)，收集有机相并用无水硫酸钠干燥，减压浓缩得粗品32b。To a solution of compound 32a (3.85 g, 15.27 mmol) in DMF (50 mL) was added DIEA (5.92 g, 45.80 mmol, 7.98 mL), followed by N-phenylbis(trifluoromethanesulfonyl)imide (8.18 g, 22.90 mmol), stirred at 20°C for 16 hours. The reaction solution was added with water (200 mL), extracted with ethyl acetate (200 mL*3), and the combined organic phase was backwashed with water (300 mL*3), washed with saturated aqueous sodium chloride solution (300 mL), and the organic phase was collected and dried over anhydrous sodium sulfate. , Concentrate under reduced pressure to obtain crude product 32b.

LCMS(ESI)m/z:384.8[M+1]+LCMS(ESI)m/z: 384.8[M+1]+

步骤三Step three

将化合物32b(13g,33.83mmol)溶于乙醇(130mL)和水(13mL)中，加入氯化铵(18.10g,338.33mmol)和锌粉(22.12g,338.33mmol)，室温20℃搅拌反应16小时。反应液直接过滤，滤液旋干得粗品，不做纯化得到化合物32c。Compound 32b (13g, 33.83mmol) was dissolved in ethanol (130mL) and water (13mL), ammonium chloride (18.10g, 338.33mmol) and zinc powder (22.12g, 338.33mmol) were added, the reaction was stirred at room temperature 20 ℃ 16 hour. The reaction solution was directly filtered, and the filtrate was spin-dried to obtain a crude product, and compound 32c was obtained without purification.

LCMS(ESI)m/z:354.8[M+1]+LCMS(ESI)m/z:354.8[M+1]+

步骤四Step four

将化合物32c(5g,14.11mmol)溶于吡啶(25mL)中，滴加甲烷磺酰氯(2.43g,21.17mmol,1.64mL)，室温20℃搅拌反应16小时。反应液加水50mL淬灭，加乙酸乙酯50mL*2萃取，再用水50mL*3洗涤，有机相用无水硫酸钠干燥，旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化,得到化合物32d。Compound 32c (5g, 14.11mmol) was dissolved in pyridine (25mL), methanesulfonyl chloride (2.43g, 21.17mmol, 1.64mL) was added dropwise, and the reaction was stirred at room temperature 20°C for 16 hours. The reaction solution was quenched with 50mL of water, extracted with 50mL*2 of ethyl acetate, and washed with 50mL*3 of water. The organic phase was dried over anhydrous sodium sulfate and vortexed to obtain the crude product. The crude product was passed through the column with PE/EA=5/1 Purify to obtain compound 32d.

LCMS(ESI)m/z:432.9[M+1]+LCMS(ESI)m/z:432.9[M+1]+

步骤五Step five

将化合物32d(2.3g,5.32mmol)和双联嚬哪醇硼酸酯(2.03g,7.98mmol)溶于二氧六环(20mL)中，加入Pd(dppf)Cl2(389.26mg,531.99μmol)和KOAc(1.04g,10.64mmol)，氮气保护下90℃搅拌反应16小时。反应液直接过滤，滤液浓缩得粗品,粗品以PE/EA＝5/1进行过柱纯化得到化合物32e。Compound 32d (2.3g, 5.32mmol) and bis knit the brows pinacolato boronate (2.03g, 7.98mmol) was dissolved in dioxane (20mL), was addedPd (dppf) Cl 2 (389.26mg , 531.99μmol ) And KOAc (1.04g, 10.64mmol), and the reaction was stirred at 90°C for 16 hours under nitrogen protection. The reaction solution was directly filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to column purification with PE/EA=5/1 to obtain compound 32e.

LCMS(ESI)m/z:411.0[M+1]+LCMS(ESI)m/z:411.0[M+1]+

步骤六Step six

将1g(50mg,154.26μmol)和化合物32e(94.93mg,231.39μmol)溶于二氧六环(2mL)和H2O(0.5mL)中，加入Pd(dppf)Cl2(11.29mg,15.43μmol)和硫酸钾(65.49mg,308.52μmol)，氮气保护下90℃搅拌反应16小时。反应液加入水3mL和乙酸乙酯5mL萃取，有机相旋干得粗品，粗品再经制备高效液相色谱纯化(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,7min)纯化得到化合物32的三氟乙酸盐。The 1g (50mg, 154.26μmol) and Compound 32e (94.93mg, 231.39μmol) was dissolved in dioxane (2mL) and H2 O (0.5mL), was addedPd (dppf) Cl 2 (11.29mg , 15.43μmol ) And potassium sulfate (65.49 mg, 308.52 μmol), and the reaction was stirred at 90° C. for 16 hours under nitrogen protection. The reaction solution was extracted by adding 3mL of water and 5mL of ethyl acetate, and the organic phase was spin-dried to obtain a crude product, which was then purified by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.075% three (Fluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 7 min) purification to obtain the trifluoroacetate salt of compound 32.

LCMS(ESI)m/z:480.9[M+1]+LCMS(ESI)m/z: 480.9[M+1]+

1H NMR(400MHz,CD3OD):δ8.71-8.76(m,1H),8.54-8.57(m,1H),8.38-8.41(m,1H),8.17-8.21(m,1H),8.16(s,1H),8.08(s,1H),7.97-8.03(m,2H),7.70-7.81(m,3H),4.01(s,3H),3.13(s,3H).1 H NMR (400 MHz, CD3 OD): δ 8.71-8.76 (m, 1H), 8.54-8.57 (m, 1H), 8.38-8.41 (m, 1H), 8.17-8.21 (m, 1H), 8.16 (s,1H), 8.08 (s, 1H), 7.97-8.03 (m, 2H), 7.70-7.81 (m, 3H), 4.01 (s, 3H), 3.13 (s, 3H).

化合物32的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物32。The trifluoroacetate salt of compound 32 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 32.

实施例33Example 33

Figure PCTCN2019130053-appb-000103
Figure PCTCN2019130053-appb-000103

步骤一step one

向化合物16c(50mg,107.42μmol)的DMF(2mL)溶液中加入3-溴丙烷-1,2-二醇(83.24mg,537.09μmol,47.03μL)，碳酸铯(105.00mg,322.25μmol)。80℃搅拌16小时。补加3-溴丙烷-1,2-二醇(83.24mg,537.09μmol,47.03μL)，碳酸铯(50mg)，升温至100℃搅拌16小时。反应液直接过滤，收集滤液。滤液 经制备高效液相色谱分离(column:Phenomenex Gemini-NX 80*40mm*3μm；mobile phase:[水(0.05％氨水+10mM碳酸氢铵)-乙腈]；B(乙腈)％:18％-48％,8min)后得到化合物33。To a solution of compound 16c (50 mg, 107.42 μmol) in DMF (2 mL) was added 3-bromopropane-1,2-diol (83.24 mg, 537.09 μmol, 47.03 μL), cesium carbonate (105.00 mg, 322.25 μmol). Stir at 80°C for 16 hours. Additional 3-bromopropane-1,2-diol (83.24 mg, 537.09 μmol, 47.03 μL) and cesium carbonate (50 mg) were heated to 100° C. and stirred for 16 hours. The reaction solution was directly filtered, and the filtrate was collected. The filtrate was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water + 10mM ammonium bicarbonate)-acetonitrile]; B (acetonitrile)%: 18%-48 %, 8 min) to obtain compound 33.

LCMS(ESI)m/z:540.1[M+1]+LCMS(ESI)m/z:540.1[M+1]+

1H NMR(400MHz,CD3OD)δ8.54(d,J＝7.28Hz,1H),8.21(s,1H),8.02(s,1H),7.77(s,1H),7.72(s,1H),7.58-7.68(m,1H),7.54(dd,J＝1.64,4.90Hz,2H),7.47(d,J＝1.52Hz,1H),7.29(dd,J＝1.76,7.28Hz,1H),7.05-7.18(m,2H),4.37(dd,J＝4.02,14.06Hz,1H),4.16-4.24(m,1H),3.98-4.10(m,1H),3.52-3.58(m,2H),3.08(s,3H)1 H NMR (400 MHz, CD3 OD) δ 8.54 (d, J = 7.28 Hz, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H ), 7.58-7.68 (m, 1H), 7.54 (dd, J = 1.64, 4.90 Hz, 2H), 7.47 (d, J = 1.52 Hz, 1H), 7.29 (dd, J = 1.76, 7.28 Hz, 1H) , 7.05-7.18 (m, 2H), 4.37 (dd, J = 4.02, 14.06 Hz, 1H), 4.16-4.24 (m, 1H), 3.98-4.10 (m, 1H), 3.52-3.58 (m, 2H) ,3.08(s,3H)

生物测试数据：Biological test data:

实验例1：本发明化合物的体外酶活性测试Experimental Example 1: In vitro enzyme activity test of the compound of the present invention

采用33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC50值来评价受试化合物对人FGFR1、FGFR4、VEGFR2的抑制能力。33 P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC50 value to evaluate the inhibitory ability of the test compound on human FGFR1, FGFR4, and VEGFR2.

缓冲液条件：20mM Hepes(4-羟乙基哌嗪乙磺酸)(pH 7.5),10mM MgCl2,1mM EGTA(乙二醇双(2-氨基乙基醚)四乙酸),0.02％BriJ35(表面活性剂),0.02mg/ml BSA(牛血清白蛋白),0.1mM Na3VO4,2mM DTT,1％DMSO。Buffer conditions: 20mM Hepes (4- hydroxyethylpiperazine-ethanesulfonic acid) (pH 7.5), 10mM MgCl 2, 1mM EGTA ( ethylene glycol bis (2-aminoethyl ether) tetraacetic acid), 0.02% BriJ35 ( Surfactant), 0.02 mg/ml BSA (bovine serum albumin), 0.1 mM Na3 VO4 , 2 mM DTT, 1% DMSO.

试验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测激酶并混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中。反应液中化合物浓度为10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM或3μM,1μM,0.333μM,0.111μM,37.0nM,12.3nM,4.12nM,1.37nM,0.457nM,0.152nM。孵化15分钟后，加入33P-ATP(活度0.01μCi/μl，相应浓度列在表4中)开始反应。FGFR1、FGFR4、KDR和在反应液中的浓度信息列在表2中。反应在室温下进行120分钟后，将反应液点在P81离子交换滤纸(Whatman#3698-915)上。用0.75％磷酸溶液反复清洗滤纸后，测定滤纸上残留的磷酸化底物的放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC50值，实验结果如表5所示。Test procedure: Dissolve the test compound in DMSO at room temperature to prepare a 10 mM solution for use. Dissolve the substrate in the newly prepared buffer, add the tested kinase to it and mix well. Using the acoustic technique (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above mixed reaction solution. The compound concentration in the reaction solution is 10 μM, 2.50 μM, 0.62 μM, 0.156 μM, 39.1 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM or 3 μM, 1 μM, 0.333 μM, 0.111 μM, 37.0 nM, 12.3 nM , 4.12nM, 1.37nM, 0.457nM, 0.152nM. After incubating for 15 minutes,33 P-ATP (activity 0.01 μCi/μl, corresponding concentration listed in Table 4) was added to start the reaction. FGFR1, FGFR4, KDR and the concentration information in the reaction solution are listed in Table 2. After the reaction was carried out at room temperature for 120 minutes, the reaction solution was spotted on P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured. The kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (containing only DMSO), and the IC50 value is obtained by curve fitting using Prism4 software (GraphPad). The experimental results are shown in Table 5.

表4：体外测试中激酶、底物和ATP的相关信息。Table 4: Information about kinases, substrates and ATP in in vitro tests.

Figure PCTCN2019130053-appb-000104
Figure PCTCN2019130053-appb-000104

Figure PCTCN2019130053-appb-000105
Figure PCTCN2019130053-appb-000105

表5 本发明化合物激酶活性IC50测试结果Table 5 IC50 test results of kinase activity of the compounds of the present invention

Figure PCTCN2019130053-appb-000106
Figure PCTCN2019130053-appb-000106

Figure PCTCN2019130053-appb-000107
Figure PCTCN2019130053-appb-000107

Figure PCTCN2019130053-appb-000108
Figure PCTCN2019130053-appb-000108

N/A：未检测。N/A: Not detected.

结论：本发明的化合物具有优异的FGFR1,FGFR2,FGFR4,VEGFR2激酶抑制活性。Conclusion: The compounds of the present invention have excellent FGFR1, FGFR2, FGFR4, VEGFR2 kinase inhibitory activity.

实验例2：本发明化合物的动力学溶解度数据测试Experimental Example 2: Kinetic solubility data test of the compound of the present invention

动力学溶解度样品先过滤采样。最终样品中含2％DMSO。通过紫外测定，并通过3条标准曲线(1、20、200μM)进行校准。K.S.摇动时间：室温下24小时。The kinetic solubility samples are filtered and sampled first. The final sample contains 2% DMSO. By UV measurement, and calibration by 3 standard curves (1, 20, 200 μM). K.S. shaking time: 24 hours at room temperature.

表6 本发明化合物动力学溶解度数据Table 6 Kinetic solubility data of the compounds of the present invention

Figure PCTCN2019130053-appb-000109
Figure PCTCN2019130053-appb-000109

Figure PCTCN2019130053-appb-000110
Figure PCTCN2019130053-appb-000110

结论：本发明的化合物具有优异的溶解度(pH 2.0)，成药性质提高。Conclusion: The compound of the present invention has excellent solubility (pH 2.0) and improved medicine properties.

实验例3：本发明化合物的胃癌细胞系SNU-16细胞活性测试Experimental Example 3: Activity test of gastric cancer cell line SNU-16 of the compound of the present invention

实验目的Purpose

测试化合物对FGFR2表达的人胃癌SNU-16细胞的增殖抑制作用。The test compound inhibits the proliferation of human gastric cancer SNU-16 cells expressing FGFR2.

实验方法experimental method

测试所用化合物进行3倍浓度稀释，浓度为从10μM，3倍系列稀释液开始，9个浓度，10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM。The compound used in the test was diluted at a 3-fold concentration, starting from 10 μM, 3-fold serial dilutions, 9 concentrations, 10 μM, 2.50 μM, 0.62 μM, 0.156 μM, 39.1 nM, 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM .

仪器instrument

(1)Promega CellTiter-Glo发光细胞活力测定试剂盒(Promega-G7573)。(1) Promega CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega-G7573).

(2)2104EnVision多标签阅读器，PerkinElmer。(2) 2104EnVision multi-tag reader, PerkinElmer.

结果分析：被测化合物的抑制率(IR)由下式确定：IR(％)＝(1–(RLU化合物–RLU空白)/(RLU对照–RLU空白))*100％。将在Excel文件中计算不同剂量化合物的抑制率，参数曲线拟合(GraphPad Software)得到化合物IC50数据。Analysis of results: The inhibition rate (IR) of the test compound is determined by the following formula: IR (%) = (1-(RLU compound-RLU blank)/(RLU control-RLU blank))*100%. Inhibition rates of different doses of compounds will be calculated in Excel files, and parameter curve fitting (GraphPad Software) will yield compound IC50 data.

表7 本发明化合物激酶活性IC50测试结果Table 7 IC50 test results of kinase activity of the compounds of the present invention

 ASNU-16IC50(nM)SNU-16IC50 (nM)对照例1的三氟乙酸盐Trifluoroacetate of Comparative Example 16666化合物2的三氟乙酸盐Trifluoroacetate of compound 21111化合物6Compound 61111

化合物10Compound 1023twenty three化合物30的三氟乙酸盐Trifluoroacetate of compound 301818化合物31的三氟乙酸盐Compound 31trifluoroacetate1010

结论：本发明化合物相比对照例具有更优异SNU-16细胞活性(3-5倍)。Conclusion: The compound of the present invention has more excellent SNU-16 cell activity (3-5 times) than the control.

实验例4：在体内动物肿瘤模型上的抗肿瘤活性测试Experimental Example 4: Anti-tumor activity test on animal tumor model in vivo

实验目的Purpose

在小鼠人胃癌SNU-16皮下异种移植肿瘤模型该发明化合物的抑瘤效果Antitumor effect of the compound of the present invention in mouse human gastric cancer SNU-16 subcutaneous xenograft tumor model

实验方法：experimental method:

1)肿瘤组织准备1) Tumor tissue preparation

肿瘤组织准备：在5％CO2、37℃、饱和湿度条件下，SNU-16细胞在含10％胎牛血清的RPMI-1640培养基中进行常规细胞培养。根据细胞生长情况，每周传代或补液1到2次，传代比例1:3到1:4Tumor tissue preparation: SNU-16 cells were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum under 5% CO2 , 37°C, and saturated humidity. Passage orrehydration 1 to 2 times per week according to cell growth, with a passage ratio of 1:3 to 1:4

2)组织接种及分组2) Tissue inoculation and grouping

收取对数生长期SNU-16细胞，细胞计数后重悬于于50％不含血清的RPMI-1640培养基及50％Matrigel中，调整细胞浓度至4×107细胞/mL；将细胞置于冰盒中，用1mL注射器吸取细胞悬液，注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(8×106细胞/只)，建立SNU-16移植瘤模型。定期观察动物状态，使用电子游标卡尺测量瘤径，数据输入Excel电子表格，计算肿瘤体积，监测肿瘤生长情况。待瘤体积达到100～300mm3，挑选健康状况良好、肿瘤体积相近的荷瘤鼠60只(肿瘤体积104～179mm3)，采用随机区组法分为10(n＝6)，每组平均肿瘤体积约143mm3。Collect SNU-16 cells in logarithmic growth phase, resuspend in 50% serum-free RPMI-1640 medium and 50% Matrigel after adjusting the cell count, adjust the cell concentration to 4×107 cells/mL; place the cells in In the ice box, draw the cell suspension with a 1 mL syringe and inject it into the subcutaneous anterior right armpit of nude mice.Inoculate 200 μL (8×106 cells/animal) per animal to establish the SNU-16 transplanted tumor model. Regularly observe the animal status, use an electronic vernier caliper to measure the tumor diameter, input the data into an Excel spreadsheet, calculate the tumor volume, and monitor tumor growth. When the tumor volume reaches 100-300 mm3 , select 60 tumor-bearing mice with good health and similar tumor volume (tumor volume 104-179 mm3 ), and divide them into 10 (n=6) by random block method. The average tumor in each group The volume is about 143mm3 .

3)每周测量2次瘤径，计算肿瘤体积，同时称量动物体重并记录。3) Measure the tumor diameter twice a week, calculate the tumor volume, and weigh and record the weight of the animal.

肿瘤体积(TV)计算公式如下：TV(mm3)＝l×w2/2其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。The calculation formula of the tumor volume (TV) is as follows: TV (mm3 )=l×w2 /2, where l represents the long diameter of the tumor (mm); w represents the short diameter of the tumor (mm).

化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组平均RTV；CRTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得肿瘤体积，Vt为对应小鼠某一次测量时的肿瘤体积，TRTV与CRTV取同一天数据。The antitumor efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C(%)=TRTV /CRTV ×100% (TRTV : average RTV of treatment group; CRTV : average RTV of negative control group). Calculate the relative tumor volume (RTV) according to the tumor measurement results. The calculation formula is RTV=Vt /V0 , where V0 is the tumor volume measured during group administration (ie D0), and Vt is the corresponding For the tumor volume of a mouse at a certain measurement, TRTV and CRTV are taken on the same day.

TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。TGI (%), reflecting the tumor growth inhibition rate. TGI (%) = [(1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group))/(average tumor volume at the end of treatment in the solvent control group-start treatment at the solvent control group Mean tumor volume)]×100%.

实验结果：Experimental results:

在小鼠胃癌SNU-16模型上，连续给药25天，与溶媒组相比，本发明化合物表现出了显著的抗肿瘤活性，肿瘤生长抑制率(％TGI)分别为：76％,80％,76％，相对肿瘤增值率(％T/C)为：34％，33％，35％，相比对照例1，本发明化合物展示了更优的抑制效果。具体结果见表8、附图1和附图2(附图中QD表示一天一次)。On the mouse gastric cancer SNU-16 model, continuous administration for 25 days, compared with the vehicle group, the compound of the present invention showed significant anti-tumor activity, tumor growth inhibition rate (%TGI): 76%, 80% 76%, the relative tumor growth rate (%T/C) is: 34%, 33%, 35%. Compared with Comparative Example 1, the compound of the present invention exhibits a better inhibitory effect. The specific results are shown in Table 8, Figure 1 and Figure 2 (QD in the figure means once a day).

表8 SNU-16肿瘤生长抑制率和相对肿瘤增殖率汇总表Table 8 Summary table of SNU-16 tumor growth inhibition rate and relative tumor proliferation rate

Figure PCTCN2019130053-appb-000111
Figure PCTCN2019130053-appb-000111

*所有给药组，第9天给药剂量变更为30mg/kg/天，第12天给药剂量均变更为20mg/kg/天。*In all administration groups, the dosage on the 9th day was changed to 30 mg/kg/day, and the dosage on the 12th day was changed to 20 mg/kg/day.

实验结论：本发明化合物在临床前动物模型中在较低的剂量下展示了优异的肿瘤治疗效果。Experimental conclusion: The compound of the present invention exhibits excellent tumor therapeutic effects at lower doses in preclinical animal models.

Claims (21)

Translated fromChinese
式(III)所示化合物或其药学上可接受的盐，A compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2019130053-appb-100001
Figure PCTCN2019130053-appb-100001
其中，among them,R1选自H、-S(＝O)2CH3、C1-6烷基、C1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基，所述C1-6烷基、C1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个Ra取代；R1 is selected from H, —S(═O)2 CH3 , C1-6 alkyl, C1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, said C1-6 alkyl group, C1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with one, two or three Ra;R2和R3分别独立地选自H、F、Cl、Br、I、OH、NH2、CH3和OCH3；R2 and R3 are independently selected from H, F, Cl, Br, I, OH, NH2 , CH3 and OCH3 ;R4选自H、NH2、C1-6烷基、C1-3烷氧基、C3-5环烷基和
Figure PCTCN2019130053-appb-100002
所述C1-6烷基、C1-3烷氧基、C3-5环烷基和
Figure PCTCN2019130053-appb-100003
任选被1、2或3个Rb取代；R4 is selected from H, NH2 , C1-6 alkyl, C1-3 alkoxy, C3-5 cycloalkyl and
Figure PCTCN2019130053-appb-100002
The C1-6 alkyl, C1-3 alkoxy, C3-5 cycloalkyl and
Figure PCTCN2019130053-appb-100003
Optionally substituted by 1, 2 or 3 Rb ;m选自1和2；m is selected from 1 and 2;L选自-N(R5)C(＝O)-、-N(R5)S(＝O)2-、-N(R5)C(＝O)N(R5)-、N(R5)S(＝O)2N(R5)-和-N(R5)-；L is selected from -N(R5 )C(=O)-, -N(R5 )S(=O)2 -, -N(R5 )C(=O)N(R5 )-, N( R5 )S(=O)2 N(R5 )- and -N(R5 )-;环A选自苯基、吡咯基、嘧啶基和吡啶基；Ring A is selected from phenyl, pyrrolyl, pyrimidinyl and pyridyl;环B不存在；Ring B does not exist;或者，环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基；Alternatively, ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3,6-dihydro-2H-pyranyl;R5分别独立地选自H和C1-3烷基；R5 is independently selected from H and C1-3 alkyl;Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述-S(＝O)2CH3、C1-3烷基、C1-3烷氧基和C1-3烷氨基任选被1、2或3个R取代；Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, —S(═O)2 CH3 , C1-3 alkyl, C1-3 alkoxy Group and C1-3 alkylamino, the -S(=O)2 CH3 , C1-3 alkyl, C1-3 alkoxy and C1-3 alkylamino are optionally substituted by 1, 2 or 3 R substitutions;R选自H、F、Cl、Br、I、OH和NH2。R is selected from H, F, Cl, Br, I, OH and NH2 .根据权利要求1所述化合物或其药学上可接受的盐，其中，Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2，所述-S(＝O)2CH3、CH3、-OCH3、-N(CH3)2和-NHCH(CH3)2任选被1、2或3个R取代。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, -S(=O )2 CH3 , CH3 , -OCH3 , -N(CH3 )2 and -NHCH(CH3 )2 , the -S(=O)2 CH3 , CH3 , -OCH3 , -N( CH3 )2 and -NHCH(CH3 )2 are optionally substituted with 1, 2, or 3 R's.根据权利要求2所述化合物或其药学上可接受的盐，其中，Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3、CH2OH、-OCH3、-S(＝O)2CH3、-N(CH3)2和-NHCH(CH3)2。The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are independently selected from H, F, Cl, Br, I, OH, NH2 , CN, CH3 , CH2 OH, -OCH3 , -S(=O)2 CH3 , -N(CH3 )2 and -NHCH(CH3 )2 .根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R1选自H、-S(＝O)2CH3、CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、OCH2CH3、四氢吡喃基、四氢呋喃基和哌啶基，所述CH3、CH2CH3、CH2CH2CH3、CH2CH(CH3)2、OCH2CH3、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个Ra取代。The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, —S(═O)2 CH3 , CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2 CH(CH3 )2 , OCH2 CH3 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, the CH3 , CH2 CH3 , CH2 CH2 CH3 , CH2CH (CH 3) 2, OCH 2 CH 3, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with 1, 2 or 3 Ra.根据权利要求4所述化合物或其药学上可接受的盐，其中，R1选自H、-S(＝O)2CH3、CH3、CH2OH、CH2CH3、CH2CH2OH、OCH2CH3、
Figure PCTCN2019130053-appb-100004
Figure PCTCN2019130053-appb-100005
The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, —S(═O)2 CH3 , CH3 , CH2 OH, CH2 CH3 , CH2 CH2 OH, OCH2 CH3 ,
Figure PCTCN2019130053-appb-100004
Figure PCTCN2019130053-appb-100005
根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、OCH3、OCH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、OCH3、OCH2CH3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个Rb取代。The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , and C(CH3) 3, CH 2 CH 2 CH 3, OCH 3, OCH 2 CH 3, cyclopropyl, pyrrolidinyl and azetidine, theCH 3, CH 2 CH 3, CH (CH 3) 2, C(CH3 )3 , CH2 CH2 CH3 , OCH3 , OCH2 CH3 , cyclopropanyl, azetidine and pyrrolidinyl are optionally substituted with 1, 2 or 3 Rb .根据权利要求6所述化合物或其药学上可接受的盐，其中，R4选自H、NH2、CH3、CH2CH3、CH(CH3)2、C(CH3)3、CH2CH2CH3、CH2CH2N(CH3)2、OCH3、
Figure PCTCN2019130053-appb-100006
Figure PCTCN2019130053-appb-100007
The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H, NH2 , CH3 , CH2 CH3 , CH(CH3 )2 , C(CH3 )3 , CH2 CH2 CH3 , CH2 CH2 N(CH3 )2 , OCH3 ,
Figure PCTCN2019130053-appb-100006
Figure PCTCN2019130053-appb-100007
根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R5分别独立地选自H、CH3和CH2CH3。The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R5 is independently selected from H, CH3 and CH2 CH3 .根据权利要求7所述化合物或其药学上可接受的盐，其中，L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O)2-、-NHS(＝O)2NH-和-NH-。The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein L is selected from -NHC(=O)-, -NHC(=O)NH-, -NHS(=O)2 -, -NHS( =O)2 NH- and -NH-.根据权利要求7或9所述化合物或其药学上可接受的盐，其中，-L-R4选自
Figure PCTCN2019130053-appb-100008
Figure PCTCN2019130053-appb-100009
The compound according to claim 7 or 9 or a pharmaceutically acceptable salt thereof, wherein -LR4 is selected from
Figure PCTCN2019130053-appb-100008
Figure PCTCN2019130053-appb-100009
根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，环A选自
Figure PCTCN2019130053-appb-100010
Figure PCTCN2019130053-appb-100011
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
Figure PCTCN2019130053-appb-100010
Figure PCTCN2019130053-appb-100011
根据权利要求11所述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2019130053-appb-100012
选自
Figure PCTCN2019130053-appb-100013
Figure PCTCN2019130053-appb-100014
The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure PCTCN2019130053-appb-100012
Select from
Figure PCTCN2019130053-appb-100013
Figure PCTCN2019130053-appb-100014
根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，环B选自
Figure PCTCN2019130053-appb-100015
Figure PCTCN2019130053-appb-100016
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from
Figure PCTCN2019130053-appb-100015
Figure PCTCN2019130053-appb-100016
根据权利要求13所述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2019130053-appb-100017
选自
Figure PCTCN2019130053-appb-100018
Figure PCTCN2019130053-appb-100019
The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure PCTCN2019130053-appb-100017
Select from
Figure PCTCN2019130053-appb-100018
Figure PCTCN2019130053-appb-100019
根据权利要求5或13所述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2019130053-appb-100020
选自OCH2CH3、
Figure PCTCN2019130053-appb-100021
The compound according to claim 5 or 13 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure PCTCN2019130053-appb-100020
Selected from OCH2 CH3 ,
Figure PCTCN2019130053-appb-100021
根据权利要求1～6任意一项所述化合物或其药学上可接受的盐，其选自The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, which is selected from
Figure PCTCN2019130053-appb-100022
Figure PCTCN2019130053-appb-100022
其中，among them,T1选自CH和N；T1 is selected from CH and N;R2和R3如权利要求1所定义；R2 and R3 are as defined in claim 1;R1如权利要求1、4或5所定义；R1 is as defined in claims 1, 4 or 5;R4如权利要求1、6或7所定义；R4 is as defined in claims 1, 6 or 7;L如权利要求1或9所定义。L is as defined in claim 1 or 9.根据权利要求16所述化合物或其药学上可接受的盐，其选自The compound according to claim 16 or a pharmaceutically acceptable salt thereof, which is selected from
Figure PCTCN2019130053-appb-100023
Figure PCTCN2019130053-appb-100023
Figure PCTCN2019130053-appb-100024
Figure PCTCN2019130053-appb-100024
其中，among them,T1选自CH和N；T1 is selected from CH and N;R1、R2、R3和R4如权利要求16所定义。R1 , R2 , R3 and R4 are as defined in claim 16.下式所示化合物或其药学上可接受的盐，The compound represented by the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2019130053-appb-100025
Figure PCTCN2019130053-appb-100025
Figure PCTCN2019130053-appb-100026
Figure PCTCN2019130053-appb-100026
Figure PCTCN2019130053-appb-100027
Figure PCTCN2019130053-appb-100027
一种药物组合物，包括治疗有效量的根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐或者权利要求19所述的组合物在制备FGFR和VEGFR双重抑制剂相关药物上的应用。Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or the composition according to claim 19 in the preparation of drugs related to dual inhibitors of FGFR and VEGFR.根据权利要求20所述的应用，其特征在于，所述FGFR和VEGFR双重抑制剂相关药物是用于实体瘤的药物。The use according to claim 20, characterized in that the drug associated with the dual inhibitors of FGFR and VEGFR is a drug for solid tumors.
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