WO2024255762A1

WO2024255762A1 - Cbl-b inhibitor

Info

Publication number: WO2024255762A1
Application number: PCT/CN2024/098687
Authority: WO
Inventors: 王军飞; 程沧; 王洁; 石谷沁; 张宇星; 董迪飞; 王奉莉; 付乃洁; 程兴华; 杨冬; 董华; 陈平; 吴燕; 郝俊国; 孙维梅; 孙大庆; 陶维康
Original assignee: Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
Current assignee: Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
Priority date: 2023-06-13
Filing date: 2024-06-12
Publication date: 2024-12-19
Anticipated expiration: 2025-12-13
Also published as: TW202502751A

Abstract

A new compound having a CBL-B inhibitory activity, a pharmaceutical composition containing same, an intermediate for preparing same, and a method for treating cancer by means of using same.

Description

CBL-B inhibitors

相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS

本公开要求向中国知识产权局提交的第2023107008395号中国专利申请、第2023110661226号中国专利申请、第202311314264X号中国专利申请、第2024100391121号中国专利申请以及第2024107340614号中国专利申请的优先权和权益，上述中国专利申请的全部内容通过援引并入本文。This disclosure claims the priority and benefits of Chinese Patent Application No. 2023107008395, Chinese Patent Application No. 2023110661226, Chinese Patent Application No. 202311314264X, Chinese Patent Application No. 2024100391121 and Chinese Patent Application No. 2024107340614 filed with the China Intellectual Property Office, the entire contents of the above Chinese patent applications are incorporated herein by reference.

Technical Field

本公开属于药物化学领域，涉及具有E3连接酶Casitas b-linege淋巴瘤B(CBL-B)抑制活性的新型化合物，含有所述化合物的药物组合物、制备所述化合物的有用中间体，以及利用含有本公开化合物的药物治疗由CBL-B介导的相关疾病的方法。The present disclosure belongs to the field of medicinal chemistry and relates to novel compounds having E3 ligase Casitas b-linege lymphoma B (CBL-B) inhibitory activity, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods for treating CBL-B-mediated related diseases using drugs containing the compounds of the present disclosure.

Background Art

CBL-B是一种环E3连接酶,也是高度保守的CBL蛋白家族的成员，该家族在哺乳动物中由三个CBL基因组成:CBL，CBL-B和CBL-C。CBL蛋白通过其蛋白质-蛋白质相互作用结构域与靶蛋白相互作用，从而调节多种信号通路，包括多种细胞类型中的酪氨酸激酶(TK)信号。CBL蛋白的结构包括氨基末端酪氨酸激酶结合结构域(TKBD)，接头螺旋区域(LHR)和一个非常有趣的新基因(环)结构域，然后是含有SRC同源性2(SH2)和SRC同源性结合位点的羧基末端区域(SH3)域。CBL TKBD由一个四螺旋束(4H)，EF手和一个变体SH2结构域组成,该域以磷酸酪氨酸依赖性方式结合底物,例如活化的TKS。CBL-B对活化受体TK的泛素化调节膜上和分选内体的内吞蛋白的组装，以促进溶酶体靶向,降解和信号终止。CBL-B对于通过泛素化受体链和相关的胞质TKS来降低信号传导从抗原和细胞因子受体中的信号传导也很重要，从而导致失活和/或蛋白酶体降解。CBL-B在免疫细胞谱系中表达,并作选自免疫细胞激活和维持外周耐受性的主要调节剂。CBL-B抑制剂可能会增强癌症疫苗的活性。此外，在多种疾病和癌症中发现了CBL蛋白和CBL-B接头序列的环形域突变，包括luvenile脊髓细胞细胞性白血病(IMMF)，普雷克病慢性脊髓细胞细胞性白血病(CMMF)，脊髓脂蛋白膜和急性髓样白血病(AMF)。因此，CBL-B抑制作用代表了肿瘤内在和肿瘤外毒性疗法的机会。CBL-B is a RING E3 ligase and a member of the highly conserved CBL protein family, which consists of three CBL genes in mammals: CBL, CBL-B and CBL-C. CBL proteins interact with target proteins through their protein-protein interaction domains, thereby regulating multiple signaling pathways, including tyrosine kinase (TK) signaling in multiple cell types. The structure of CBL proteins includes an amino-terminal tyrosine kinase binding domain (TKBD), a linker helix region (LHR) and a very interesting novel gene (RING) domain, followed by a carboxyl-terminal region (SH3) domain containing SRC homology 2 (SH2) and SRC homology binding sites. The CBL TKBD consists of a four-helix bundle (4H), EF-hand and a variant SH2 domain, which binds substrates such as activated TKS in a phosphotyrosine-dependent manner. Ubiquitination of activated receptor TKs by CBL-B regulates the assembly of endocytic proteins on membranes and sorting endosomes to promote lysosomal targeting, degradation and signal termination. CBL-B is also important for reducing signaling from antigen and cytokine receptors by ubiquitinating receptor chains and associated cytosolic TKSs, resulting in inactivation and/or proteasomal degradation. CBL-B is expressed in the immune cell lineage and functions as a master regulator of immune cell activation and maintenance of peripheral tolerance. CBL-B inhibitors may enhance the activity of cancer vaccines. In addition, mutations in the RING domain of the CBL protein and the CBL-B linker sequence have been found in a variety of diseases and cancers, including luvenile myelocytic leukemia (IMMF), Pleukopenia chronic myelocytic leukemia (CMMF), myeloid membrane leukemia, and acute myeloid leukemia (AMF). Therefore, CBL-B inhibition represents an opportunity for both tumor-intrinsic and extra-tumor toxic therapies.

目前根据此类作用机制进行的研究很多，但是并未发现CBL-B抑制剂类药物上市，因此急需开发有效的CBL-B抑制剂应用于临床患者。Currently, there are many studies based on this mechanism of action, but no CBL-B inhibitor drugs have been found on the market. Therefore, there is an urgent need to develop effective CBL-B inhibitors for clinical patients.

发明内容Summary of the invention

本公开提供式(II)的化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，
The present disclosure provides a compound of formula (II), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

其中，in,

环A选自6-10元芳基、5-6元杂芳基；Ring A is selected from 6-10 membered aryl, 5-6 membered heteroaryl;

X₁和X₂之间的键“--”代表单键或双键；The bond "--" between _X1 and _X2 represents a single bond or a double bond;

X₁选自-C(＝CH₂)、CR_a1R_a2、N、NH、CR_a3； _X1 is selected _from -C(= _CH2 ), _CRa1Ra2 , N, NH, _CRa3 ;

R_a1、R_a2、R_a3各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CORe₃、-SO₂CH₃； _Ra1 , _Ra2 , _Ra3 are each independently selected from hydrogen, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkylamino, nitro, substituted or unsubstituted _C2-4 alkenyl, substituted or _{unsubstituted} _C3-6 cycloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy _, _C1-4 alkylene- _OC1-4 alkyl, _-NRe1Re2 , _-CORe3 , _-SO2CH3 ;

Re₁、Re₂、Re₃各自独立的为氢、C_1-4烷基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基；Re ₁ , Re ₂ , and Re ₃ are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, -NH ₂ , or -NH-C _1-4 alkyl;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

R_b1、R_b2各自独立的选自氢、卤素、C_1-4烷基，或者所述R_a1和R_b1、或R_a1和R_b2、或R_a2和R_b1、或R_a2和R_b2与共同链接的碳原子形成取代或未取代的C_3-6环烷基；R _b1 and R _b2 are each independently selected from hydrogen, halogen, C _1-4 alkyl, or said R _a1 and R _b1 , or R _a1 and R _b2 , or R _a2 and R _b1 , or R _a2 and R _b2 , together with the carbon atom to which they are linked, form a substituted or unsubstituted C _3-6 cycloalkyl;

R_b3选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、-W-C_3-6环烷基；R _b3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, -WC _3-6 cycloalkyl;

R₁选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、氰基、硝基、取代或未取代的C_3-6环烷基、C_1-4烷基-C_1-4卤代烷基、氘、C_1-4氘代烷基、C_1-4氘代烷氧基；或者R₁与X₁结合形成取代或未取代的5-6元杂环基； _R1 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, cyano, nitro, substituted or unsubstituted _C3-6 cycloalkyl, _C1-4 alkyl- _C1-4 haloalkyl, deuterium, _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy; or _R1 and _X1 are combined to form a substituted or unsubstituted 5-6 membered heterocyclic ring base;

L₁选自C_1-4亚烷基、C_1-4氘代亚烷基、-NH-C_1-4亚烷基、C_3-6亚环烷基；L ₁ is selected from C _1-4 alkylene, C _1-4 deuterated alkylene, -NH-C _1-4 alkylene, C _3-6 cycloalkylene;

环B选自C_3-6环烷基、5-10元杂环基；Ring B is selected from C _3-6 cycloalkyl, 5-10 membered heterocyclyl;

R₂选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4烷基-O-C_1-4烷基、氘、C_1-4氘代烷基、C_1-4氘代烷氧基、NH＝； _R2 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 alkyl- _OC1-4 alkyl, deuterium, _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, NH=;

m选自0、1、2、3、4，当存在多个时R₂，相邻的R₂与其连接的原子任选的形成取代或未取代的C_3-6环烷基；m is selected from 0, 1, 2, 3, 4. When there are multiple R ₂ , adjacent R ₂ and the atoms to which they are connected optionally form a substituted or unsubstituted C _3-6 cycloalkyl group;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基、-NH-C_1-4亚烷基-C_1-4卤代烷基、-NH-C_1-4亚烷基-CONH₂、-O-C_1-4亚烷基-CN、-O-C_3-6亚环烷基-CN、-W-C_3-6环烷基、-W-(3-6元杂环基)、C_2-6烯基-CN、氰基、-CO-NH-C_1-4烷基，所述C_3-6环烷基、3-6杂环基可以任选被卤素、氰基、C_1-4烷基、C_1-4亚烷基-CN取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3-6 cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -NH-C _1-4 alkylene-C _1-4 haloalkyl, -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene _- CN, -OC _3-6 cycloalkylene-CN, -W-C _3-6 cycloalkyl, -W-(3-6 membered heterocyclyl), C _2-6 alkenyl-CN, cyano, and -CO-NH-C _1-4 alkyl; the C _3-6 cycloalkyl and C 3-6 heterocyclyl may be optionally substituted by halogen, cyano, C _1-4 alkyl, C 1-4 _1-4 alkylene-CN substitution;

W选自O、NH、S；W is selected from O, NH, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、C_2-4烯基、-O-C_1-4卤代烷基、氧代，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基、3-6元杂环基；Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _{1-4 haloalkoxy, C 2-4} _alkenyl , -OC _1-4 haloalkyl, oxo, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are linked together;

R₃选自氢、卤素、C_1-4烷基、C_1-4氘代烷基、C_1-4卤代烷基、C_1-4烷氧基。 _R3 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 deuterated alkyl, _C1-4 haloalkyl, _C1-4 alkoxy.

其中，in,

X₁选自CRa₁Ra₂、N、NH、CR_a3； _X1 is selected _{from CRa1Ra2} _, N, NH, _CRa3 ;

Ra₁、Ra₂、R_a3各自独立的选自氢、卤素、氰基、硝基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CHO、-CONH₂、-SO₂CH₃；Ra ₁ , Ra ₂ , and _Ra3 are each independently selected from hydrogen, halogen, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylene-OC _1-4 alkyl, -NRe ₁ Re ₂ , -CHO, -CONH ₂ , and -SO ₂ CH ₃ ;

Re₁、Re₂各自独立的为氢、C_1-4烷基、C_3-6环烷基；Re ₁ and Re ₂ are each independently hydrogen, C _1-4 alkyl, or C _3-6 cycloalkyl;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

R_b1、R_b2各自独立的选自氢、卤素、C_1-4烷基，或者所述R_a1和R_b1、或R_a1和R_b2、或R_a2和R_b1、或R_a2和R_b2与共同链接的碳原子形成C_3-6环烷基；R _b1 and R _b2 are each independently selected from hydrogen, halogen, C _1-4 alkyl, or said R _a1 and R _b1 , or R _a1 and R _b2 , or R _a2 and R _b1 , or R _a2 and R _b2 and the carbon atom to which they are linked together form a C _3-6 cycloalkyl;

R_b3选自氢、卤素、C_1-4烷基、C_1-4卤代烷基；R _b3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl;

R₁选自卤素、C_1-4烷基、C_1-4卤代烷基、C_3-6环烷基、C_1-4烷基；R ₁ is selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkyl;

L₁选自C_1-4亚烷基、-NH-C_1-4亚烷基；L ₁ is selected from C _1-4 alkylene, -NH-C _1-4 alkylene;

R₂选自卤素、氘、C_1-4烷基、C_1-4卤代烷基、C_1-4氘代烷基； _R2 is selected from halogen, deuterium, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 deuterated alkyl;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3-6环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基、-O-C_1-4亚烷基-CN、-W-C_3-6环烷基、-W-(3-6元杂环基)，所述环烷基、杂环基可以任选被卤素、氰基、C_1-4烷基取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3-6 cycloalkylamino, C _{1-4 alkoxy, C 1-4} _haloalkoxy , C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -OC _1-4 alkylene-CN, -W-C _3-6 cycloalkyl, -W-(3-6 membered heterocyclyl), and the cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, cyano, and C _1-4 alkyl;

W选自O、NH、S；W is selected from O, NH, S;

Z选自O、S、CR_d1R_d2，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、氧代，或者R_d1、R_d2与共同链接的碳原子形成3-6元杂环基； Z is selected from O, S, CR _d1 R _d2 , wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, oxo, or R _d1 and R _d2 form a 3-6 membered heterocyclic group with the carbon atom to which they are linked together;

R₃选自卤素、C_1-4烷基。R ₃ is selected from halogen, C _1-4 alkyl.

本公开提供式(I)的化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，
The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

其中，in,

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

R₁选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、氰基、硝基、取代或未取代的C_3-6环烷基、C_1-4烷基-C_1-4卤代烷基、氘、C_1-4氘代烷基、C_1-4氘代烷氧基；或者R₁与X₁结合形成取代或未取代的5-6元杂环基；R ₁ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, nitro, substituted or unsubstituted C _3-6 cycloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, deuterium, C _1-4 deuterated alkyl, C _1-4 deuterated alkoxy; or R ₁ and X ₁ are combined to form a substituted or unsubstituted 5-6 membered heterocyclic group;

W选自O、NH、S；W is selected from O, NH, S;

其中，in,

R_a1、R_a2、R_a3各自独立的选自氢、卤素、氰基、硝基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CHO、-CONH₂、-SO₂CH₃； _Ra1 , _Ra2 , _Ra3 are each independently selected from hydrogen, halogen, cyano, nitro, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 _alkoxy , _C1-4 haloalkoxy, _C1-4 alkylene- _OC1-4 _alkyl , -NRe1Re2, -CHO, _-CONH2 , _-SO2CH3 _;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

W选自O、NH、S；W is selected from O, NH, S;

Z选自O、S、CR_d1R_d2，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、氧代，或者R_d1、R_d2与共同链接的碳原子形成3-6元杂环基；Z is selected from O, S, CR _d1 R _d2 , wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, oxo, or R _d1 and R _d2 form a 3-6 membered heterocyclic group with the carbon atom to which they are linked together;

R₃选自卤素、C_1-4烷基。R ₃ is selected from halogen, C _1-4 alkyl.

本公开提供式(Ⅰ)的化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，
The present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isotope-labeled substance thereof, a solvate thereof, and a hydrate thereof.

其中，in,

环A选自芳基、5-6元杂芳基；Ring A is selected from aryl, 5-6 membered heteroaryl;

R_a1、R_a2各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CONH₂、-SO₂CH₃、-CHO； _Ra1 and _Ra2 are each independently selected from hydrogen, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkylamino, nitro, substituted or unsubstituted _C2-4 alkenyl, substituted or unsubstituted _C3-6 cycloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy _, _C1-4 alkylene- _OC1-4 _alkyl , -NRe1Re2, _-CONH2 , _-SO2CH3 , _-CHO ;

R_a3选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_3-6环烷基、氰基；R _a3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

R₁选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、氰基、硝基、取代或未取代的C_3-6环烷基、C_1-4烷基-C_1-4卤代烷基、氘、C_1-4氘代烷基、C_1-4氘代烷氧基；R ₁ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, nitro, substituted or unsubstituted C _3-6 cycloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, deuterium, C _1-4 deuterated alkyl, C _1-4 deuterated alkoxy;

R₂选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4烷基-O-C_1-4烷基、氘、C_1-4氘代烷基、C_1-4 氘代烷氧基、 _R2 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 alkyl- _OC1-4 alkyl, deuterium, _C1-4 deuterated alkyl, _C1-4 Deuterated alkoxy,

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基、-NH-C_1-4亚烷基-C_1-4卤代烷基、-NH-C_1-4亚烷基-CONH₂、-O-C_1-4亚烷基-CN、W-C_3-6环烷基、W-(3-6元杂环基)、C_2-6烯基-CN、氰基、C_1-4烷基-NHCO-，所述C_3-6环烷基、3-6元杂环基可以任意被卤素、C_1-4烷基、氰基、C_1-4亚烷基-CN取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3- ₆ cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -NH-C _{1-4 alkylene-C 1-4} _haloalkyl , -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene-CN, W-C _3-6 cycloalkyl, W-(3-6 membered heterocyclyl), C _2-6 alkenyl-CN, cyano, and C _1-4 alkyl-NHCO-, wherein the C _3-6 cycloalkyl and 3-6 membered heterocyclyl may be arbitrarily substituted with halogen, C _1-4 alkyl, cyano, or C _1-4 alkylene-CN;

W选自O、N、S；W is selected from O, N, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、烯基、O-C_1-4卤代烷基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基、3-6元杂环基；R₃选自氢、卤素、C_1-4烷基、C_1-4氘代烷基、C_1-4卤代烷基、C_1-4烷氧基。Z is selected from CR _d1 R _d2 , O, S, and N, wherein R _d1 and R _d2 are each independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C 1-4 haloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, alkenyl, OC _1-4 haloalkyl, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atoms to which they are linked; R ₃ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 deuterated alkyl, _C _1-4 haloalkyl, and C _1-4 alkoxy.

其中，in,

R_a1、R_a2各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CONH₂、-SO₂CH₃； _Ra1 and _Ra2 are each independently selected from hydrogen, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkylamino, nitro, substituted or unsubstituted _C2-4 alkenyl, substituted or unsubstituted _C3-6 cycloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C1-4 alkylene- _OC1-4 alkyl, _-NRe1Re2 _, _-CONH2 , _-SO2CH3 _;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

R₂选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4烷基-O-C_1-4烷基、氘、C_1-4氘代烷基、C_1-4氘代烷氧基、 _R2 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 alkyl- _OC1-4 alkyl, deuterium, _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy,

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基、-NH-C_1-4亚烷基-C_1-4卤代烷基、-NH-C_1-4亚烷基-CONH₂、-O-C_1-4亚烷基-CN、W-C_3-6环烷基、W-(3-6元杂环基)，所述环烷基、杂环基可以任意被卤素、C_1-4烷基取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3- ₆ cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -NH-C _{1-4 alkylene-C 1-4} _haloalkyl , -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene-CN, W-C _3-6 cycloalkyl, and W-(3-6 membered heterocyclyl), wherein the cycloalkyl and heterocyclyl groups may be arbitrarily substituted by halogen or C _1-4 alkyl;

W选自O、N、S；W is selected from O, N, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、烯基、O-C_1-4卤代烷基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基、3-6元杂环基；R₃选自氢、卤素、C_1-4烷基、C_1-4氘代烷基、C_1-4卤代烷基、C_1-4烷氧基。Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 halo Alkyl, C _1-4 alkyl-C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl- _{C 1-4} alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, alkenyl, OC _1-4 haloalkyl, or R _d1 , R _d2 and the carbon atom to which they are linked together form a substituted or unsubstituted C _3-6 cycloalkyl, 3-6 membered heterocyclyl; R ₃ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 deuterated alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

其中，in,

X₁选自-C(＝CH₂)、CRa₁Ra₂、N、NH、CR_a3； _X1 is selected from -C(= _CH2 ), _CRa1Ra2 _, N, NH, _CRa3 ;

Ra₁、Ra₂各自独立的选自C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CONH₂、-SO₂CH₃；Ra ₁ and Ra ₂ are each independently selected from C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylene-OC _1-4 alkyl, -NRe ₁ Re ₂ , -CONH ₂ , -SO ₂ CH ₃ ;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自-NH₂、-NH-C_1-4烷基、-NH-C_1-4亚烷基-C_1-4卤代烷基、-NH-C_1-4亚烷基-CONH₂、-O-C_1-4亚烷基-CN、W-C_3-6环烷基、W-3-6元杂环基，所述环烷基、杂环基可以任意被卤素、C_1-4烷基取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from -NH ₂ , -NH-C _1-4 alkyl, -NH-C _1-4 alkylene-C _1-4 haloalkyl, -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene-CN, W-C _3-6 cycloalkyl, W-3-6 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl may be arbitrarily substituted by halogen or C _1-4 alkyl;

W选自O、N、S；W is selected from O, N, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为O-C_1-4卤代烷基；Z is selected from CR _d1 R _d2 , O, S, and N, wherein R _d1 and R _d2 are each independently OC _1-4 haloalkyl;

其中， in,

Ra₁、Ra₂各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基；Ra ₁ and Ra ₂ are each independently selected from hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, nitro, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C₃-₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、W-C_3-6环烷基；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3-6 cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, and _C _3-6 cycloalkyl;

W选自O、N、S；W is selected from O, N, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、烯基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基、3-6元杂环基；Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, C _1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, alkenyl, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are linked;

其中，in,

R_a1、R_a2各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4亚烷基-O-C_1-4烷基、-NRe₁Re₂、-CORe₃、-SO₂CH₃； _Ra1 and _Ra2 are each independently selected from hydrogen, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkylamino, nitro, substituted or unsubstituted _C2-4 alkenyl, substituted or unsubstituted _C3-6 cycloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C1-4 alkylene- _OC1-4 _alkyl , _-NRe1Re2 _, _{-CORe3, -SO2CH3} _;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

L₁选自C_1-4亚烷基、C_1-4氘代亚烷基、-NH-C_1-4亚烷基、C_3-6亚环烷基； L ₁ is selected from C _1-4 alkylene, C _1-4 deuterated alkylene, -NH-C _1-4 alkylene, C _3-6 cycloalkylene;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、-NH₂、-NH-C_1-4烷基、-NH-C_1-4亚烷基-C_1-4卤代烷基、-NH-C_1-4亚烷基-CONH₂、-O-C_1-4亚烷基-CN、W-C_3-6环烷基、W-(3-6元杂环基)、C_2-6烯基-CN、氰基、-CO-NH-C_1-4烷基，所述C_3-6环烷基、3-6元杂环基可以任意被卤素、C_1-4烷基、氰基、C_1-4亚烷基-CN取代；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3- ₆ cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -NH-C _{1-4 alkylene-C 1-4} _haloalkyl , -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene-CN, W-C _3-6 cycloalkyl, W-(3-6 membered heterocyclyl), C _2-6 alkenyl-CN, cyano, and -CO-NH-C _1-4 alkyl; the C _3-6 cycloalkyl and 3-6 membered heterocyclyl may be arbitrarily substituted with halogen, C _1-4 alkyl, cyano, or C _1-4 alkylene-CN;

W选自O、N、S；W is selected from O, N, S;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基、C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、烯基、O-C_1-4卤代烷基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基、3-6元杂环基；R₃选自氢、卤素、C_1-4烷基、C_1-4氘代烷基、C_1-4卤代烷基、C_1-4烷氧基。Z is selected from CR _d1 R _d2 , O, S, and N, wherein R _d1 and R _d2 are each independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, C 1-4 alkyl-cyano, C _1-4 alkyl-C _1-4 alkoxy, C _1-4 deuterated alkoxy, C _1-4 haloalkoxy, alkenyl, OC _1-4 haloalkyl, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atoms to which they are linked; R ₃ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 deuterated alkyl, _C _1-4 haloalkyl, and C _1-4 alkoxy.

R_a1、R_a2各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基；R _a1 and R _a2 are each independently selected from hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, nitro, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl;

X₂选自CR_b1R_b2、CR_b3； _X2 is selected from CR _b1 R _b2 , CR _b3 ;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基、C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、W-C_3-6环烷基；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3-6 cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, and _C _3-6 cycloalkyl;

W选自O、N、S；W is selected from O, N, S;

其中，in,

X₁选自CR_a3，所述R_a3选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_3-6环烷基、氰基； _X1 is selected from CR _a3 , wherein R _a3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, cyano;

X₂选自CR_b3，所述R _b3选自氢、卤素、C_1-4烷基、C_1-4卤代烷基； _X2 is selected from CR _b3 , wherein R _b3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl;

R₁选自氘、C_1-4氘代烷基、C_1-4氘代烷氧基；R ₁ is selected from deuterium, C _1-4 deuterated alkyl, C _1-4 deuterated alkoxy;

R₂选自 R ₂ is selected from

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自C_1-4烷氧基、C_1-4卤代烷氧基、C_3-6环烷基、W-C_3-6环烷基；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, and C _3-6 cycloalkyl;

W选自O、N、S；W is selected from O, N, S;

Z选自-C(R_d1)(R_d2)、O、S、N，所述R_d1、R_d2各自独立的为C_1-4卤代烷基、C_1-4烷基-C_1-4卤代烷基、C_1-4烷基-氰基、C_1-4烷基-C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、烯基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的3-6元杂环基；Z is selected from -C( _Rd1 )( _Rd2 ), O, S, N, wherein _Rd1 and _Rd2 are each independently _C1-4 haloalkyl, _C1-4 alkyl- _C1-4 haloalkyl, _C1-4 alkyl-cyano, C1-4 alkyl- _C1-4 alkoxy, _C1-4 deuterated alkoxy, _C1-4 haloalkoxy, alkenyl, or _Rd1 and _Rd2 form a substituted or unsubstituted 3-6 membered heterocyclic group with the carbon _atoms to which they are linked;

其中，in,

X1和X2之间的键“--”代表单键或双键；The bond “--” between X1 and X2 represents a single bond or a double bond;

X₁选自N、NH； _X1 is selected from N, NH;

X₂选自CR_b1R_b2，所述R_b1、R_b2各自独立的选自氢、卤素、C_1-4烷基，或者所述R_a1和R_b1、或R_a1和R_b2、或R_a2和R_b1、或R_a2和R_b2与共同链接的碳原子形成取代或未取代的C_3-6环烷基； _X2 is selected from CR _b1 R _b2 , wherein R _b1 and R _b2 are independently selected from hydrogen, halogen, C _1-4 alkyl, or R _a1 and R _b1 , or R _a1 and R _b2 , or R _a2 and R _b1 , or R _a2 and R _b2 form a substituted or unsubstituted C _3-6 cycloalkyl with the carbon atom to which they are linked;

R₂选自氘、C_1-4氘代烷基、C_1-4氘代烷氧基； _R2 is selected from deuterium, _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Y₁、Y₂各自独立的选自CH、N、CR_c，所述R_c选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷基氨基、C_3- ₆环烷基氨基；Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c _is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, and C _3-6 cycloalkylamino;

Z选自-C(R_d1)(R_d2)、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基； Z is selected from -C( _Rd1 )( _Rd2 ), O, S, N, wherein _Rd1 and _Rd2 are independently hydrogen, halogen, _C1-4 alkyl, cyano, _C1-4 alkoxy, or _Rd1 and _Rd2 form a substituted or unsubstituted _C3-6 cycloalkyl with the carbon atom to which they are linked;

其中，in,

X₁选自-C(＝CH₂)、CRa₁Ra₂，所述Ra₁、Ra₂各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1- ₄烷基氨基、硝基、取代或未取代的C_2--4烯基、取代或未取代的C_3-6环烷基；X ₁ is selected from -C(＝CH ₂ ), CRa ₁ Ra ₂ , wherein Ra ₁ and Ra ₂ are each independently selected from hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, nitro, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl _;

R₁选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、氰基、硝基、取代或未取代的C_3-6环烷基、C_1-4烷基-C_1-4卤代烷基；R ₁ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, nitro, substituted or unsubstituted C _3-6 cycloalkyl, C _1-4 alkyl-C _1-4 haloalkyl;

R₂选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4烷基-O-C_1-4烷基； _R2 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 alkyl- _OC1-4 alkyl;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基；Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl with the carbon atom to which they are linked;

其中，in,

X₁选自-C(＝CH₂)、CRa₁Ra₂，所述Ra₁、Ra₂各自独立的选自氢、卤素、氰基、C_1-4烷基、C_1-4卤代烷基、C_1- ₄烷基氨基、取代或未取代的C_2-4烯基、取代或未取代的C_3-6环烷基；X ₁ is selected from -C(＝CH ₂ ), CRa ₁ Ra ₂ , wherein Ra ₁ and Ra ₂ are each independently selected from hydrogen, halogen, _cyano , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, substituted or unsubstituted C _2-4 alkenyl, substituted or unsubstituted C _3-6 cycloalkyl;

X₂选自CR_b1R _b2，所述Rb₁、Rb₂各自独立的选自氢、卤素、C_1-4烷基，或者所述R_a1和R_b1、或R_a1和R_b2、或R_a2和R_b1、或R_a2和R_b2与共同链接的碳原子形成取代或未取代的C_3-6环烷基； _X2 is selected from _CRb1Rb2 _, wherein _Rb1 and _Rb2 are independently selected from hydrogen, halogen, _C1-4 alkyl, or _Ral and _Rb1 , or _Ral and _Rb2 , or _Ral and _Rb1 , or _Ral and _Rb2 form a substituted or unsubstituted _C3-6 cycloalkyl with the carbon atom to which they are linked;

R₁选自氢、卤素、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、氰基、硝基、取代或未取代的C_3-6环烷基；R ₁ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, nitro, substituted or unsubstituted C _3-6 cycloalkyl;

m选自0、1、2、3、4；m is selected from 0, 1, 2, 3, 4;

Z选自CR_d1R_d2、O、S、N，所述R_d1、R_d2各自独立的为氢、卤素、C_1-4烷基、氰基、C_1-4烷氧基，或者R_d1、R_d2与共同链接的碳原子形成取代或未取代的C_3-6环烷基； Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl with the carbon atom to which they are linked;

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于环A选自苯基、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, is characterized in that ring A is selected from phenyl,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于环A选自 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, is characterized in that ring A is selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Ra₁、Ra₂各自独立的选自-F、-Cl、-Br、-I、-CH₃、-CF₃、-CHF₂、-NH-CH₃、-CH＝CH₂、-C(CH₃)＝CH_2、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are characterized in that Ra ₁ and Ra ₂ are each independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -CHF ₂ , -NH-CH ₃ , -CH＝CH ₂ , -C(CH ₃ )＝CH _2,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Ra₁、Ra₂各自独立的选自-CH₂CH₃、-CH(CH₃)₂、-OCF₃、-OCH₃、-N(CH₃)₂、-CH₂OCH₃、-CONH₂、-SO₂CH₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are characterized in that Ra ₁ and Ra ₂ are each independently selected from -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCF ₃ , -OCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CONH ₂ , -SO ₂ CH ₃ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Ra₁、Ra₂各自独立的选自-CHO、-CONHCH₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that Ra ₁ and Ra ₂ are each independently selected from -CHO and -CONHCH ₃ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Ra₁、Ra₂各自独立的选自-F、-Cl、-Br、-I、-CH₃、-CF₃、-CHF₂、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are characterized in that Ra ₁ and Ra ₂ are each independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -CHF ₂ ,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₁选自-Br、-F、-Cl、-CF₃、环丙基。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R ₁ is selected from -Br, -F, -Cl, -CF ₃ , cyclopropyl.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₁选自-CH₃、-C₂H₅、-CH₂-CF₃、-CHF₂。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R ₁ is selected from -CH ₃ , -C ₂ H ₅ , -CH ₂ -CF ₃ , -CHF ₂ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₁选自H、-Br、-F、-Cl、-CH₃、-CF₃、环丙基。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R ₁ is selected from H, -Br, -F, -Cl, -CH ₃ , -CF ₃ , cyclopropyl.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Rb₁、Rb₂各自独立的选自-CH₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that Rb ₁ and Rb ₂ are each independently selected from -CH ₃ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Rb₁、Rb₂各自独立的选自H。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, or hydrate thereof is characterized in that Rb ₁ and Rb ₂ are each independently selected from H.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于Rb₃各自独立的选自 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, is characterized in that Rb ₃ is independently selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于结构单元选自 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, is characterized by the structural unit Selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于结构单元选自 In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope A molecule-labeled substance, a solvate thereof, or a hydrate thereof, characterized in that the structural unit Selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于L₁选自-CH₂-、-CH(CH₃)-、-CD₂-、-NH-CH₂-、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that _L1 is selected from _-CH2- , -CH( _CH3 )-, _-CD2- , -NH- _CH2- ,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于L₁选自 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, is characterized in that L ₁ is selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于L₁选自-NH-CH₂-、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that L ₁ is selected from -NH-CH ₂ -,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于L₁选自-CH₂-。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that L ₁ is selected from -CH ₂ -.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于环B选自 In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that ring B is selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₂选自-F、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-(CH₂)₂OCH₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R ₂ is selected from -F, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -(CH ₂ ) ₂ OCH ₃ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₂选自氘。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, and its hydrate are characterized in that R ₂ is selected from deuterium.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₂与环B的碳原子一起形成其中表示与环B其余部分的连接位点。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that _R2 together with the carbon atom of ring B forms in Indicates the site of attachment to the rest of loop B.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_c选自-CF₃、环丙基、甲氨基、环丙基氨基。In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isomer The isotope-labeled substance, its solvate and its hydrate are characterized in that R _c is selected from -CF ₃ , cyclopropyl, methylamino and cyclopropylamino.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_c选自-OC₂H₅、-OCF₃、在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_c选自-NH₂、-NH-C₂H₅、-NH-CH₂-CHF₂、-NH-CH₂-CONH₂、-OCH₂-CN、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, characterized in that R _c is selected from -OC ₂ H ₅ , -OCF ₃ , In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R _c is selected from -NH ₂ , -NH-C ₂ H ₅ , -NH-CH ₂ -CHF ₂ , -NH-CH ₂ -CONH ₂ , -OCH ₂ -CN,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_c选自-OCH₂F、CN、 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, characterized in that R _c is selected from -OCH ₂ F, CN,

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_d1、R_d2选自-F、-CH₃、氰基、-OCH₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R _d1 and R _d2 are selected from -F, -CH ₃ , cyano, and -OCH ₃ .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_d1、R_d2选自-CHF₂、-CH₂-CHF₂、-CH₂-CN、-CH₂-OCH₃、-OCD₃、-OCHF₂、-CH＝CH₂。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, or hydrate thereof, is characterized in that _Rd1 and _Rd2 are selected from _-CHF2 , -CH2 _- _CHF2 , -CH2 _- CN, -CH2 _- _OCH3 , _-OCD3 , _-OCHF2 , or -CH= _CH2 .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_d1、R_d2选自-CH₂F、-CHF₂、-CF₃、-CH₂-CHF₂、-CH₂-CN、-CH₂-OCH₃、-OCD₃、-OCH₃、-OCHF₂、-OCF₃、-CH＝CH₂。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, or hydrate thereof, is characterized in that _Rd1 and _Rd2 are selected from _-CH2F , -CHF2, _-CF3 , -CH2- _CHF2 , -CH2 _- _CN , -CH2 _- _OCH3 , _-OCD3 , _-OCH3 , _-OCHF2 , _-OCF3 , or -CH ₌ _CH2 .

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_d1、R_d2与共同链接的碳原子形成 In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate, is characterized in that R _d1 , R _d2 and the carbon atom linked together form

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R_d1、R_d2选自OCF₃、C₂H₅、CH₂CH₂F。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R _d1 and R _d2 are selected from OCF ₃ , C ₂ H ₅ , CH ₂ CH ₂ F.

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于结构单元选自 In some embodiments of the present disclosure, the compound of formula (I) or formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isomer The isotope-labeled substance, its solvate, and its hydrate are characterized by a structural unit Selected from

在本公开的一些方案中，上述式(Ⅰ)或式(II)化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，其特征在于R₃选自-CH₃、-CD₃。In some embodiments of the present disclosure, the compound of formula (I) or (II), its pharmaceutically acceptable salt, stereoisomer, isotope-labeled substance, solvate, hydrate thereof, is characterized in that R ₃ is selected from -CH ₃ and -CD ₃ .

本公开还提供了下列所示化合物、其药学上可接受的盐、其立体异构体、其同位素标记物、其溶剂合物、其水合物，
The present disclosure also provides the following compounds, their pharmaceutically acceptable salts, their stereoisomers, their isotope-labeled substances, their solvates, and their hydrates:

其中，X₁、X₂、Y₂、R₁、R₂、R₃、L₁、环B、Z、m同上述定义。wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , Ring B, Z and m are the same as defined above.

其中，X₁、X₂、Y₂、R₁、R₂、R₃、L₁、环B、Z、m、R_d1、R_d2同上述定义。wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , ring B, Z, m, R _d1 and R _d2 are the same as defined above.

其中，X₁、X₂、Y₂、R₁、R₂、R₃、L₁、环B、m、R_d1、R_d2同上述定义。wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , ring B, m, R _d1 and R _d2 are the same as defined above.

本公开还提供一种药物组合物，其含有治疗有效量的上述化合物、异构体或其药学上可接受的盐和药学上可接受的载体。The present disclosure also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound, isomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

在本发明的某些实施方案中，所述的药物组合物中，所述的化合物、立体异构体或其药学上可接受的盐的含量选自0.1mg-1000mg。In certain embodiments of the present invention, in the pharmaceutical composition, the content of the compound, stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg.

在本发明的某些实施方案中，所述的药物组合物中，所述的药学上可接受的载体包括填充剂、崩解剂、粘合剂、助流剂、润滑剂中的一种或多种。In certain embodiments of the present invention, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

本公开还提供上述化合物、异构体或其药学上可接受的盐或上述的药物组合物在制备治疗CBL-B靶点介导的相关疾病药物中的应用。The present disclosure also provides use of the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for treating CBL-B target-mediated related diseases.

本公开还提供上述化合物、异构体或其药学上可接受的盐或上述的药物组合物在制备治疗CBL-B介导的相关疾病药物中的应用，例如所述CBL-B介导的相关疾病包括癌症。The present disclosure also provides use of the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in preparing a drug for treating CBL-B-mediated related diseases, for example, the CBL-B-mediated related diseases include cancer.

本公开还提供上述化合物、异构体或其药学上可接受的盐或上述的药物组合物在治疗CBL-B介导的相关疾病中的用途，例如所述CBL-B介导的相关疾病包括癌症。The present disclosure also provides use of the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in treating CBL-B-mediated related diseases, for example, the CBL-B-mediated related diseases include cancer.

本公开还提供用于治疗CBL-B介导的相关疾病的上述化合物、异构体或其药学上可接受的盐或上述药物组合物，例如所述CBL-B介导的相关疾病包括癌症。The present disclosure also provides the above-mentioned compound, isomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for use in treating CBL-B-mediated related diseases, for example, the CBL-B-mediated related diseases include cancer.

本公开还提供用于治疗CBL-B介导的相关疾病的方法，所述方法包括向有需要的个体施用治疗有效量的上述化合物、异构体或其药学上可接受的盐或上述药物组合物，例如所述CBL-B介导的相关疾病包括癌症。The present disclosure also provides a method for treating a CBL-B-mediated disease, comprising administering a therapeutically effective amount of the above compound, isomer or pharmaceutically acceptable salt thereof or the above pharmaceutical composition to an individual in need thereof, for example, the CBL-B-mediated disease includes cancer.

在本公开中，CBL-B介导相关疾病是CBL-B介导的癌症。In the present disclosure, the CBL-B mediated related disease is CBL-B mediated cancer.

在本公开中，CBL-B介导的癌症包括泌尿生殖道癌症(例如,膀胱癌、肾癌、肾细胞癌、阴茎癌、前列腺癌、睾丸癌、Von Hippel-Lindau病等)、子宫癌、子宫颈癌、卵巢癌、乳腺癌、胃肠道癌(例如食道癌、口咽癌、胃癌、小肠癌或大肠癌、结肠癌或直肠癌)、骨骼瘤、骨髓瘤、皮肤癌(例如黑色素瘤)、头颈癌、肝癌、胆囊癌、胆管癌、心脏癌、肺癌、胰腺癌、唾液腺癌、肾上腺癌、甲状腺癌、脑瘤(例如神经胶质瘤)、神经节癌、中枢神经系统(CNS)瘤、周围神经系统(PNS)瘤、造血系统瘤(即血液恶性肿瘤)和免疫系统瘤(例如脾脏瘤或胸腺瘤)。In the present disclosure, CBL-B-mediated cancers include urogenital tract cancers (e.g., bladder cancer, kidney cancer, renal cell carcinoma, penile cancer, prostate cancer, testicular cancer, Von Hippel-Lindau disease, etc.), uterine cancer, cervical cancer, ovarian cancer, breast cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or large intestine cancer, colon cancer or rectal cancer), bone tumors, myeloma, skin cancer (e.g., melanoma), head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain tumors (e.g., gliomas), ganglion cancers, central nervous system (CNS) tumors, peripheral nervous system (PNS) tumors, hematopoietic system tumors (i.e., blood malignancies) and immune system tumors (e.g., spleen tumors or thymomas).

技术效果Technical Effects

本公开化合物有明显的CBL-B酶学抑制活性，可用于相关癌症的治疗。The disclosed compounds have significant CBL-B enzymatic inhibitory activity and can be used for the treatment of related cancers.

说明和定义Description and Definition

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选自是不确定的或不清楚的，而应该按照普通的含义去理解。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being ambiguous or unclear without a special definition, but should be understood according to the ordinary meaning.

本公开的化合物存在几何异构体以及立体异构体，例如顺反异构体、对映异构体、非对映异构体、及其外消旋混合物和其他混合物，所有这些混合物都属于本公开的范围之内。The compounds disclosed herein exist in geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, and all such mixtures are within the scope of the present disclosure.

术语“对映异构体”是指互选自镜像关系的立体异构体。The term "enantiomer" refers to stereoisomers that are mirror images of each other.

术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间选自非镜像的关系的立体异构体。The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are selected from molecules that are not mirror images of each other.

术语“顺反异构体”是指分子中双键或者成环碳原子单键不能自由旋转而存在的构型。The term "cis-trans isomers" refers to configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely.

除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。例如代表甲基和氨基位于环戊烷同侧。本公开化合物的立体异构体可以通过手性合成或手性试剂或者其它常规技术制备。例如本公开某化合物的一种对映体，可以通过不对称催化技术或者手性助剂衍生技术制备得到。或者通过手性拆分技术，从混合物中得到单一立体构型的化合物。或者用手性起始原料，直接制备得到。本公开中的光学纯化合物的分离通常是使用制备色谱完成的，采用手性色谱柱，达到分离手性化合物的目的。Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key Indicates the relative configuration of a stereocenter. For example The methyl group and the amino group are located on the same side of the cyclopentane. The stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, an enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology. Alternatively, a compound of a single stereo configuration can be obtained from a mixture by chiral resolution technology. Alternatively, it can be directly prepared using chiral starting materials. The separation of optically pure compounds disclosed herein is usually accomplished using preparative chromatography, using a chiral chromatographic column to achieve the purpose of separating chiral compounds.

化合物的绝对立体构型通过可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法，也可以通过原料的手性结构以及不对称合成的反应机理来确证化合物的绝对构型。本文中标记选自“绝对构型未测定”的化合物，通常是由消旋体化合物通过手性制备型SFC拆分选自单一异构体，然后进行表征和测试。The absolute stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can also be used to confirm the absolute configuration of a compound by the chiral structure of the raw materials and the reaction mechanism of asymmetric synthesis. The "determined" compounds are usually selected from the racemic compounds by chiral preparative SFC separation to form single isomers, which are then characterized and tested.

术语“药学上可接受的”指在合理的医学判断范围内适合与人类和动物的组织接触使用而无过度的毒性、刺激、过敏反应或其它的问题或并发症，与合理的收益/风险比相当的那些化合物、材料、组合物和/或剂型。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“药学上可接受的盐”是指本公开化合物与相对无毒的酸或碱制备得到的衍生物。这些盐可以在化合物合成、分离、纯化期间就被制备，或者单独使用经过纯化的化合物的游离形式与适合的酸或碱反应。当化合物中含有相对酸性的官能团时，与碱金属、碱土金属氢氧化物或有机胺反应得到碱加成盐，包括基于碱金属与碱土金属的阳离子以及无毒的铵、季铵和胺阳离子，还涵盖氨基酸的盐等。当化合物中含有相对碱性的官能团时，与有机酸或无机酸反应得到酸加成盐。The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound prepared with a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the purified free form of the compound can be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group, it reacts with an alkali metal, alkaline earth metal hydroxide or an organic amine to obtain a base addition salt, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations, and also covers amino acid salts. When the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to obtain an acid addition salt.

术语“药学上可接受的载体”是指本领域通常可接受的用于将生物活性药剂递送给动物、特别是哺乳动物的介质，根据给药方式和剂型的性质包括例如佐剂、赋形剂或赋形物，例如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、润湿剂、乳化剂、助悬剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂。药学上可接受的载体在本领域普通技术人员的眼界范围内根据大量因素配制。其包括但不限于：配制的活性药剂的类型和性质，要将含有该药剂的组合物给药的对象，组合物的预期给药途径，和目标治疗适应症。药学上可接受的载体包括含水介质和非水介质这两者以及多种固体和半固体剂型。除了活性药剂以外，这样的载体包括许多不同的成分和添加剂，因多种原因(例如稳定活性药剂、粘合剂等)在处方中包括的这样的另外的成分对于本领域普通技术人员是众所周知的。The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form. Pharmaceutically acceptable carriers are formulated within the scope of ordinary technicians in the field according to a large number of factors. They include, but are not limited to: the type and nature of the active agent to be formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in the prescription for various reasons (e.g., stabilizing the active agent, adhesives, etc.) are well known to ordinary technicians in the field.

术语“赋形剂”通常是指配制有效的药物组合物所需要稀释剂和/或介质。The term "excipient" generally refers to a diluent and/or vehicle required to formulate an effective pharmaceutical composition.

除非另有说明，结构单元与其他基团的链接方式为 Unless otherwise stated, structural units Links to other groups are

除非另有说明，“取代或未取代”是指可以被取代，也可以不被取代。此处，取代是指被选自以下的一个或多个取代基取代：氘、卤素、氰基、硝基、C_1-4烷基、C_1-4卤代烷基、C_1-4氘代烷基、C_1-4烷氧基、C_1-4氘代烷氧基、C_1-4卤代烷氧基、C_3-6环烷基。所述“取代或未取代C_3-6环烷基”的实例包括但不限于 Unless otherwise specified, "substituted or unsubstituted" means that it may be substituted or unsubstituted. Here, substitution means substitution by one or more substituents selected from the following: deuterium, halogen, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuterated alkyl, _C _1-4 alkoxy, C _1-4 deuterated alkoxy, C 1-4 haloalkoxy, C _3-6 cycloalkyl. Examples of the "substituted or unsubstituted C _3-6 cycloalkyl" include, but are not limited to

术语“芳基”是指具有共轭π电子体系的单环或双环基团。术语“6-10元芳基”是指由6-10个环碳原子组成的具有共轭π电子体系的单环或双环基团。所述“芳基”的实例包括但不限于苯基、萘基。The term "aryl" refers to a monocyclic or bicyclic group having a conjugated π electron system. The term "6-10 membered aryl" refers to a monocyclic or bicyclic group having a conjugated π electron system consisting of 6-10 ring carbon atoms. Examples of the "aryl" include, but are not limited to, phenyl and naphthyl.

术语“5-6元杂芳基”，表示由5-6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)。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)、吡啶基、嘧啶基等。The term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π electron system consisting of 5-6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). 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-pyrazolyl, 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 and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl), pyridyl, pyrimidinyl, etc.

术语“卤素”表示氟、氯、溴或碘原子。The term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.

术语“C_1-4烷基”用于表示C_1-4直链或支链的饱和烃基。烷基的实例包括，但不限于甲基、乙基、正丙基、异丙基、丁基、异丁基等。The term "C _1-4 alkyl" is used to represent a C _1-4 straight or branched saturated hydrocarbon group. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.

术语“C_1-4卤代烷基”是指一个或多个氢原子被卤原子取代的烷基，实例包括但不仅限于一氟甲基、二氟甲基、三氟甲基、三氯甲基、三溴甲基、2,2,2-三氟乙基，2,2,2三氯乙基等。The term "C _1-4 haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by halogen atoms. Examples include but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and the like.

术语“C_1-4氘代烷基”是指一个或多个氢原子被氘原子取代的烷基，实例包括但不仅限于一氘甲基、二氘甲基、三氘甲基、2,2,2-三氘乙基等。The term "C _1-4 deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom. Examples include, but are not limited to, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, 2,2,2-trideuterioethyl, and the like.

术语“C_1-4烷氧基”是指通过氧桥连接的C_1-4烷基。所述C_1-4烷氧基实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基。The term "C _1-4 alkoxy" refers to a C _1-4 alkyl group connected via an oxygen bridge. Examples of the C _1-4 alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

术语“C_1-4亚烷基”用于表示C_1-4直链或支链的饱和亚烃基。C_1-4亚烷基的实例包括但不限于-CH₂-、-(CH₂)₂-、-(CH₂)₃、-(CH₂)₄-、-CH(CH₃)-、-C(CH₃)₂-。 The term "C _1-4 alkylene" is used to represent a C _1-4 straight or branched saturated alkylene group. Examples of C _1-4 alkylene include, but are not limited to, -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ , -(CH ₂ ) ₄ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -.

术语“C_1-4氘代亚烷基”用于表示C_1-4直链或支链的饱和亚烃基中氢原子被D原子取代。C_1-4氘代亚烷基实例包括但不限于-CD₂-、-CH(CD₃)-。The term "C _1-4 deuterated alkylene" is used to indicate a C _1-4 straight or branched saturated alkylene group in which hydrogen atoms are replaced by D atoms. Examples of C _1-4 deuterated alkylene groups include, but are not limited to, -CD ₂ - and -CH(CD ₃ )-.

术语“C_3-6环烷基”是指3-6元单环烷基，这些C_3-6环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基。The term "C _3-6 cycloalkyl" refers to a 3-6 membered monocyclic alkyl group. Examples of such C _3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

术语“C_3-6亚环烷基”用于表示C_3-6环状亚烃基。环状亚烃基的实例包括，但不限于 The term "C _3-6 cycloalkylene" is used to represent a C _3-6 cyclic alkylene group. Examples of cyclic alkylene groups include, but are not limited to

术语“5-10元杂环基”是指取代或未取代的5-10元饱和或不饱和的非芳香环基团，且包含1-3个选自N、O或S的杂原子。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)。本公开所述的“杂环基”是指含有至少一个杂原子作为环原子、去除一个氢原子所衍生的、非芳族的环状基团；包括饱和或部分饱和的单环杂环基和双环杂环基；其中双环杂环基可以是稠环杂环基，可以是3-4元环烷基并3-4元杂环基、3-4元环烷基并5-6元杂环基。所述杂环基与连接位置无关(即，可以通过碳原子或杂原子结合)。“杂环基”实例包括但不限于 The term "5-10 membered heterocyclyl" refers to a substituted or unsubstituted 5-10 membered saturated or unsaturated non-aromatic cyclic group, and contains 1-3 heteroatoms selected from N, O or S. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). The "heterocyclyl" described in the present disclosure refers to a non-aromatic cyclic group derived from removing a hydrogen atom and containing at least one heteroatom as a ring atom; including saturated or partially saturated monocyclic heterocyclyls and bicyclic heterocyclyls; wherein the bicyclic heterocyclyl may be a fused ring heterocyclyl, and may be a 3-4 membered cycloalkyl and 3-4 membered heterocyclyl, or a 3-4 membered cycloalkyl and 5-6 membered heterocyclyl. The heterocyclyl is independent of the attachment position (i.e., it may be bonded through a carbon atom or a heteroatom). Examples of "heterocyclyl" include, but are not limited to

本公开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公开的实施例。The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

本公开所使用的溶剂可经市售获得。The solvents used in the present disclosure are commercially available.

本公开的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)，或超高效液质联用色谱(UPLC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker Neo 400M或者Bruker Ascend 400核磁仪器，测定溶剂选自氘代二甲基亚砜(DMSO-d₆)，氘代甲醇(CD₃OD)和氘代氯仿(CDCl₃)，重水(D₂O)，内标选自四甲基硅烷(TMS)。The structures of the compounds disclosed in the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS), or ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shift (δ) is given in parts per million (ppm). NMR is measured using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic resonance instrument, and the measurement solvent is selected from deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), heavy water (D ₂ O), and the internal standard is selected from tetramethylsilane (TMS).

液质联用色谱LC-MS的测定用Agilent 1260-6125B single quadrupole mass spectrometer，质谱仪(离子源选自电喷雾离子化)。Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer (the ion source was selected from electrospray ionization).

超高效液质联用色谱UPLC-MS的测定用Waters UPLC H-class SQD质谱仪(离子源选自电喷雾离子化)。Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was determined using a Waters UPLC H-class SQD mass spectrometer (the ion source was selected from electrospray ionization).

HPLC的测定使用Waters e2695-2998或Waters ARC和Agilent 1260或Agilent Poroshell HPH高效液相色谱。HPLC determinations were performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

制备HPLC使用Waters 2555-2489(10μm，ODS250cm×5cm)或GILSON Trilution LC。Preparative HPLC used Waters 2555-2489 (10 μm, ODS 250 cm × 5 cm) or GILSON Trilution LC.

手性HPLC测定使用waters acquity UPC2；柱子选自Daicel chi环Clpak AD-H(5um,4.6*250mm)。Chiral HPLC determination used waters acquity UPC2; the column was selected from Daicel chi ring Clpak AD-H (5um, 4.6*250mm).

超临界流体色谱(SFC)使用waters SFC 80Q。Supercritical fluid chromatography (SFC) was performed using waters SFC 80Q.

本公开实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized using or according to methods known in the art.

在无特殊说明的情况下，本公开的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气气氛下进行，溶剂选自干燥溶剂，反应温度单位选自℃。Unless otherwise specified, all reactions disclosed herein are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is selected from a dry solvent, and the reaction temperature unit is selected from °C.

DETAILED DESCRIPTION

下文中，本公开将通过如下实施例进行详细解释以便更好地理解本申请的各个方面及其优点。然而，应当理解，以下的实施例是非限制性的而且仅用于说明本申请的某些实施方案。Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

实施例1Example 1

5-溴-2-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-7-(((S)-3-甲基哌啶-1-基)甲基)异喹啉-1(2H)-酮
5-Bromo-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在0℃下，将化合物7-异喹啉甲酸甲酯(1.0g,5.34mmol)溶于浓硫酸(9.0mL)中。随后，向上述溶液中依次加入N-溴代丁二酰亚胺(1.43g,8.01mmol)。然后该反应体系在室温下继续搅拌16小时。Step A: At 0°C, compound 7-isoquinolinecarboxylic acid methyl ester (1.0 g, 5.34 mmol) was dissolved in concentrated sulfuric acid (9.0 mL). Subsequently, N-bromosuccinimide (1.43 g, 8.01 mmol) was added to the above solution in sequence. The reaction system was then stirred at room temperature for 16 hours.

LCMS监测显示原料消失后，向反应液中滴加2M氢氧化钠水溶液至pH选自9。混合液用乙酸乙酯(25mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.11g化合物5-溴-7-异喹啉甲酸甲酯。After LCMS monitoring showed that the raw material disappeared, 2M sodium hydroxide aqueous solution was added dropwise to the reaction solution until the pH was selected from 9. The mixed solution was extracted with ethyl acetate (25 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.11 g of compound 5-bromo-7-isoquinolinecarboxylic acid methyl ester.

MS(ESI)M/Z:266.1[M+H]⁺。MS (ESI) M/Z: 266.1 [M+H] ⁺ .

步骤B：在0℃下，氮气保护，将化合物5-溴-7-异喹啉甲酸甲酯(1.11g,4.19mmol)溶于干燥的二氯甲烷(28mL)中。随后，向上述溶液中加入间氯过氧苯甲酸(1.09g,6.29mmol)。然后该反应体系在室温条件下继续搅拌16小时。Step B: At 0°C, under nitrogen protection, compound 5-bromo-7-isoquinolinecarboxylic acid methyl ester (1.11 g, 4.19 mmol) was dissolved in dry dichloromethane (28 mL). Subsequently, m-chloroperbenzoic acid (1.09 g, 6.29 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours.

LCMS监测显示原料消失后，向反应液中加入二氯甲烷(20mL)稀释，混合液用饱和的硫代硫酸钠(40mL×3次)洗涤，再用饱和食盐水(40mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物化合物1.12g 5-溴-7-(甲氧羰基)异喹啉2-氧化物粗品直接用于下一步，无需进一步纯化。After LCMS monitoring showed that the raw material disappeared, dichloromethane (20 mL) was added to the reaction solution for dilution, and the mixed solution was washed with saturated sodium thiosulfate (40 mL × 3 times), and then washed with saturated brine (40 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue compound 1.12 g 5-bromo-7-(methoxycarbonyl)isoquinoline 2-oxide crude product was directly used in the next step without further purification.

MS(ESI)M/Z:282.1[M+H]⁺。MS (ESI) M/Z: 282.1 [M+H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物5-溴-7-(甲氧羰基)异喹啉2-氧化物(1.12g,3.99mmol)溶于醋酸酐(18mL)中。随后，将上述溶液升至160℃，搅拌2小时后，减压浓缩。然后向上述残余物中加入2M氢氧化钠水溶液(54mL)，升温至120℃，继续搅拌2小时。Step C: Under nitrogen protection at room temperature, dissolve the compound 5-bromo-7-(methoxycarbonyl)isoquinoline 2-oxide (1.12 g, 3.99 mmol) in acetic anhydride (18 mL). Then, heat the solution to 160°C, stir for 2 hours, and concentrate under reduced pressure. Then, add 2M sodium hydroxide aqueous solution (54 mL) to the residue, heat to 120°C, and continue stirring for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加2M稀盐酸水溶液至pH＝3。混合液用乙酸乙酯(25mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得550mg残余物化合物5-溴-1-氧-1,2-二羟基喹啉-7-羧酸直接用于下一步，无需进一步纯化。After LCMS monitoring showed that the starting material disappeared, 2M dilute hydrochloric acid aqueous solution was added dropwise to the reaction solution until pH = 3. The mixed solution was extracted with ethyl acetate (25 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 550 mg residue compound 5-bromo-1-oxo-1,2-dihydroxyquinoline-7-carboxylic acid was directly used in the next step without further purification.

MS(ESI)M/Z:268.1[M+H]⁺。MS (ESI) M/Z: 268.1 [M+H] ⁺ .

步骤D：在0℃下，将化合物5-溴-1-氧-1,2-二羟基喹啉-7-羧酸(550mg,2.06mmol)溶于干燥的四氢呋喃(5mL)中。随后，向上述溶液中缓慢滴加1M的硼烷四氢呋喃溶液(10mL,10.03mmol)。然后该反应体系在室温条件下搅拌16小时。Step D: Dissolve the compound 5-bromo-1-oxo-1,2-dihydroxyquinoline-7-carboxylic acid (550 mg, 2.06 mmol) in dry tetrahydrofuran (5 mL) at 0°C. Then, slowly add 1 M borane tetrahydrofuran solution (10 mL, 10.03 mmol) to the above solution. Then, stir the reaction system at room temperature for 16 hours.

LCMS监测显示原料消失后，向反应液中缓慢滴加甲醇淬灭，减压浓缩。所得残余物用硅胶柱层析纯化得到化合物280mg 5-溴-7-(羟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the starting material disappeared, methanol was slowly added dropwise to the reaction solution to quench it, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 280 mg of compound 5-bromo-7-(hydroxymethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:254.1[M+H]⁺。MS (ESI) M/Z: 254.1 [M+H] ⁺ .

步骤E：在0℃下，将化合物5-溴-7-(羟甲基)异喹啉-1(2H)-酮(280mg,1.11mmol)溶于甲苯(5.5mL) 中。随后，向上述溶液中缓慢滴加氯化亚砜(5.5mL)。然后该反应体系在70℃下继续搅拌2小时。Step E: Dissolve 5-bromo-7-(hydroxymethyl)isoquinolin-1(2H)-one (280 mg, 1.11 mmol) in toluene (5.5 mL) at 0 °C. Subsequently, thionyl chloride (5.5 mL) was slowly added dropwise to the above solution. The reaction system was then stirred at 70° C. for 2 hours.

LCMS监测显示原料消失后，将上述反应液减压浓缩。所得残余物用硅胶柱层析纯化得到150mg化合物5-溴-7-(氯甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 150 mg of the compound 5-bromo-7-(chloromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:272.1[M+H]⁺。MS (ESI) M/Z: 272.1 [M+H] ⁺ .

步骤F：在室温条件下，将化合物(S)-3-甲基哌啶盐酸盐(113mg,0.83mmol)溶于乙腈(5.5mL)中。随后，向上述溶液中依次加入碘化钾(92mg,0.55mmol)和碳酸钾(153mg,1.11mmol)，并搅拌0.5小时。然后再加入化合物5-溴-7-(氯甲基)异喹啉-1(2H)-酮(150mg,0.55mmol)，继续搅拌16小时。Step F: Dissolve the compound (S)-3-methylpiperidine hydrochloride (113 mg, 0.83 mmol) in acetonitrile (5.5 mL) at room temperature. Then, add potassium iodide (92 mg, 0.55 mmol) and potassium carbonate (153 mg, 1.11 mmol) to the solution and stir for 0.5 hours. Then add the compound 5-bromo-7-(chloromethyl)isoquinolin-1(2H)-one (150 mg, 0.55 mmol) and continue stirring for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到105mg化合物(S)-5-溴-7-((3-甲基哌啶-1-基)甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 105 mg of compound (S)-5-bromo-7-((3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:335.2[M+H]⁺。MS (ESI) M/Z: 335.2 [M+H] ⁺ .

步骤G：在室温条件下，氮气保护，将化合物(S)-5-溴-7-((3-甲基哌啶-1-基)甲基)异喹啉-1(2H)-酮(95mg,0.28mmol)、3-((1S，3S)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(111mg,0.36mmol)、左旋-反式-1,2-环己二胺(23mg,0.20mmol)、碘化亚铜(38mg,0.20mmol)和碳酸铯(183mg,0.56mmol)溶于1,4-二氧六环(2.8mL)中。然后将上述溶液升温至110℃，搅拌6小时。Step G: Under nitrogen protection at room temperature, compound (S)-5-bromo-7-((3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one (95 mg, 0.28 mmol), 3-((1S, 3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (111 mg, 0.36 mmol), levorotatory-trans-1,2-cyclohexanediamine (23 mg, 0.20 mmol), cuprous iodide (38 mg, 0.20 mmol) and cesium carbonate (183 mg, 0.56 mmol) were dissolved in 1,4-dioxane (2.8 mL). The solution was then heated to 110° C. and stirred for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化。纯化条件如下，制备柱：YMC-Actus Triart C18 20.0mm*150mm；流动相：水(含有0.1％碳酸氢铵)和乙腈。得到11.58mg标题化合物5-溴-2-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-7-(((S)-3-甲基哌啶-1-基)甲基)异喹啉-1(2H)-酮(化合物1)。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography. The purification conditions were as follows: preparative column: YMC-Actus Triart C18 20.0 mm*150 mm; mobile phase: water (containing 0.1% ammonium bicarbonate) and acetonitrile. 11.58 mg of the title compound 5-bromo-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)isoquinolin-1(2H)-one (Compound 1) was obtained.

MS(ESI)M/Z:560.3[M+H]⁺。MS (ESI) M/Z: 560.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ8.30(s,1H),8.18(s,1H),7.99(d,J＝1.2Hz,1H),7.61(d,J＝7.6Hz,1H),7.57-7.48(m,2H),7.40-7.32(m,2H),6.78(d,J＝7.6Hz,1H),3.56(s,2H),3.23(s,3H),2.94-2.79(m,2H),2.77-2.66(m,2H),2.60-2.52(m,3H),1.95-1.85(m,1H),1.69-1.54(m,4H),1.53-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.90-0.84(m,1H),0.81(d,J＝5.6Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ )δ8.30(s,1H),8.18(s,1H),7.99(d,J＝1.2Hz,1H),7.61(d,J＝7.6Hz,1H),7.57-7.48 (m,2H),7.40-7.32(m,2H),6.78(d,J＝7.6Hz,1H),3.56(s,2H),3.23(s,3H),2.94-2. 79(m,2H),2.77-2.66(m,2H),2.60-2.52(m,3H),1.95-1.85(m,1H),1.69-1.54(m,4H ),1.53-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.90-0.84(m,1H),0.81(d,J＝5.6Hz,3H).

参考上述实施例1的合成方法制备如下目标化合物：

The following target compound was prepared by referring to the synthesis method of Example 1 above:

实施例8Example 8

6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温下，将化合物7-氯-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(1g,4.45mmol)溶于N,N-二甲基甲酰胺(20mL)中。随后，向上述溶液中依次加入碳酸钾(0.68g,4.9mmol)和2-(三甲基硅烷基)乙氧甲基氯(1.63g,9.8mmol)。然后该反应体系在升至80℃继续搅拌2小时。Step A: Dissolve the compound 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (1 g, 4.45 mmol) in N,N-dimethylformamide (20 mL) at room temperature. Then, potassium carbonate (0.68 g, 4.9 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.63 g, 9.8 mmol) were added to the above solution in sequence. The reaction system was then heated to 80°C and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加入水(20mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.69g化合物乙基7-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸酯。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.69 g of the compound ethyl 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate.

MS(ESI)M/Z:355.1[M+H]⁺。MS (ESI) M/Z: 355.1 [M+H] ⁺ .

步骤B：在0℃，氮气保护下，将化合物乙基7-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸酯(0.67g,1.94mmol)溶于干燥的四氢呋喃(10mL)中。随后，向上述溶液中加入四氢锂铝溶液(0.92mL,2.3mmol,2.5M)。然后该反应体系继续在0℃搅拌0.5小时。Step B: At 0°C, under nitrogen protection, the compound ethyl 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.67 g, 1.94 mmol) was dissolved in dry tetrahydrofuran (10 mL). Subsequently, lithium aluminum tetrahydride solution (0.92 mL, 2.3 mmol, 2.5 M) was added to the above solution. The reaction system was then stirred at 0°C for 0.5 hours.

LCMS监测显示原料消失后，向反应液中加入氯化铵溶液(20mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.41g化合物(7-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇。After LCMS monitoring showed that the raw material disappeared, ammonium chloride solution (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.41 g of the compound (7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

MS(ESI)M/Z:313.2[M+H]⁺。MS (ESI) M/Z: 313.2 [M+H] ⁺ .

步骤C：在0℃条件，氮气保护下，将化合物(7-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇(0.41g,1.31mmol)溶于乙腈(5mL)中。随后，向反应体系中滴加二氯亚砜(0.62g,5.24mmol)。继续搅拌2小时。Step C: Dissolve the compound (7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (0.41 g, 1.31 mmol) in acetonitrile (5 mL) at 0°C under nitrogen protection. Then, add thionyl chloride (0.62 g, 5.24 mmol) dropwise to the reaction system. Continue stirring for 2 hours.

LCMS监测显示原料消失后，向反应液中加入碳酸氢钠溶液(10mL)淬灭。混合液用二氯甲烷(25mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.27g化合物7-氯-2-(氯甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed that the raw material disappeared, sodium bicarbonate solution (10 mL) was added to the reaction solution to quench. The mixed solution was extracted with dichloromethane (25 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.27 g of compound 7-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:331.1[M+H]⁺。MS (ESI) M/Z: 331.1 [M+H] ⁺ .

步骤D：在室温条件下，氮气保护，将化合物7-氯-2-(氯甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(0.27g,0.81mmol)和(3S)-3-哌啶(0.16g,1.62mmol)溶于乙腈(5mL)中。随后，向上述反应液中加入碳酸钾(0.45g,3.24mmol)和碘化钾(0.013g,0.081mmol)。该反应体系升至80度，继续搅拌2小时。Step D: Under nitrogen protection at room temperature, compound 7-chloro-2-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (0.27 g, 0.81 mmol) and (3S)-3-piperidine (0.16 g, 1.62 mmol) were dissolved in acetonitrile (5 mL). Subsequently, potassium carbonate (0.45 g, 3.24 mmol) and potassium iodide (0.013 g, 0.081 mmol) were added to the above reaction solution. The reaction system was heated to 80 degrees and stirred for 2 hours.

LCMS监测显示原料转化为产物后，将混合物减压浓缩。所得残余物用硅胶柱层析纯化得到0.23g化合物(S)-7-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed that the raw material was converted into the product, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.23 g of compound (S)-7-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:394.3[M+H]⁺。MS (ESI) M/Z: 394.3 [M+H] ⁺ .

步骤E：在室温条件下，氮气保护，将化合物(S)-7-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(220mg,0.56mmol)、三二亚苄基丙酮二钯(409mg,0.45mmol)、2-二环己基磷-2',4',6'-三异丙基联苯(266mg,0.56mmol)和氢氧化钾(376mg,6.7mmol)溶于1,4-二氧六环(5mL)和水(5mL)中。然后将上述溶液升温至100℃，搅拌12小时。Step E: Under nitrogen protection at room temperature, compound (S)-7-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (220 mg, 0.56 mmol), trisdibenzylideneacetone dipalladium (409 mg, 0.45 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (266 mg, 0.56 mmol) and potassium hydroxide (376 mg, 6.7 mmol) were dissolved in 1,4-dioxane (5 mL) and water (5 mL). The solution was then heated to 100°C and stirred for 12 hours.

LCMS监测显示原料消失后，向混合液中加入水(20mL)稀释，用二氯甲烷(25mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.13g化合物(S)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the mixed solution for dilution, and the mixture was extracted with dichloromethane (25 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.13 g of compound (S)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:376.3[M+H]⁺。MS (ESI) M/Z: 376.3 [M+H] ⁺ .

步骤F：在室温条件下，氮气保护，将化合物(S)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(110mg,0.29mmol)、3-((1S,3S)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(120mg,0.38mmol)、碘化亚铜(11mg,0.058mmol)、N,N,N',N'-四甲基乙二胺(6.7mg,0.058mmol)和碳酸钾(120mg,0.87mmol)溶于N,N-二甲基甲酰胺(3mL)中。然后将上述溶液微波加热至150℃，搅拌12小时。Step F: Under nitrogen protection at room temperature, compound (S)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.29 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (120 mg, 0.38 mmol), cuprous iodide (11 mg, 0.058 mmol), N,N,N',N'-tetramethylethylenediamine (6.7 mg, 0.058 mmol) and potassium carbonate (120 mg, 0.87 mmol) were dissolved in N,N-dimethylformamide (3 mL). The solution was then heated to 150° C. by microwave and stirred for 12 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到40mg化合物6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of compound 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:601.4[M+H]⁺。MS (ESI) M/Z: 601.4 [M+H] ⁺ .

步骤G：在室温条件下，氮气保护，将化合物6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基) 苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(40mg,0.067mmol)溶于四丁基氟化铵的四氢呋喃溶液(1.34mL,1.34mmol,1M)中。该反应体系升至80度，继续搅拌36小时。Step G: At room temperature, under nitrogen protection, compound 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.067 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1.34 mL, 1.34 mmol, 1 M). The reaction system was heated to 80 degrees and stirred for 36 hours.

LCMS监测显示原料转化为产物后，将反应液减压浓缩。所得粗品经制备型高效液相色谱纯化。纯化条件如下，制备柱：制备柱：SNAP Ultra C18 30g 25μm；流动相：0.1％甲酸水溶液和乙腈。得到7mg标题化合物6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material was converted into the product, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography. The purification conditions were as follows: preparative column: SNAP Ultra C18 30g 25μm; mobile phase: 0.1% formic acid aqueous solution and acetonitrile. 7mg of the title compound 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was obtained.

MS(ESI)M/Z:471.2[M+H]⁺。MS (ESI) M/Z: 471.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ11.92(s,1H),8.28(s,1H),7.55–7.43(m,1H),7.43–7.36(m,1H),7.36–7.25(m,2H),7.16–7.08(m,1H),6.55(d,J＝7.1Hz,1H),6.21(d,J＝1.9Hz,1H),3.66–3.49(m,2H),3.25(s,3H),2.96–2.81(m,2H),2.82–2.71(m,2H),2.58–2.52(m,3H),1.96–1.80(m,1H),1.68–1.52(m,4H),1.52–1.36(m,1H),1.07(d,J＝5.1Hz,3H),0.86–0.70(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ11.92(s,1H),8.28(s,1H),7.55–7.43(m,1H),7.43–7.36(m,1H),7.36–7.25(m,2H ),7.16–7.08(m,1H),6.55(d,J＝7.1Hz,1H),6.21(d,J＝1.9Hz,1H),3.66–3.49(m,2H) ,3.25(s,3H),2.96–2.81(m,2H),2.82–2.71(m,2H),2.58–2.52(m,3H),1.96–1.80(m ,1H),1.68–1.52(m,4H),1.52–1.36(m,1H),1.07(d,J=5.1Hz,3H),0.86–0.70(m,4H).

参考上述实施例8的合成方法制备如下目标化合物：

The following target compound was prepared by referring to the synthesis method of Example 8 above:

实施例42Embodiment 42

4-氯-6-(3-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(100.0mg,0.24mmol)溶于二甲基亚砜(6mL)中。随后，向上述溶液中依次加入3-((1R,3R)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(73.2mg,0.24mmol)、碳酸氢钠(28.0mg,0.48mmol)和醋酸铜(144.0mg,0.72mmol)。然后该反应体系在80℃条件下搅拌2小时。Step A: Under nitrogen protection at room temperature, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100.0 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (6 mL). Subsequently, 3-((1R,3R)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (73.2 mg, 0.24 mmol), sodium bicarbonate (28.0 mg, 0.48 mmol) and copper acetate (144.0 mg, 0.72 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(40mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到109mg 4-氯-6-(3-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (40 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain 109 mg 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:635.2[M+H]⁺.MS (ESI) M/Z: 635.2 [M + H] ⁺ .

步骤B:在0℃条件下，将化合物4-氯-6-(3-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(109mg,0.17mmol)溶于二氯甲烷(1.7mL)中。随后，向上述溶液中滴加三氟乙酸(0.85mL)。然后该反应体系在室温条件下搅拌2小时。Step B: Compound 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (109 mg, 0.17 mmol) was dissolved in dichloromethane (1.7 mL) at 0°C. Trifluoroacetic acid (0.85 mL) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，减压浓缩，所得残余物经制备型高效液相色谱纯化，得到28mg 4-氯-6-(3-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and the product was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 28 mg of 4-chloro-6-(3-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:505.2[M+H]⁺.MS (ESI) M/Z: 505.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.37(s,1H),8.37(s,1H),7.47(t,J＝8.2Hz,1H),7.42(s,1H),7.33-7.27(m,2H),7.15(d,J＝7.6Hz,1H),6.26(s,1H),3.59(s,2H),3.29(s,3H),3.15-3.07(m,2H),2.86-2.69(m,2H),2.37-2.22(m,3H),1.95-1.82(m,1H),1.68-1.52(m,4H),1.51-1.38(m,1H),1.09(d,J＝6.0Hz,3H),0.86-0.73(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.37(s,1H),8.37(s,1H),7.47(t,J＝8.2Hz,1H),7.42(s,1H),7.33-7.2 7(m,2H),7.15(d,J＝7.6Hz,1H),6.26(s,1H),3.59(s,2H),3.29(s,3H),3.15 -3.07(m,2H),2.86-2.69(m,2H),2.37-2.22(m,3H),1.95-1.82(m,1H),1.6 8-1.52(m,4H),1.51-1.38(m,1H),1.09(d,J＝6.0Hz,3H),0.86-0.73(m,4H).

实施例43Embodiment 43

4-氯-6-(3-((1S,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在0℃条件下，将化合物2-(3-溴苯基)乙酸(10.0g,46.7mmol)溶于无水四氢呋喃(100.0mL)中，随后，向上述溶液中滴加2.0M异丙基氯化镁的四氢呋喃溶液(52.0mL)，搅拌1小时。再加2-(氯甲基)环氧乙烷(7.3mL,93.4mmol)，继续搅拌1.5小时。然后再加入2.0M异丙基氯化镁的四氢呋喃溶液(52.0mL)，升至室温，搅拌12小时。Step A: Dissolve the compound 2-(3-bromophenyl)acetic acid (10.0 g, 46.7 mmol) in anhydrous tetrahydrofuran (100.0 mL) at 0°C, then dropwise add 2.0 M isopropylmagnesium chloride in tetrahydrofuran (52.0 mL) to the solution and stir for 1 hour. Add 2-(chloromethyl)oxirane (7.3 mL, 93.4 mmol) and continue stirring for 1.5 hours. Then add 2.0 M isopropylmagnesium chloride in tetrahydrofuran (52.0 mL), warm to room temperature and stir for 12 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(100mL)中淬灭，向混合液中滴加浓盐酸调节至pH＝4。混合液用乙酸乙酯(100mL×2次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到5.4g(1S,3S)-1-(3-溴苯基)-3-羟基环丁烷-1-甲酸粗品。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water (100 mL) to quench, and concentrated hydrochloric acid was added dropwise to the mixed solution to adjust the pH to 4. The mixed solution was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5.4 g of crude (1S, 3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid.

MS(ESI)M/Z:271.0[M+H]⁺.MS (ESI) M/Z: 271.0 [M+H] ⁺ .

步骤B:在0℃条件下，将化合物(1S,3S)-1-(3-溴苯基)-3-羟基环丁烷-1-甲酸(2.0g,7.10mmol)和N-甲基肼甲硫酰胺(900.0mg,8.5mmol)溶于N,N-二甲基甲酰胺(24.0mL)中。随后，向上述溶液中依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(2.9g,7.8mmol)和N,N-二异丙基乙胺(2.75g,21.3mmol)。然后该反应体系在室温下继续搅拌1小时。Step B: Compound (1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carboxylic acid (2.0 g, 7.10 mmol) and N-methylhydrazine methylsulfamide (900.0 mg, 8.5 mmol) were dissolved in N,N-dimethylformamide (24.0 mL) at 0°C. Subsequently, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.9 g, 7.8 mmol) and N,N-diisopropylethylamine (2.75 g, 21.3 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(100mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(100mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩得到3.1g 2-((1S,3S)-1-(3-溴苯基)-3-羟基环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺粗品。After LCMS monitoring showed that the raw material disappeared, water (100 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.1 g of 2-((1S, 3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide crude product.

MS(ESI)M/Z:358.0[M+H]⁺.MS (ESI) M/Z: 358.0 [M+H] ⁺ .

步骤C：在室温条件下，将化合物2-((1S,3S)-1-(3-溴苯基)-3-羟基环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺(2.5g,7.1mmol)溶于四氢呋喃(80.0mL)中。随后，向上述溶液中滴加2M氢氧化钠的水溶液(40.0mL)。然后该反应体系80℃条件下搅拌12小时。Step C: Dissolve the compound 2-((1S,3S)-1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (2.5 g, 7.1 mmol) in tetrahydrofuran (80.0 mL) at room temperature. Then, add a 2M aqueous solution of sodium hydroxide (40.0 mL) dropwise to the solution. Then, stir the reaction system at 80°C for 12 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)中淬灭，向混合液中滴加浓盐酸调节至pH＝3。混合液用乙酸乙酯(100mL×3次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，得到粗品2.7g(1S,3S)-3-(3-溴苯基)-3-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water (30 mL) to quench, and concentrated hydrochloric acid was added dropwise to the mixed solution to adjust the pH to 3. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 2.7 g (1S, 3S)-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol.

MS(ESI)M/Z:340.0[M+H]⁺.MS (ESI) M/Z: 340.0 [M + H] ⁺ .

步骤D：在室温条件下，将化合物(1S,3S)-3-(3-溴苯基)-3-(5-巯基-4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1- 醇(2.7g,7.1mmol)溶于二氯甲烷(100mL)中。随后，向上述溶液中滴加醋酸(8.0mL)和双氧水(1.2g)。然后该反应体系继续搅拌1小时。Step D: At room temperature, the compound (1S,3S)-3-(3-bromophenyl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1- Alcohol (2.7 g, 7.1 mmol) was dissolved in dichloromethane (100 mL). Acetic acid (8.0 mL) and hydrogen peroxide (1.2 g) were then added dropwise to the solution. The reaction system was then stirred for 1 hour.

LCMS监测显示原料消失后，向反应液中滴加1M氢氧化钠溶液调节至pH＝10，混合液用二氯甲烷(50mL×3次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化得到550mg(1S,3S)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇。After LCMS monitoring showed that the raw material disappeared, 1M sodium hydroxide solution was added dropwise to the reaction solution to adjust the pH to 10, and the mixed solution was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 550 mg of (1S, 3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol.

MS(ESI)M/Z:308.0[M+H]⁺.MS (ESI) M/Z: 308.0 [M+H] ⁺ .

步骤E:在0℃条件下，氮气保护，将化合物(1S,3S)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇(92mg,0.3mmol)溶于N,N-二甲基甲酰胺(1.5mL)中。随后，向上述溶液中缓慢加入氢化钠(21.6mg,0.5mmol)，搅拌20分钟。然后再滴加碘甲烷(64mg,0.45mmol)，升至室温条，继续搅拌1小时。Step E: Under nitrogen protection at 0°C, compound (1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (92 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). Then, sodium hydride (21.6 mg, 0.5 mmol) was slowly added to the above solution and stirred for 20 minutes. Then, iodomethane (64 mg, 0.45 mmol) was added dropwise, the temperature was warmed to room temperature, and stirring was continued for 1 hour.

LCMS监测显示原料消失后，将反应液滴加到冰水(20mL)中淬灭，混合液用乙酸乙酯(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到98mg 3-((1S,3S)-1-(3-溴苯基)-3-甲氧基环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, the reaction solution was added dropwise to ice water (20 mL) to quench, the mixed solution was extracted with ethyl acetate (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 98 mg 3-((1S, 3S)-1-(3-bromophenyl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:322.0[M+H]⁺.MS (ESI) M/Z: 322.0 [M + H] ⁺ .

步骤F:在室温条件下，氮气保护，将化合物3-((1S,3S)-1-(3-溴苯基)-3-甲氧基环丁基)-4-甲基-4H-1,2,4-三唑(50mg,0.15mmol)溶于二甲亚砜(1.5mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(65mg,0.15mmol)、碘化亚铜(28mg,0.15mmol)、N,N'-二甲基乙二胺(16mg,0.18mmol)和碳酸钾(41.4mg,0.3mmol)。然后该反应体系在150℃条件下搅拌3小时。Step F: Under nitrogen protection at room temperature, compound 3-((1S,3S)-1-(3-bromophenyl)-3-methoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (50 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (1.5 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (65 mg, 0.15 mmol), cuprous iodide (28 mg, 0.15 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到55mg 4-氯-6-(3-((1S,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:651.2[M+H]+.MS (ESI) M/Z: 651.2 [M+H] +.

步骤G:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(55mg,0.08mmol)溶于二氯甲烷(0.8mL)。随后，向上述溶液中滴加三氟乙酸(0.8mL)。然后该反应体系继续搅拌2小时。Step G: Compound 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (55 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Subsequently, trifluoroacetic acid (0.8 mL) was added dropwise to the above solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到12mg 4-氯-6-(3-((1S,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 12 mg 4-chloro-6-(3-((1S,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:521.3[M+H]⁺.MS (ESI) M/Z: 521.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.31(s,1H),7.50(t,J＝7.8Hz,1H),7.47-7.40(m,2H),7.38-7.33(m,1H),7.30(d,J＝8.0,1H),6.27(s,1H),4.12-4.02(m,1H),3.60(s,2H),3.27(s,3H),3.16(s,3H),3.14-3.05(m,2H),2.86-2.70(m,4H),1.99-1.79(m,1H),1.73-1.53(m,4H),1.51-1.37(m,1H),0.90-0.73(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.38(s,1H),8.31(s,1H),7.50(t,J＝7.8Hz,1H),7.47-7.40(m,2H),7. 38-7.33(m,1H),7.30(d,J＝8.0,1H),6.27(s,1H),4.12-4.02(m,1H),3.60 (s,2H),3.27(s,3H),3.16(s,3H),3.14-3.05(m,2H),2.86-2.70(m,4H),1 .99-1.79(m,1H),1.73-1.53(m,4H),1.51-1.37(m,1H),0.90-0.73(m,4H).

实施例44Embodiment 44

4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤： Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(62mg,0.15mmol)、3-((1S,3R)-1-(3-溴-5-(三氟甲氧基)苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(60mg,0.15mmol)、N,N'-二甲基乙二胺(16mg,0.18mmol)、碘化亚铜(29mg,0.15mmol)和碳酸钾(42mg,0.30mmol)溶于二甲基亚砜(1.0mL)中。然后该反应体系在150℃条件下搅拌3小时。Step A: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (62 mg, 0.15 mmol), 3-((1S,3R)-1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (60 mg, 0.15 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (29 mg, 0.15 mmol) and potassium carbonate (42 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (1.0 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到80mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:719.3[M+H]⁺.MS (ESI) M/Z: 719.3 [M + H] ⁺ .

步骤B:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(70mg,0.10mmol)溶于二氯甲烷(1mL)中。随后，向上述溶液中滴加三氟乙酸(2mL)，继续搅拌1小时。LCMS监测显示原料消失后，向反应液中滴加氨水(7mL)，继续搅拌2小时。Step B: At room temperature, compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (70 mg, 0.10 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (2 mL) was added dropwise to the above solution and stirring was continued for 1 hour. After LCMS monitoring showed that the raw material disappeared, ammonia water (7 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

LCMS监测显示中间体消失后，向反应液中加水(10mL)，混合液用二氯甲烷(8mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到5.8mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution, and the mixed solution was extracted with dichloromethane (8 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 5.8 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:589.2[M+H]⁺.MS (ESI) M/Z: 589.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.39(s,1H),7.49(s,1H),7.45(s,1H),7.39(t,J＝1.6Hz,1H),7.06(s,1H),6.27(s,1H),3.59(s,2H),3.31(s,3H),3.16-3.07(m,2H),2.81-2.70(m,2H),2.39-2.25(m,3H),1.94-1.84(m,1H),1.67-1.53(m,4H),1.52-1.38(m,1H),1.09(d,J＝6.0Hz,3H),0.88-0.75(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.39(s,1H),7.49(s,1H),7.45(s,1H),7.39(t,J＝1.6H z,1H),7.06(s,1H),6.27(s,1H),3.59(s,2H),3.31(s,3H),3.16-3.07( m,2H),2.81-2.70(m,2H),2.39-2.25(m,3H),1.94-1.84(m,1H),1.67-1 .53(m,4H),1.52-1.38(m,1H),1.09(d,J＝6.0Hz,3H),0.88-0.75(m,4H).

实施例45Embodiment 45

4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(33mg,0.08mmol)、3-((1R,3R)-1-(3-溴-5-(三氟甲基)苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(30mg,0.08mmol)、N,N'-二甲基乙二胺(9mg,0.10mmol)、碘化亚铜(16mg,0.08mmol)和碳酸钾(23mg,0.16mmol)溶于二甲基亚砜(0.5mL)中。然后该反应体系在150℃条件下搅拌3小时。Step A: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (33 mg, 0.08 mmol), 3-((1R,3R)-1-(3-bromo-5-(trifluoromethyl)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (30 mg, 0.08 mmol), N,N'-dimethylethylenediamine (9 mg, 0.10 mmol), cuprous iodide (16 mg, 0.08 mmol) and potassium carbonate (23 mg, 0.16 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(5mL)淬灭，混合液用二氯甲烷(6mL×2次)萃取，合并有机相，有机相用饱和食盐水(8mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到36mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (5 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (6 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (8 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 36 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:703.3[M+H]⁺.MS (ESI) M/Z: 703.3 [M + H] ⁺ .

步骤B:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(36mg,0.05mmol)溶于二氯甲烷(1mL)中。随后，向上述溶液中滴加三氟乙酸(1mL)，继续搅拌1小时。LCMS监测显示原料消失后，向反应液中滴加氨水(5mL)，继续搅拌2小时。Step B: At room temperature, the compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(tri 1-((((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (36 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL). Then, trifluoroacetic acid (1 mL) was added dropwise to the above solution and stirring was continued for 1 hour. After LCMS monitoring showed that the starting material disappeared, ammonia water (5 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

LCMS监测显示中间体消失后，向反应液中加水(8mL)淬灭，混合液用二氯甲烷(8mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到12.6mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (8 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (8 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 12.6 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:573.2[M+H]⁺.MS (ESI) M/Z: 573.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.40(s,1H),8.39(s,1H),7.77(s,1H),7.71(s,1H),7.55(s,1H),7.37(s,1H),6.27(s,1H),3.59(s,2H),3.32(s,3H),3.20-3.11(m,2H),2.81-2.71(m,2H),2.40-2.27(m,3H),1.94-1.83(m,1H),1.68-1.53(m,4H),1.50-1.39(m,1H),1.09(d,J＝5.6Hz,3H),0.88-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.40(s,1H),8.39(s,1H),7.77(s,1H),7.71(s,1H),7.55(s,1H),7.37(s,1H),6.27(s,1H ),3.59(s,2H),3.32(s,3H),3.20-3.11(m,2H ),2.81-2.71(m,2H),2.40-2.27(m,3H),1.94-1.83(m,1H),1.68-1.53(m,4H),1.50-1.39(m,1H),1.09(d ,J＝5.6Hz,3H),0.88-0.72(m,4H).

实施例46Embodiment 46

2-((1S,3R)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈
2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2-((1R,3R)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈(70mg,0.21mmol)和(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(86mg,0.21mmol)溶于二甲基亚砜(1.1mL)中。随后，向上述溶液中依次加入N,N'-二甲基乙二胺(18mg,0.21mmol)、碘化亚铜(40mg,0.21mmol)和碳酸钾(58mg,0.42mmol)。然后该反应体系在150℃条件下搅拌3小时。Step A: Under nitrogen protection at room temperature, compound 2-((1R,3R)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (70 mg, 0.21 mmol) and (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (86 mg, 0.21 mmol) were dissolved in dimethyl sulfoxide (1.1 mL). Subsequently, N,N'-dimethylethylenediamine (18 mg, 0.21 mmol), cuprous iodide (40 mg, 0.21 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到50mg 2-((1S,3R)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

MS(ESI)M/Z:330.7[M/2+H]⁺.MS (ESI) M/Z: 330.7 [M/2+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物2-((1S,3R)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈(50mg,0.08mmol)溶于二氯甲烷(0.8mL)中。随后，向上述溶液中滴加三氟乙酸(0.8mL)，继续搅拌2小时。然后降温至0℃，缓慢滴加氨水(5.0mL)，升至室温，继续搅拌2小时。Step B: Under nitrogen protection at room temperature, compound 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (50 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL). Subsequently, trifluoroacetic acid (0.8 mL) was added dropwise to the above solution and stirring was continued for 2 hours. Then the temperature was lowered to 0°C, ammonia water (5.0 mL) was slowly added dropwise, the temperature was raised to room temperature, and stirring was continued for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到17.7mg 2-((1S,3R)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 17.7 mg 2-((1S,3R)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

MS(ESI)M/Z:530.3[M+H]⁺.MS (ESI) M/Z: 530.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.41(s,1H),7.49(t,J＝8.2Hz,1H),7.42(s,1H),7.36-7.30(m,2H),7.20-7.14(m,1H),6.26(s,1H),3.59(s,2H),3.31(s,3H),3.18-3.09(m,2H),2.81-2.69(m,4H),2.61-2.51(m,2H),2.49-2.41(m,1H),1.94-1.81(m,1H),1.67-1.37(m,5H),0.87-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.41(s,1H),7.49(t,J＝8.2Hz,1H),7.42(s,1H),7.36-7.30(m,2H),7.20-7.14(m ,1H),6.26(s,1H),3.59(s,2H),3.31(s, 3H),3.18-3.09(m,2H),2.81-2.69(m,4H),2.61-2.51(m,2H),2.49-2 .41(m,1H),1.94-1.81(m,1H),1.67-1.37(m,5H),0.87-0.72(m,4H).

实施例47 Embodiment 47

(S)-3'-(4-氯-2-((3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)-4-氟-N,N-二甲基-[1,1'-联苯]-2-羧酰胺
(S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，将化合物5-氟-2-碘苯甲酸(1.50g,5.64mmol)溶于N,N-二甲基甲酰胺(28mL)中。随后，向上述溶液中依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(2.57g,6.77mmol)和N,N-二异丙基乙胺(2.18g,16.92mmol)，搅拌30分钟。然后再滴加二甲胺(50％wt)(609mg,8.46mmol)，继续搅拌1小时。Step A: Dissolve the compound 5-fluoro-2-iodobenzoic acid (1.50 g, 5.64 mmol) in N,N-dimethylformamide (28 mL) at room temperature. Then, add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.57 g, 6.77 mmol) and N,N-diisopropylethylamine (2.18 g, 16.92 mmol) to the above solution in sequence and stir for 30 minutes. Then add dimethylamine (50% wt) (609 mg, 8.46 mmol) dropwise and continue stirring for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(50mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.5g 5-氟-2-碘-N,N-二甲基苯甲酰胺。After LCMS monitoring showed that the raw material disappeared, water (50 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.5 g 5-fluoro-2-iodo-N,N-dimethylbenzamide.

MS(ESI)M/Z:294.0[M+H]⁺.MS (ESI) M/Z: 294.0 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将5-氟-2-碘-N,N-二甲基苯甲酰胺(500mg,1.71mmol)、2-(3-溴苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(530mg,1.87mmol)、碳酸钠(450mg,4.26mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(110mg,0.17mmol)溶于1,4-二氧六环(6mL)和水(0.6mL)中。然后该反应体系在90℃下搅拌16小时。Step B: Under nitrogen protection at room temperature, 5-fluoro-2-iodo-N,N-dimethylbenzamide (500 mg, 1.71 mmol), 2-(3-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (530 mg, 1.87 mmol), sodium carbonate (450 mg, 4.26 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (110 mg, 0.17 mmol) were dissolved in 1,4-dioxane (6 mL) and water (0.6 mL). The reaction system was then stirred at 90°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(30mL)淬灭，混合液用乙酸乙酯(20mL×2次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到400mg 3'-溴-4-氟-N,N-二甲基-[1,1'-联苯]-2-甲酰胺。After LCMS monitoring showed that the raw material disappeared, water (30 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg 3'-bromo-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

MS(ESI)M/Z:322.0[M+H]⁺.MS (ESI) M/Z: 322.0 [M + H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物3'-溴-4-氟-N,N-二甲基-[1,1'-联苯]-2-甲酰胺(400mg,1.25mmol)、(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(200mg,0.49mmol)、碳酸钾(206mg,1.49mmol)和碘化亚铜(236mg,1.24mmol)溶于二甲基亚砜(3.0mL)中。然后该反应体系在150℃条件下搅拌3小时。Step C: Under nitrogen protection at room temperature, compound 3'-bromo-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide (400 mg, 1.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.49 mmol), potassium carbonate (206 mg, 1.49 mmol) and cuprous iodide (236 mg, 1.24 mmol) were dissolved in dimethyl sulfoxide (3.0 mL). The reaction system was then stirred at 150° C. for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(8mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到200mg(S)-3'-(4-氯-2-((3-甲基哌啶-1-基)甲基)-7-氧代-1-(2-(三甲基甲硅烷基)乙氧基)甲基-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-4-氟-N,N-二甲基-[1,1'-联苯]-2-甲酰胺。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (8 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

MS(ESI)M/Z:651.2[M+H]⁺.MS (ESI) M/Z: 651.2 [M+H] ⁺ .

步骤D：在室温条件下，将化合物(S)-3'-(4-氯-2-((3-甲基哌啶-1-基)甲基)-7-氧代-1-(2-(三甲基甲硅烷基)乙氧基)甲基-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-4-氟-N,N-二甲基-[1,1'-联苯]-2-甲酰胺(200mg,0.31mmol)溶于二氯甲烷(1.5mL)中。随后，向上述溶液中滴加三氟乙酸(1.5mL)。然后该反应体系继续搅拌2小时。 Step D: Compound (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide (200 mg, 0.31 mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (1.5 mL) was then added dropwise to the solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到89.47mg(S)-3'-(4-氯-2-((3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)-4-氟-N,N-二甲基-[1,1'-联苯]-2-羧酰胺。After LCMS monitoring showed that the raw material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 89.47 mg (S)-3'-(4-chloro-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-4-fluoro-N,N-dimethyl-[1,1'-biphenyl]-2-carboxamide.

MS(ESI)M/Z:521.3[M+H]⁺.MS (ESI) M/Z: 521.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),7.64-7.54(m,2H),7.53-7.47(m,1H),7.46-7.35(m,4H),7.26(dd,J＝9.2,2.8Hz,1H),6.28(s,1H),3.60(s,2H),2.86-2.72(m,5H),2.52(s,3H),1.97-1.82(m,1H),1.69-1.53(m,4H),1.52-1.39(m,1H),0.88-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),7.64-7.54(m,2H),7.53-7.47(m,1H),7.46-7.35(m,4H),7.26(dd,J＝9.2,2.8Hz,1H) ,6.28(s,1H),3. 60(s,2H),2.86-2.72(m,5H),2.52(s,3H),1.97-1.82(m,1H),1.69-1.53(m,4H),1.52-1.39(m,1H), 0.88-0.73(m,4H).

实施例48Embodiment 48

4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl-2,2,6,6- _d4 )methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(3-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((((R)-3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((((R)-3-methylpiperidin-1-yl-2,2,6,6-d ₄ )methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，将化合物3-甲基哌啶-2,6-二酮(2.0g,15.74mmol)溶于N,N-二甲基甲酰胺(52mL)中。随后，向上述溶液中依次加入碳酸钾(4.35g,31.48mmol)和溴化苄(3.77g,22.04mmol)。然后该反应体系在45℃条件下搅拌16小时。Step A: Dissolve the compound 3-methylpiperidine-2,6-dione (2.0 g, 15.74 mmol) in N,N-dimethylformamide (52 mL) at room temperature. Then, potassium carbonate (4.35 g, 31.48 mmol) and benzyl bromide (3.77 g, 22.04 mmol) were added to the solution in sequence. The reaction system was then stirred at 45°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加入水(150mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.55g 1-苄基-3-甲基哌啶-2,6-二酮。After LCMS monitoring showed that the raw material disappeared, water (150 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.55 g 1-benzyl-3-methylpiperidine-2,6-dione.

MS(ESI)M/Z:218.3[M+H]⁺. MS (ESI) M/Z: 218.3 [M + H] ⁺ .

步骤B:在-78℃条件下，氮气保护，将化合物1-苄基-3-甲基哌啶-2,6-二酮(500mg,2.30mmol)溶于干燥的四氢呋喃(11.5mL)中。随后，向上述溶液中加入氘代氢化铝锂(193mg,4.60mmol)。然后该反应体系在室温条件下搅拌3小时。Step B: Under nitrogen protection at -78°C, compound 1-benzyl-3-methylpiperidine-2,6-dione (500 mg, 2.30 mmol) was dissolved in dry tetrahydrofuran (11.5 mL). Subsequently, lithium aluminum hydride (193 mg, 4.60 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 3 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)和乙酸乙酯(30mL)的混合溶液中。混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到185mg 1-苄基-3-甲基哌啶-2,2,6,6-d₄。After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into a mixed solution of ice water (30 mL) and ethyl acetate (30 mL). The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 185 mg of 1-benzyl-3-methylpiperidine-2,2,6,6-d ₄ .

MS(ESI)M/Z:194.4[M+H]⁺.MS (ESI) M/Z: 194.4 [M + H] ⁺ .

步骤C:在室温条件下，将化合物1-苄基-3-甲基哌啶-2,2,6,6-d₄(185mg,0.96mmol)溶于甲醇(5.5mL)中。随后，向上述溶液中加入10％湿钯碳(37mg)。然后该反应体系在氢气氛围条件下继续搅拌16小时。Step C: Dissolve the compound 1-benzyl-3-methylpiperidine-2,2,6,6-d ₄ (185 mg, 0.96 mmol) in methanol (5.5 mL) at room temperature, then add 10% wet palladium carbon (37 mg) to the solution, and then continue to stir the reaction system under hydrogen atmosphere for 16 hours.

LCMS监测显示原料消失后，将上述反应液过滤。然后向滤液中滴加4M盐酸的1,4-二氧六环溶液(1.0mL)，减压浓缩得到102mg 3-甲基哌啶-2,2,6,6-d₄盐酸盐。After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, and then a 4M hydrochloric acid solution in 1,4-dioxane (1.0 mL) was added dropwise to the filtrate, and the mixture was concentrated under reduced pressure to obtain 102 mg of 3-methylpiperidine-2,2,6,6-d ₄ hydrochloride.

MS(ESI)M/Z:104.3[M+H]⁺.MS (ESI) M/Z: 104.3 [M + H] ⁺ .

步骤D:在室温条件下，将化合物4-氯-2-(氯甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(205mg,0.57mmol)溶于乙腈(2.9mL)中。随后，向上述溶液中依次加入碳酸钾(157mg,1.14mmol)、碘化钾(95mg,0.57mmol)和3-甲基哌啶-2,2,6,6-d₄盐酸盐(102mg,0.74mmol)。然后该反应体系在室温条件下搅拌4小时。Step D: Compound 4-chloro-2-(chloromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (205 mg, 0.57 mmol) was dissolved in acetonitrile (2.9 mL) at room temperature. Subsequently, potassium carbonate (157 mg, 1.14 mmol), potassium iodide (95 mg, 0.57 mmol) and 3-methylpiperidine-2,2,6,6-d ₄ hydrochloride (102 mg, 0.74 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 4 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到175mg 4-氯-7-甲氧基-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 175 mg of 4-chloro-7-methoxy-2-((3-methylpiperidin-1-yl-2,2,6,6-d ₄ )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:428.4[M+H]⁺.MS (ESI) M/Z: 428.4 [M+H] ⁺ .

步骤E:在室温条件下，将化合物4-氯-7-甲氧基-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(175mg,0.41mmol)溶于乙腈(2.1mL)中。随后，向上述溶液中依次加入碘化钠(93mg,0.62mmol)和三甲基氯硅烷(68mg,0.62mmol)。然后该反应体系在室温条件下搅拌2小时。Step E: Dissolve the compound 4-chloro-7-methoxy-2-((3-methylpiperidin-1-yl-2,2,6,6- _d4 )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (175 mg, 0.41 mmol) in acetonitrile (2.1 mL) at room temperature. Then, sodium iodide (93 mg, 0.62 mmol) and trimethylsilyl chloride (68 mg, 0.62 mmol) were added to the solution in sequence. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加饱和碳酸氢钠溶液(10mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到105mg 4-氯-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 105 mg of 4-chloro-2-((3-methylpiperidin-1-yl-2,2,6,6-d ₄ )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:414.2[M+H]⁺.MS (ESI) M/Z: 414.2 [M+H] ⁺ .

步骤F:在室温条件下，氮气保护，将化合物4-氯-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(105mg,0.25mmol)、3-((1S,3S)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(85mg,0.28mmol)和N,N'-二甲基乙二胺(26mg,0.30mmol)溶于二甲基亚砜(2.5mL)中。随后，向上述溶液中加入碘化亚铜(48mg,0.25mmol)和碳酸钾(69mg,0.50mmol)。然后该反应体系在150℃条件下搅拌3小时。Step F: Under nitrogen protection at room temperature, compound 4-chloro-2-((3-methylpiperidin-1-yl-2,2,6,6-d ₄ )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (105 mg, 0.25 mmol), 3-((1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (85 mg, 0.28 mmol) and N,N'-dimethylethylenediamine (26 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (2.5 mL). Subsequently, cuprous iodide (48 mg, 0.25 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to the above solution. The reaction system was then stirred at 150° C. for 3 hours.

LCMS监测显示原料消失后，将上述反应液过滤，所得滤液加水(25mL)稀释。混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到125mg 4-氯-6-(3-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered and the filtrate was diluted with water (25 mL). The mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 125 mg of 4-chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl-2,2,6,6-d ₄ )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:639.4[M+H]⁺.MS (ESI) M/Z: 639.4 [M + H] ⁺ .

步骤G:在室温条件下，将化合物4-氯-6-(3-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基-2,2,6,6-d₄)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(125mg,0.20mmol)溶于二氯甲烷(1.0mL)中。随后，向上述溶液中滴加三氟乙酸(1.0mL)。然后该反应体系在室温条件下搅拌3小时。Step G: Compound 4-chloro-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl-2,2,6,6- _d4 )methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (125 mg, 0.20 mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Subsequently, trifluoroacetic acid (1.0 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 3 hours.

LCMS监测显示原料消失后，向反应液中滴加30％氨水调至pH＝8，加水(10mL)稀释。混合液用二氯甲烷(10mL×3次)萃取，合并有机相，减压浓缩，所得残余物用硅胶柱层析纯化，得到100mg粗品。然后再手性拆分(色谱柱：Daicel AD-3,流动相：EtOH[1％NH₃(7M in MeOH))，得化合物48-P1(保留时间2.316min)和化合物48-P2(保留时间2.803min).After LCMS monitoring showed that the raw material disappeared, 30% ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and water (10 mL) was added to dilute. The mixed solution was extracted with dichloromethane (10 mL × 3 times), the organic phases were combined, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 100 mg of crude product. Then chiral separation (chromatographic column: Daicel AD-3, mobile phase: EtOH [1% NH ₃ (7M in MeOH)) was performed to obtain compound 48-P1 (retention time 2.316 min) and compound 48-P2 (retention time 2.803 min).

化合物48-P1:Compound 48-P1:

MS(ESI)M/Z:509.2[M+H]⁺.MS (ESI) M/Z: 509.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.29(s,1H),7.50(t,J＝7.8Hz,1H),7.46(t,J＝1.8Hz,1H), 7.44(s,1H),7.36-7.29(m,2H),6.26(s,1H),3.59(s,2H),3.24(s,3H),2.94-2.82(m,2H),2.59-2.51(m,3H),1.66-1.50(m,3H),1.49-1.39(m,1H),1.07(d,J＝5.2Hz,3H),0.85-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.36(s,1H),8.29(s,1H),7.50(t,J＝7.8Hz,1H),7.46(t,J＝1.8Hz,1H) , 7.44(s,1H),7.36-7.29(m,2H),6.26(s,1H),3.59(s,2H),3.24(s,3H),2.94-2.82(m,2H),2.5 9-2.51(m,3H),1.66-1.50(m,3H),1.49-1.39(m,1H),1.07(d,J＝5.2Hz,3H),0.85-0.73(m,4H).

化合物48-P2:Compound 48-P2:

MS(ESI)M/Z:509.2[M+H]⁺.MS (ESI) M/Z: 509.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.29(s,1H),7.50(t,J＝7.8Hz,1H),7.46(t,J＝1.8Hz,1H),7.44(s,1H),7.37-7.29(m,2H),6.26(s,1H),3.59(s,2H),3.24(s,3H),2.94-2.82(m,2H),2.59-2.51(m,3H),1.66-1.52(m,3H),1.49-1.38(m,1H),1.07(d,J＝5.2Hz,3H),0.87-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),8.29(s,1H),7.50(t,J＝7.8Hz,1H),7.46(t,J＝1.8Hz,1H),7.44(s,1H),7.37- 7.29(m,2H),6.26(s,1H),3.59(s,2H) ,3.24(s,3H),2.94-2.82(m,2H),2.59-2.51(m,3H),1.66-1.52(m,3H),1.49-1.38(m,1H),1.07(d,J＝ 5.2Hz,3H),0.87-0.73(m,4H).

实施例49Embodiment 49

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在-45℃条件下，氮气保护，将化合物4-甲基-4H-1,2,4-三唑(935mg,11.15mmol)溶于乙二醇二甲醚(52mL)中。随后，向上述溶液中缓慢滴加2.5M正丁基锂的正己烷溶液(4.5mL,11.15mmol)，搅拌30分钟后。然后再滴加3-溴-5-(三氟甲氧基)苯甲醛(3g,11.15mmol)的乙二醇二甲醚(3mL)溶液。然后该反应体系在0℃条件下搅拌1小时。Step A: Under nitrogen protection at -45°C, compound 4-methyl-4H-1,2,4-triazole (935 mg, 11.15 mmol) was dissolved in ethylene glycol dimethyl ether (52 mL). Subsequently, 2.5 M n-butyl lithium in n-hexane solution (4.5 mL, 11.15 mmol) was slowly added dropwise to the above solution and stirred for 30 minutes. Then, a solution of 3-bromo-5-(trifluoromethoxy)benzaldehyde (3 g, 11.15 mmol) in ethylene glycol dimethyl ether (3 mL) was added dropwise. The reaction system was then stirred at 0°C for 1 hour.

LCMS监测显示原料消失后，向反应液中先加入饱和氯化铵水溶液(10mL)淬灭，再加水(80mL)稀释。混合液用二氯甲烷(40mL×2次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.3g(3-溴-5-(三氟甲氧基)苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench, and then water (80 mL) was added to dilute. The mixed solution was extracted with dichloromethane (40 mL × 2 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.3 g (3-bromo-5-(trifluoromethoxy)phenyl) (4-methyl-4H-1,2,4-triazol-3-yl) methanol.

MS(ESI)M/Z:351.9[M+H]⁺.MS (ESI) M/Z: 351.9 [M+H] ⁺ .

步骤B：在0℃条件下，氮气保护，将化合物(3-溴-5-(三氟甲氧基)苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇(1.3g,3.69mmol)溶于四氢呋喃(40mL)中。随后，向上述溶液中加入咪唑(1.25g,18.45mmol)、碘(3.28g,12.91mmol)和三苯基膦(3.38g,12.91mmol)。然后该反应体系在80℃条件下搅拌3小时。Step B: Under nitrogen protection at 0°C, compound (3-bromo-5-(trifluoromethoxy)phenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (1.3 g, 3.69 mmol) was dissolved in tetrahydrofuran (40 mL). Subsequently, imidazole (1.25 g, 18.45 mmol), iodine (3.28 g, 12.91 mmol) and triphenylphosphine (3.38 g, 12.91 mmol) were added to the above solution. The reaction system was then stirred at 80°C for 3 hours.

LCMS监测显示原料消失后，向反应液中滴加10％的硫代硫酸钠水溶液至反应液无色，再加入水(40mL)稀释。混合液用二氯甲烷(50mL×2次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到600mg 3-(3-溴-5-(三氟甲氧基)苄基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, 10% sodium thiosulfate aqueous solution was added dropwise to the reaction solution until the reaction solution was colorless, and then water (40 mL) was added to dilute it. The mixed solution was extracted with dichloromethane (50 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 600 mg 3-(3-bromo-5-(trifluoromethoxy)benzyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:335.9[M+H]⁺.MS (ESI) M/Z: 335.9 [M + H] ⁺ .

步骤C：在0℃条件下，氮气保护，将化合物3-(3-溴-5-(三氟甲氧基)苄基)-4-甲基-4H-1,2,4-三唑(600mg,1.78mmol)和1,3-二溴-2-甲基丙烷(384mg,1.78mmol)溶于四氢呋喃(18mL)中。随后，向上述溶液中缓慢滴加1M双三甲基硅基胺基锂的四氢呋喃溶液(3.6mL,3.56mmol)。然后该反应体系继续搅拌1小时。Step C: Under nitrogen protection at 0°C, compound 3-(3-bromo-5-(trifluoromethoxy)benzyl)-4-methyl-4H-1,2,4-triazole (600 mg, 1.78 mmol) and 1,3-dibromo-2-methylpropane (384 mg, 1.78 mmol) were dissolved in tetrahydrofuran (18 mL). Subsequently, 1M lithium bistrimethylsilylamide tetrahydrofuran solution (3.6 mL, 3.56 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred for 1 hour.

LCMS监测显示原料消失后，向上述反应液中加入饱和氯化铵水溶液(2mL)淬灭，再加水(20mL)稀释。混合液用二氯甲烷(15mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到280mg 3-(1-(3-溴-5-(三氟甲氧基)苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the starting material disappeared, saturated aqueous ammonium chloride solution (2 mL) was added to the above reaction solution to quench, and then water (20 mL) was added to dilute. The mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 280 mg of 3-(1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:MS 390.2[M+H]⁺.MS(ESI)M/Z:MS 390.2[M+H] ⁺ .

所得粗品经制备型高效液相色谱纯化，得到130mg化合物P1(保留时间短)和60mg化合物P2(保留时间长)。The crude product was purified by preparative HPLC to obtain 130 mg of compound P1 (short retention time) and 60 mg of compound P2 (long retention time).

化合物P1Compound P1

¹H NMR(400MHz,CD₃Cl)δ8.05(s,1H),7.43(t,J＝1.6Hz,1H),7.30(s,1H),7.15(s,1H),3.22(s,3H),2.84-2.74(m,2H),2.73-2.58(m,3H),1.15(d,J＝6.0Hz,3H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.05(s,1H),7.43(t,J＝1.6Hz,1H),7.30(s,1H),7.15(s,1H),3.22(s,3H),2.84-2.74(m, 2H),2.73-2.58(m,3H),1.15(d,J＝6.0Hz,3H).

化合物P2Compound P2

¹H NMR(400MHz,CD₃Cl)δ8.10(s,1H),7.27(s,2H),7.00(s,1H),3.26(s,3H),3.20-3.10(m,2H),2.66-2.49(m,1H),2.30-2.19(m,2H),1.13(d,J＝6.8Hz,3H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.10(s,1H),7.27(s,2H),7.00(s,1H),3.26(s,3H),3.20-3.10(m,2H),2.66-2.49(m,1H), 2.30-2.19(m,2H),1.13(d,J＝6.8Hz,3H).

步骤D：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(123mg,0.30mmol)、3-((1S,3S)-1-(3-溴-5-(三氟甲氧基)苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(120mg,0.30mmol)、N,N'-二甲基乙二胺(32mg,0.36mmol)、碘化亚铜(57mg,0.30mmol)和碳酸钾(83mg,0.60mmol)溶于二甲基亚砜(2.0mL)中。然后该反应体系在150℃条件下搅拌3小时。Step D: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (123 mg, 0.30 mmol), 3-((1S,3S)-1-(3-bromo-5-(trifluoromethoxy)phenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (120 mg, 0.30 mmol), N,N'-dimethylethylenediamine (32 mg, 0.36 mmol), cuprous iodide (57 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (2.0 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到120mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 120 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:719.3[M+H]⁺.MS (ESI) M/Z: 719.3 [M + H] ⁺ .

步骤E:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(120mg,0.16mmol)溶于二氯甲烷(2mL)中。随后，向上述溶液中滴加三氟乙酸(2mL)，继续搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水(7mL)，继续搅拌2小时。Step E: Compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (120 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Subsequently, trifluoroacetic acid (2 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water (7 mL) was added dropwise to the reaction solution and stirring was continued for 2 hours.

LCMS监测显示中间体消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到23.8mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(三氟甲氧基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 23.8 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(trifluoromethoxy)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:589.2[M+H]⁺.MS (ESI) M/Z: 589.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.40(s,1H),8.31(s,1H),7.55(t,J＝1.6Hz,1H),7.52(s,1H),7.48(s,1H),7.23(s,1H),6.27(s,1H),3.59(s,2H),3.27(s,3H),2.96-2.85(m,2H),2.82-2.70(m,2H),2.62-2.51(m,3H),1.95-1.83(m,1H),1.67-1.53(m,4H),1.51-1.39(m,1H),1.07(d,J＝5.6Hz,3H),0.88-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.40(s,1H),8.31(s,1H),7.55(t,J＝1.6Hz,1H),7.52(s,1H),7.48( s,1H),7.23(s,1H),6.27(s,1H),3.59(s,2H),3.27(s,3H),2.96-2.85( m,2H),2.82-2.70(m,2H),2.62-2.51(m,3H),1.95-1.83(m,1H),1.67-1 .53(m,4H),1.51-1.39(m,1H),1.07(d,J＝5.6Hz,3H),0.88-0.73(m,4H).

实施例50Embodiment 50

2-((1R,3S)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈
2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2-(3-溴苯基)乙腈(10.0g,51.02mmol)溶于N,N-二甲基甲酰胺(100mL)中。随后，向上述溶液中分批加入氢化钠(4.49g,112.24mmol,60％)，搅拌10分钟。然后再滴加1,3-二溴-2,2-二甲氧基丙烷(14.70g,56.12mmol)升至60℃，继续搅拌16小时。Step A: Under nitrogen protection at room temperature, dissolve the compound 2-(3-bromophenyl)acetonitrile (10.0 g, 51.02 mmol) in N,N-dimethylformamide (100 mL). Then, add sodium hydride (4.49 g, 112.24 mmol, 60%) to the above solution in batches and stir for 10 minutes. Then add 1,3-dibromo-2,2-dimethoxypropane (14.70 g, 56.12 mmol) dropwise and raise the temperature to 60°C, and continue stirring for 16 hours.

LCMS监测显示原料消失后，将反应液倒入饱和的氯化铵溶液(400mL)中淬灭，混合液用乙酸乙酯(70mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到6.15g 1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-腈。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a saturated ammonium chloride solution (400 mL) for quenching, and the mixed solution was extracted with ethyl acetate (70 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.15 g 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile.

MS(ESI)M/Z:318.0[M+Na]⁺.MS (ESI) M/Z: 318.0 [M + Na] ⁺ .

步骤B:在0℃条件下，将化合物1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-腈(6.15g,20.85mmol)溶于乙醇(27mL)和水(25mL)中。随后，向上述溶液中缓慢加入氢氧化钠(2.51g,62.55mmol)。然后该反应体系在85℃条件下搅拌16小时。Step B: Dissolve the compound 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile (6.15 g, 20.85 mmol) in ethanol (27 mL) and water (25 mL) at 0°C. Then, slowly add sodium hydroxide (2.51 g, 62.55 mmol) to the solution. Then stir the reaction system at 85°C for 16 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)和乙酸乙酯(30mL)的混合溶液中淬灭，用2M的稀盐酸调至pH＝2。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到6.30g 1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-甲酸粗品。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (30 mL) and ethyl acetate (30 mL) to quench, and adjusted to pH = 2 with 2M dilute hydrochloric acid. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.30 g of 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid crude product was obtained.

MS(ESI)M/Z:315.1[M+H]⁺.MS (ESI) M/Z: 315.1 [M+H] ⁺ .

步骤C:在0℃条件下，氮气保护，将化合物1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-甲酸(6.30g,20.06mmol)溶于二氯甲烷(67mL)中。随后，向上述溶液中滴加三乙胺(4.05g,40.12mmol)和氯甲酸异丁酯(4.12g,30.09mmol)，搅拌10分钟。然后再滴加水合肼(2.57g,80.24mmol)，升至室温，继续搅拌3小时。Step C: Under nitrogen protection at 0°C, dissolve the compound 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (6.30 g, 20.06 mmol) in dichloromethane (67 mL). Then, add triethylamine (4.05 g, 40.12 mmol) and isobutyl chloroformate (4.12 g, 30.09 mmol) dropwise to the above solution and stir for 10 minutes. Then, add hydrazine hydrate (2.57 g, 80.24 mmol) dropwise, warm to room temperature, and continue stirring for 3 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(40mL)和二氯甲烷(30mL)的混合溶液中淬灭，混合液用二氯甲烷(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到4.02g 1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-甲酰肼。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (40 mL) and dichloromethane (30 mL) to quench, the mixed solution was extracted with dichloromethane (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 4.02 g 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid hydrazide.

MS(ESI)M/Z:297.2[M-N₂H₃]⁺.MS(ESI)M/Z:297.2[MN ₂ H ₃ ] ⁺ .

步骤D:在室温条件下，氮气保护，将化合物1-(3-溴苯基)-3,3-二甲氧基环丁烷-1-甲酰肼(4.02g,12.25mmol)溶于四氢呋喃(61mL)中。随后，向上述溶液中加入异硫氰酸甲酯(2.68g,36.75mmol)，升至65℃，搅拌1小时。然后降至0℃，滴加10M氢氧化钾水溶液(61.25mmol,6.1mL)，升至65℃，继续搅拌3小时。Step D: Under nitrogen protection at room temperature, the compound 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carboxylic acid hydrazide (4.02 g, 12.25 mmol) was dissolved in tetrahydrofuran (61 mL). Subsequently, methyl isothiocyanate (2.68 g, 36.75 mmol) was added to the above solution, the temperature was raised to 65°C, and stirred for 1 hour. Then the temperature was lowered to 0°C, 10M potassium hydroxide aqueous solution (61.25 mmol, 6.1 mL) was added dropwise, the temperature was raised to 65°C, and stirring was continued for 3 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)和乙酸乙酯(30mL)的混合溶液中淬灭，用1M的稀盐酸调至pH＝2。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化得到3.81g 5-(1-(3-溴苯基)-3,3-二甲氧基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into a mixed solution of ice water (30 mL) and ethyl acetate (30 mL) to quench. The pH was adjusted to 2 with 1M dilute hydrochloric acid. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.81 g of 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol.

MS(ESI)M/Z:384.1[M+H]⁺.MS (ESI) M/Z: 384.1 [M+H] ⁺ .

步骤E:在0℃条件下，将化合物5-(1-(3-溴苯基)-3,3-二甲氧基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(3.81g,9.95mmol)溶于二氯甲烷(50mL)和醋酸(10mL)中。随后，向上述溶液中滴加双氧水(5.6mL,49.75mmol,30％)。然后该反应体系在室温条件下搅拌1小时。Step E: Compound 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (3.81 g, 9.95 mmol) was dissolved in dichloromethane (50 mL) and acetic acid (10 mL) at 0°C. Hydrogen peroxide (5.6 mL, 49.75 mmol, 30%) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)和二氯甲烷(30mL)的混合溶液中淬灭，用1M的氢氧化钠溶液调至pH＝2。混合液用二氯甲烷(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.91g 3-(1-(3-溴苯基)-3,3-二甲氧基环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (30 mL) and dichloromethane (30 mL) to quench, and adjusted to pH = 2 with 1M sodium hydroxide solution. The mixed solution was extracted with dichloromethane (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.91 g 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:352.2[M+H]⁺.MS (ESI) M/Z: 352.2 [M + H] ⁺ .

步骤F:在0℃条件下，将化合物3-(1-(3-溴苯基)-3,3-二甲氧基环丁基)-4-甲基-4H-1,2,4-三唑(2.91g,8.29mmol)溶于丙酮(41mL)中。随后，向上述溶液中滴加12M浓盐酸(20mL)。然后该反应体系在室温条件下搅拌16小时。Step F: Dissolve the compound 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (2.91 g, 8.29 mmol) in acetone (41 mL) at 0°C. Then, add 12M concentrated hydrochloric acid (20 mL) dropwise to the solution. The reaction system is then stirred at room temperature for 16 hours.

LCMS监测显示原料消失后，将反应液倒入冰水(20mL)和乙酸乙酯(30mL)的混合溶液中淬灭，用2M的氢氧化钠溶液调至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化得到1.11g 3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-酮。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (20 mL) and ethyl acetate (30 mL) to quench, and the pH was adjusted to 8 with 2M sodium hydroxide solution. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.11 g 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one.

MS(ESI)M/Z:306.1[M+H]⁺.MS (ESI) M/Z: 306.1 [M+H] ⁺ .

步骤G:在0℃条件下，氮气保护，将化合物3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-酮(500mg,1.64mmol)溶于四氢呋喃(10mL)中。随后，向上述溶液中加入氰甲基磷酸二乙酯(321mg,1.81mmol)和叔丁醇钾(203mg,1.81mmol)。然后该反应体系在室温条件下搅拌2小时。Step G: Under nitrogen protection at 0°C, compound 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one (500 mg, 1.64 mmol) was dissolved in tetrahydrofuran (10 mL). Subsequently, diethyl cyanomethylphosphonate (321 mg, 1.81 mmol) and potassium tert-butoxide (203 mg, 1.81 mmol) were added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到480mg 2-(3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烯基)乙腈。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 480 mg 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutenyl)acetonitrile.

MS(ESI)M/Z:329.1[M+H]⁺.MS (ESI) M/Z: 329.1 [M+H] ⁺ .

步骤H:在0℃条件下，将化合物2-(3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烯基)乙腈(480mg,1.46mmol)溶于乙醇(4.6mL)和异丙醇(4.6mL)中。随后，向上述溶液中缓慢加入硼氢化钠(162mg,4.38mmol)。然后该反应体系在60℃条件下搅拌6小时。Step H: Dissolve the compound 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutenyl)acetonitrile (480 mg, 1.46 mmol) in ethanol (4.6 mL) and isopropanol (4.6 mL) at 0°C. Then, slowly add sodium borohydride (162 mg, 4.38 mmol) to the above solution. Then stir the reaction system at 60°C for 6 hours.

LCMS监测显示原料消失后，将反应液倒入冰的饱和氯化铵溶液(30mL)中淬灭。混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(15mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到400mg粗品，所得粗品经手性拆分，得到135mg化合物Q1(保留时间短)和90mg化合物Q2(保留时间长)。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into an iced saturated ammonium chloride solution (30 mL) for quenching. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of crude product, and the resulting crude product was chirally resolved to obtain 135 mg of compound Q1 (short retention time) and 90 mg of compound Q2 (long retention time).

化合物Q1Compound Q1

MS(ESI)M/Z:331.2[M+H]⁺.MS (ESI) M/Z: 331.2 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d₆)δ8.33(s,1H),7.53-7.46(m,2H),7.39-7.32(m,2H),3.19(s,3H),2.92-2.80(m,2H),2.78-2.64(m,5H).1H NMR (400MHz, DMSO-d ₆ ) δ8.33(s,1H),7.53-7.46(m,2H),7.39-7.32(m,2H),3.19(s,3H),2.92-2.80(m, 2H),2.78-2.64(m,5H).

化合物Q2Compound Q2

MS(ESI)M/Z:331.2[M+H]⁺.MS (ESI) M/Z: 331.2 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d₆)δ8.41(s,1H),7.49-7.44(m,2H),7.36(t,J＝1.8Hz,1H),7.32(t,J＝8.0Hz,1H),7.18-7.12(m,1H),3.21(s,3H),3.13-3.04(m,2H),2.73(d,J＝6.4Hz,2H),2.29-2.51(m,1H),2.48-2.39(m,2H).1H NMR (400MHz, DMSO-d ₆ )δ8.41(s,1H),7.49-7.44(m,2H),7.36(t,J＝1.8Hz,1H),7.32(t,J＝8.0Hz,1H),7.18-7.12(m,1 H),3.21(s,3H),3.13-3.04(m,2H),2.73(d,J＝6.4Hz,2H),2.29-2.51(m,1H),2.48-2.39(m,2H).

步骤I：在室温条件下，氮气保护，将化合物P1(70mg,0.21mmol)和(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(86mg,0.21mmol)溶于二甲基亚砜(1.1mL)中。随后，向上述溶液中依次加入N,N'-二甲基乙二胺(18mg,0.21mmol)、碘化亚铜(40mg,0.21mmol)和碳酸钾(58mg,0.42mmol)。然后该反应体系在150℃条件下搅拌3小时。Step I: Compound P1 (70 mg, 0.21 mmol) and (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (86 mg, 0.21 mmol) were dissolved in dimethyl sulfoxide (1.1 mL) under nitrogen protection at room temperature. Subsequently, N,N'-dimethylethylenediamine (18 mg, 0.21 mmol), cuprous iodide (40 mg, 0.21 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到45mg 2-((1R,3S)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈。 After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 45 mg of 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

MS(ESI)M/Z:660.1[M+H]⁺.MS (ESI) M/Z: 660.1 [M+H] ⁺ .

步骤J：在室温条件下，将化合物2-((1R,3S)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈(45mg,0.07mmol)溶于二氯甲烷(0.7mL)中。随后，向上述溶液中加入滴加三氟乙酸(0.7mL)，搅拌2小时。然后降温至0℃，缓慢滴加氨水(5.0mL)，升至室温，继续搅拌2小时。Step J: Dissolve compound 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (45 mg, 0.07 mmol) in dichloromethane (0.7 mL) at room temperature. Then, trifluoroacetic acid (0.7 mL) was added dropwise to the above solution and stirred for 2 hours. Then, the temperature was lowered to 0°C, ammonia (5.0 mL) was slowly added dropwise, the temperature was raised to room temperature, and stirring was continued for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到22.69mg 2-((1R,3S)-3-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6H-吡咯并[2,3-c]吡啶-6-基)苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)乙腈。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 22.69 mg 2-((1R,3S)-3-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile.

MS(ESI)M/Z:530.3[M+H]⁺.MS (ESI) M/Z: 530.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),8.32(s,1H),7.55-7.49(m,2H),7.47(s,1H),7.37(d,J＝8.0Hz,1H),7.33(d,J＝7.6Hz,1H),6.28(s,1H),3.62(s,2H),3.26(s,3H),3.00-2.87(m,2H),2.84-2.64(m,7H),2.01-1.84(m,1H),1.68-1.53(m,4H),1.52-1.39(m,1H),0.89-0.74(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),8.32(s,1H),7.55-7.49(m,2H),7.47(s,1H),7.37(d,J＝8.0Hz,1H),7.33(d,J ＝7.6Hz,1H),6.28(s,1H),3.62(s,2 H),3.26(s,3H),3.00-2.87(m,2H),2.84-2.64(m,7H),2.01-1.84(m,1H),1.68-1.53(m,4H),1.52-1.39( m,1H),0.89-0.74(m,4H).

实施例51Embodiment 51

4-氯-6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物2-溴-6-氯-4-甲基吡啶(5g,24.3mmol)、环丙基硼酸(4.5g,52.0mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1g,1.2mmol)和磷酸钾(15g,71.9mmol)溶于甲苯/水(60mL/6mL)中。然后该反应体系在95℃条件下搅拌4小时。Step A: Under nitrogen protection at room temperature, compound 2-bromo-6-chloro-4-methylpyridine (5 g, 24.3 mmol), cyclopropylboronic acid (4.5 g, 52.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1 g, 1.2 mmol) and potassium phosphate (15 g, 71.9 mmol) were dissolved in toluene/water (60 mL/6 mL). The reaction system was then stirred at 95 ° C for 4 hours.

LCMS监测显示原料消失后，向反应液中加水(50mL)淬灭，混合液用乙酸乙酯(30mL×2次)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3.4g 2-氯-6-环丙基-4-甲基吡啶。After LCMS monitoring showed that the starting material disappeared, water (50 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (30 mL × 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.4 g 2-chloro-6-cyclopropyl-4-methylpyridine.

MS(ESI)M/Z:168.0[M+H]⁺.MS (ESI) M/Z: 168.0 [M+H] ⁺ .

步骤B：在-70℃条件下，氮气保护，将化合物2-氯-6-环丙基-4-甲基吡啶(3.4g,20.4mmol)溶于四氢呋喃(34mL)中。随后，向上述溶液中滴加2M二异丙基氨基锂的四氢呋喃/正庚烷溶液(25.5mL,51.0 mmol)，搅拌1小时。然后再加入碳酸二甲酯(2.7g,30.6mmol)，升温至0℃，继续搅拌2小时。Step B: Under nitrogen protection at -70°C, dissolve 2-chloro-6-cyclopropyl-4-methylpyridine (3.4 g, 20.4 mmol) in tetrahydrofuran (34 mL). Then, add 2M lithium diisopropylamide in tetrahydrofuran/n-heptane (25.5 mL, 51.0 mmol), stirred for 1 hour. Then dimethyl carbonate (2.7 g, 30.6 mmol) was added, the temperature was raised to 0°C, and stirring was continued for 2 hours.

LCMS监测显示原料消失后，向反应液中先加入饱和氯化铵水溶液(30mL)淬灭，混合液用乙酸乙酯(20mL×2次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3.2g 2-(2-氯-6-环丙基吡啶-4-基)乙酸甲酯。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.2 g of methyl 2-(2-chloro-6-cyclopropylpyridin-4-yl)acetate.

MS(ESI)M/Z:226.0[M+H]⁺.MS (ESI) M/Z: 226.0 [M+H] ⁺ .

步骤C：在0℃条件下，氮气保护，将化合物2-(2-氯-6-环丙基吡啶-4-基)乙酸甲酯(3.2g,14.1mmol)和1,3-二溴-2-甲基丙烷(3.1g,14.3mmol)溶于四氢呋喃(70mL)中。随后，向上述溶液中缓慢加入60％wt氢化钠(1.25g,31.0mmol)。然后该反应体系继续搅拌4小时。Step C: Under nitrogen protection at 0°C, compound 2-(2-chloro-6-cyclopropylpyridin-4-yl)acetic acid methyl ester (3.2 g, 14.1 mmol) and 1,3-dibromo-2-methylpropane (3.1 g, 14.3 mmol) were dissolved in tetrahydrofuran (70 mL). Subsequently, 60% wt sodium hydride (1.25 g, 31.0 mmol) was slowly added to the above solution. The reaction system was then stirred for 4 hours.

LCMS监测显示原料消失后，向上述反应液中加入饱和氯化铵水溶液(10mL)淬灭，再加水(50mL)稀释。混合液用乙酸乙酯(40mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3g 1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-甲酸甲酯。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (10 mL) was added to the above reaction solution to quench, and then water (50 mL) was added to dilute. The mixed solution was extracted with ethyl acetate (40 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3 g of 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid methyl ester.

MS(ESI)M/Z:MS280.0[M+H]⁺.MS (ESI) M/Z: MS 280.0 [M+H] ⁺ .

步骤D：在室温条件下，将化合物1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-甲酸甲酯(3g,10.7mmol)溶于甲醇/四氢呋喃(40mL/10mL)中。随后，向上述溶液中加入氢氧化锂(770mg,32.1mmol)的水溶液(20mL)。然后该反应体系继续搅拌1小时。Step D: Dissolve the compound 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid methyl ester (3 g, 10.7 mmol) in methanol/tetrahydrofuran (40 mL/10 mL) at room temperature. Then, add an aqueous solution (20 mL) of lithium hydroxide (770 mg, 32.1 mmol) to the above solution. Then continue to stir the reaction system for 1 hour.

LCMS监测显示原料消失后，将上述反应液减压浓缩去除有机溶剂，接着用2M的稀盐酸水溶液调节至pH＝5。混合液用二氯甲烷(40mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩得到粗品2.2g 1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-甲酸。After LCMS monitoring showed that the raw material disappeared, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and then adjusted to pH = 5 with a 2M dilute hydrochloric acid solution. The mixed solution was extracted with dichloromethane (40 mL × 2 times), and the organic phases were combined. Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 2.2 g 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid.

MS(ESI)M/Z:MS266.0[M+H]⁺.MS (ESI) M/Z: MS 266.0 [M+H] ⁺ .

步骤E：在室温条件下，将化合物1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-甲酸(2.2g,8.27mmol)溶于N,N-二甲基甲酰胺(36mL)中。随后，向上述溶液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.08g,10.75mmol)和N,N-二异丙基乙胺(3.2g,24.81mmol)，搅拌10分钟。然后再加入N-甲基肼甲硫酰胺(1.04g,9.92mmol)，继续搅拌1小时。Step E: Dissolve the compound 1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (2.2 g, 8.27 mmol) in N,N-dimethylformamide (36 mL) at room temperature. Then, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.08 g, 10.75 mmol) and N,N-diisopropylethylamine (3.2 g, 24.81 mmol) to the above solution and stir for 10 minutes. Then add N-methylhydrazine methylthioamide (1.04 g, 9.92 mmol) and continue stirring for 1 hour.

LCMS监测显示原料消失后，向上述反应液中加水(50mL)淬灭，混合液用乙酸乙酯(50mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩。粗品用石油醚/乙酸乙酯(20mL/6mL)打浆得到2.5g 2-(1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺。After LCMS monitoring showed that the raw material disappeared, water (50 mL) was added to the above reaction solution to quench, and the mixed solution was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with petroleum ether/ethyl acetate (20 mL/6 mL) to obtain 2.5 g 2-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide.

MS(ESI)M/Z:MS 353.0[M+H]⁺.MS(ESI)M/Z:MS 353.0[M+H] ⁺ .

步骤F：在室温条件下，将化合物2-(1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺(2.5g,7.08mmol)溶于四氢呋喃(44mL)中。随后，向上述溶液中加入氢氧化钠(2.83g,70.8mmol)的水溶液(22mL)。然后该反应体系在80℃条件下搅拌4小时。Step F: Dissolve the compound 2-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (2.5 g, 7.08 mmol) in tetrahydrofuran (44 mL) at room temperature. Then, add an aqueous solution (22 mL) of sodium hydroxide (2.83 g, 70.8 mmol) to the above solution. Then, stir the reaction system at 80°C for 4 hours.

LCMS监测显示原料消失后，向反应液中滴加2M的稀盐酸水溶液调节至pH＝5。混合液用乙酸乙酯(30mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩得到粗品2.6g 5-(1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the starting material disappeared, 2M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 5. The mixed solution was extracted with ethyl acetate (30 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 2.6 g 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol.

MS(ESI)M/Z:MS 335.0[M+H]⁺.MS(ESI)M/Z:MS 335.0[M+H] ⁺ .

步骤G：在0℃条件下，将化合物5-(1-(2-氯-6-环丙基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(2.6g,7.78mmol)溶于二氯甲烷/乙酸(40mL/6mL)中。随后，向上述溶液中缓慢滴加30％wt双氧水(6mL)，继续搅拌30分钟。Step G: Dissolve the compound 5-(1-(2-chloro-6-cyclopropylpyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (2.6 g, 7.78 mmol) in dichloromethane/acetic acid (40 mL/6 mL) at 0°C. Then, slowly add 30% wt hydrogen peroxide (6 mL) to the solution and continue stirring for 30 minutes.

LCMS监测显示原料消失后，将上述反应液倒入冰水(80mL)中淬灭，混合液用二氯甲烷(30mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到混合物1g。将混合物450mg经制备型高效液相色谱纯化，得到240mg化合物X1(保留时间短)和60mg化合物X2(保留时间长)。After LCMS monitoring showed that the raw material disappeared, the above reaction solution was poured into ice water (80 mL) for quenching, and the mixed solution was extracted with dichloromethane (30 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1 g of the mixture. 450 mg of the mixture was purified by preparative high performance liquid chromatography to obtain 240 mg of compound X1 (short retention time) and 60 mg of compound X2 (long retention time).

化合物X1Compound X1

¹H NMR(400MHz,CD₃Cl)δ8.05(s,1H),7.07(d,J＝1.6Hz,1H),6.95(d,J＝1.2Hz,1H),3.23(s,3H),2.85-2.75(m,2H),2.70-2.61(m,3H),1.96-1.88(m,1H),1.14(d,J＝5.6Hz,3H),1.07-1.01(m,2H),1.00-0.95(m,2H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.05(s,1H),7.07(d,J＝1.6Hz,1H),6.95(d,J＝1.2Hz,1H),3.23(s,3H),2.85-2.75(m,2H) ,2 .70-2.61(m,3H),1.96-1.88(m,1H),1.14(d,J=5.6Hz,3H),1.07-1.01(m,2H),1.00-0.95(m,2H).

化合物X2Compound X2

¹H NMR(400MHz,CD₃Cl)δ8.12(s,1H),6.92(d,J＝1.2Hz,1H),6.81(d,J＝1.2Hz,1H),3.27(s,3H),3.19-3.06(m,2H),2.62-2.51(m,1H),2.32-2.19(m,2H),1.95-1.86(m,1H),1.13(d,J＝6.4Hz,3H),1.05-1.00(m,2H),0.99-0.93(m,2H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.12(s,1H),6.92(d,J＝1.2Hz,1H),6.81(d,J＝1.2Hz,1H),3.27(s,3H),3.19-3.06(m,2H) ,2.62-2.51 (m,1H),2.32-2.19(m,2H),1.95-1.86(m,1H),1.13(d,J＝6.4Hz,3H),1.05-1.00(m,2H),0.99-0.93(m ,2H).

步骤H：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(230mg,0.56mmol)、2-氯-6-环丙基-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(化合物X1,170mg,0.56mmol)、N,N'-二甲基乙二胺(59mg,0.67 mmol)、碘化亚铜(106mg,0.56mmol)和碳酸钾(155mg,1.12mmol)溶于二甲基亚砜(2.5mL)中。然后该反应体系在150℃条件下搅拌6小时。Step H: At room temperature, under nitrogen protection, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (230 mg, 0.56 mmol), 2-chloro-6-cyclopropyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (compound X1, 170 mg, 0.56 mmol), N,N'-dimethylethylenediamine (59 mg, 0.67 mmol), cuprous iodide (106 mg, 0.56 mmol) and potassium carbonate (155 mg, 1.12 mmol) were dissolved in dimethyl sulfoxide (2.5 mL), and the reaction system was stirred at 150°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到250mg 4-氯-6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 250 mg 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:676.3[M+H]⁺.MS (ESI) M/Z: 676.3 [M + H] ⁺ .

步骤I：在室温条件下，将化合物4-氯-6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(250mg,0.37mmol)溶于二氯甲烷(2.5mL)中。随后，向上述溶液中滴加三氟乙酸(3.0mL)，继续搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水(5.5mL)至碱性，继续搅拌16小时。Step I: Dissolve the compound 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (250 mg, 0.37 mmol) in dichloromethane (2.5 mL) at room temperature. Then, trifluoroacetic acid (3.0 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia (5.5 mL) was added dropwise to the reaction solution until it was alkaline and stirring was continued for 16 hours.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(15mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到90mg 4-氯-6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 90 mg 4-chloro-6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:546.2[M+H]⁺.MS (ESI) M/Z: 546.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.43(s,1H),8.34(s,1H),7.60(s,1H),7.47(d,J＝1.2Hz,1H),7.32(d,J＝1.6Hz,1H),6.25(s,1H),3.59(s,2H),3.28(s,3H),2.94-2.84(m,2H),2.82-2.70(m,2H),2.63-2.53(m,3H),2.24-2.15(m,1H),1.94-1.83(m,1H),1.66-1.53(m,4H),1.50-1.39(m,1H),1.08(d,J＝5.6Hz,3H),1.01-0.92(m,4H),0.85-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.43(s,1H),8.34(s,1H),7.60(s,1H),7.47(d,J＝1.2Hz,1H),7.32(d,J＝1.6 Hz,1H),6.25(s,1H),3.59(s,2H),3.28(s,3H),2.94-2.84(m,2H),2.82-2.70(m, 2H),2.63-2.53(m,3H),2.24-2.15(m,1H),1.94-1.83(m,1H),1.66-1.53(m,4H) ,1.50-1.39(m,1H),1.08(d,J＝5.6Hz,3H),1.01-0.92(m,4H),0.85-0.72(m,4H).

实施例52Embodiment 52

4-氯-6-(6-环丙基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(82mg,0.56mmol)、2-氯-6-环丙基-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(60mg,0.20mmol)、N,N'-二甲基乙二胺(21mg,0.24mmol)、碘化亚铜(38mg,0.20mmol)和碳酸钾(55mg,0.40mmol)溶于二甲基亚砜(1mL)中。然后该反应体系在150℃条件下搅拌6小时。Step A: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (82 mg, 0.56 mmol), 2-chloro-6-cyclopropyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (60 mg, 0.20 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol), cuprous iodide (38 mg, 0.20 mmol) and potassium carbonate (55 mg, 0.40 mmol) were dissolved in dimethyl sulfoxide (1 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到80mg 4-氯-6-(6-环丙基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:676.3[M+H]⁺.MS (ESI) M/Z: 676.3 [M + H] ⁺ .

步骤B：在室温条件下，将化合物4-氯-6-(6-环丙基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(80mg,0.12mmol)溶于二氯甲烷(2.2mL)中。随后，向上述溶液中滴加三氟乙酸(2.2 mL)，继续搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水(5.0mL)至碱性，继续搅拌4小时。Step B: Compound 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (80 mg, 0.12 mmol) was dissolved in dichloromethane (2.2 mL) at room temperature. Trifluoroacetic acid (2.2 mL) was then added dropwise to the solution. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia (5.0 mL) was added dropwise to the reaction solution until it became alkaline, and stirring was continued for 4 hours.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(15mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到7.9mg 4-氯-6-(6-环丙基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain 7.9 mg 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:546.2[M+H]⁺.MS (ESI) M/Z: 546.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.43(s,1H),8.40(s,1H),7.59(s,1H),7.34(d,J＝1.6Hz,1H),7.18(d,J＝1.6Hz,1H),6.25(s,1H),3.59(s,2H),3.34(s,3H),3.17-3.08(m,2H),2.81-2.70(m,2H),2.41-2.24(m,3H),2.22-2.13(m,1H),1.95-1.83(m,1H),1.66-1.53(m,4H),1.50-1.40(m,1H),1.10(d,J＝6.0Hz,3H),0.99-0.90(m,4H),0.86-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.43(s,1H),8.40(s,1H),7.59(s,1H),7.34(d,J＝1.6Hz,1H),7.18(d,J＝1.6 Hz,1H),6.25(s,1H),3.59(s,2H),3.34(s,3H),3.17-3.08(m,2H),2.81-2.70(m, 2H),2.41-2.24(m,3H),2.22-2.13(m,1H),1.95-1.83(m,1H),1.66-1.53(m,4H) ,1.50-1.40(m,1H),1.10(d,J＝6.0Hz,3H),0.99-0.90(m,4H),0.86-0.72(m,4H).

实施例53Embodiment 53

4-氯-6-(6-乙氧基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
4-Chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(45mg,0.11mmol)、2-氯-6-乙氧基-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(40mg,0.12mmol)、N,N'-二甲基乙二胺(10mg,0.11mmol)、碘化亚铜(21mg,0.11mmol)和碳酸钾(30mg,0.22mmol)溶于二甲基亚砜(0.5mL)中。然后该反应体系在150℃条件下搅拌3小时。Step A: Under nitrogen protection at room temperature, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 mg, 0.11 mmol), 2-chloro-6-ethoxy-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (40 mg, 0.12 mmol), N,N'-dimethylethylenediamine (10 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol) and potassium carbonate (30 mg, 0.22 mmol) were dissolved in dimethyl sulfoxide (0.5 mL). The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到55mg 4-氯-6-(6-乙氧基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:680.3[M+H]⁺.MS (ESI) M/Z: 680.3 [M + H] ⁺ .

步骤B：在0℃条件下，将化合物4-氯-6-(6-乙氧基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(55mg,0.08mmol)溶于二氯甲烷(0.8mL)中。随后，向上述溶液中滴加三氟乙酸(0.4mL)，然后该反应体系在室温条件下搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水至碱性，继续搅拌1小时。Step B: Compound 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (55 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL) at 0°C. Subsequently, trifluoroacetic acid (0.4 mL) was added dropwise to the above solution, and the reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution until it was alkaline and stirring was continued for 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到21.67mg 4-氯-6-(6-乙氧基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 21.67 mg 4-chloro-6-(6-ethoxy-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:550.2[M+H]⁺.MS (ESI) M/Z: 550.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.44(s,1H),8.41(s,1H),7.68(s,1H),7.15(d,J＝1.2Hz,1H),6.62(d,J＝1.2Hz,1H),6.26(s,1H),4.30(q,J＝7.2Hz,2H),3.59(s,2H),3.31(s,3H),3.13-3.04(m,2H),2.81-2.70(m,2H),2.42-2.21(m,3H),1.94-1.83(m,1H),1.66-1.53(m,4H),1.51-1.39(m,1H),1.32(t,J＝7.0Hz,3H),1.10(d,J＝6.0Hz,3H),0.86-0.74(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.44(s,1H),8.41(s,1H),7.68(s,1H),7.15(d,J＝1.2Hz,1H),6.62(d,J＝1.2Hz ,1H),6.26(s,1H),4.30(q,J＝7.2Hz,2H),3.59(s,2H),3.31(s,3H),3.13-3.04(m, 2H),2.81-2.70(m,2H),2.42-2.21(m,3H),1.94-1.83(m,1H),1.66-1.53(m,4H),1 .51-1.39(m,1H),1.32(t,J＝7.0Hz,3H),1.10(d,J＝6.0Hz,3H),0.86-0.74(m,4H).

实施例54Embodiment 54

4-氯-6-(3-乙氧基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，将化合物3-溴-5-羟基苯甲酸(5.0g,23.04mmol)溶于N,N-二甲基甲酰胺(52mL)中。随后，向上述溶液中依次加入碳酸钾(12.72g,92.16mmol)和碘乙烷(8.98g,57.60mmol)。然后该反应体系在50℃条件下搅拌2小时。Step A: Dissolve the compound 3-bromo-5-hydroxybenzoic acid (5.0 g, 23.04 mmol) in N,N-dimethylformamide (52 mL) at room temperature. Then, potassium carbonate (12.72 g, 92.16 mmol) and iodoethane (8.98 g, 57.60 mmol) were added to the solution in sequence. The reaction system was then stirred at 50°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加入乙酸乙酯(50mL)稀释，过滤。滤液用饱和食盐水(100mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，减压浓缩，得到6.1g 3-溴-5-乙氧基苯甲酸乙酯。After LCMS monitoring showed that the starting material disappeared, ethyl acetate (50 mL) was added to the reaction solution to dilute it and filter it. The filtrate was washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.1 g of ethyl 3-bromo-5-ethoxybenzoate.

MS(ESI)M/Z:273.0[M+H]⁺.MS (ESI) M/Z: 273.0 [M+H] ⁺ .

步骤B：在-70℃条件下，氮气保护，将化合物3-溴-5-乙氧基苯甲酸乙酯(6.1g,22.34mmol)溶于四氢呋喃(70mL)中。随后，向上述溶液中滴加2.5M氢化铝锂的四氢呋喃溶液(9.0mL,22.34mmol)。然后该反应体系在-50℃条件下搅拌1小时。Step B: Dissolve ethyl 3-bromo-5-ethoxybenzoate (6.1 g, 22.34 mmol) in tetrahydrofuran (70 mL) at -70 °C under nitrogen protection. Then, add 2.5 M lithium aluminum hydride tetrahydrofuran solution (9.0 mL, 22.34 mmol) dropwise to the above solution. Then, stir the reaction system at -50 °C for 1 hour.

LCMS监测显示原料消失后，将反应液倒入冰水(150mL)和乙酸乙酯(60mL)的混合溶液中淬灭。混合液用乙酸乙酯(30mL×2次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，得到5g(3-溴-5-乙氧基苯基)甲醇。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into a mixed solution of ice water (150 mL) and ethyl acetate (60 mL) to quench. The mixed solution was extracted with ethyl acetate (30 mL × 2 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5 g of (3-bromo-5-ethoxyphenyl)methanol.

MS(ESI)M/Z:230.9[M+H]⁺.MS (ESI) M/Z: 230.9 [M + H] ⁺ .

步骤C：在室温条件下，将化合物(3-溴-5-乙氧基苯基)甲醇(5g,21.64mmol)溶于二氯甲烷(100mL)中。随后，向上述溶液中分批加入戴斯-马丁氧化剂(11g,25.97mmol)。然后该反应体系继续搅拌1小时。Step C: Dissolve (3-bromo-5-ethoxyphenyl)methanol (5 g, 21.64 mmol) in dichloromethane (100 mL) at room temperature. Then, add Dess-Martin periodinane (11 g, 25.97 mmol) in batches to the solution. Then, continue stirring the reaction system for 1 hour.

LCMS监测显示原料消失后，向反应液中加入饱和碳酸氢钠水溶液/饱和硫代硫酸钠水溶液的混合液(20mL/20mL)淬灭，并加水(80mL)稀释。混合液用二氯甲烷(30mL×2次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到4.3g 3-溴-5-乙氧基苯甲醛。After LCMS monitoring showed that the raw material disappeared, a mixture of saturated sodium bicarbonate aqueous solution/saturated sodium thiosulfate aqueous solution (20 mL/20 mL) was added to the reaction solution to quench, and water (80 mL) was added to dilute. The mixed solution was extracted with dichloromethane (30 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (50 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 4.3 g 3-bromo-5-ethoxybenzaldehyde.

MS(ESI)M/Z:228.9[M+H]⁺.MS (ESI) M/Z: 228.9 [M + H] ⁺ .

步骤D：在-45℃条件下，氮气保护，将化合物4-甲基-4H-1,2,4-三唑(2.2g,26.29mmol)溶于乙二醇二甲醚(100mL)中。随后，向上述溶液中缓慢滴加2.5M正丁基锂的正己烷溶液(12mL,30.05mmol)，搅拌30分钟。然后再滴加3-溴-5-乙氧基苯甲醛(4.3g,18.78mmol)的乙二醇二甲醚(10mL)溶液，升温至0℃，继续搅拌1小时。Step D: Under nitrogen protection at -45°C, dissolve the compound 4-methyl-4H-1,2,4-triazole (2.2 g, 26.29 mmol) in ethylene glycol dimethyl ether (100 mL). Then, slowly add 2.5 M n-butyl lithium in n-hexane (12 mL, 30.05 mmol) to the above solution and stir for 30 minutes. Then, add 3-bromo-5-ethoxybenzaldehyde (4.3 g, 18.78 mmol) in ethylene glycol dimethyl ether (10 mL) and heat to 0°C. Continue stirring for 1 hour.

LCMS监测显示原料消失后，向反应液中先加入饱和氯化铵水溶液(15mL)淬灭，再加水(80mL) 稀释。接着混合液经减压浓缩，除去乙二醇二甲醚，所得混合液用二氯甲烷(80mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到5.0g(3-溴-5-乙氧基苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇。After LCMS monitoring showed that the starting material disappeared, saturated aqueous ammonium chloride solution (15 mL) was added to the reaction solution to quench, and then water (80 mL) was added. Dilute. Then the mixed solution was concentrated under reduced pressure to remove ethylene glycol dimethyl ether, and the obtained mixed solution was extracted with dichloromethane (80 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 5.0 g (3-bromo-5-ethoxyphenyl) (4-methyl-4H-1,2,4-triazol-3-yl) methanol.

MS(ESI)M/Z:312.0[M+H]⁺.MS (ESI) M/Z: 312.0 [M+H] ⁺ .

步骤E：在0℃条件下，氮气保护，将化合物(3-溴-5-乙氧基苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇(2.0g,6.41mmol)溶于四氢呋喃(60mL)中。随后，向上述溶液中依次加入咪唑(2.18g,32.05mmol)、碘单质(5.69g,22.43mmol)和三苯基膦(5.87g,22.43mmol)。然后该反应体系在80℃条件下搅拌3小时。Step E: Under nitrogen protection at 0°C, compound (3-bromo-5-ethoxyphenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (2.0 g, 6.41 mmol) was dissolved in tetrahydrofuran (60 mL). Subsequently, imidazole (2.18 g, 32.05 mmol), iodine (5.69 g, 22.43 mmol) and triphenylphosphine (5.87 g, 22.43 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加入10％的硫代硫酸钠水溶液至反应液无色，再加入水(60mL)稀释。混合液用二氯甲烷(60mL×2次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.9g 3-(3-溴-5-乙氧基苄基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, 10% sodium thiosulfate aqueous solution was added to the reaction solution until the reaction solution was colorless, and then water (60 mL) was added to dilute. The mixed solution was extracted with dichloromethane (60 mL × 2 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.9 g 3-(3-bromo-5-ethoxybenzyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:296.0[M+H]⁺.MS (ESI) M/Z: 296.0 [M+H] ⁺ .

步骤F：在0℃条件下，氮气保护，将化合物3-(3-溴-5-乙氧基苄基)-4-甲基-4H-1,2,4-三唑(1.9g,6.42mmol)和1,3-二溴-2-甲基丙烷(1.38g,6.42mmol)溶于四氢呋喃(35mL)中。随后，向上述溶液中缓慢滴加1M双三甲基硅基胺基锂的四氢呋喃溶液(12.8mL,12.84mmol)。然后该反应体系继续搅拌1小时。Step F: Under nitrogen protection at 0°C, compound 3-(3-bromo-5-ethoxybenzyl)-4-methyl-4H-1,2,4-triazole (1.9 g, 6.42 mmol) and 1,3-dibromo-2-methylpropane (1.38 g, 6.42 mmol) were dissolved in tetrahydrofuran (35 mL). Subsequently, 1M lithium bistrimethylsilylamide tetrahydrofuran solution (12.8 mL, 12.84 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred for 1 hour.

LCMS监测显示原料消失后，向上述反应液中加入饱和氯化铵水溶液(8mL)淬灭，再加水(40mL)稀释。混合液用二氯甲烷(30mL×2次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到异构体混合物700mg，经制备型高效液相色谱纯化，得到190mg化合物Y1(保留时间短)和80mg化合物Y2(保留时间长)。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (8 mL) was added to the above reaction solution to quench, and then water (40 mL) was added to dilute. The mixed solution was extracted with dichloromethane (30 mL × 2 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 700 mg of an isomer mixture, which was purified by preparative high performance liquid chromatography to obtain 190 mg of compound Y1 (short retention time) and 80 mg of compound Y2 (long retention time).

化合物Y1Compound Y1

¹H NMR(400MHz,CD₃Cl)δ8.11(s,1H),7.08(t,J＝1.6Hz,1H),6.93(t,J＝1.8Hz,1H),6.76(t,J＝2.0Hz,1H),3.95(q,J＝6.8Hz,2H),3.23(s,3H),2.84-2.73(m,2H),2.68-2.57(m,3H),1.38(t,J＝7.0Hz,3H),1.13(d,J＝5.6Hz,3H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.11(s,1H),7.08(t,J＝1.6Hz,1H),6.93(t,J＝1.8Hz,1H),6.76(t,J＝2.0Hz,1H),3.95(q ,J＝6.8Hz ,2H),3.23(s,3H),2.84-2.73(m,2H),2.68-2.57(m,3H),1.38(t,J＝7.0Hz,3H),1.13(d,J＝5.6Hz, 3H).

化合物Y2Compound Y2

¹H NMR(400MHz,CD₃Cl)δ8.13(s,1H),6.92(t,J＝1.6Hz,1H),6.89(t,J＝2.0Hz,1H),6.61(t,J＝1.8Hz,1H),3.94(q,J＝6.8Hz,2H),3.25(s,3H),3.13-3.04(m,2H),2.59-2.48(m,1H),2.29-2.19(m,2H),1.38(t,J＝7.0Hz,3H),1.11(d,J＝6.8Hz,3H). ¹ H NMR (400MHz, CD ₃ Cl)δ8.13(s,1H),6.92(t,J＝1.6Hz,1H),6.89(t,J＝2.0Hz,1H),6.61(t,J＝1.8Hz,1H),3.94(q ,J＝6.8Hz,2H),3.2 5(s,3H),3.13-3.04(m,2H),2.59-2.48(m,1H),2.29-2.19(m,2H),1.38(t,J＝7.0Hz,3H),1.11(d, J＝6.8Hz,3H).

步骤G：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(117mg,0.28mmol)、3-((1S,3S)-1-(3-溴-5-乙氧基苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(100mg,0.28mmol)、N,N'-二甲基乙二胺(30mg,0.34mmol)、碘化亚铜(54mg,0.28mmol)和碳酸钾(83mg,0.57mmol)溶于二甲基亚砜(1.5mL)中。然后该反应体系在150℃条件下搅拌3小时。Step G: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (117 mg, 0.28 mmol), 3-((1S,3S)-1-(3-bromo-5-ethoxyphenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (100 mg, 0.28 mmol), N,N'-dimethylethylenediamine (30 mg, 0.34 mmol), cuprous iodide (54 mg, 0.28 mmol) and potassium carbonate (83 mg, 0.57 mmol) were dissolved in dimethyl sulfoxide (1.5 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到130mg 4-氯-6-(3-乙氧基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 130 mg 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:679.4[M+H]⁺.MS (ESI) M/Z: 679.4 [M+H] ⁺ .

步骤H：在室温条件下，将化合物4-氯-6-(3-乙氧基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(130mg,0.19mmol)溶于二氯甲烷(1.5mL)中。随后，向上述溶液中滴加三氟乙酸(2mL)，搅拌2小时。然后降温至0℃，缓慢滴加氨水调节至pH＝8，继续搅拌2小时。Step H: Dissolve the compound 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (130 mg, 0.19 mmol) in dichloromethane (1.5 mL) at room temperature. Then, trifluoroacetic acid (2 mL) was added dropwise to the above solution and stirred for 2 hours. Then, the temperature was lowered to 0°C, and ammonia was slowly added dropwise to adjust the pH to 8, and stirring was continued for 2 hours.

LCMS监测显示中间体消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到58.7mg 4-氯-6-(3-乙氧基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the intermediate disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain 58.7 mg 4-chloro-6-(3-ethoxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:549.3[M+H]⁺.MS (ESI) M/Z: 549.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.34(s,1H),8.29(s,1H),7.42(s,1H),6.99(t,J＝1.6Hz,1H),6.92(t,J＝2.0Hz,1H),6.80(t,J＝2.0Hz,1H),6.25(s,1H),4.02(q,J＝6.8Hz,2H),3.59(s,2H),3.25(s,3H),2.92-2.82(m,2H),2.80-2.69(m,2H),2.59-2.51(m,3H),1.95-1.82(m,1H),1.72-1.52(m,4H),1.51-1.41(m,1H),1.31(t,J＝7.0Hz,3H),1.06(d,J＝5.2Hz,3H),0.89-0.71(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.34(s,1H),8.29(s,1H),7.42(s,1H),6.99(t,J＝1.6Hz,1H),6.92(t,J＝2.0Hz,1H) ,6.80(t,J＝2.0Hz,1H),6.25(s,1H),4.02(q,J＝6.8Hz,2H),3.59(s,2H),3.25(s,3H),2. 92-2.82(m,2H),2.80-2.69(m,2H),2.59-2.51(m,3H),1.95-1.82(m,1H),1.72-1.52(m, 4H),1.51-1.41(m,1H),1.31(t,J＝7.0Hz,3H),1.06(d,J＝5.2Hz,3H),0.89-0.71(m,4H).

参考上述实施例42-54的合成方法制备如下目标化合物：
The following target compounds were prepared by referring to the synthetic methods of Examples 42-54 above:

实施例61 Embodiment 61

(S)-4-氯-6-(3-(3-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-3-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
(S)-4-Chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetan-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2-(3-溴苯基)乙酸甲酯(36g,157.2mmol)溶于N,N-二甲基甲酰胺(270mL)中。随后，向上述溶液中依次加入多聚甲醛(19.2g,628.8mmol)和甲醇钠(1.73g,31.44mmol)。然后该反应体系在室温条件下搅拌48小时。Step A: Under nitrogen protection at room temperature, compound 2-(3-bromophenyl)acetic acid methyl ester (36 g, 157.2 mmol) was dissolved in N,N-dimethylformamide (270 mL). Subsequently, paraformaldehyde (19.2 g, 628.8 mmol) and sodium methoxide (1.73 g, 31.44 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 48 hours.

LCMS监测显示原料消失后，向反应液中加水(70mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到10g 2-(3-溴苯基)-3-羟基-2-(羟甲基)丙酸甲酯。After LCMS monitoring showed that the raw material disappeared, water (70 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10 g of methyl 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl) propionate.

MS(ESI)M/Z:289.0[M+H]⁺.MS (ESI) M/Z: 289.0 [M+H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物2-(3-溴苯基)-3-羟基-2-(羟甲基)丙酸甲酯(10g,36.46mmol)溶于四氢呋喃(182mL)中。随后，将上述溶液降温至-78℃，缓慢滴加2.5M氢化铝锂的四氢呋喃溶液(29mL,72.92mmol)。然后该反应体系在-78℃条件下继续搅拌1小时。Step B: Under nitrogen protection at room temperature, the compound 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propionic acid methyl ester (10 g, 36.46 mmol) was dissolved in tetrahydrofuran (182 mL). Subsequently, the solution was cooled to -78°C, and a 2.5 M tetrahydrofuran solution of lithium aluminum hydride (29 mL, 72.92 mmol) was slowly added dropwise. The reaction system was then stirred at -78°C for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3.4g 2-(3-溴苯基)-2-(羟甲基)丙烷-1,3-二醇。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.4 g 2-(3-bromophenyl)-2-(hydroxymethyl)propane-1,3-diol.

MS(ESI)M/Z:283.0[M+Na]⁺.MS (ESI) M/Z: 283.0 [M + Na] ⁺ .

步骤C:在室温条件下，将化合物2-(3-溴苯基)-2-(羟甲基)丙烷-1,3-二醇(3.4g,13.03mmol)溶于二氯甲烷(65mL)中。随后，向上述溶液中依次加入三乙胺(5.26g,52.12mmol)、4-二甲氨基吡啶(795mg,6.52mmol)和对甲苯磺酰氯(2.24g,11.73mmol)。然后该反应体系继续搅拌24小时。Step C: Dissolve the compound 2-(3-bromophenyl)-2-(hydroxymethyl)propane-1,3-diol (3.4 g, 13.03 mmol) in dichloromethane (65 mL) at room temperature. Then, triethylamine (5.26 g, 52.12 mmol), 4-dimethylaminopyridine (795 mg, 6.52 mmol) and p-toluenesulfonyl chloride (2.24 g, 11.73 mmol) were added to the above solution in sequence. The reaction system was then stirred for 24 hours.

LCMS监测显示原料消失后，向反应液中加冰水(25mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.15g 2-(3-溴苯基)-3-羟基-2-(羟甲基)丙基-4-甲基苯磺酸盐。After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.15 g 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propyl-4-methylbenzenesulfonate.

MS(ESI)M/Z:437.0[M+Na]⁺.MS (ESI) M/Z: 437.0 [M + Na] ⁺ .

步骤D:在室温条件下，氮气保护，将化合物2-(3-溴苯基)-3-羟基-2-(羟甲基)丙基-4-甲基苯磺酸盐(1.15g,2.78mmol)溶于四氢呋喃(28mL)中。随后，将上述溶液降温至0℃，加入乙醇钾(467mg,5.56mmol)。然后该反应体系在室温条件下搅拌18小时。Step D: Under nitrogen protection at room temperature, the compound 2-(3-bromophenyl)-3-hydroxy-2-(hydroxymethyl)propyl-4-methylbenzenesulfonate (1.15 g, 2.78 mmol) was dissolved in tetrahydrofuran (28 mL). Subsequently, the solution was cooled to 0°C and potassium ethoxide (467 mg, 5.56 mmol) was added. The reaction was then stirred at room temperature for 18 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到330mg(3-(3-溴苯基)氧杂环丁烷-3-基)甲醇。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 330 mg (3-(3-bromophenyl)oxetane-3-yl)methanol.

MS(ESI)M/Z:265.0[M+Na]⁺.MS (ESI) M/Z: 265.0 [M + Na] ⁺ .

步骤E:在0℃条件下，将化合物(3-(3-溴苯基)氧杂环丁烷-3-基)甲醇(330mg,1.36mmol)溶于乙腈(6.8mL)中。随后，向上述溶液中依次加入2,2,6,6-四甲基哌啶-氮-氧化物(21mg,0.14mmol)、7.5％wt次氯酸钠溶液(6.5g,5.44mmol)和亚氯酸钠(81mg,1.09mmol)。然后该反应体系在室温条件下继续搅拌18小时。Step E: Dissolve the compound (3-(3-bromophenyl)oxetane-3-yl)methanol (330 mg, 1.36 mmol) in acetonitrile (6.8 mL) at 0°C. Then, add 2,2,6,6-tetramethylpiperidine-nitrogen-oxide (21 mg, 0.14 mmol), 7.5%wt sodium hypochlorite solution (6.5 g, 5.44 mmol) and sodium chlorite (81 mg, 1.09 mmol) to the solution. Then, stir the reaction system at room temperature for 18 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到270mg 3-(3-溴苯基)氧杂环丁烷-3-羧酸。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 270 mg 3-(3-bromophenyl)oxetane-3-carboxylic acid.

MS(ESI)M/Z:279.0[M+Na]⁺.MS (ESI) M/Z: 279.0 [M + Na] ⁺ .

步骤F:在室温条件下，将化合物3-(3-溴苯基)氧杂环丁烷-3-羧酸(265mg,1.04mmol)溶于N,N-二甲基甲酰胺(5mL)中。随后，向上述溶液中依次加入N-甲基肼甲硫酰胺(130mg,1.24mmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(435mg,1.14mmol)和N,N-二异丙基乙胺(403mg,3.12mmol)。然后该反应体系继续搅拌0.5小时。Step F: At room temperature, compound 3-(3-bromophenyl)oxetane-3-carboxylic acid (265 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (5 mL). Subsequently, N-methylhydrazine methylsulfamide (130 mg, 1.24 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (435 mg, 1.14 mmol) and N,N-diisopropylethylamine (403 mg, 3.12 mmol) were added to the above solution in sequence. The reaction system was then stirred for 0.5 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到225mg 2-(3-(3-溴苯基)氧杂环丁烷-3-羰基)-N-甲基肼-1-甲硫酰胺。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 225 mg of 2-(3-(3-bromophenyl)oxetane-3-carbonyl)-N-methylhydrazine-1-methylsulfamide was obtained.

MS(ESI)M/Z:344.1[M+H]⁺.MS (ESI) M/Z: 344.1 [M+H] ⁺ .

步骤G:在室温条件下，将化合物2-(3-(3-溴苯基)氧杂环丁烷-3-羰基)-N-甲基肼-1-甲硫酰胺(210mg,0.61mmol)溶于四氢呋喃(3.1mL)中。随后，向上述溶液中加入2M氢氧化钠(0.34mL,0.67mmol)水溶液。然后该反应体系继续搅拌2小时。Step G: Dissolve the compound 2-(3-(3-bromophenyl)oxetane-3-carbonyl)-N-methylhydrazine-1-methylsulfamide (210 mg, 0.61 mmol) in tetrahydrofuran (3.1 mL) at room temperature. Then, add 2M sodium hydroxide (0.34 mL, 0.67 mmol) aqueous solution to the above solution. Then continue to stir the reaction system for 2 hours.

LCMS监测显示原料消失后，向反应液中加冰水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到170mg 5-(3-(3-溴苯基)氧杂环丁烷-3-基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 170 mg 5-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol was obtained.

MS(ESI)M/Z:326.1[M+H]⁺.MS (ESI) M/Z: 326.1 [M+H] ⁺ .

步骤H:在室温条件下，氮气保护，将化合物5-(3-(3-溴苯基)氧杂环丁烷-3-基)-4-甲基-4H-1,2,4-三唑-3-硫醇(160mg,0.49mmol)溶于二氯甲烷(2.5mL)中。随后，将上述溶液降温至0℃，依次滴加乙酸(0.49mL)和30％过氧化氢水溶液(278mg,2.45mmol)。然后该反应体系继续搅拌0.5小时。Step H: Under nitrogen protection at room temperature, compound 5-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (160 mg, 0.49 mmol) was dissolved in dichloromethane (2.5 mL). Subsequently, the solution was cooled to 0°C, and acetic acid (0.49 mL) and 30% aqueous hydrogen peroxide solution (278 mg, 2.45 mmol) were added dropwise. The reaction system was then stirred for 0.5 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到50mg 3-(3-(3-溴苯基)氧杂环丁烷-3-基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg 3-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:294.0[M+H]⁺.MS (ESI) M/Z: 294.0 [M+H] ⁺ .

步骤I:在室温条件下，氮气保护，将化合物3-(3-(3-溴苯基)氧杂环丁烷-3-基)-4-甲基-4H-1,2,4-三唑(40mg,0.14mmol)、(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(46mg,0.12mmol)、N,N'-二甲基乙二胺(12mg,0.14mmol)、碘化亚铜(22mg,0.12mmol)和碳酸钾(32mg,0.24mmol)溶于二甲基亚砜(2mL)中。然后该反应体系在140℃条件下搅拌2小时。Step I: Under nitrogen protection at room temperature, compound 3-(3-(3-bromophenyl)oxetane-3-yl)-4-methyl-4H-1,2,4-triazole (40 mg, 0.14 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (46 mg, 0.12 mmol), N,N'-dimethylethylenediamine (12 mg, 0.14 mmol), cuprous iodide (22 mg, 0.12 mmol) and potassium carbonate (32 mg, 0.24 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction system was then stirred at 140°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到34mg(S)-4-氯-6-(3-(3-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-3-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 34 mg of (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:623.3[M+H]⁺.MS (ESI) M/Z: 623.3 [M + H] ⁺ .

步骤J:在室温条件下，将化合物(S)-4-氯-6-(3-(3-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-3-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(34mg,0.06mmol)溶于二氯甲烷(1.0mL)中。随后，向上述溶液中滴加三氟乙酸(0.5mL)。然后该反应体系在室温条件下搅拌2小时。Step J: Compound (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (34 mg, 0.06 mmol) was dissolved in dichloromethane (1.0 mL) at room temperature. Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水，调节至pH＝8，继续搅拌30分钟。接着向上述溶液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25 mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到12mg(S)-4-氯-6-(3-(3-(4-甲基-4H-1,2,4-三唑-3-基)氧杂环丁烷-3-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 30 minutes. Then water (25 mL) was added to the above solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 3 times). mL×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain 12 mg of (S)-4-chloro-6-(3-(3-(4-methyl-4H-1,2,4-triazol-3-yl)oxetane-3-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:493.3[M+H]⁺.MS (ESI) M/Z: 493.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.47(s,1H),7.56(t,J＝7.8Hz,1H),7.47(s,1H),7.46-7.40(m,2H),7.30(d,J＝8.0Hz,1H),6.26(s,1H),5.39(d,J＝6.4Hz,2H),5.13(d,J＝6.4Hz,2H),3.59(s,2H),3.30(s,3H),2.81-2.70(m,2H),1.93-1.83(m,1H),1.67-1.52(m,4H),1.52-1.38(m,1H),0.85-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.47(s,1H),7.56(t,J＝7.8Hz,1H),7.47(s,1H),7.46- 7.40(m,2H),7.30(d,J＝8.0Hz,1H),6.26(s,1H),5.39(d,J＝6.4Hz,2H), 5.13(d,J＝6.4Hz,2H),3.59(s,2H),3.30(s,3H),2.81-2.70(m,2H),1.9 3-1.83(m,1H),1.67-1.52(m,4H),1.52-1.38(m,1H),0.85-0.73(m,4H).

实施例62Embodiment 62

4-氯-6-(3-(((1R,3S)-3-(甲氧基-d₃)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-(((1R,3S)-3-(methoxy-d ₃ )-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在0℃条件下，氮气保护，将化合物(1R,3R)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇(150mg,0.49mmol)溶于N,N-二甲基甲酰胺(2.5mL)中。随后，向上述溶液中加入氢化钠(30mg,0.74mmol)，搅拌30分钟。然后再滴加氘代碘甲烷(213mg,1.47mmol)，升至室温，继续搅拌10分钟。Step A: Under nitrogen protection at 0°C, compound (1R,3R)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (150 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). Then, sodium hydride (30 mg, 0.74 mmol) was added to the above solution and stirred for 30 minutes. Then, deuterated iodomethane (213 mg, 1.47 mmol) was added dropwise, the temperature was raised to room temperature, and stirring was continued for 10 minutes.

LCMS监测显示原料消失后，向反应液中加入冰水(10mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到140mg 3-((1R,3R)-1-(3-溴苯基)-3-(甲氧基-d₃)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the starting material disappeared, ice water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 140 mg of 3-((1R,3R)-1-(3-bromophenyl)-3-(methoxy-d ₃ )cyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:325.0[M+H]⁺.MS (ESI) M/Z: 325.0 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物3-((1R,3R)-1-(3-溴苯基)-3-(甲氧基-d₃)环丁基)-4-甲基-4H-1,2,4-三唑(140mg,0.43mmol)溶于干燥的二甲基亚砜(4.6mL)中。随后，向上述溶液中加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(90mg,0.22mmol)、碘化亚铜(82mg,0.43mmol)、N,N'-二甲基乙二胺(46mg,0.52mmol)和碳酸钾(120mg,0.86mmol)。然后该反应体系在150℃条件下搅拌3小时。Step B: Under nitrogen protection at room temperature, compound 3-((1R,3R)-1-(3-bromophenyl)-3-(methoxy-d ₃ )cyclobutyl)-4-methyl-4H-1,2,4-triazole (140 mg, 0.43 mmol) was dissolved in dry dimethyl sulfoxide (4.6 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90 mg, 0.22 mmol), cuprous iodide (82 mg, 0.43 mmol), N,N'-dimethylethylenediamine (46 mg, 0.52 mmol) and potassium carbonate (120 mg, 0.86 mmol) were added to the above solution. Then the reaction system was stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到200mg 4-氯-6-(3-(((1R,3S)-3-(甲氧基-d₃)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL×3 times), and the organic phases were combined and washed with saturated brine (20 mL×2 times). Then, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of 4-chloro-6-(3-(((1R,3S)-3-(methoxy-d ₃ )-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:654.2[M+H]⁺.MS (ESI) M/Z: 654.2 [M+H] ⁺ .

步骤C：在0℃条件下，氮气保护，将化合物4-氯-6-(3-(((1R,3S)-3-(甲氧基-d₃)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(200mg,0.31mmol)溶于二氯甲烷(1.8mL)中。随后，向上述溶液中滴加三氟乙酸(1.7mL)，升至室温，搅拌2小时。然后降温至0℃，向反应液中滴加氨水调节至pH＝8，升至室温，继续搅拌1小时。Step C: Under nitrogen protection at 0°C, compound 4-chloro-6-(3-(((1R,3S)-3-(methoxy- _d3 )-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.31 mmol) was dissolved in dichloromethane (1.8 mL). Subsequently, trifluoroacetic acid (1.7 mL) was added dropwise to the above solution, the temperature was raised to room temperature, and stirring was continued for 2 hours. Then the temperature was lowered to 0°C, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, the temperature was raised to room temperature, and stirring was continued for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(15mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到40.27mg 4-氯-6-(3-(((1R,3S)-3-(甲氧基-d₃)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。 After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 40.27 mg of 4-chloro-6-(3-(((1R,3S)-3-(methoxy-d ₃ )-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:524.3[M+H]⁺.MS (ESI) M/Z: 524.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ11.59(s,1H),8.39(s,1H),7.48(t,J＝7.8Hz,1H),7.43(s,1H),7.36-7.28(m,2H),7.16(d,J＝8.0Hz,1H),6.26(s,1H),3.90-3.80(m,1H),3.59(s,2H),3.33-3.31(m,2H),3.29(s,3H),2.82-2.69(m,2H),2.56-2.53(m,1H),2.50-2.46(m,1H),1.94-1.83(m,1H),1.67-1.53(m,4H),1.52-1.37(m,1H),0.87-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ11.59(s,1H),8.39(s,1H),7.48(t,J＝7.8Hz,1H),7.43(s,1H),7.36-7.28(m ,2H),7.16(d,J＝8.0Hz,1H),6.26(s,1H),3.90-3.80(m,1H),3.59(s,2H),3.33- 3.31(m,2H),3.29(s,3H),2.82-2.69(m,2H),2.56-2.53(m,1H),2.50-2.46(m,1 H),1.94-1.83(m,1H),1.67-1.53(m,4H),1.52-1.37(m,1H),0.87-0.72(m,4H).

实施例67Embodiment 67

4-氯-6-(3-((2,2-二氟乙基)氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
4-Chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在-50℃条件下，氮气保护，将化合物4-甲基-4H-1,2,4-三唑(3.8g,45.4mmol)溶于乙二醇二甲醚(200mL)中。随后，向上述溶液中缓慢滴加2.5M正丁基锂/正己烷溶液(18mL,30.3mmol)，搅拌1小时。然后缓慢滴加3,5-二溴苯甲醛(8.0g,45.4mmol)的乙二醇二甲醚(20mL)溶液，升温至0℃，继续搅拌1小时。Step A: Under nitrogen protection at -50°C, dissolve the compound 4-methyl-4H-1,2,4-triazole (3.8 g, 45.4 mmol) in ethylene glycol dimethyl ether (200 mL). Then, slowly drop 2.5 M n-butyl lithium/n-hexane solution (18 mL, 30.3 mmol) into the above solution and stir for 1 hour. Then slowly drop 3,5-dibromobenzaldehyde (8.0 g, 45.4 mmol) in ethylene glycol dimethyl ether (20 mL), heat to 0°C, and continue stirring for 1 hour.

LCMS监测显示原料消失后，向反应液中加饱和氯化铵水溶液(20mL)淬灭，混合液用乙酸乙酯(50mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物经石油醚/乙酸乙酯打浆，得到5.2g(3,5-二溴苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was slurried with petroleum ether/ethyl acetate to obtain 5.2 g (3,5-dibromophenyl) (4-methyl-4H-1,2,4-triazol-3-yl) methanol.

MS(ESI)M/Z:347.9[M+H]⁺.MS (ESI) M/Z: 347.9 [M + H] ⁺ .

步骤B：在0℃条件下，氮气保护，将化合物(3,5-二溴苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇(5.0g,14.4mmol)溶于四氢呋喃(70mL)中。随后，向上述溶液中依次加入咪唑(3.9g,57.6mmol)、碘单质(11.0g,43.2mmol)和三苯基膦(11.3g,43.2mmol)。然后该反应体系在80℃条件下搅拌16小时。Step B: Under nitrogen protection at 0°C, compound (3,5-dibromophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (5.0 g, 14.4 mmol) was dissolved in tetrahydrofuran (70 mL). Subsequently, imidazole (3.9 g, 57.6 mmol), iodine (11.0 g, 43.2 mmol) and triphenylphosphine (11.3 g, 43.2 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加饱和硫代硫酸钠水溶液(20mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3.0g 3-(3,5-二溴苄基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, saturated sodium thiosulfate aqueous solution (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.0 g 3-(3,5-dibromobenzyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:331.9[M+H]⁺.MS (ESI) M/Z: 331.9 [M + H] ⁺ .

步骤C：在0℃条件下，氮气保护，将化合物3-(3,5-二溴苄基)-4-甲基-4H-1,2,4-三唑(1.5g,4.5mmol)和1,3-二溴-2-甲基丙烷(972mg,4.5mmol)溶于四氢呋喃(15mL)中。随后，向上述溶液中缓慢滴加1.0M双三甲基硅基胺基锂的四氢呋喃溶液(9.0mL,9.0mmol)。然后该反应体系继续搅拌2小时。Step C: Under nitrogen protection at 0°C, compound 3-(3,5-dibromobenzyl)-4-methyl-4H-1,2,4-triazole (1.5 g, 4.5 mmol) and 1,3-dibromo-2-methylpropane (972 mg, 4.5 mmol) were dissolved in tetrahydrofuran (15 mL). Subsequently, a 1.0 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (9.0 mL, 9.0 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加入饱和氯化铵水溶液(10mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品，再经制备型高效液相色谱纯化，得到340mg化合物Z1(保留时间短)和125mg化合物Z2(保留时间长)。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product, which was then purified by preparative high performance liquid chromatography to obtain 340 mg of compound Z1 (short retention time) and 125 mg of compound Z2 (long retention time).

化合物Z1Compound Z1

¹H NMR(400MHz,CDCl₃)δ7.57(t,J＝1.6Hz,1H),7.42(d,J＝1.6Hz,2H),3.22(s,3H),2.86-2.73(m,2H),2.71-2.56(m,3H),1.14(d,J＝5.6Hz,3H). ¹ H NMR (400MHz, CDCl ₃ ) δ7.57 (t, J = 1.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 2H), 3.22 (s, 3H), 2.86-2.73 (m, 2H) ,2.71-2.56(m,3H),1.14(d,J＝5.6Hz,3H).

化合物Z2Compound Z2

¹H NMR(400MHz,CDCl₃)δ7.54(t,J＝1.6Hz,1H),7.31-7.23(m,2H),3.26(s,3H),3.23-3.08(m,2H),2.62-2.49(m,1H),2.28-2.18(m,2H),1.13(d,J＝6.4Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ7.54(t,J＝1.6Hz,1H),7.31-7.23(m,2H),3.26(s,3H),3.23-3.08(m,2H),2.62-2.49(m,1H),2.28 -2.18(m,2H),1.13(d,J＝6.4Hz,3H).

步骤D：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60mg,0.15mmol)、3-((1S,3S)-1-(3,5-二溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(90mg,0.22mmol)、N,N'-二甲基乙二胺(13mg,0.15mmol)、碘化亚铜(28mg,0.15mmol)和碳酸钾(42mg,0.30mmol)溶于二甲基亚砜(1.0mL)中。然后该反应体系在130℃条件下搅拌2小时。Step D: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (60 mg, 0.15 mmol), 3-((1S,3S)-1-(3,5-dibromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (90 mg, 0.22 mmol), N,N'-dimethylethylenediamine (13 mg, 0.15 mmol), cuprous iodide (28 mg, 0.15 mmol) and potassium carbonate (42 mg, 0.30 mmol) were dissolved in dimethyl sulfoxide (1.0 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 130°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到58mg 6-(3-溴-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 58 mg 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:713.3[M+H]⁺.MS (ESI) M/Z: 713.3 [M + H] ⁺ .

步骤E：在室温条件下，氮气保护，将化合物6-(3-溴-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(28mg,0.039mmol)、2,2-二氟乙胺(16mg,0.20mmol)、甲烷磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯)(2'-甲胺基-1,1'-联苯-2-基)钯(7mg,0.0078mmol)和碳酸铯(25mg,0.078mmol)溶于四氢呋喃(0.4mL)中。然后该反应体系在100℃条件下搅拌2小时。Step E: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) =1H-pyrrolo[2,3-c]pyridin-7(6H)-one (28 mg, 0.039 mmol), 2,2-difluoroethylamine (16 mg, 0.20 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium (7 mg, 0.0078 mmol) and cesium carbonate (25 mg, 0.078 mmol) were dissolved in tetrahydrofuran (0.4 mL). The reaction system was then stirred at 100° C. for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到22mg 4-氯-6-(3-((2,2-二氟乙基)氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 22 mg 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:714.4[M+H]⁺.MS (ESI) M/Z: 714.4 [M+H] ⁺ .

步骤F:在0℃条件下，将化合物4-氯-6-(3-((2,2-二氟乙基)氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(22mg,0.03mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(0.2mL)，升至室温，搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水至pH＝8，继续搅拌1小时。Step F: At 0°C, compound 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (22 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.2 mL) was added dropwise to the above solution, warmed to room temperature, and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution until pH = 8, and stirring was continued for 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到0.98mg 4-氯-6-(3-((2,2-二氟乙基)氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 0.98 mg 4-chloro-6-(3-((2,2-difluoroethyl)amino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:584.3[M+H]⁺.MS (ESI) M/Z: 584.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.72(s,1H),9.70(s,1H),8.44(s,1H),7.46(s,1H),6.72(s,1H),6.66(d,J＝2.0Hz,1H),6.60(s,1H),6.55(s,1H),6.10(tt,J₁＝4.0Hz,J₂＝56.0Hz,1H),4.38(s,2H),3.59-3.54(m,2H),3.35-3.32(m,2H),3.29(s,3H),2.87-2.71(m,3H),2.60-2.51(m,2H),2.08-1.92(m,1H),1.91-1.75(m,2H),1.74-1.58(m,2H),1.53-1.38(m,1H),1.13-0.94(m,4H),0.89(d,J＝6.4Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.72(s,1H),9.70(s,1H),8.44(s,1H),7.46(s,1H),6.72(s,1H),6.66(d,J＝2.0Hz,1H), 6.60(s,1H),6.55(s,1H),6.10(tt,J ₁ =4.0Hz,J ₂ ＝56.0Hz,1H),4.38(s,2H),3.59-3.54(m,2H),3.35-3.32(m,2H),3.29(s,3H),2.87-2.71(m,3H),2.60- 2.51(m,2H), 2.08-1.92(m,1H),1.91-1.75(m,2H),1.74-1.58(m,2H),1.53-1.38(m,1H),1.13-0.94(m,4H),0.89(d,J =6.4Hz,3H).

实施例79Embodiment 79

4-氯-6-(3-((1s,3R)-3-(2,2-二氟乙基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1s,3R)-3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(3-((1r,3S)-3-(2,2-二氟乙基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1r,3S)-3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在0℃条件下，氮气保护，将化合物甲基三苯基溴化膦(1.75g,4.91mmol)溶于四氢呋喃(20mL)中。随后，向上述反应液中滴加双(三甲基硅烷基)氨基钾(4.91mmol,4.91mL,1M)。继续搅拌1小时。然后把化合物3-(3-溴苯)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁基-1-酮(1g,3.27mmol)溶于四氢呋喃中(S1,10mL)加入反应体系，该反应体系升至室温，继续搅拌12小时。Step A: Under nitrogen protection at 0°C, dissolve the compound methyl triphenylphosphonium bromide (1.75 g, 4.91 mmol) in tetrahydrofuran (20 mL). Then, add potassium bis(trimethylsilyl)amide (4.91 mmol, 4.91 mL, 1 M) dropwise to the above reaction solution. Continue stirring for 1 hour. Then dissolve the compound 3-(3-bromobenzene)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl-1-one (1 g, 3.27 mmol) in tetrahydrofuran (S1, 10 mL) and add it to the reaction system. The reaction system is warmed to room temperature and stirred for 12 hours.

LCMS监测显示原料转化为产物后，向反应液中加入水(40mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.38g化合物3-(1-(3-溴苯基)-3-亚甲基二环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material was converted into the product, water (40 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.38 g of compound 3-(1-(3-bromophenyl)-3-methylenebicyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:304.0[M+H]⁺。MS (ESI) M/Z: 304.0 [M+H] ⁺ .

步骤B：在室温条件下，将化合物3-(1-(3-溴苯基)-3-亚甲基二环丁基)-4-甲基-4H-1,2,4-三唑(0.3g,0.99mmol)溶于四氢呋喃(1mL)中。随后，向上述反应液中加碘苯二乙酸(0.96g,2.97mmol)和2,2-二氟乙酸(0.57g,5.94mmol)。该反应体系升至50度，在蓝光(波长450nm)条件下继续搅拌4小时，然后再补加碘苯二乙酸(0.96g,2.97mmol)继续反应2小时。Step B: Dissolve the compound 3-(1-(3-bromophenyl)-3-methylenebicyclobutyl)-4-methyl-4H-1,2,4-triazole (0.3 g, 0.99 mmol) in tetrahydrofuran (1 mL) at room temperature. Then, add iodobenzenediacetic acid (0.96 g, 2.97 mmol) and 2,2-difluoroacetic acid (0.57 g, 5.94 mmol) to the above reaction solution. The reaction system is heated to 50 degrees and stirred for 4 hours under blue light (wavelength 450 nm), and then iodobenzenediacetic acid (0.96 g, 2.97 mmol) is added to continue the reaction for 2 hours.

LCMS监测显示原料转化为产物后，向反应液中加入碳酸氢钠(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.12g化合物3-(1-(3-溴苯)-3-(2,2-二氟乙基)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material was converted into the product, sodium bicarbonate (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.12 g of compound 3-(1-(3-bromobenzene)-3-(2,2-difluoroethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:356.1[M+H]⁺。MS (ESI) M/Z: 356.1 [M+H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物4-氯-2-{[(3S)-3-甲基哌啶-1-基]甲基}-1-[(2-(三甲基硅基)乙氧基)甲基]-1H,6H,7H-吡咯[2,3-c]吡啶-7-酮(0.12g,0.29mmol)、3-(1-(3-溴苯)-3-(2,2-二氟乙基)环丁基)-4-甲基-4H-1,2,4-三唑(0.10g,0.29mmol)、N,N,N',N'-四甲基乙二胺(0.034g,0.29mmol)、碘化亚铜(0.055g,0.29mmol)和碳酸钾(0.080g,0.58mmol)溶于二甲亚砜(1mL)中。该反应体系升至150℃，继续搅拌6小时。Step C: Under nitrogen protection at room temperature, compound 4-chloro-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.12 g, 0.29 mmol), 3-(1-(3-bromophenyl)-3-(2,2-difluoroethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole (0.10 g, 0.29 mmol), N,N,N',N'-tetramethylethylenediamine (0.034 g, 0.29 mmol), cuprous iodide (0.055 g, 0.29 mmol) and potassium carbonate (0.080 g, 0.58 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction system was heated to 150° C. and stirred for 6 hours.

LCMS监测显示原料转化为产物后，减压浓缩。所得残余物用硅胶柱层析纯化得到0.15g化合物4-氯-6-(3-(3-(2,2-二氟乙基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-{[(3S)-3-甲基哌啶-1-基]甲基}-1-[(2-(三甲基硅基)乙氧基)甲基]-1H,6H,7H-吡咯[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material was converted into the product, the product was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.15 g of the compound 4-chloro-6-(3-(3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:685.3[M+H]⁺。MS (ESI) M/Z: 685.3 [M+H] ⁺ .

步骤D：在室温条件下，将化合物4-氯-6-(3-(3-(2,2-二氟乙基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-{[(3S)-3-甲基哌啶-1-基]甲基}-1-[(2-(三甲基硅基)乙氧基)甲基]-1H,6H,7H-吡咯[2,3-c]吡啶-7-酮(0.12g,0.18mmol)溶于二氯甲烷(1mL)中。随后，向上述溶液中滴加三氟乙酸(1mL)，搅拌2小时。然后降温至0℃，缓慢滴加氨水(10.0mL)调节至pH＝8，升至室温，继续搅拌2小时。Step D: At room temperature, the compound 4-chloro-6-(3-(3-(2,2-difluoroethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.12 g, 0.18 mmol) was dissolved in dichloromethane (1 mL). Subsequently, trifluoroacetic acid (1 mL) was added dropwise to the above solution and stirred for 2 hours. Then the temperature was lowered to 0°C, and ammonia (10.0 mL) was slowly added dropwise to adjust to pH = 8, and the temperature was raised to room temperature and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化(色谱柱：Daicel IG-3；流动相:CO₂/EtOH[1.0％NH₃(7M in MeOH)]＝55/45)，得到10mg化合物79-P1(保留时间：2.346min)和8mg化合物79-P2(保留时间：2.692min)。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography (chromatographic column: Daicel IG-3; mobile phase: CO ₂ /EtOH [1.0% NH ₃ (7M in MeOH)] = 55/45) to obtain 10 mg of compound 79-P1 (retention time: 2.346 min) and 8 mg of compound 79-P2 (retention time: 2.692 min).

化合物79-P1Compound 79-P1

MS(ESI)M/Z:555.3[M+H]⁺。MS (ESI) M/Z: 555.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.29(s,1H),7.54–7.48(m,2H),7.44(s,1H),7.40–7.30(m,2H),6.26(s,1H),6.18–5.87(m,1H),3.59(s,2H),3.25(s,3H),2.93–2.88(m,2H),2.78–2.59(m,5H),2.06–1.85(m,3H),1.64–1.57(m,4H),1.47–1.44(m,1H),0.82–0.81(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),8.29(s,1H),7.54–7.48(m,2H),7.44(s,1H),7.40–7.30(m,2H),6.26(s,1H),6.18 –5.87(m,1H),3.59(s,2H), 3.25(s,3H),2.93–2.88(m,2H),2.78–2.59(m,5H),2.06–1.85(m,3H),1.64–1.57(m,4H),1.47–1.44(m,1H ),0.82–0.81(m,4H).

化合物79-P2Compound 79-P2

MS(ESI)M/Z:555.3[M+H]⁺。MS (ESI) M/Z: 555.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.39(s,1H),7.48–7.41(m,1H),7.41(s,1H),7.39–7.29(m,2H),7.14–7.12(m,1H),6.26(s,1H),6.20–5.86(m,1H),3.59(s,2H),3.29(s,3H),3.10(s,2H),2.76–2.75(m,2H),2.49–2.44(m,3H),2.11–1.89(m,2H),1.99–1.98(m,1H),1.64–1.57(m,4H),1.47 -1.44(m,1H),0.82–0.81(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),8.39(s,1H),7.48–7.41(m,1H),7.41(s,1H),7.39–7.29(m,2H),7.14–7.12(m,1H) ,6.26(s,1H),6.20–5.86(m,1H),3.5 9(s,2H),3.29(s,3H),3.10(s,2H),2.76–2.75(m,2H),2.49–2.44(m,3H),2.11–1.89(m,2H),1.99– 1.98(m,1H),1.64–1.57(m,4H),1.47 -1.44(m,1H),0.82–0.81(m,4H).

实施例80Embodiment 80

2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮
2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物N-Boc-氨基丙炔(15g,96.66mmol)和异氰基乙酸乙酯(9.84g,86.99mmol)溶于1,4-二氧六环(200mL)中。随后，向上述反应液中加碳酸银(2.67g,9.67mmol)。该反应体系升至100℃，继续搅拌12小时。Step A: At room temperature, under nitrogen protection, dissolve the compound N-Boc-aminopropyne (15 g, 96.66 mmol) and ethyl isocyanoacetate (9.84 g, 86.99 mmol) in 1,4-dioxane (200 mL). Then, add silver carbonate (2.67 g, 9.67 mmol) to the above reaction solution. The reaction system is heated to 100°C and stirred for 12 hours.

LCMS监测显示原料转化为产物后，向反应液中加入水(50mL)淬灭，混合液用乙酸乙酯(100mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化6.8g得到化合物3-(((叔丁氧羰基)氨基)甲基)-1H-吡咯-2-羧酸乙酯。After LCMS monitoring showed that the raw material was converted into the product, water (50 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (100 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.8 g of compound 3-(((tert-butyloxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:169.2[M-99]⁺。MS (ESI) M/Z: 169.2 [M-99] ⁺ .

步骤B：在室温条件下，将化合物3-(((叔丁氧羰基)氨基)甲基)-1H-吡咯-2-羧酸乙酯(6.8g,25.34mmol)溶于乙醇(60mL)和水(30mL)中。随后，向上述反应液中加一水合氢氧化锂(4.25g,101.36mmol)。然后将该反应体系升至60℃，继续搅拌过夜。Step B: Dissolve the compound 3-(((tert-butyloxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylic acid ethyl ester (6.8 g, 25.34 mmol) in ethanol (60 mL) and water (30 mL) at room temperature. Then, add lithium hydroxide monohydrate (4.25 g, 101.36 mmol) to the above reaction solution. Then, raise the reaction system to 60°C and continue stirring overnight.

LCMS监测显示原料转化为产物后，用盐酸(2M)将反应体系调制弱酸性(pH＝4)，混合液用乙酸乙酯(100mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩所得粗产物直接用于下一步。After LCMS monitoring showed that the raw material was converted into the product, the reaction system was adjusted to weak acidity (pH = 4) with hydrochloric acid (2M), the mixed solution was extracted with ethyl acetate (100 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (20 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product that was directly used in the next step.

MS(ESI)M/Z:141.1[M+H]⁺。MS (ESI) M/Z: 141.1 [M+H] ⁺ .

步骤C：在氮气保护下，将化合物3-(((叔丁氧羰基)氨基)甲基)-1H-吡咯-2-羧酸(5.2g,21.64mmol)溶于二氯甲烷(80mL)中。随后，将反应液冷却到0℃。再向上述反应液中滴加二氯亚砜(10.30g,86.56mmol)。该反应体系慢慢升至室温，继续搅拌8小时。然后将反应液慢慢加入到饱和的碳酸氢钠溶液中，直到体系呈弱碱性。Step C: Under nitrogen protection, compound 3-(((tert-butyloxycarbonyl)amino)methyl)-1H-pyrrole-2-carboxylic acid (5.2 g, 21.64 mmol) was dissolved in dichloromethane (80 mL). Then, the reaction solution was cooled to 0°C. Dichlorothionyl (10.30 g, 86.56 mmol) was added dropwise to the above reaction solution. The reaction system was slowly warmed to room temperature and stirred for 8 hours. Then, the reaction solution was slowly added to a saturated sodium bicarbonate solution until the system was weakly alkaline.

LCMS监测显示原料转化为产物后，将析出来的固体过滤烘干得到2.4g目标产物1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮。After LCMS monitoring showed that the raw material was converted into the product, the precipitated solid was filtered and dried to obtain 2.4 g of the target product 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole-6-one.

MS(ESI)M/Z:123.2[M+H]⁺。MS (ESI) M/Z: 123.2 [M+H] ⁺ .

步骤D：在氮气保护下，将化合物1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮(1g,8.19mmol)溶于四氢呋喃(50mL)中。随后，将反应体系冷却至-78℃，将N-碘代丁二酰亚胺(1.84g,8.19mmol)溶于四氢呋喃溶液(4mL)加入上诉反应体系中。然后将反应体系缓慢升至室温，继续搅拌过夜。Step D: Under nitrogen protection, compound 1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole-6-one (1 g, 8.19 mmol) was dissolved in tetrahydrofuran (50 mL). Subsequently, the reaction system was cooled to -78°C, N-iodosuccinimide (1.84 g, 8.19 mmol) was dissolved in tetrahydrofuran solution (4 mL) and added to the above reaction system. The reaction system was then slowly warmed to room temperature and stirred overnight.

LCMS监测显示原料转化为产物后，直接旋干。所得残余物用硅胶柱层析纯化得到0.75g化合物2-碘-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮。After LCMS monitoring showed that the raw material was converted into the product, it was directly spin-dried. The obtained residue was purified by silica gel column chromatography to obtain 0.75 g of the compound 2-iodo-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole-6-one.

MS(ESI)M/Z:248.6[M+H]⁺。MS (ESI) M/Z: 248.6 [M+H] ⁺ .

步骤E：在室温条件下，氮气保护，将化合物2-碘-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮(0.7g,2.82mmol)、(S)-三氟((3-甲基哌啶-1-基)甲基)硼酸钾(0.93g,4.23mmol)、XPhos G3(0.48g,0.56mmol)、碳酸钾(0.78g,5.64 mmol)和2-二环己基膦-2',4',6'-三异丙基联苯(0.27g,0.56mmol)溶于1,4-二氧六环(15mL)和水(1.5mL)中。随后，将该反应体系升至100℃，继续搅拌过夜。Step E: At room temperature, under nitrogen protection, compound 2-iodo-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (0.7 g, 2.82 mmol), (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium (0.93 g, 4.23 mmol), XPhos G3 (0.48 g, 0.56 mmol), potassium carbonate (0.78 g, 5.64 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.27 g, 0.56 mmol) were dissolved in 1,4-dioxane (15 mL) and water (1.5 mL). Subsequently, the reaction system was heated to 100° C. and stirred overnight.

LCMS监测显示原料转化为产物后，向反应液中加入水(10mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到200mg化合物2-{[(3S)-3-甲基哌啶-1-基]甲基}-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮。After LCMS monitoring showed that the raw material was converted into the product, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole-6-one.

MS(ESI)M/Z:234.2[M+H]⁺。MS (ESI) M/Z: 234.2 [M+H] ⁺ .

步骤F：在室温条件下，氮气保护，将化合物2-{[(3S)-3-甲基哌啶-1-基]甲基}-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮(0.2g,0.86mmol)、4-甲基-3-[(1s,3S)-1-(3-溴苯)-3-甲基环丁基]-4H-1,2,4-三唑(0.34g,1.12mmol)、醋酸钯(0.039g,0.17mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.18g,0.31mmol)和碳酸铯(0.56g,1.72mmol)溶于1,4-二氧六环(5mL)中。该反应体系升至120℃，继续搅拌2小时。Step F: Under nitrogen protection at room temperature, compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrol-6-one (0.2 g, 0.86 mmol), 4-methyl-3-[(1s,3S)-1-(3-bromophenyl)-3-methylcyclobutyl]-4H-1,2,4-triazole (0.34 g, 1.12 mmol), palladium acetate (0.039 g, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.18 g, 0.31 mmol) and cesium carbonate (0.56 g, 1.72 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was heated to 120°C and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加入水(15mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用氯化钠水溶液(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残留物经制备型高效液相色谱纯化得到0.006g化合物2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-1H,4H,5H,6H-吡咯[2,3-c]吡咯-6-酮。After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with sodium chloride aqueous solution (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 0.006 g of compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-1H,4H,5H,6H-pyrrolo[2,3-c]pyrrole-6-one.

MS(ESI)M/Z:460.2[M+H]⁺。MS (ESI) M/Z: 460.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ11.77(s,1H),8.28(s,2H),7.86–7.85(m,1H),7.61–7.58(m,1H),7.35-7.31(m,1H),6.95–6.93(m,1H),6.04(s,1H),4.68(s,2H),3.48–3.27(m,2H),3.20(s,3H),2.83–2.81(m,2H),2.77–2.72(m,2H),2.53(s,3H),1.88–1.83(m,1H),1.63–1.52(m,4H),1.49–1.41(m,1H),1.09–1.07(m,3H),0.84–0.77(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.77(s,1H),8.28(s,2H),7.86–7.85(m,1H),7.61–7.58(m,1H),7.35-7.3 1(m,1H),6.95–6.93(m,1H),6.04(s,1H),4.68(s,2H),3.48–3.27(m,2H),3.2 0(s,3H),2.83–2.81(m,2H),2.77–2.72(m,2H),2.53(s,3H),1.88–1.83(m,1H ),1.63–1.52(m,4H),1.49–1.41(m,1H),1.09–1.07(m,3H),0.84–0.77(m,4H).

实施例83Embodiment 83

4-(二氟甲基)-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-(Difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-甲醛
6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物4-溴-7-甲氧基-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(2g,4.66mmol)溶于1,4-二氧六环(23mL)和水(4mL)中。随后，向上述溶液中依次加入乙烯基三氟硼酸钾(1.25g,9.32mmol)、碳酸钾(1.29g,9.32mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(287mg,0.70mmol)和醋酸钯(157mg,0.70mmol)。然后该反应体系在90℃条件下搅拌4小时。Step A: Under nitrogen protection at room temperature, the compound 4-bromo-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (2g, 4.66mmol) was dissolved in 1,4-dioxane (23mL) and water (4mL). Subsequently, potassium trifluoroborate (1.25g, 9.32mmol), potassium carbonate (1.29g, 9.32mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (287mg, 0.70mmol) and palladium acetate (157mg, 0.70mmol) were added to the above solution in sequence. The reaction system was then stirred at 90°C for 4 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.6g 7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4-乙烯基-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.6 g of 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:377.2[M+H]⁺.MS (ESI) M/Z: 377.2 [M+H] ⁺ .

步骤B:在室温条件下，将化合物7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4-乙烯基-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(1.55g,4.11mmol)溶于叔丁醇(21mL)和水(21mL)中。随后，向上述溶液中加入4-甲基吗啡-N-氧化物(625mg,5.35mmol)和二水合锇酸钾(151mg,0.41mmol)，搅拌0.5小时。然后再加入高碘酸钠(1.76g,8.22mmol)，继续搅拌1小时。Step B: Dissolve the compound 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (1.55 g, 4.11 mmol) in tert-butyl alcohol (21 mL) and water (21 mL) at room temperature. Then, add 4-methylmorphine-N-oxide (625 mg, 5.35 mmol) and potassium osmate dihydrate (151 mg, 0.41 mmol) to the above solution and stir for 0.5 hours. Then add sodium periodate (1.76 g, 8.22 mmol) and continue stirring for 1 hour.

LCMS监测显示原料消失后，将上述反应液减压浓缩，所得残余物用硅胶柱层析纯化，得到1.2g 4-甲酰基-7-甲氧基-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯。After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.2 g of 4-formyl-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:379.3[M+H]⁺.MS (ESI) M/Z: 379.3 [M + H] ⁺ .

步骤C:在室温条件下，氮气保护，将化合物4-甲酰基-7-甲氧基-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(1.1g,2.91mmol)溶于二氯甲烷(9.7mL)中。随后，向上述溶液中滴加二乙胺基三氟化硫(2.34g,14.55mmol)。然后该反应体系在室温条件下搅拌18小时。Step C: Under nitrogen protection at room temperature, compound 4-formyl-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (1.1 g, 2.91 mmol) was dissolved in dichloromethane (9.7 mL). Subsequently, diethylaminosulfur trifluoride (2.34 g, 14.55 mmol) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 18 hours.

LCMS监测显示原料消失后，向反应液中加冰水(25mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到450mg 4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯。After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 450 mg 4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:401.2[M+H]⁺.MS (ESI) M/Z: 401.2 [M + H] ⁺ .

步骤D:在室温条件下，氮气保护，将化合物4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(450mg,1.12mmol)溶于四氢呋喃(11mL)中。随后，将温度降至-78℃，向上述溶液中滴加2.5M氢化铝锂的四氢呋喃溶液(0.45mL,1.12mmol)。然后该反应体系在-78℃条件下搅拌1小时。Step D: Under nitrogen protection at room temperature, the compound 4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (450 mg, 1.12 mmol) was dissolved in tetrahydrofuran (11 mL). Subsequently, the temperature was lowered to -78°C, and a 2.5 M tetrahydrofuran solution of lithium aluminum hydride (0.45 mL, 1.12 mmol) was added dropwise to the above solution. The reaction system was then stirred at -78°C for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到390mg(4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined and washed with saturated brine (20 mL x 2 times). The organic phases were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 390 mg of (4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

MS(ESI)M/Z:359.2[M+H]⁺.MS (ESI) M/Z: 359.2 [M+H] ⁺ .

步骤E:在室温条件下，将化合物(4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇(390mg,1.09mmol)溶于二氯甲烷(1.1mL)中。随后，向上述溶液中滴加氯化亚砜(0.14mL)。然后该反应体系在室温条件下搅拌2小时。Step E: Compound (4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (390 mg, 1.09 mmol) was dissolved in dichloromethane (1.1 mL) at room temperature. Subsequently, thionyl chloride (0.14 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，将上述反应液减压浓缩，得到粗品390mg 2-(氯甲基)-4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 390 mg of a crude product 2-(chloromethyl)-4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:377.2[M+H]⁺.MS (ESI) M/Z: 377.2 [M+H] ⁺ .

步骤F:在室温条件下，将化合物(S)-3-甲基哌啶盐酸盐(210mg,1.55mmol)溶于乙腈(5mL)中。随后，向上述溶液中依次加入碘化钾(256mg,1.55mmol)和碳酸钾(426mg,3.09mmol)，搅拌0.5小时。然后再加入化合物2-(氯甲基)-4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(388mg,1.03mmol)，继续搅拌16小时。Step F: Compound (S)-3-methylpiperidine hydrochloride (210 mg, 1.55 mmol) was dissolved in acetonitrile (5 mL) at room temperature. Potassium iodide (256 mg, 1.55 mmol) and potassium carbonate (426 mg, 3.09 mmol) were then added to the solution and stirred for 0.5 hours. Compound 2-(chloromethyl)-4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (388 mg, 1.03 mmol) was then added and stirred for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到200mg(S)-4-(二氟甲基)-7-甲氧基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 200 mg of (S)-4-(difluoromethyl)-7-methoxy-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:440.2[M+H]⁺.MS (ESI) M/Z: 440.2 [M+H] ⁺ .

步骤G:在室温条件下，氮气保护，将化合物(S)-4-(二氟甲基)-7-甲氧基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶(200mg,0.45mmol)溶于乙腈(2.3mL)中。随后，向上述溶液中加入碘化钠(102mg,0.68mmol)和三甲基氯硅烷(74mg,0.68mmol)。然后该反应体系在室温条件下搅拌2小时。Step G: Under nitrogen protection at room temperature, compound (S)-4-(difluoromethyl)-7-methoxy-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.45 mmol) was dissolved in acetonitrile (2.3 mL). Subsequently, sodium iodide (102 mg, 0.68 mmol) and trimethylsilyl chloride (74 mg, 0.68 mmol) were added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加冰水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到110mg(S)-4-(二氟甲基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg of (S)-4-(difluoromethyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:426.2[M+H]⁺.MS (ESI) M/Z: 426.2 [M+H] ⁺ .

步骤H:在室温条件下，将化合物(S)-4-(二氟甲基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(110mg,0.22mmol)、4-甲基-3-((1s，3s)-3-甲基-1-(3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)苯基)环丁基)-4H-12,4-三唑(272mg,0.77mmol)、碳酸氢钠(26mg,0.44mmol)和醋酸铜(131mg,0.66mmol)溶于二甲基亚砜(3mL)中。真空置换氧气三次，反应体系在90℃条件下搅拌3小时。Step H: Compound (S)-4-(difluoromethyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.22 mmol), 4-methyl-3-((1s, 3s)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (272 mg, 0.77 mmol), sodium bicarbonate (26 mg, 0.44 mmol) and cupric acetate (131 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (3 mL) at room temperature. The oxygen was replaced by vacuum three times, and the reaction system was stirred at 90° C. for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到40mg 4-(二氟甲基)-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:651.3[M+H]⁺.MS (ESI) M/Z: 651.3 [M + H] ⁺ .

步骤I:在室温条件下，将化合物4-(二氟甲基)-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(35mg,0.05mmol)溶于二氯甲烷(0.27mL)中。随后，向上述溶液中滴加三氟乙酸(0.27mL)。然后该反应体系在室温条件下搅拌2小时。Step I: Compound 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (35 mg, 0.05 mmol) was dissolved in dichloromethane (0.27 mL) at room temperature. Subsequently, trifluoroacetic acid (0.27 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化得到4.5mg 4-(二氟甲基)-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(化合物83-P1)和3.3mg 6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-甲醛(化合物83-P2)。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative HPLC to give 4.5 mg 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 83-P1) and 3.3 mg 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde (Compound 83-P2).

化合物83-P1Compound 83-P1

MS(ESI)M/Z:521.2[M+H]⁺. MS (ESI) M/Z: 521.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.27(s,1H),8.29(s,1H),7.62(s,1H),7.56-7.45(m,2H),7.38-7.30(m,2H),6.94(t,J＝54.8Hz,1H),6.33(s,1H),3.61(s,2H),3.25(s,3H),2.92-2.85(m,2H),2.83-2.72(m,2H),2.61-2.53(m,3H),1.99-1.83(m,1H),1.69-1.54(m,4H),1.52-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.86-0.74(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.27(s,1H),8.29(s,1H),7.62(s,1H),7.56-7.45(m,2H),7.38-7.30(m ,2H),6.94(t,J＝54.8Hz,1H),6.33(s,1H),3.61(s,2H),3.25(s,3H),2.92- 2.85(m,2H),2.83-2.72(m,2H),2.61-2.53(m,3H),1.99-1.83(m,1H),1.69 -1.54(m,4H),1.52-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.86-0.74(m,4H).

化合物83-P2Compound 83-P2

MS(ESI)M/Z:499.3[M+H]⁺.MS (ESI) M/Z: 499.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.32(s,1H),9.75(s,1H),8.30(s,1H),8.22(s,1H),7.60-7.52(m,2H),7.43-7.37(m,2H),6.78(s,1H),3.61(s,2H),3.26(s,3H),2.95-2.84(m,2H),2.83-2.72(m,2H),2.62-2.54(m,3H),1.97 -1.83(m,1H),1.68-1.53(m,4H),1.52-1.39(m,1H),1.08(d,J＝5.6Hz,3H),0.87-0.75(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.32(s,1H),9.75(s,1H),8.30(s,1H),8.22(s,1H),7.60-7.52(m,2H),7.43-7.37(m,2H),6.7 8(s,1H),3.61(s,2H),3.26(s,3H),2.95-2.84(m,2H),2.83-2.72(m,2H),2.62-2.54(m,3H),1.97 -1.83(m,1H),1.68-1.53(m,4H),1.52-1.39(m,1H),1.08(d,J＝5.6Hz,3H),0.87-0.75(m,4H).

实施例84Embodiment 84

4-氯-2-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-7-(((S)-3-甲基哌啶-1-基)甲基)-5-(三氟甲基)异喹啉-1(2H)-酮
4-Chloro-2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物7-溴-5-(三氟甲基)异喹啉-1(2H)-酮(500mg,1.72mmol)溶于N,N-二甲基甲酰胺(5mL)中。随后，向上述溶液中加入N-氯代丁二酰亚胺(298mg,2.24mmol)。然后该反应体系在20℃条件下搅拌16小时。Step A: Under nitrogen protection at room temperature, compound 7-bromo-5-(trifluoromethyl)isoquinolin-1(2H)-one (500 mg, 1.72 mmol) was dissolved in N,N-dimethylformamide (5 mL). Subsequently, N-chlorosuccinimide (298 mg, 2.24 mmol) was added to the above solution. The reaction system was then stirred at 20°C for 16 hours.

LCMS监测显示原料消失后，反应液直接用C18反相柱纯化得到224mg 7-溴-4-氯-5-(三氟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was directly purified using a C18 reverse phase column to obtain 224 mg 7-bromo-4-chloro-5-(trifluoromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:325.1[M+H]⁺.MS (ESI) M/Z: 325.1 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物7-溴-4-氯-5-(三氟甲基)异喹啉-1(2H)-酮(224mg,0.72mmol)溶于N,N-二甲基甲酰胺(3.6mL)中。随后，向上述溶液中依次加入草酸(92mg,1.08mmol)、乙酸酐(110mg,1.08mmol)、N,N-二异丙基乙胺、醋酸钯(16mg,0.07mmol)和4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(84mg,0.14mmol)。然后该反应体系在100℃条件下搅拌2小时。Step B: Under nitrogen protection at room temperature, compound 7-bromo-4-chloro-5-(trifluoromethyl)isoquinolin-1(2H)-one (224 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (3.6 mL). Subsequently, oxalic acid (92 mg, 1.08 mmol), acetic anhydride (110 mg, 1.08 mmol), N,N-diisopropylethylamine, palladium acetate (16 mg, 0.07 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (84 mg, 0.14 mmol) were added to the above solution in sequence. The reaction system was then stirred at 100°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到110mg 4-氯-1-氧代-5-(三氟甲基)-1,2-二氢异喹啉-7-甲酸。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 110 mg 4-chloro-1-oxo-5-(trifluoromethyl)-1,2-dihydroisoquinoline-7-carboxylic acid.

MS(ESI)M/Z:292.0[M+H]⁺.MS (ESI) M/Z: 292.0 [M+H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物4-氯-1-氧代-5-(三氟甲基)-1,2-二氢异喹啉-7-甲酸(100mg,0.39mmol)溶于四氢呋喃(2mL)中。随后，向上述溶液中加入1M硼烷四氢呋喃溶液(2.4mL,2.34mmol)。然后该反应体系在50℃条件下搅拌1小时。 Step C: Under nitrogen protection at room temperature, compound 4-chloro-1-oxo-5-(trifluoromethyl)-1,2-dihydroisoquinoline-7-carboxylic acid (100 mg, 0.39 mmol) was dissolved in tetrahydrofuran (2 mL). Subsequently, 1 M borane tetrahydrofuran solution (2.4 mL, 2.34 mmol) was added to the above solution. The reaction system was then stirred at 50°C for 1 hour.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到75mg 4-氯-7-(羟甲基)-5-(三氟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 75 mg 4-chloro-7-(hydroxymethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:278.1[M+H]⁺.MS (ESI) M/Z: 278.1 [M+H] ⁺ .

步骤D：在0℃条件下，将化合物4-氯-7-(羟甲基)-5-(三氟甲基)异喹啉-1(2H)-酮(75mg,0.31mmol)溶于二氯甲烷(1.6mL)中。随后，向上述溶液中缓慢滴加氯化亚砜(0.22mL)。然后该反应体系在50℃条件下搅拌2小时。Step D: Dissolve the compound 4-chloro-7-(hydroxymethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (75 mg, 0.31 mmol) in dichloromethane (1.6 mL) at 0°C. Then, slowly add thionyl chloride (0.22 mL) dropwise to the solution. The reaction system is then stirred at 50°C for 2 hours.

LCMS监测显示原料消失后，将上述反应液减压浓缩，得到80mg 4-氯-7-(氯甲基)-5-(三氟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 80 mg 4-chloro-7-(chloromethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:N/A[M+H]⁺.MS(ESI)M/Z:N/A[M+H] ⁺ .

步骤E：在室温条件下，将化合物(S)-3-甲基哌啶盐酸盐(55mg,0.40mmol)溶于乙腈(1.6mL)中。随后，向上述溶液中依次加入碘化钾(67mg,0.40mmol)和碳酸钾(127mg,0.92mmol)，并搅拌0.5小时。然后再加入化合物4-氯-7-(氯甲基)-5-(三氟甲基)异喹啉-1(2H)-酮(80mg,0.31mmol)，继续搅拌16小时。Step E: Dissolve the compound (S)-3-methylpiperidine hydrochloride (55 mg, 0.40 mmol) in acetonitrile (1.6 mL) at room temperature. Then, add potassium iodide (67 mg, 0.40 mmol) and potassium carbonate (127 mg, 0.92 mmol) to the above solution in sequence and stir for 0.5 hours. Then add the compound 4-chloro-7-(chloromethyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (80 mg, 0.31 mmol) and continue stirring for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到40mg(S)-4-氯-7-((3-甲基哌啶-1-基)甲基)-5-(三氟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of (S)-4-chloro-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:359.1[M+H]⁺.MS (ESI) M/Z: 359.1 [M+H] ⁺ .

步骤F：在室温条件下，氮气保护，将化合物(S)-4-氯-7-((3-甲基哌啶-1-基)甲基)-5-(三氟甲基)异喹啉-1(2H)-酮(40mg,0.12mmol)、4-甲基-3-((1s,3s)-3-甲基-1-(3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)苯基)环丁基)-4H-1,2,4-三唑(40mg,0.12mmol)、醋酸铜(100mg,0.551mmol)、吡啶(87mg,1.11mmol)溶于二甲基亚砜(0.8mL)中。然后该反应体系在80℃条件下搅拌2小时。Step F: Under nitrogen protection at room temperature, compound (S)-4-chloro-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one (40 mg, 0.12 mmol), 4-methyl-3-((1s,3s)-3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-1,2,4-triazole (40 mg, 0.12 mmol), copper acetate (100 mg, 0.551 mmol), and pyridine (87 mg, 1.11 mmol) were dissolved in dimethyl sulfoxide (0.8 mL). The reaction system was then stirred at 80° C. for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到7.11mg 4-氯-2-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-7-(((S)-3-甲基哌啶-1-基)甲基)-5-(三氟甲基)异喹啉-1(2H)-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography to obtain 7.11 mg 4-chloro-2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)isoquinolin-1(2H)-one.

MS(ESI)M/Z:584.5[M+H]⁺.MS (ESI) M/Z: 584.5 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ8.63–8.56(m,1H),8.30(s,1H),8.28–8.23(m,1H),7.97(s,1H),7.64–7.58(m,1H),7.57–7.48(m,1H),7.46–7.39(m,1H),7.37–7.30(m,1H),3.67(s,2H),3.23(s,3H),2.92–2.83(m,2H),2.75–2.67(m,2H),2.57–2.51(m,3H),2.01–1.89(m,1H),1.71–1.55(m,4H),1.54–1.39(m,1H),1.07(d,J＝5.1Hz,3H),0.92–0.77(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ8.63–8.56(m,1H),8.30(s,1H),8.28–8.23(m,1H),7.97(s,1H),7.64–7.58(m, 1H),7.57–7.48(m,1H),7.46–7.39(m,1H),7.37–7.30(m,1H),3.67(s,2H),3.23( s,3H),2.92–2.83(m,2H),2.75–2.67(m,2H),2.57–2.51(m,3H),2.01–1.89(m,1H ),1.71–1.55(m,4H),1.54–1.39(m,1H),1.07(d,J＝5.1Hz,3H),0.92–0.77(m,4H).

实施例85Embodiment 85

2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-乙基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-3H,4H,5H-咪唑并[4,5-c]吡啶-4-酮
2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-ethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3H,4H,5H-imidazo[4,5-c]pyridin-4-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，将化合物2-氯吡啶-3,4-二胺(1.43g,9.96mmol)溶于1,4-二氧六环(20mL)中。随后，向上述溶液中加入1,1,1-三甲氧基-2-氯乙烷(3.08g,19.92mmol)、甲苯-4-磺酸(0.86g,4.98mmol)。然后该反应体系在120℃条件下搅拌3小时。Step A: Dissolve the compound 2-chloropyridine-3,4-diamine (1.43 g, 9.96 mmol) in 1,4-dioxane (20 mL) at room temperature. Then, add 1,1,1-trimethoxy-2-chloroethane (3.08 g, 19.92 mmol) and toluene-4-sulfonic acid (0.86 g, 4.98 mmol) to the above solution. Then stir the reaction system at 120°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加入二氯甲烷和甲醇10：1(70mL×)稀释，混合液用水(10mL×3次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到0.8g 4-氯-2-(氯甲基)-3H-咪唑并[4,5-c]吡啶。After LCMS monitoring showed that the starting material disappeared, dichloromethane and methanol were added to the reaction solution in a ratio of 10:1 (70 mL×), and the mixture was washed with water (10 mL×3 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 0.8 g of 4-chloro-2-(chloromethyl)-3H-imidazo[4,5-c]pyridine was obtained.

MS(ESI)M/Z:202.1[M+H]+.MS (ESI) M/Z: 202.1 [M+H] +.

步骤B：在室温条件下，将化合物4-氯-2-(氯甲基)-3H-咪唑并[4,5-c]吡啶(500mg,2.47mmol)溶于乙腈(7mL)中。随后，向上述溶液中依次加入(S)-3-甲基哌啶盐酸盐(0.34g,2.47mmol)、碳酸钾(1.02g,7.41mmol)和碘化钾(0.082g,0.49mmol)。然后该反应体系继续搅拌16小时。Step B: Dissolve the compound 4-chloro-2-(chloromethyl)-3H-imidazo[4,5-c]pyridine (500 mg, 2.47 mmol) in acetonitrile (7 mL) at room temperature. Then, add (S)-3-methylpiperidine hydrochloride (0.34 g, 2.47 mmol), potassium carbonate (1.02 g, 7.41 mmol) and potassium iodide (0.082 g, 0.49 mmol) to the above solution. Then, continue to stir the reaction system for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(2mL)淬灭，混合液用二氯甲烷和甲醇10：1(4mL×3次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到400mg(3S)-1-[(4-氯-3H-咪唑并[4,5-c]吡啶-2-基)甲基]-3-甲基哌啶。After LCMS monitoring showed that the raw material disappeared, water (2 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (4 mL × 3 times), and the organic phases were combined and washed with saturated brine (2 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 400 mg (3S)-1-[(4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine.

MS(ESI)M/Z:265.2[M+H]⁺.MS (ESI) M/Z: 265.2 [M + H] ⁺ .

步骤C：在0℃条件下，将化合物(3S)-1-[(4-氯-3H-咪唑并[4,5-c]吡啶-2-基)甲基]-3-甲基哌啶(350mg,1.32mmol)溶于N,N-二甲基甲酰胺(5mL)中。随后，向上述溶液中滴加碳酸钾(0.55g,3.96mmol)、2-(三甲硅烷基)乙氧基甲基氯(0.33g,1.98mmol)。然后该反应体系在25℃条件下搅拌2小时。Step C: Compound (3S)-1-[(4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine (350 mg, 1.32 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 0°C. Potassium carbonate (0.55 g, 3.96 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.33 g, 1.98 mmol) were then added dropwise to the solution. The reaction system was then stirred at 25°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加冰水(2mL)淬灭，混合液用二氯甲烷和甲醇10：1(5mL×2次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化得到300mg(3S)-1-[(4-氯-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H咪唑并[4,5-c]吡啶-2-基)甲基]-3-甲基哌啶。After LCMS monitoring showed that the raw material disappeared, ice water (2 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (5 mL×2 times), and the organic phases were combined and washed with saturated brine (2 mL×2 times). Then, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of (3S)-1-[(4-chloro-3-[(2-(trimethylsilyl)ethoxy)methyl]-3Himidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine.

MS(ESI)M/Z:395.2[M+H]⁺.MS (ESI) M/Z: 395.2 [M + H] ⁺ .

步骤D：在室温条件下，氮气保护，将化合物(3S)-1-[(4-氯-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H咪唑并[4,5-c]吡啶-2-基)甲基]-3-甲基哌啶(270mg,0.68mmol)溶于1,4-二氧六环(3mL)和水(3mL)的混合溶液中。随后，向上述溶液中依次加入氢氧化钾(0.38g,6.80mmol)、三(二亚苄基丙酮)二钯(0)(0.12g,0.14mmol)、2-(二环己基膦基)-2,4,6-三异丙基联苯(0.097g,0.20mmol)。然后该反应体系在80℃条件下搅拌2小时。Step D: Under nitrogen protection at room temperature, compound (3S)-1-[(4-chloro-3-[(2-(trimethylsilyl)ethoxy)methyl]-3Himidazo[4,5-c]pyridin-2-yl)methyl]-3-methylpiperidine (270 mg, 0.68 mmol) was dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (3 mL). Subsequently, potassium hydroxide (0.38 g, 6.80 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.14 mmol), and 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.097 g, 0.20 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(2mL)和二氯甲烷和甲醇10：1(4mL)的混合溶液。混合液用二氯甲烷和甲醇10：1(4mL×3次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到180mg 2-{[(3S)-3-甲基哌啶-1-基]甲基}-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H-咪唑并[4,5-c]吡啶-4-醇。After LCMS monitoring showed that the raw material disappeared, water (2 mL) and a mixed solution of dichloromethane and methanol 10:1 (4 mL) were added to the reaction solution. The mixed solution was extracted with dichloromethane and methanol 10:1 (4 mL × 3 times), and the organic phases were combined and washed with saturated brine (2 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 180 mg 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H-imidazo[4,5-c]pyridine-4-ol.

MS(ESI)M/Z:377.3[M+H]⁺.MS (ESI) M/Z: 377.3 [M + H] ⁺ .

步骤E：在室温条件下，氮气保护，将化合物2-{[(3S)-3-甲基哌啶-1-基]甲基}-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H-咪唑并[4,5-c]吡啶-4-醇(60mg,0.16mmol)溶于N,N-二甲基甲酰胺(0.6mL)中。随后，向上述溶液中依次加入4-甲基-3-[(1s,3S)-1-(3-溴苯基)-3-甲基环丁基]-4H-1,2,4-三唑(0.049g,0.16mmol)、碳酸钾(0.066g,0.48mmol)、碘化亚铜(0.030g,0.16mmol)和N,N'-二甲基乙二胺(0.017g,0.19mmol)。然后该反应体系在150℃条件下搅拌3小时。Step E: Under nitrogen protection at room temperature, compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H-imidazo[4,5-c]pyridin-4-ol (60 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (0.6 mL). Subsequently, 4-methyl-3-[(1s,3S)-1-(3-bromophenyl)-3-methylcyclobutyl]-4H-1,2,4-triazole (0.049 g, 0.16 mmol), potassium carbonate (0.066 g, 0.48 mmol), cuprous iodide (0.030 g, 0.16 mmol) and N,N'-dimethylethylenediamine (0.017 g, 0.19 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(2mL)淬灭，混合液用二氯甲烷和甲醇10：1(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到18mg 2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-甲-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H,4H,5H-咪唑并[4,5-c]吡啶-4-酮。After LCMS monitoring showed that the starting material disappeared, water (2 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 18 mg 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H,4H,5H-imidazo[4,5-c]pyridin-4-one.

MS(ESI)M/Z:602.3[M+H]+.MS (ESI) M/Z: 602.3 [M+H] +.

步骤F：在室温条件下，将化合物2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-甲-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-3-[(2-(三甲基甲硅烷基)乙氧基)甲基]-3H,4H,5H-咪唑并[4,5-c]吡啶-4-酮(16mg,0.027mmol)溶于二氯甲烷(0.6mL)。随后，向上述溶液中滴加三氟乙酸(2.49g,21.81mmol)。然后该反应体系继续搅拌2小时。Step F: Compound 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3-[(2-(trimethylsilyl)ethoxy)methyl]-3H,4H,5H-imidazo[4,5-c]pyridin-4-one (16 mg, 0.027 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Trifluoroacetic acid (2.49 g, 21.81 mmol) was then added dropwise to the solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到3mg 2-{[(3S)-3-甲基哌啶-1-基]甲基}-5-(3-[(1s,3S)-3-乙基 -1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基]苯基)-3H,4H,5H-咪唑并[4,5-c]吡啶-4-酮。After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated aqueous sodium chloride solution (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 3 mg of 2-{[(3S)-3-methylpiperidin-1-yl]methyl}-5-(3-[(1s,3S)-3-ethyl -1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl)-3H,4H,5H-imidazo[4,5-c]pyridin-4-one.

MS(ESI)M/Z:472.3[M+H]+.MS (ESI) M/Z: 472.3 [M+H] +.

¹H NMR(400MHz,DMSO-d₆)δ12.63(s,1H),8.29(s,1H),7.55–7.46(m,1H),7.43–7.33(m,3H),7.33–7.27(m,1H),6.59(s,1H),3.71–3.57(m,2H),3.24(s,3H),2.93–2.82(m,2H),2.81–2.72(m,2H),2.58–2.52(m,3H),2.02–1.92(m,1H),1.72–1.40(m,5H),1.07(d,J＝4.8Hz,3H),0.82(d,J＝6.1Hz,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.63(s,1H),8.29(s,1H),7.55–7.46(m,1H),7.43–7.33(m,3H),7.33–7.27(m,1H),6.59(s,1H) ,3.71–3.57(m,2H),3.24(s,3H),2.9 3–2.82(m,2H),2.81–2.72(m,2H),2.58–2.52(m,3H),2.02–1.92(m,1H),1.72–1.40(m,5H),1.07(d,J ＝4.8Hz,3H),0.82(d,J＝6.1Hz,4H).

实施例86Embodiment 86

4-氯-6-(3-((1s，3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((R)-1-((1-甲基环丁基)氨基)乙基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((R)-1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((S)-1-((1-甲基环丁基)氨基)乙基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((S)-1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在-78℃条件下，氮气保护，将化合物4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(2.41g,6.16mmol)溶于四氢呋喃(40mL)中。随后，向上述溶液中滴加2M氢化铝锂的四氢呋喃溶液(1.23mL,2.46mmol)。然后该反应体系零度条件下搅拌0.5小时。 Step A: Under nitrogen protection at -78°C, compound 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (2.41 g, 6.16 mmol) was dissolved in tetrahydrofuran (40 mL). Subsequently, 2M lithium aluminum hydride tetrahydrofuran solution (1.23 mL, 2.46 mmol) was added dropwise to the above solution. The reaction system was then stirred at zero temperature for 0.5 hours.

LCMS监测显示原料消失后，向反应液中加入饱和氯化铵(40mL)淬灭，混合液用乙酸乙酯(15mL×2次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.7g(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇。After LCMS monitoring showed that the raw material disappeared, saturated ammonium chloride (40 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.7 g (4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

MS(ESI)M/Z:347.1[M+H]⁺.MS (ESI) M/Z: 347.1 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇(1.7g,4.89mmol)溶于二氯甲烷(30mL)中。随后，向上述溶液中滴加戴斯-马丁氧化剂(4.15g,9.78mmol)。然后该反应体系继续搅拌3小时。Step B: Under nitrogen protection at room temperature, compound (4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (1.7 g, 4.89 mmol) was dissolved in dichloromethane (30 mL). Subsequently, Dess-Martin periodinane (4.15 g, 9.78 mmol) was added dropwise to the above solution. The reaction system was then stirred for 3 hours.

LCMS监测显示原料消失后，向反应液中加乙酸乙酯(200mL)，混合液依次用饱和硫代硫酸钠溶液(20mL)、碳酸钠水溶液(20mL)、食盐水(20mL)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.8g 4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醛。After LCMS monitoring showed that the raw material disappeared, ethyl acetate (200 mL) was added to the reaction solution, and the mixed solution was washed with saturated sodium thiosulfate solution (20 mL), sodium carbonate aqueous solution (20 mL), and brine (20 mL) in sequence. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde.

MS(ESI)M/Z:344.6[M+H]⁺.MS (ESI) M/Z: 344.6 [M + H] ⁺ .

步骤C：在0℃条件下，将化合物4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-甲醛(1.7g,4.92mmol)溶于四氢呋喃(30mL)中。随后，向上述溶液中滴加甲基溴化镁溶液(7.87mL,7.87mmol,1M)。然后该反应体系在25℃条件下搅拌2小时。Step C: Dissolve the compound 4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (1.7 g, 4.92 mmol) in tetrahydrofuran (30 mL) at 0°C. Then, add methylmagnesium bromide solution (7.87 mL, 7.87 mmol, 1 M) dropwise to the solution. The reaction system is then stirred at 25°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加冰水(50mL)淬灭，混合液用乙酸乙酯(50mL×2次)萃取，，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，所得残余物用硅胶柱层析纯化得到0.9g 1-(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)乙烷-1-醇。After LCMS monitoring showed that the raw material disappeared, ice water (50 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.9 g 1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-ol.

MS(ESI)M/Z:360.6[M+H]⁺.MS (ESI) M/Z: 360.6 [M + H] ⁺ .

步骤D：在室温条件下，将化合物1-(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)乙烷-1-醇(0.3g,0.83mmol)溶于二氯甲烷中。随后，向上述溶液中加入氯化亚砜(0.15g,1.24mmol)。然后该反应体系在25℃条件下搅拌1小时。Step D: Dissolve the compound 1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethane-1-ol (0.3 g, 0.83 mmol) in dichloromethane at room temperature. Then, add thionyl chloride (0.15 g, 1.24 mmol) to the solution. Then stir the reaction system at 25°C for 1 hour.

LCMS监测显示原料消失后，向反应液中加入二氯甲烷(10mL)稀释，混合液用水(10mL×3次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到500mg 4,7-二氯-2-(1-氯乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶粗品。After LCMS monitoring showed that the raw material disappeared, dichloromethane (10 mL) was added to the reaction solution for dilution, and the mixed solution was washed with water (10 mL × 3 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 500 mg of crude 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine was obtained.

MS(ESI)M/Z:N/A[M+H]⁺.MS(ESI)M/Z:N/A[M+H] ⁺ .

步骤E：在室温条件下，将化合物4,7-二氯-2-(1-氯乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶粗品(400mg,1.05mmol)溶于乙腈(8mL)中。随后，向上述溶液中依次加入1-甲基环丁烷-1-胺盐酸盐(320mg,2.63mmol)、碘化钾(79mg,0.53mmol)和碳酸钾(580mg,4.2mmol)。然后该反应体系继续搅拌16小时。向反应液中补加1-甲基环丁烷-1-胺盐酸盐(320mg,2.63mmol)、碘化钾(79mg,0.53mmol)和碳酸钾(580mg,4.2mmol)。Step E: The crude compound 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.05 mmol) was dissolved in acetonitrile (8 mL) at room temperature. Subsequently, 1-methylcyclobutane-1-amine hydrochloride (320 mg, 2.63 mmol), potassium iodide (79 mg, 0.53 mmol) and potassium carbonate (580 mg, 4.2 mmol) were added to the above solution in sequence. The reaction system was then stirred for 16 hours. 1-Methylcyclobutane-1-amine hydrochloride (320 mg, 2.63 mmol), potassium iodide (79 mg, 0.53 mmol) and potassium carbonate (580 mg, 4.2 mmol) were added to the reaction solution.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(8mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到240mg N-(1-(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)乙基)-1-甲基环丁烷-1-胺。After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (8 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 240 mg of N-(1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl)-1-methylcyclobutane-1-amine.

MS(ESI)M/Z:428.2[M+H]⁺.MS (ESI) M/Z: 428.2 [M + H] ⁺ .

步骤F：在室温条件下，氮气保护，将化合物N-(1-(4,7-二氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)乙基)-1-甲基环丁烷-1-胺(200mg,0.47mmol)溶于1,4-二氧六环(2mL)和水(2mL)的混合溶液中。随后，向上述溶液中依次加入三(二亚苄基丙酮)二钯(0.086g,0.094mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(0.045g,0.094mmol)、氢氧化钾(0.13g,2.35mmol)。然后该反应体系在80℃条件下搅拌2小时。Step F: Under nitrogen protection at room temperature, the compound N-(1-(4,7-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl)-1-methylcyclobutane-1-amine (200 mg, 0.47 mmol) was dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (2 mL). Subsequently, tris(dibenzylideneacetone)dipalladium (0.086 g, 0.094 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.045 g, 0.094 mmol), and potassium hydroxide (0.13 g, 2.35 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(4mL)和乙酸乙酯(4mL)的混合溶液中。混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(4mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到3.5g 4-氯-2-(1-((1-甲基环丁基)氨基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, a mixed solution of water (4 mL) and ethyl acetate (4 mL) was added to the reaction solution. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (4 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.5 g 4-chloro-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:410.2[M+H]⁺.MS (ESI) M/Z: 410.2 [M + H] ⁺ .

步骤G：在室温条件下，氮气保护，将化合物4-氯-2-(1-((1-甲基环丁基)氨基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(98mg,0.24mmol)溶于N,N-二甲基甲酰胺(1mL)中。随后，向上述溶液中依次加入3-((1s,3s)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(74mg,0.24 mmol)、碘化亚铜(46mg,0.24mmol)、N,N'-二甲基乙二胺(21mg,0.24mmol)和碳酸钾(100mg,0.72mmol)。然后该反应体系在150℃条件下搅拌3小时。Step G: Under nitrogen protection at room temperature, compound 4-chloro-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (98 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL). Subsequently, 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (74 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(2mL)淬灭，混合液用二氯甲烷和甲醇10：1(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到40mg 4-氯-6-(3-((1s,3s)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(1-((1-甲基环丁基)氨基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (2 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:635.3[M+H]⁺.MS (ESI) M/Z: 635.3 [M + H] ⁺ .

步骤H：在室温条件下，将化合物4-氯-6-(3-((1s,3s)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(1-((1-甲基环丁基)氨基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(40mg,0.054mmol)溶于二氯甲烷(0.8mL)。随后，向上述溶液中滴加三氟乙酸(0.8mL)。然后该反应体系继续搅拌2小时。Step H: Compound 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.054 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was then added dropwise to the solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到30mg 4-氯-6-(3-((1s,3s)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(1-((1-甲基环丁基)氨基)乙基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 30 mg 4-chloro-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((1-methylcyclobutyl)amino)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

产物通过手性拆分(色谱柱：Daicel IC-3；流动相:CO₂/MeOH[0.2％NH₃(7M in MeOH)]＝50/50,流速:3mL/min)得到4.61mg化合物86-P1(保留时间:3.614min)和5.42mg化合物86-P2(保留时间:4.014min)。The product was separated by chiral separation (chromatographic column: Daicel IC-3; mobile phase: CO ₂ /MeOH [0.2% NH ₃ (7M in MeOH)]=50/50, flow rate: 3 mL/min) to give 4.61 mg of compound 86-P1 (retention time: 3.614 min) and 5.42 mg of compound 86-P2 (retention time: 4.014 min).

化合物86-P1:Compound 86-P1:

MS(ESI)M/Z:505.3[M+H]⁺.MS (ESI) M/Z: 505.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.17(s,1H),8.28(s,1H),7.52–7.45(m,2H),7.41(s,1H),7.36–7.28(m,2H),6.30(s,1H),4.07–3.99(m,1H),3.24(s,3H),2.92–2.84(m,2H),2.58–2.51(m,4H),1.84–1.77(m,1H),1.74–1.61(m,2H),1.59–1.45(m,2H),1.40–1.27(m,4H),1.17(s,3H),1.07(d,J＝4.9Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.17(s,1H),8.28(s,1H),7.52–7.45(m,2H),7.41(s,1H),7.36–7.28(m,2H),6.30(s,1H),4.07 –3.99(m,1H),3.24(s,3H),2.92–2.84( m,2H),2.58–2.51(m,4H),1.84–1.77(m,1H),1.74–1.61(m,2H),1.59–1.45(m,2H),1.40–1.27(m,4H), 1.17(s,3H),1.07(d,J＝4.9Hz,3H).

化合物86-P2:Compound 86-P2:

MS(ESI)M/Z:505.3[M+H]⁺.MS (ESI) M/Z: 505.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.15(s,1H),8.28(s,1H),7.53–7.44(m,2H),7.40(s,1H),7.35–7.28(m,2H),6.29(s,1H),4.10–3.96(m,1H),3.24(s,3H),2.94–2.81(m,2H),2.55–2.51(m,3H),2.37–2.31(m,1H),1.85–1.76(m,1H),1.72–1.61(m,2H),1.58–1.46(m,2H),1.38–1.27(m,4H),1.17(s,3H),1.07(d,J＝5.1Hz,3H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.15(s,1H),8.28(s,1H),7.53–7.44(m,2H),7.40(s,1H),7.35–7.28( m,2H),6.29(s,1H),4.10–3.96(m,1H),3.24(s,3H),2.94–2.81(m,2H),2. 55–2.51(m,3H),2.37–2.31(m,1H),1.85–1.76(m,1H),1.72–1.61(m,2H), 1.58–1.46(m,2H),1.38–1.27(m,4H),1.17(s,3H),1.07(d,J＝5.1Hz,3H).

实施例87Embodiment 87

4-氯-6-(3-(((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((S)-1-((S)-3-甲基哌啶-1-基)乙基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-(((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((S)-1-((S)-3-methylpiperidin-1-yl)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(3-((1s,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((R)-1-((S)-3-甲基哌啶-1-基)乙基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((R)-1-((S)-3-methylpiperidin-1-yl)ethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，将化合物4,7-二氯-2-(1-氯乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶粗品(400mg,1.05mmol)溶于乙腈(8mL)中。随后，向上述溶液中依次加入(S)-3-甲基哌啶盐酸盐(283mg,2.11mmol)、碘化钾(79mg,0.53mmol)和碳酸钾(434mg,3.15mmol)。然后该反应体系继续搅拌16小时。Step A: The crude compound 4,7-dichloro-2-(1-chloroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.05 mmol) was dissolved in acetonitrile (8 mL) at room temperature. Subsequently, (S)-3-methylpiperidine hydrochloride (283 mg, 2.11 mmol), potassium iodide (79 mg, 0.53 mmol) and potassium carbonate (434 mg, 3.15 mmol) were added to the above solution in sequence. The reaction system was then stirred for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(8mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到240mg 4,7-二氯-2-(1-((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (8 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 240 mg 4,7-dichloro-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:442.2[M+H]⁺.MS (ESI) M/Z: 442.2 [M + H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物4,7-二氯-2-(1-((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶(200mg,0.47mmol)溶于1，4-二氧六环(2mL)和水(2mL)的混合溶液中。随后，向上述溶液中依次加入三(二亚苄基丙酮)二钯(0.086g,0.094mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(0.045g,0.094mmol)、氢氧化钾(0.13g,2.35mmol)。然后该反应体系在80℃条件下搅拌2小时。Step B: Under nitrogen protection at room temperature, compound 4,7-dichloro-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.47 mmol) was dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (2 mL). Subsequently, tri(dibenzylideneacetone)dipalladium (0.086 g, 0.094 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.045 g, 0.094 mmol), and potassium hydroxide (0.13 g, 2.35 mmol) were added to the above solution in sequence. The reaction system was then stirred at 80°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(4mL)和乙酸乙酯(4mL)的混合溶液中。混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(4mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到102mg 4-氯-2-(1-(((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7-醇。After LCMS monitoring showed that the starting material disappeared, a mixed solution of water (4 mL) and ethyl acetate (4 mL) was added to the reaction solution. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (4 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 102 mg 4-chloro-2-(1-(((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-7-ol.

MS(ESI)M/Z:424.2[M+H]⁺.MS (ESI) M/Z: 424.2 [M+H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物4-氯-2-(1-(((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7-醇(102mg,0.24mmol)溶于N,N-二甲基甲酰胺(1mL)中。随后，向上述溶液中依次加入3-((1s,3s)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(74mg,0.24mmol)、碘化亚铜(46mg,0.24mmol)、N,N'-二甲基乙二胺(21mg,0.24mmol)和碳酸钾(100mg,0.72mmol)。然后该反应体系在150℃条件下搅拌3小时。Step C: Under nitrogen protection at room temperature, compound 4-chloro-2-(1-(((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-ol (102 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL). Subsequently, 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (74 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol) and potassium carbonate (100 mg, 0.72 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(2mL)淬灭，混合液用二氯甲烷和甲醇10：1(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到45mg 4-氯-6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(1-((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (2 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (5 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 45 mg 4-chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:649.3[M+H]⁺.MS (ESI) M/Z: 649.3 [M + H] ⁺ .

步骤D：在室温条件下，将化合物4-氯-6-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(1-((S)-3-甲基哌啶-1-基)乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(45mg,0.054mmol)溶于二氯甲烷(0.8mL)。随后，向上述溶液中滴加三氟乙酸(0.8mL)。然后该反应体系继续搅拌2小时。Step D: Compound 4-chloro-6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(1-((S)-3-methylpiperidin-1-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 mg, 0.054 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.8 mL) was then added dropwise to the solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到32mg消旋体化合物。 After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (30 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography to obtain 32 mg of the racemic compound.

所得产物通过手性拆分(色谱柱：Daicel AD-3；流动相:CO₂/IPA[1％NH₃(7M in MeOH)]＝60/40)得到7.42mg化合物87-P1(保留时间:0.742min)和5.33mg化合物87-P2(保留时间:0.927min)。The obtained product was subjected to chiral separation (chromatographic column: Daicel AD-3; mobile phase: CO ₂ /IPA [1% NH ₃ (7M in MeOH)]=60/40) to obtain 7.42 mg of compound 87-P1 (retention time: 0.742 min) and 5.33 mg of compound 87-P2 (retention time: 0.927 min).

化合物87-P1Compound 87-P1

MS(ESI)M/Z:519.2[M+H]⁺.MS (ESI) M/Z: 519.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.20(s,1H),8.28(s,1H),7.53–7.45(m,2H),7.43(s,1H),7.35–7.28(m,2H),6.23(s,1H),3.89–3.81(m,1H),3.24(s,3H),2.93–2.79(m,3H),2.78–2.71(m,1H),2.58–2.52(m,3H),1.82–1.74(m,1H),1.64–1.51(m,4H),1.42–1.36(m,3H),1.27–1.20(m,1H),1.07(d,J＝5.0Hz,3H),0.79(d,J＝5.2Hz,3H),0.76–0.66(m,1H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.20(s,1H),8.28(s,1H),7.53–7.45(m,2H),7.43(s,1H),7.35–7.28(m,2H), 6.23(s,1H),3.89–3.81(m,1H),3.24(s,3H),2.93–2.79(m,3H),2.78–2.71(m,1H ),2.58–2.52(m,3H),1.82–1.74(m,1H),1.64–1.51(m,4H),1.42–1.36(m,3H),1. 27–1.20(m,1H),1.07(d,J＝5.0Hz,3H),0.79(d,J＝5.2Hz,3H),0.76–0.66(m,1H).

化合物87-P2Compound 87-P2

MS(ESI)M/Z:519.2[M+H]⁺.MS (ESI) M/Z: 519.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.20(s,1H),8.28(s,1H),7.53–7.46(m,2H),7.43(s,1H),7.36–7.29(m,2H),6.23(s,1H),3.87–3.81(m,1H),3.24(s,3H),2.89–2.75(m,4H),2.56–2.53(m,3H),1.88–1.80(m,1H),1.64–1.51(m,3H),1.51–1.43(m,2H),1.42–1.36(m,3H),1.07(d,J＝4.8Hz,3H),0.81(d,J＝6.1Hz,3H),0.77–0.69(m,1H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.20(s,1H),8.28(s,1H),7.53–7.46(m,2H),7.43(s,1H),7.36–7.29(m, 2H),6.23(s,1H),3.87–3.81(m,1H),3.24(s,3H),2.89–2.75(m,4H),2.56–2 .53(m,3H),1.88–1.80(m,1H),1.64–1.51(m,3H),1.51–1.43(m,2H),1.42–1 .36(m,3H),1.07(d,J＝4.8Hz,3H),0.81(d,J＝6.1Hz,3H),0.77–0.69(m,1H).

实施例91Embodiment 91

2-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-5-(((S)-3-甲基哌啶-1-基)甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮
2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2-溴-3-(三氟甲基)苯甲酸(2.0g,7.43mmol)溶于N,N-二甲基甲酰胺(20mL)中。随后，向上述溶液中依次加入N-(4-甲氧基苄基)环丙胺(1.58g,8.92mmol)、N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(3.39g,8.92mmol)和N,N-二异丙基乙胺(2.88g,22.29mmol)。室温搅拌16小时。Step A: Under nitrogen protection at room temperature, dissolve the compound 2-bromo-3-(trifluoromethyl)benzoic acid (2.0 g, 7.43 mmol) in N,N-dimethylformamide (20 mL). Then, add N-(4-methoxybenzyl)cyclopropylamine (1.58 g, 8.92 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (3.39 g, 8.92 mmol) and N,N-diisopropylethylamine (2.88 g, 22.29 mmol) to the above solution in sequence. Stir at room temperature for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(50mL)，混合液用乙酸乙酯(70mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.2g 2-溴-N-环丙基-N-(4-甲氧基苄基)-3-(三氟甲基)苯甲酰胺。After LCMS monitoring showed that the raw material disappeared, water (50 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (70 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.2 g 2-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-3-(trifluoromethyl)benzamide.

MS(ESI)M/Z:428.0[M+H]⁺.MS (ESI) M/Z: 428.0 [M+H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物2-溴-N-环丙基-N-(4-甲氧基苄基)-3-(三氟甲基)苯甲酰胺(2.2g,5.14mmol)溶于1,3,5-三甲苯(40mL)中。随后，向上述溶液中依次加入三(二亚苄基丙酮)二钯(0.47g,0.51mmol)、特戊酸(0.79g,7.71mmol)、碳酸铯(5.02g,15.42mmol)。然后该反应体系在118℃条件下搅拌16小时。Step B: Under nitrogen protection at room temperature, the compound 2-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-3-(trifluoromethyl)benzamide (2.2 g, 5.14 mmol) was dissolved in 1,3,5-trimethylbenzene (40 mL). Subsequently, tris(dibenzylideneacetone)dipalladium (0.47 g, 0.51 mmol), pivalic acid (0.79 g, 7.71 mmol), and cesium carbonate (5.02 g, 15.42 mmol) were added to the above solution in sequence. The reaction system was then stirred at 118°C for 16 hours.

LCMS监测显示原料消失后，将反应液直接减压浓缩。所得残余物用硅胶柱层析纯化得到7.5g 2-(4-甲氧基苄基)-7-(三氟甲基)-1,1a，2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。 After LCMS monitoring showed that the starting material disappeared, the reaction solution was directly concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 7.5 g of 2-(4-methoxybenzyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

MS(ESI)M/Z:348.4[M+H]⁺.MS (ESI) M/Z: 348.4 [M+H] ⁺ .

步骤C:在室温条件下，氮气保护，将化合物2-(4-甲氧基苄基)-7-(三氟甲基)-1,1a，2,7b-四氢-3H-环丙基[c]异喹啉-3-酮(6.30g,20.06mmol)溶于三氟乙酸(20mL)，升至60℃，继续搅拌16小时。Step C: At room temperature, under nitrogen protection, dissolve the compound 2-(4-methoxybenzyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (6.30 g, 20.06 mmol) in trifluoroacetic acid (20 mL), raise the temperature to 60°C, and continue stirring for 16 hours.

LCMS监测显示原料消失后，将反应液旋蒸除去部分溶剂，倒入水(40mL)中淬灭，混合液用饱和碳酸钠水溶液调至pH＝9，混合液用二氯甲烷和甲醇10:1(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1g 7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。After LCMS monitoring showed that the raw material disappeared, the reaction solution was evaporated to remove part of the solvent, poured into water (40 mL) for quenching, the mixed solution was adjusted to pH = 9 with saturated sodium carbonate aqueous solution, the mixed solution was extracted with dichloromethane and methanol 10:1 (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1 g 7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

MS(ESI)M/Z:227.6[M+H]⁺.MS (ESI) M/Z: 227.6 [M + H] ⁺ .

步骤D:在室温条件下，氮气保护，将化合物7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮(1g,4.44mmol)溶于浓硫酸(10mL)中。随后，向上述溶液中加入N-溴代丁二酰亚胺(1.03g,5.81mmol)，室温搅拌16小时。Step D: Under nitrogen protection at room temperature, compound 7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (1 g, 4.44 mmol) was dissolved in concentrated sulfuric acid (10 mL). Subsequently, N-bromosuccinimide (1.03 g, 5.81 mmol) was added to the above solution and stirred at room temperature for 16 hours.

LCMS监测显示原料消失后，将反应液倒入剧烈搅拌的冰水中(30mL)中淬灭，用饱和碳酸钠水溶液调至pH＝9。得到白色悬浮液，过滤所的固体用甲醇溶解并用C18反相柱纯化得到0.81g 5-溴-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into vigorously stirred ice water (30 mL) to quench, and the pH was adjusted to 9 with saturated sodium carbonate aqueous solution. A white suspension was obtained, and the solid was filtered, dissolved in methanol and purified with a C18 reverse phase column to obtain 0.81 g 5-bromo-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

步骤E:在室温条件下，氮气保护，将化合物5-溴-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮(400mg,1.31mmol)溶于N,N-二甲基甲酰胺(10mL)中。随后，依次向上述溶液中加入草酸(0.18mL,1.97mmol)、乙酸酐(0.18mL,1.97mmol,30％)、N,N-二异丙基乙胺(0.65mL,3.93mmol)、醋酸钯(29mg,0.13mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(150mg,0.26mmol)。然后该反应体系在100℃条件下搅拌5小时。Step E: Under nitrogen protection at room temperature, compound 5-bromo-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (400 mg, 1.31 mmol) was dissolved in N,N-dimethylformamide (10 mL). Subsequently, oxalic acid (0.18 mL, 1.97 mmol), acetic anhydride (0.18 mL, 1.97 mmol, 30%), N,N-diisopropylethylamine (0.65 mL, 3.93 mmol), palladium acetate (29 mg, 0.13 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (150 mg, 0.26 mmol) were added to the above solution in sequence. The reaction system was then stirred at 100°C for 5 hours.

LCMS监测显示原料消失后，将反应液直接用C18反相柱纯化得到0.2g 3-氧代-7-(三氟甲基)-1a,2,3,7b-四氢-1H-环丙基[c]异喹啉-5-羧酸。After LCMS monitoring showed that the starting material disappeared, the reaction solution was directly purified using a C18 reverse phase column to obtain 0.2 g of 3-oxo-7-(trifluoromethyl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c]isoquinoline-5-carboxylic acid.

MS(ESI)M/Z:272.1[M+H]⁺.MS (ESI) M/Z: 272.1 [M+H] ⁺ .

步骤F:在0℃条件下，将化合物3-氧代-7-(三氟甲基)-1a,2,3,7b-四氢-1H-环丙基[c]异喹啉-5-羧酸(0.2g,0.74mmol)溶于四氢呋喃(5mL)中。随后，向上述溶液中滴加硼烷四氢呋喃溶液(2.96mL,2.96mmol)。然后该反应体系在60℃条件下搅拌16小时。Step F: Dissolve the compound 3-oxo-7-(trifluoromethyl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c]isoquinoline-5-carboxylic acid (0.2 g, 0.74 mmol) in tetrahydrofuran (5 mL) at 0°C. Then, add borane tetrahydrofuran solution (2.96 mL, 2.96 mmol) dropwise to the solution. The reaction system is then stirred at 60°C for 16 hours.

LCMS监测显示原料消失后，反应液冷却至0℃，滴加甲醇(1mL)和1M盐酸(3mL)。所得混合溶液搅拌0.5小时直接旋干，所得残余物用硅胶柱层析纯化得到0.15g 5-(羟甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to 0°C, and methanol (1 mL) and 1 M hydrochloric acid (3 mL) were added dropwise. The resulting mixed solution was stirred for 0.5 hours and directly dried by spin drying. The resulting residue was purified by silica gel column chromatography to obtain 0.15 g 5-(hydroxymethyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

MS(ESI)M/Z:258.1[M+H]⁺.MS (ESI) M/Z: 258.1 [M+H] ⁺ .

步骤G:在0℃条件下，氮气保护，将化合物5-(羟甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮(150mg,0.58mmol)溶于二氯甲烷(3mL)中。随后，向上述溶液中加入氯化亚砜(690mg,5.8mmol)。所得反应液直接旋干，粗品直接溶于乙腈(4mL)中，向上述溶液中依次加入碘化钾(22mg,0.15mmol)、碳酸钠(230mg,2.19mmol)和(S)-3-甲基哌啶盐酸盐(150mg,1.09mmol)。然后该反应体系在室温条件下搅拌5小时。Step G: Under nitrogen protection at 0°C, compound 5-(hydroxymethyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (150 mg, 0.58 mmol) was dissolved in dichloromethane (3 mL). Subsequently, thionyl chloride (690 mg, 5.8 mmol) was added to the above solution. The resulting reaction solution was directly spin-dried, and the crude product was directly dissolved in acetonitrile (4 mL). Potassium iodide (22 mg, 0.15 mmol), sodium carbonate (230 mg, 2.19 mmol) and (S)-3-methylpiperidine hydrochloride (150 mg, 1.09 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 5 hours.

LCMS监测显示原料消失后，向反应液中加水(4mL)淬灭，混合液用二氯甲烷和甲醇10：1(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到100mg 5-(((S)-3-甲基哌啶-1-基)甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。After LCMS monitoring showed that the raw material disappeared, water (4 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg 5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

MS(ESI)M/Z:339.2[M+H]⁺.MS (ESI) M/Z: 339.2 [M+H] ⁺ .

步骤H:在室温条件下，氮气保护，将化合物5-(((S)-3-甲基哌啶-1-基)甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮(50mg,0.15mmol)溶于1,4二氧六环(2mL)中。随后，向上述溶液中依次加入碳酸铯(150mg,0.45mmol)、3-((1s,3s)-1-(3-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(46mg,0.15mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(17mg,0.03mmol)、三(二亚苄基丙酮)二钯(14mg,0.015mmol)。然后该反应体系在120℃条件下搅拌6小时。Step H: Under nitrogen protection at room temperature, compound 5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one (50 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL). Subsequently, cesium carbonate (150 mg, 0.45 mmol), 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (46 mg, 0.15 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol) were added to the above solution in sequence. The reaction system was then stirred at 120°C for 6 hours.

LCMS监测显示原料消失后，将反应液加水(2mL)中淬灭。混合液用二氯甲烷和甲醇10:1(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化得到6mg 2-(3-((1s,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-5-(((S)-3-甲基哌啶-1-基)甲基)-7-(三氟甲基)-1,1a,2,7b-四氢-3H-环丙基[c]异喹啉-3-酮。After LCMS monitoring showed that the raw material disappeared, the reaction solution was quenched by adding water (2 mL). The mixed solution was extracted with dichloromethane and methanol 10:1 (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 6 mg 2-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)-1,1a,2,7b-tetrahydro-3H-cyclopropyl[c]isoquinolin-3-one.

MS(ESI)M/Z:564.6[M+H]⁺.MS (ESI) M/Z: 564.6 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ8.29(s,1H),8.15(s,1H),7.87–7.82(m,1H),7.59–7.53(m,1H),7.52–7.42(m,2H),7.30–7.23(m,1H),3.62–3.55(m,1H),3.57–3.51(m,2H),3.23(s,3H),2.90–2.79(m,2H),2.73 –2.65(m,2H),2.61–2.52(m,4H),1.95–1.84(m,1H),1.69–1.54(m,5H),1.51–1.40(m,1H),1.08(d,J＝5.3Hz,3H),0.91–0.78(m,4H),0.80–0.73(m,1H). ¹ H NMR (400MHz, DMSO-d ₆ )δ8.29(s,1H),8.15(s,1H),7.87–7.82(m,1H),7.59–7.53(m,1H),7.52–7.42(m,2H),7.3 0–7.23(m,1H),3.62–3.55(m,1H),3.57–3.51(m,2H),3.23(s,3H),2.90–2.79(m,2H),2.73 –2.65(m,2H),2.61–2.52(m,4H),1.95–1.84(m,1H),1.69–1.54(m,5H),1.5 1–1.40(m,1H),1.08(d,J＝5.3Hz,3H),0.91–0.78(m,4H),0.80–0.73(m,1H).

实施例92Embodiment 92

4-氯-6-(6-((3,3-二氟环丁基)氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2,6-二氯-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(90mg,0.30mmol)溶于二甲基亚砜(1.6mL)中。随后，向上述溶液中加入3,3-二氟环丁烷-1-胺(325mg,3.04mmol)。然后该反应体系在138℃条件下搅拌18小时。Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (90 mg, 0.30 mmol) was dissolved in dimethyl sulfoxide (1.6 mL). Subsequently, 3,3-difluorocyclobutane-1-amine (325 mg, 3.04 mmol) was added to the above solution. The reaction system was then stirred at 138°C for 18 hours.

LCMS监测显示原料消失后，向反应液中加冰水(20mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到90mg 6-氯-N-(3,3-二氟环丁基)-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺。After LCMS monitoring showed that the raw material disappeared, ice water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg 6-chloro-N-(3,3-difluorocyclobutyl)-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine.

MS(ESI)M/Z:368.2[M+H]⁺.MS (ESI) M/Z: 368.2 [M+H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物6-氯-N-(3,3-二氟环丁基)-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺(90mg,0.25mmol)、(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(72mg,0.18mmol)、N,N'-二甲基乙二胺(16mg,0.18mmol)、碘化亚铜(34mg,0.18mmol)和碳酸钾(50mg,0.36mmol)溶于N-甲基吡咯烷酮(0.9mL)中。然后该反应体系在180℃条件下搅拌8小时。Step B: At room temperature, under nitrogen protection, compound 6-chloro-N-(3,3-difluorocyclobutyl)-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine (90 mg, 0.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (72 mg, 0.18 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) were dissolved in N-methylpyrrolidone (0.9 mL). The reaction system was then stirred at 180°C for 8 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到20mg 4-氯-6-(6-((3,3-二氟环丁基)氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 20 mg 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:741.2[M+H]⁺.MS (ESI) M/Z: 741.2 [M + H] ⁺ .

步骤C:在室温条件下，将化合物4-氯-6-(6-((3,3-二氟环丁基)氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(20mg,0.03mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中加入三氟乙酸(0.5mL)，搅拌2小时。Step C: Compound 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (20 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, trifluoroacetic acid (0.5 mL) was added to the above solution and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，然后继续搅拌30分钟。随后，向上述溶液中加水(15mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到7mg 4-氯-6-(6-((3,3-二氟环丁基)氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring shows that the raw material disappears, ammonia water is added dropwise to the reaction solution to adjust to pH=8, and then stirring is continued for 30 minutes. Subsequently, water (15 mL) is added to the above solution to quench, the mixed solution is extracted with ethyl acetate (15 mL×3 times), the organic phases are combined, and the organic phases are washed with saturated brine (25 mL×2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative HPLC to give 7 mg of 4-chloro-6-(6-((3,3-difluorocyclobutyl)amino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:611.3[M+H]⁺.MS (ESI) M/Z: 611.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),8.34(s,1H),7.63(s,1H),7.38(d,J＝6.0Hz,1H),6.97(s,1H),6.34(s,1H),6.25(s,1H),4.15-4.02(m,1H),3.59(s,2H),3.28(s,3H),3.02-2.88(m,2H),2.87-2.67(m, 4H),2.63-2.51(m,5H),1.96-1.82(m,1H),1.68-1.52(m,4H),1.51-1.37(m,1H),1.07(d,J＝5.6Hz,3H),0.88-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),8.34(s,1H),7.63(s,1H),7.38(d,J＝6.0Hz,1H),6.97(s,1H),6.34(s,1H), 6.25(s,1H),4.15-4.02(m,1H),3.59(s,2H),3.28(s,3H),3.02-2.88(m,2H),2.87-2.67(m, 4H),2.63-2.51(m,5H),1.96-1.82(m,1H),1.68-1.52(m,4H),1.51-1.37(m,1H),1.07(d,J＝5.6Hz,3H) ,0.88-0.73(m,4H).

实施例93Embodiment 93

4-氯-6-(3-(乙基氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
4-Chloro-6-(3-(ethylamino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物6-(3-溴-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(40mg,0.056mmol)、氨基甲酸叔丁酯(33mg,0.280mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(5mg,0.011mmol)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(10mg,0.011mmol)和碳酸铯(36mg,0.112mmol)溶于1,4-二氧六环(0.4mL)中。然后该反应体系在110℃条件下搅拌2小时。Step A: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (40 mg, 0.056 mmol), tert-aminocarbamic acid Butyl ester (33 mg, 0.280 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 0.011 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (10 mg, 0.011 mmol) and cesium carbonate (36 mg, 0.112 mmol) were dissolved in 1,4-dioxane (0.4 mL). The reaction system was then stirred at 110°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到25mg叔丁基(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-6(7H)-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)氨基甲酸酯。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 25 mg of tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate.

MS(ESI)M/Z:750.4[M+H]⁺.MS (ESI) M/Z: 750.4 [M + H] ⁺ .

步骤B：在0℃条件下，氮气保护，将化合物叔丁基(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-6(7H)-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)氨基甲酸酯(25mg,0.033mmol)溶于N,N-二甲基甲酰胺(0.5mL)中。随后，向上述溶液中依次加入60％wt氢化钠(1.5mg,0.036mmol)和碘乙烷(6mg,0.040mmol)。然后该反应体系在室温条件下搅拌2小时。Step B: Under nitrogen protection at 0°C, the compound tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate (25 mg, 0.033 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). Subsequently, 60% wt sodium hydride (1.5 mg, 0.036 mmol) and iodoethane (6 mg, 0.040 mmol) were added to the above solution in sequence. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加入饱和氯化铵水溶液(5mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到12mg叔丁基(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-6(7H)-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)(乙基)氨基甲酸酯。After LCMS monitoring showed that the starting material disappeared, saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 12 mg of tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)(ethyl)carbamate.

MS(ESI)M/Z:778.4[M+H]⁺.MS (ESI) M/Z: 778.4 [M+H] ⁺ .

步骤C：在0℃条件下，将化合物叔丁基(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-6(7H)-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)(乙基)氨基甲酸酯(12mg,0.018mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中加入三氟乙酸(0.2mL)，搅拌2小时。LCMS监测显示原料消失后，向反应液中加氨水至碱性，继续搅拌1小时。Step C: At 0°C, tert-butyl (3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-6(7H)-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane 1-(2-(4-(2-(4-(2-phenyl)-1-yl)phenyl)(ethyl)carbamate (12 mg, 0.018 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.2 mL) was added to the above solution and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution to make it alkaline and stirring was continued for 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到0.72mg 4-氯-6-(3-(乙基氨基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 0.72 mg 4-chloro-6-(3-(ethylamino)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:548.2[M+H]⁺.MS (ESI) M/Z: 548.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.71(s,1H),9.70(s,1H),8.50(s,1H),7.46(s,1H),6.66(d,J＝2.0Hz,1H),6.56(s,1H),6.50(s,1H),6.43(s,1H),4.38(s,2H),3.44-3.39(m,1H),3.37-3.27(m,4H),3.01(q,J＝7.0Hz,2H),2.86-2.73(m,3H),2.62-2.51(m,4H),1.91-1.75(m,2H),1.74-1.60(m,2H),1.13(t,J＝7.2Hz,3H),1.09-0.99(m,4H),0.89(d,J＝6.8Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.71(s,1H),9.70(s,1H),8.50(s,1H),7.46(s,1H),6.66(d,J＝2.0Hz,1H),6.5 6(s,1H),6.50(s,1H),6.43(s,1H),4.38(s,2H),3.44-3.39(m,1H),3.37-3.27(m,4 H),3.01(q,J＝7.0Hz,2H),2.86-2.73(m,3H),2.62-2.51(m,4H),1.91-1.75(m,2H), 1.74-1.60(m,2H),1.13(t,J＝7.2Hz,3H),1.09-0.99(m,4H),0.89(d,J＝6.8Hz,3H).

实施例95Embodiment 95

(S)-4-氯-6-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
(S)-4-Chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在-78℃条件下，氮气保护，将化合物2-(3-溴苯基)乙腈(5g,25.6mmol)溶于四氢呋喃(64mL)中。随后，向上述溶液中滴加2.7M甲基锂(9.5mL)，搅拌1小时。接着滴加2-(氯甲基)环氧乙烷(2.37g,25.6mmol)，继续搅拌1小时。然后再滴加3M甲基溴化镁的四氢呋喃溶液(28mL)，升至室温，搅拌2小时。Step A: Under nitrogen protection at -78°C, dissolve the compound 2-(3-bromophenyl)acetonitrile (5 g, 25.6 mmol) in tetrahydrofuran (64 mL). Then, add 2.7 M methyl lithium (9.5 mL) dropwise to the above solution and stir for 1 hour. Then, add 2-(chloromethyl) oxirane (2.37 g, 25.6 mmol) dropwise and continue stirring for 1 hour. Then, add 3 M methyl magnesium bromide in tetrahydrofuran (28 mL) dropwise, warm to room temperature, and stir for 2 hours.

LCMS监测显示原料消失后，向反应液中加冰水(40mL)淬灭。随后，用1M稀盐酸调节至pH＝6，混合液用二氯甲烷(30mL×2次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到6.0g 1-(3-溴苯基)-3-羟基环丁烷-1-腈。After LCMS monitoring showed that the raw material disappeared, ice water (40 mL) was added to the reaction solution to quench. Subsequently, 1M dilute hydrochloric acid was used to adjust the pH to 6, the mixed solution was extracted with dichloromethane (30 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.0 g 1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonitrile.

步骤B：在室温条件下，氮气保护，将化合物1-(3-溴苯基)-3-羟基环丁烷-1-腈(5.7g,22.7mmol)溶于乙酸乙酯(174mL)中。随后，向上述溶液中加入2-碘酰基苯甲酸(19g,68.1mmol)。然后该反应体系在80℃条件下搅拌5小时。Step B: Under nitrogen protection at room temperature, compound 1-(3-bromophenyl)-3-hydroxycyclobutane-1-carbonitrile (5.7 g, 22.7 mmol) was dissolved in ethyl acetate (174 mL). Subsequently, 2-iodoacylbenzoic acid (19 g, 68.1 mmol) was added to the above solution. The reaction system was then stirred at 80°C for 5 hours.

LCMS监测显示原料消失后，将反应液过滤，滤液减压浓缩。所得残余物用硅胶柱层析纯化，得到3.6g 1-(3-溴苯基)-3-氧代环丁烷-1-腈。After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.6 g of 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile.

MS(ESI)M/Z:267.3[M+18]⁺.MS (ESI) M/Z: 267.3 [M+18] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物1-(3-溴苯基)-3-氧代环丁烷-1-腈(3.6g,14.5mmol)溶于二氯甲烷(73mL)中。随后，向上述溶液中滴加二乙胺基三氟化硫(11.7g,72.3mmol)。然后该反应体系在室温条件下搅拌16小时。Step C: Under nitrogen protection at room temperature, compound 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile (3.6 g, 14.5 mmol) was dissolved in Dichloromethane (73 mL) was added. Diethylaminosulfur trifluoride (11.7 g, 72.3 mmol) was then added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.3g 1-(3-溴苯基)-3,3-二氟环丁烷-1-腈。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (8 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.3 g 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile.

步骤D：在室温条件下，将化合物1-(3-溴苯基)-3,3-二氟环丁烷-1-腈(1.3g,5mmol)溶于乙醇(6.3mL)和水(6.3mL)中。随后，向上述溶液中加入氢氧化钠(602mg,15mmol)。然后该反应体系在80℃条件下搅拌16小时。Step D: Dissolve the compound 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile (1.3 g, 5 mmol) in ethanol (6.3 mL) and water (6.3 mL) at room temperature. Then, add sodium hydroxide (602 mg, 15 mmol) to the solution. Then, stir the reaction system at 80°C for 16 hours.

LCMS监测显示原料消失后，用1M稀盐酸调节至pH＝3，混合液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩得到421mg 1-(3-溴苯基)-3,3-二氟环丁烷-1-甲酸。After LCMS monitoring showed that the raw material disappeared, the pH was adjusted to 3 with 1M dilute hydrochloric acid, the mixed solution was extracted with dichloromethane (8mL×2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10mL×2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 421 mg 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid.

步骤E：在室温条件下，将化合物1-(3-溴苯基)-3,3-二氟环丁烷-1-甲酸(421mg,1.5mmol)溶于N,N二甲基甲酰胺(7.3mL)中。随后，向上述溶液中依次加入N-甲基肼甲硫酰胺(183mg,1.7mmol)、2-(7-氧化苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸盐(606mg,1.6mmol)、N,N-二异丙基乙胺(561mg,4.4mmol)。然后该反应体系在室温条件下搅拌10分钟。Step E: Dissolve the compound 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid (421 mg, 1.5 mmol) in N,N-dimethylformamide (7.3 mL) at room temperature. Then, add N-methylhydrazine methylthioamide (183 mg, 1.7 mmol), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (606 mg, 1.6 mmol), and N,N-diisopropylethylamine (561 mg, 4.4 mmol) to the above solution in sequence. Then, stir the reaction system at room temperature for 10 minutes.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到417mg 2-(1-(3-溴苯基)-3,3-二氟环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (8 mL × 2 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 417 mg 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide was obtained.

MS(ESI)M/Z:378.2[M+H]⁺.MS (ESI) M/Z: 378.2 [M+H] ⁺ .

步骤F：在室温条件下，将化合物2-(1-(3-溴苯基)-3,3-二氟环丁烷-1-羰基)-N-甲基肼-1-甲硫酰胺(400mg,1.1mmol)溶于四氢呋喃(3.5mL)和水(1.8mL)中。随后，向上述溶液中加入氢氧化钠(127mg,3.2mmol)。然后该反应体系在90℃条件下搅拌16小时。Step F: Dissolve the compound 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide (400 mg, 1.1 mmol) in tetrahydrofuran (3.5 mL) and water (1.8 mL) at room temperature. Then, add sodium hydroxide (127 mg, 3.2 mmol) to the above solution. Then stir the reaction system at 90°C for 16 hours.

LCMS监测显示原料消失后，用1M稀盐酸调节至pH＝4，混合液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到320mg 5-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the raw material disappeared, the pH was adjusted to 4 with 1M dilute hydrochloric acid, the mixed solution was extracted with dichloromethane (8mL×2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10mL×2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 320mg 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol was obtained.

MS(ESI)M/Z:360.1[M+H]⁺.MS (ESI) M/Z: 360.1 [M+H] ⁺ .

步骤G：在0℃条件下，将化合物5-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(320mg,0.9mmol)溶于二氯甲烷(3mL)中。随后，向上述溶液中依次加入乙酸(1.5mL)和30％wt的过氧化氢水溶液(0.5mL,15mmol)。然后该反应体系在室温条件下搅拌1小时。Step G: Compound 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (320 mg, 0.9 mmol) was dissolved in dichloromethane (3 mL) at 0°C. Subsequently, acetic acid (1.5 mL) and 30% wt aqueous hydrogen peroxide solution (0.5 mL, 15 mmol) were added to the solution in sequence. The reaction system was then stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，上述反应液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到129mg 3-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, the above reaction solution was extracted with dichloromethane (8 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 129 mg 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:328.2[M+H]⁺.MS (ESI) M/Z: 328.2 [M + H] ⁺ .

步骤H：在室温条件下，氮气保护，将化合物3-(1-(3-溴苯基)-3,3-二氟环丁基)-4-甲基-4H-1,2,4-三唑(129mg,0.4mmol)溶于二甲基亚砜(1.5mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(125mg,0.3mmol)、N,N'-二甲基乙二胺(33mg,0.4mmol)、碘化亚铜(59mg,0.3mmol)和碳酸钾(85mg,0.6mmol)。然后该反应体系在150℃条件下搅拌6小时。Step H: Under nitrogen protection at room temperature, compound 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (129 mg, 0.4 mmol) was dissolved in dimethyl sulfoxide (1.5 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (125 mg, 0.3 mmol), N,N'-dimethylethylenediamine (33 mg, 0.4 mmol), cuprous iodide (59 mg, 0.3 mmol) and potassium carbonate (85 mg, 0.6 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(15mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到137mg(S)-4-氯-6-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 137 mg of (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:657.3[M+H]⁺.MS (ESI) M/Z: 657.3 [M + H] ⁺ .

步骤I：在室温条件下，将化合物(S)-4-氯-6-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(137mg,0.2mmol)溶于二氯甲烷(1mL)中。随后，向上述溶液中滴加三氟乙酸(0.5mL)，搅拌2小时。然后降温至0℃，缓慢滴加氨水(2.0mL)调至pH＝8，升至室温，继续搅拌2小时。Step I: Dissolve compound (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (137 mg, 0.2 mmol) in dichloromethane (1 mL) at room temperature. Then, add trifluoroacetic acid (0.5 mL) dropwise to the solution and stir for 2 hours. Then cool to 0°C, slowly add ammonia water (2.0 mL) dropwise to adjust to pH = 8, warm to room temperature, and continue stirring for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(15mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到43.95mg(S)-4-氯-6-(3-(3,3-二氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。 After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 43.95 mg (S)-4-chloro-6-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:527.2[M+H]⁺.MS (ESI) M/Z: 527.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.37(s,1H),8.40(s,1H),7.52(t,J＝7.8Hz,1H),7.49(t,J＝1.8Hz,1H),7.45(s,1H),7.40(d,J＝8.0Hz,1H),7.30(d,J＝8.8Hz,1H),6.26(s,1H),3.81-3.66(m,2H),3.59(s,2H),3.55-3.41(m,2H),3.35(s,3H),2.84-2.69(m,2H),1.97-1.80(m,1H),1.69-1.53(m,4H),1.52-1.38(m,1H),0.88-0.72(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.37(s,1H),8.40(s,1H),7.52(t,J＝7.8Hz,1H),7.49(t,J＝1.8Hz,1H),7 .45(s,1H),7.40(d,J＝8.0Hz,1H),7.30(d,J＝8.8Hz,1H),6.26(s,1H),3.81- 3.66(m,2H),3.59(s,2H),3.55-3.41(m,2H),3.35(s,3H),2.84-2.69(m,2H) ,1.97-1.80(m,1H),1.69-1.53(m,4H),1.52-1.38(m,1H),0.88-0.72(m,4H).

实施例96Embodiment 96

4-氯-6-(6-(乙基氨基)-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2,6-二氯-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(170mg,0.57mmol)溶于二甲基亚砜(1.5mL)中。随后，向上述溶液中依次加入乙胺的盐酸盐(935mg,11.40mmol)和N,N-二异丙基乙胺(1.47g,11.40mmol)。然后该反应体系在150℃条件下搅拌6小时。Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (170 mg, 0.57 mmol) was dissolved in dimethyl sulfoxide (1.5 mL). Subsequently, ethylamine hydrochloride (935 mg, 11.40 mmol) and N,N-diisopropylethylamine (1.47 g, 11.40 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加冰水(40mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到130mg 6-氯-N-乙基-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺。After LCMS monitoring showed that the raw material disappeared, ice water (40 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 130 mg 6-chloro-N-ethyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine.

MS(ESI)M/Z:306.4[M+H]⁺.MS (ESI) M/Z: 306.4 [M+H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物6-氯-N-乙基-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺(95mg,0.31mmol)、(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(90mg,0.22mmol)、N,N'-二甲基乙二胺(19mg,0.22mmol)、碘化亚铜(42mg,0.22mmol)和碳酸钾(61mg,0.44mmol)溶于N-甲基吡咯烷酮(1.2mL)中。然后该反应体系在180℃条件下搅拌6小时。Step B: Under nitrogen protection at room temperature, compound 6-chloro-N-ethyl-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (95 mg, 0.31 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90 mg, 0.22 mmol), N,N'-dimethylethylenediamine (19 mg, 0.22 mmol), cuprous iodide (42 mg, 0.22 mmol) and potassium carbonate (61 mg, 0.44 mmol) were dissolved in N-methylpyrrolidone (1.2 mL). The reaction system was then stirred at 180°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到83mg 4-氯-6-(6-(乙基氨基)-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 83 mg 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:340.4[M/2+H]⁺.MS (ESI) M/Z: 340.4 [M/2+H] ⁺ .

步骤C:在室温条件下，将化合物4-氯-6-(6-(乙基氨基)-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(83mg,0.12mmol)溶于二氯甲烷(0.6mL)中。随后，向上述溶液中滴加三氟乙酸(0.6mL)。然后该反应体系继续搅拌2小时。Step C: Compound 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (83 mg, 0.12 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Trifluoroacetic acid (0.6 mL) was then added dropwise to the solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，继续搅拌2小时。随后，向上述溶液中加水(25mL)稀释。混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到21.09mg 4-氯-6-(6-(乙基氨基)-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 2 hours. Subsequently, water (25 mL) was added to the above solution to dilute it. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 21.09 mg 4-chloro-6-(6-(ethylamino)-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:549.3[M+H]⁺.MS (ESI) M/Z: 549.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.40(s,1H),7.61(s,1H),6.83(t,J＝5.4Hz,1H),6.74(d,J＝1.2Hz,1H),6.23(s,1H),6.19(d,J＝0.8Hz,1H),3.58(s,2H),3.35(s,3H),3.26-3.16(m,2H),3.11-3.01(m, 2H),2.80-2.69(m,2H),2.39-2.27(m,1H),2.24-2.15(m,2H),1.94-1.83(m,1H),1.66-1.52(m,4H),1.51-1.39(m,1H),1.13-1.08(m,6H),0.85-0.75(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),8.40(s,1H),7.61(s,1H),6.83(t,J＝5.4Hz,1H),6.74(d,J＝1.2Hz,1H),6.2 3(s,1H),6.19(d,J＝0.8Hz,1H),3.58(s,2H),3.35(s,3H),3.26-3.16(m,2H),3.11-3.01(m, 2H),2.80-2.69(m,2H),2.39-2.27(m,1H),2.24-2.15(m,2H),1.94-1.83(m,1H ),1.66-1.52(m,4H),1.51-1.39(m,1H),1.13-1.08(m,6H),0.85-0.75(m,4H).

实施例97Embodiment 97

4-氯-6-(6-(环丁基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物2,6-二氯-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(100mg,0.3mmol)溶于二甲基亚砜(1.7mL)中。随后，向上述溶液中加入环丁基胺(240mg,3.4mmol)。然后该反应体系在140℃条件下搅拌4小时。Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (100 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (1.7 mL). Subsequently, cyclobutylamine (240 mg, 3.4 mmol) was added to the above solution. The reaction system was then stirred at 140°C for 4 hours.

LCMS监测显示原料消失后，向反应液中加冰水(15mL)淬灭，接着用1M稀盐酸调节至pH＝6。混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到100mg 6-氯-N-环丁基-4-(1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺。After LCMS monitoring showed that the raw material disappeared, ice water (15 mL) was added to the reaction solution to quench, and then adjusted to pH = 6 with 1M dilute hydrochloric acid. The mixed solution was extracted with dichloromethane (10 mL × 2 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg 6-chloro-N-cyclobutyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine.

MS(ESI)M/Z:332.3[M+H]⁺.MS (ESI) M/Z: 332.3 [M + H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物6-氯-N-环丁基-4-(1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺(100mg,0.3mmol)溶于N-甲基吡咯烷酮(1.1mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(88mg,0.2mmol)、N,N'-二甲基乙二胺(19mg,0.2mmol)、碘化亚铜(41mg,0.2mmol)和碳酸钾(60mg,0.4mmol)。然后该反应体系在180℃条件下搅拌3小时。Step B: Under nitrogen protection at room temperature, compound 6-chloro-N-cyclobutyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (100 mg, 0.3 mmol) was dissolved in N-methylpyrrolidone (1.1 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (88 mg, 0.2 mmol), N,N'-dimethylethylenediamine (19 mg, 0.2 mmol), cuprous iodide (41 mg, 0.2 mmol) and potassium carbonate (60 mg, 0.4 mmol) were added to the above solution in sequence. Then the reaction system was stirred at 180°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(15mL)淬灭，混合液用二氯甲烷(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到48mg 4-氯-6-(6-(环丁基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (15 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 48 mg 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:353.5[M/2+H]⁺.MS (ESI) M/Z: 353.5 [M/2+H] ⁺ .

步骤C：在室温条件下，将化合物4-氯-6-(6-(环丁基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(48mg,0.07mmol)溶于二氯甲烷(0.4mL)中。随后，向上述溶液中滴加三氟乙酸(0.2mL)，搅拌2小时。然后降温至0℃，缓慢滴加氨水(1.0mL)调节至pH＝8，升温至室温，继续搅拌2小时。Step C: Dissolve the compound 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (48 mg, 0.07 mmol) in dichloromethane (0.4 mL) at room temperature. Then, trifluoroacetic acid (0.2 mL) was added dropwise to the above solution and stirred for 2 hours. Then, the temperature was lowered to 0°C, and ammonia (1.0 mL) was slowly added dropwise to adjust to pH = 8, and the temperature was raised to room temperature and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(15mL)稀释，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到10.69mg 4-氯-6-(6-(环丁基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (15 mL) was added to the reaction solution for dilution, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 10.69 mg 4-chloro-6-(6-(cyclobutylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:575.3[M+H]⁺.MS (ESI) M/Z: 575.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.33(s,1H),7.60(s,1H),7.15(d,J＝6.8Hz,1H),6.86(s,1H),6.29(s,1H),6.24(s,1H),4.27-4.13(m,1H),3.58(s,2H),3.28(s,3H),2.86-2.69(m,4H),2.62-2.51(m,3H),2.28-2.19(m,2H),1.95-1.80(m,3H),1.73-1.52(m,6H),1.51-1.39(m,1H),1.07(d,J＝5.6Hz,3H),0.87-0.72(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.36(s,1H),8.33(s,1H),7.60(s,1H),7.15(d,J＝6.8Hz,1H),6.86(s,1H ),6.29(s,1H),6.24(s,1H),4.27-4.13(m,1H),3.58(s,2H),3.28(s,3H),2. 86-2.69(m,4H),2.62-2.51(m,3H),2.28-2.19(m,2H),1.95-1.80(m,3H),1. 73-1.52(m,6H),1.51-1.39(m,1H),1.07(d,J＝5.6Hz,3H),0.87-0.72(m,4H).

实施例98 Embodiment 98

4-氯-6-(6-(环戊基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2,6-二氯-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(100mg,0.34mmol)溶于二甲基亚砜(1.7mL)中。随后，向上述溶液中加入环戊胺(290mg,3.40mmol)。然后该反应体系在140℃条件下搅拌16小时。Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (100 mg, 0.34 mmol) was dissolved in dimethyl sulfoxide (1.7 mL). Subsequently, cyclopentylamine (290 mg, 3.40 mmol) was added to the above solution. The reaction system was then stirred at 140°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加冰水(25mL)淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到88mg 6-氯-N-环戊基-4-(1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺。After LCMS monitoring showed that the raw material disappeared, ice water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 88 mg 6-chloro-N-cyclopentyl-4-(1S, 3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine.

MS(ESI)M/Z:346.3[M+H]⁺.MS (ESI) M/Z: 346.3 [M + H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物6-氯-N-环戊基-4-(1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-胺(88mg,0.25mmol)、(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(74mg,0.18mmol)、N,N'-二甲基乙二胺(16mg,0.18mmol)、碘化亚铜(34mg,0.18mmol)和碳酸钾(50mg,0.36mmol)溶于N-甲基吡咯烷酮(1.5mL)中。然后该反应体系在180℃条件下搅拌8小时。Step B: Under nitrogen protection at room temperature, compound 6-chloro-N-cyclopentyl-4-(1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-amine (88 mg, 0.25 mmol), (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (74 mg, 0.18 mmol), N,N'-dimethylethylenediamine (16 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) were dissolved in N-methylpyrrolidone (1.5 mL). The reaction system was then stirred at 180°C for 8 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到67mg 4-氯-6-(6-(环戊基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 67 mg 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:719.4[M+H]⁺.MS (ESI) M/Z: 719.4 [M+H] ⁺ .

步骤C:在室温条件下，将化合物4-氯-6-(6-(环戊基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(65mg,0.09mmol)溶于二氯甲烷(0.6mL)中。随后，向上述溶液中滴加三氟乙酸(0.6mL)。然后该反应体系在室温条件下搅拌2小时。Step C: Compound 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (65 mg, 0.09 mmol) was dissolved in dichloromethane (0.6 mL) at room temperature. Subsequently, trifluoroacetic acid (0.6 mL) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，继续搅拌2小时。随后，向上述溶液中加水(25mL)淬灭。混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到25.78mg 4-氯-6-(6-(环戊基氨基)-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust to pH = 8, and stirring was continued for 2 hours. Subsequently, water (25 mL) was added to the above solution to quench. The mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 25.78 mg 4-chloro-6-(6-(cyclopentylamino)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:589.2[M+H]⁺.MS (ESI) M/Z: 589.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.34(s,1H),7.62(s,1H),6.88(d,J＝6.4Hz,1H),6.84(d,J＝1.2Hz,1H),6.36(d,J＝1.2Hz,1H),6.24(s,1H),4.07-3.98(m,1H),3.59(s,2H),3.29(s,3H),2.83-2.69(m,4H),2.61-2.51(m,3H),1.94-1.83(m,3H),1.72-1.37(m,12H),1.07(d,J＝6.0Hz,3H),0.86-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),8.34(s,1H),7.62(s,1H),6.88(d,J＝6.4Hz,1H),6.84( d,J＝1.2Hz,1H),6.36(d,J＝1.2Hz,1H),6.24(s,1H),4.07-3.98(m,1H),3 .59(s,2H),3.29(s,3H),2.83-2.69(m,4H),2.61-2.51(m,3H),1.94-1. 83(m,3H),1.72-1.37(m,12H),1.07(d,J＝6.0Hz,3H),0.86-0.72(m,4H).

实施例99Embodiment 99

4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(氧杂环丁烷-3-基氨基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
4-Chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetan-3-ylamino)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物6-(3-溴-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(60mg,0.084mmol)、氧杂环丁烷-3-胺(31mg,0.42mmol)、2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'三-1-丙基-1,1'-双苯基(8mg,0.017mmol)、三(二亚苄基丙酮)二钯(15mg,0.017mmol)和叔丁醇钾(19mg,0.17mmol)溶于甲苯(0.6mL)中。然后该反应体系在100℃条件下搅拌16小时。Step A: At room temperature, under nitrogen protection, compound 6-(3-bromo-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (60 mg, 0.084mmol), oxetane-3-amine (31mg, 0.42mmol), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl (8mg, 0.017mmol), tris(dibenzylideneacetone)dipalladium (15mg, 0.017mmol) and potassium tert-butoxide (19mg, 0.17mmol) were dissolved in toluene (0.6mL). The reaction system was then stirred at 100°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到25mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(氧杂环丁烷-3-基氨基)苯基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 25 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetane-3-ylamino)phenyl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:706.4[M+H]⁺.MS (ESI) M/Z: 706.4 [M+H] ⁺ .

步骤B:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(氧杂环丁烷-3-基氨基)苯基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(25mg,0.035mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中加入三氟乙酸(0.2mL)，搅拌2小时。LCMS监测显示原料消失后，向反应液中加氨水调节至pH＝8，继续搅拌1小时。Step B: At room temperature, compound 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetane-3-ylamino)phenyl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (25 mg, 0.035 mmol) was dissolved in dichloromethane (0.5 mL). Subsequently, trifluoroacetic acid (0.2 mL) was added to the above solution and stirred for 2 hours. After LCMS monitoring showed that the raw material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)稀释，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到1.02mg 4-氯-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)-5-(氧杂环丁烷-3-基氨基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution for dilution, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 1.02 mg 4-chloro-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-(oxetane-3-ylamino)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:576.3[M+H]⁺.MS (ESI) M/Z: 576.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.31(s,1H),8.28(s,1H),7.34(s,1H),6.70(d,J＝6.4Hz,1H),6.64(s,1H),6.42(s,1H),6.34(s,1H),6.24(s,1H),4.78(t,J＝6.4Hz,2H),4.55-4.45(m,1H),4.38(t,J＝6.0Hz,2H),3.58(s,2H),3.25(s,3H),2.86-2.69(m,4H),2.58-2.51(m,3H),1.94-1.81(m,1H),1.69-1.51(m,4H),1.49-1.38(m,1H),1.06(d,J＝5.6Hz,3H),0.89-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.31(s,1H),8.28(s,1H),7.34(s,1H),6.70(d,J＝6.4Hz,1H),6.64(s,1H),6.42(s ,1H),6.34(s,1H),6.24(s,1H),4.78(t,J＝6.4Hz,2H),4.55-4.45(m,1H),4.38(t,J＝6. 0Hz,2H),3.58(s,2H),3.25(s,3H),2.86-2.69(m,4H),2.58-2.51(m,3H),1.94-1.81( m,1H),1.69-1.51(m,4H),1.49-1.38(m,1H),1.06(d,J=5.6Hz,3H),0.89-0.72(m,4H).

实施例100Embodiment 100

2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)乙腈
2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(115mg,0.28mmol)、3-溴-5-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯酚(90mg,0.28mmol)、N,N'-二甲基乙二胺(30mg,0.33mmol)、碘化亚铜(54mg,0.28mmol)和碳酸钾(78mg,0.56mmol)溶于二甲基亚砜(1.4mL)中。然后该反应体系在150℃条件下搅拌4小时。Step A: Under nitrogen protection at room temperature, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (115 mg, 0.28 mmol), 3-bromo-5-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenol (90 mg, 0.28 mmol), N,N'-dimethylethylenediamine (30 mg, 0.33 mmol), cuprous iodide (54 mg, 0.28 mmol) and potassium carbonate (78 mg, 0.56 mmol) were dissolved in dimethyl sulfoxide (1.4 mL). The reaction system was then stirred at 150°C for 4 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到60mg 4-氯-6-(3-羟基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 60 mg 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:651.4[M+H]⁺.MS (ESI) M/Z: 651.4 [M+H] ⁺ .

步骤B：在0℃条件下，氮气保护，将化合物4-氯-6-(3-羟基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60mg,0.09mmol)溶于N,N-二甲基甲酰胺(0.6mL)中。随后，向上述溶液中加入60％wt氢化钠(11mg,0.27mmol)，搅拌20分钟。然后再加入溴乙腈(68mg,0.30mmol)，升温至室温，继续搅拌2小时。Step B: Under nitrogen protection at 0°C, compound 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (60 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (0.6 mL). Subsequently, 60% wt sodium hydride (11 mg, 0.27 mmol) was added to the above solution and stirred for 20 minutes. Then bromoacetonitrile (68 mg, 0.30 mmol) was added, the temperature was raised to room temperature, and stirring was continued for 2 hours.

LCMS监测显示原料消失后，向反应液中加饱和氯化铵水溶液(3mL)淬灭，混合液用乙酸乙酯(5mL×2次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到12mg 2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)乙腈。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (3 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (5 mL × 2 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 12 mg 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile.

MS(ESI)M/Z:690.4[M+H]⁺.MS (ESI) M/Z: 690.4 [M+H] ⁺ .

步骤C：在室温条件下，将化合物2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)乙腈(12mg,0.02mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(1mL)，继续搅拌2小时。LCMS监测显示原料消失后，向反应液中加氨水调节至pH＝8，继续搅拌2小时。Step C: Compound 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile (12 mg, 0.02 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, trifluoroacetic acid (1 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 2 hours.

LCMS监测显示中间体消失后，向反应液中加水(5mL)淬灭，混合液用二氯甲烷(5mL×2次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化，得到2.7mg 2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)乙腈。After LCMS monitoring showed that the intermediate disappeared, water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (5 mL × 2 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The obtained crude product was purified by preparative high performance liquid chromatography to obtain 2.7 mg 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)acetonitrile.

MS(ESI)M/Z:560.2[M+H]⁺.MS (ESI) M/Z: 560.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.29(s,1H),7.43(s,1H),7.12(s,1H),7.11(s,1H),7.00(s,1H),6.26(s,1H),5.22(s,2H),3.59(s,2H),3.26(s,3H),2.96-2.83(m,2H),2.81-2.70(m,2H),2.61-2.52(m,3H),1.95-1.82(m,1H),1.68-1.51(m,4H),1.50-1.39(m,1H),1.07(d,J＝4.8Hz,3H),0.87-0.71(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.29(s,1H),7.43(s,1H),7.12(s,1H),7.11(s,1H),7.0 0(s,1H),6.26(s,1H),5.22(s,2H),3.59(s,2H),3.26(s,3H),2.96-2.83 (m,2H),2.81-2.70(m,2H),2.61-2.52(m,3H),1.95-1.82(m,1H),1.68-1 .51(m,4H),1.50-1.39(m,1H),1.07(d,J＝4.8Hz,3H),0.87-0.71(m,4H).

实施例101Embodiment 101

6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-4-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(S)-2-((3-甲基哌啶-1-基)甲基)-4-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(70mg,0.16mmol)、2-氯-6-环丙基-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(72mg,0.24mmol)、碘化亚铜(30mg,0.16mmol)、N,N'-二甲基乙二胺(14mg,0.16mmol)和碳酸钾(44mg,0.32mmol)溶于N-甲基吡咯烷酮(0.7mL)中。然后该反应体系在180℃条件下搅拌5小时。Step A: Compound (S)-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (70 mg, 0.16 mmol), 2-chloro-6-cyclopropyl-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (72 mg, 0.24 mmol), cuprous iodide (30 mg, 0.16 mmol), N,N'-dimethylethylenediamine (14 mg, 0.16 mmol) and potassium carbonate (44 mg, 0.32 mmol) were dissolved in N-methylpyrrolidone (0.7 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 180°C for 5 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到50mg 6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-4-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:710.4[M+H]⁺.MS (ESI) M/Z: 710.4 [M+H] ⁺ .

步骤B:在室温条件下，将化合物6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-4-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(50mg,0.07mmol)溶于二氯甲烷(1.0mL)中。随后，向上述溶液中滴加三氟乙酸(0.5mL)，搅拌2小时。LCMS监测显示原料消失后，向反应液中加氨水调节至pH＝8，继续搅拌1小时。Step B: At room temperature, compound 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50 mg, 0.07 mmol) was dissolved in dichloromethane (1.0 mL). Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the above solution and stirred for 2 hours. After LCMS monitoring showed that the raw material disappeared, ammonia water was added to the reaction solution to adjust the pH to 8 and stirring was continued for 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到14.17mg 6-(6-环丙基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-4-(三氟甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 14.17 mg 6-(6-cyclopropyl-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:580.3[M+H]⁺.MS (ESI) M/Z: 580.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.51(s,1H),8.34(s,1H),7.92(s,1H),7.48(s,1H),7.35(s,1H),6.27(s,1H),3.60(s,2H),3.28(s,3H),2.95-2.83(m,2H),2.81-2.69(m,2H),2.63-2.51(m,3H),2.25-2.16(m,1H),1.95-1.83(m,1H),1.68-1.53(m,4H),1.50-1.38(m,1H),1.08(d,J＝5.2Hz,3H),1.02-0.95(m,2H),0.94-0.89(m,2H),0.86-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.51(s,1H),8.34(s,1H),7.92(s,1H),7.48(s,1H),7.35(s,1H),6.27(s,1H ),3.60(s,2H),3.28(s,3H),2.95-2.83(m,2H),2.81-2.69(m,2H),2.63-2.51(m, 3H),2.25-2.16(m,1H),1.95-1.83(m,1H),1.68-1.53(m,4H),1.50-1.38(m,1H) ,1.08(d,J=5.2Hz,3H),1.02-0.95(m,2H),0.94-0.89(m,2H),0.86-0.72(m,4H).

实施例102Embodiment 102

4-氯-6-(3-((1S,3R)-3-(甲氧基-d3)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在0°С条件下，氮气保护，将化合物(1s,3s)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇(92mg,0.3mmol)溶于N,N-二甲基甲酰胺(1.5mL)中。随后，向上述溶液中缓慢加入氢化钠(21.6mg,0.5mmol)，搅拌20分钟。然后再加入氘代碘甲烷(87mg,0.6mmol)，升温至室温，继续搅拌2小时。Step A: Under nitrogen protection at 0°C, compound (1s,3s)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (92 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). Then, sodium hydride (21.6 mg, 0.5 mmol) was slowly added to the above solution and stirred for 20 minutes. Then, deuterated iodomethane (87 mg, 0.6 mmol) was added, the temperature was raised to room temperature, and stirring was continued for 2 hours.

LCMS监测显示原料消失后，将上述反应液滴加到冰水(20mL)中淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到98mg 3-((1S,3S)-1-(3-溴苯基)-3-(甲氧基-d3)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, the above reaction solution was added dropwise to ice water (20 mL) to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 98 mg 3-((1S,3S)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:325.0[M+H]⁺. MS (ESI) M/Z: 325.0 [M+H] ⁺ .

步骤B:在室温条件下，氮气保护，将化合物3-((1S,3S)-1-(3-溴苯基)-3-(甲氧基-d3)环丁基)-4-甲基-4H-1,2,4-三唑(98mg,0.3mmol)溶于二甲亚砜(1.5mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(88mg,0.2mmol)、碘化铜(41mg,0.2mmol)、二甲基乙二胺(19mg,0.2mmol)和碳酸钾(59mg,0.4mmol)。然后该反应体系在150°С条件下搅拌3小时。Step B: Under nitrogen protection at room temperature, compound 3-((1S,3S)-1-(3-bromophenyl)-3-(methoxy-d3)cyclobutyl)-4-methyl-4H-1,2,4-triazole (98 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (1.5 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (88 mg, 0.2 mmol), copper iodide (41 mg, 0.2 mmol), dimethylethylenediamine (19 mg, 0.2 mmol) and potassium carbonate (59 mg, 0.4 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到94mg 4-氯-6-(3-((1S,3R)-3-(甲氧基-d3)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 94 mg 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:654.4[M+H]⁺.MS (ESI) M/Z: 654.4 [M + H] ⁺ .

步骤C:在室温条件下，将化合物4-氯-6-(3-((1S,3R)-3-(甲氧基-d3)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(94mg,0.2mmol)溶于二氯甲烷(0.7mL)中。随后，向上述溶液中加入三氟乙酸(0.7mL)。然后该反应体系继续搅拌2小时。Step C: Compound 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (94 mg, 0.2 mmol) was dissolved in dichloromethane (0.7 mL) at room temperature. Subsequently, trifluoroacetic acid (0.7 mL) was added to the above solution. The reaction system was then stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节pH值至8。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到16.12mg 4-氯-6-(3-((1S,3R)-3-(甲氧基-d3)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH value to 8. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 16.12 mg 4-chloro-6-(3-((1S,3R)-3-(methoxy-d3)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was obtained.

MS(ESI)M/Z:524.3[M+H]⁺.MS (ESI) M/Z: 524.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.31(s,1H),7.50(t,J＝7.8Hz,1H),7.46-7.42(m,2H),7.38-7.34(m,1H),7.30(d,J＝8.4Hz,1H),6.27(s,1H),4.11-4.01(m,1H),3.60(s,2H),3.27(s,3H),3.12-3.05(m,2H),2.84-2.70(m,4H),1.98-1.80(m,1H),1.68-1.53(m,4H),1.52-1.38(m,1H),0.87-0.71(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.31(s,1H),7.50(t,J＝7.8Hz,1H),7.46-7.42(m,2H), 7.38-7.34(m,1H),7.30(d,J＝8.4Hz,1H),6.27(s,1H),4.11-4.01(m,1H ),3.60(s,2H),3.27(s,3H),3.12-3.05(m,2H),2.84-2.70(m,4H),1.98 -1.80(m,1H),1.68-1.53(m,4H),1.52-1.38(m,1H),0.87-0.71(m,4H).

实施例103Embodiment 103

4-氯-6-(3-((1S,3R)-3-(二氟甲氧基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物(1S,3S)-3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-醇(307.0mg,1.0mmol)溶于乙腈(5.0mL)中。随后，向上述溶液中依次加入2,2-二氟-2-(氟磺酰基)乙酸(534.0mg,3.0mmol)和碘化亚铜(38.0mg,0.2mmol)。然后该反应体系在45℃条件下搅拌5小时。Step A: Under nitrogen protection at room temperature, compound (1S,3S)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol (307.0 mg, 1.0 mmol) was dissolved in acetonitrile (5.0 mL). Subsequently, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (534.0 mg, 3.0 mmol) and cuprous iodide (38.0 mg, 0.2 mmol) were added to the above solution in sequence. The reaction system was then stirred at 45°C for 5 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到90mg 3-((1S,3S)-1-(3-溴苯基)-3-(二氟甲氧基)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 90 mg 3-((1S, 3S)-1-(3-bromophenyl)-3-(difluoromethoxy)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:358.0[M+H]⁺.MS (ESI) M/Z: 358.0 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(83.0mg,0.20mmol)溶于二甲基亚砜(2.0mL)中。随后，向上述溶液中依次加入3-((1S,3S)-1-(3-溴苯基)-3-(二氟甲氧基)环丁基)-4-甲基-4H-1,2,4-三唑(87.0mg, 0.25mmol)、碳酸钾(55.2mg,0.4mmol)、N,N'-二甲基乙二胺(21.0mg,0.24mmol)和碘化亚铜(38.0mg,0.20mmol)。然后该反应体系在180℃条件下搅拌2小时。Step B: At room temperature, under nitrogen protection, compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (83.0 mg, 0.20 mmol) was dissolved in dimethyl sulfoxide (2.0 mL). Subsequently, 3-((1S,3S)-1-(3-bromophenyl)-3-(difluoromethoxy)cyclobutyl)-4-methyl-4H-1,2,4-triazole (87.0 mg, 0.20 mmol) was added to the above solution. 0.25 mmol), potassium carbonate (55.2 mg, 0.4 mmol), N,N'-dimethylethylenediamine (21.0 mg, 0.24 mmol) and cuprous iodide (38.0 mg, 0.20 mmol). The reaction system was then stirred at 180°C for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到50mg 4-氯-6-(3-((1S,3R)-3-(二氟甲氧基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:687.2[M+H]⁺.MS (ESI) M/Z: 687.2 [M+H] ⁺ .

步骤C:在0℃条件下，将化合物4-氯-6-(3-((1S,3R)-3-(二氟甲氧基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(50.0mg,0.07mmol)溶于二氯甲烷(1.0mL)中。随后，向上述溶液中滴加三氟乙酸(0.5mL)。然后该反应体系在室温条件下搅拌2小时。Step C: Compound 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50.0 mg, 0.07 mmol) was dissolved in dichloromethane (1.0 mL) at 0°C. Trifluoroacetic acid (0.5 mL) was then added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，继续搅拌30分钟。随后，向上述溶液中加水(15mL)稀释，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物经制备型高效液相色谱纯化，得到18mg 4-氯-6-(3-((1S,3R)-3-(二氟甲氧基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 30 minutes. Subsequently, water (15 mL) was added to dilute the above solution, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 18 mg 4-chloro-6-(3-((1S,3R)-3-(difluoromethoxy)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:557.2[M+H]⁺.MS (ESI) M/Z: 557.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),8.33(s,1H),7.54-7.48(m,2H),7.47(s,1H),7.38(d,J＝8.4Hz,1H),7.31(d,J＝8.0Hz,1H),6.67(t,J＝75.4Hz,1H),6.27(s,1H),4.86-4.76(m,1H),3.61(s,2H),3.27(s,3H),3.25-3.18(m,2H),3.07-2.98(m,2H),2.83-2.72(m,2H),1.99-1.82(m,1H),1.67-1.52(m,4H),1.51-1.38(m,1H),0.88-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),8.33(s,1H),7.54-7.48(m,2H),7.47(s,1H),7.38(d,J＝8.4Hz, 1H),7.31(d,J＝8.0Hz,1H),6.67(t,J＝75.4Hz,1H),6.27(s,1H),4.86-4.76(m,1H ),3.61(s,2H),3.27(s,3H),3.25-3.18(m,2H),3.07-2.98(m,2H),2.83-2.72(m, 2H),1.99-1.82(m,1H),1.67-1.52(m,4H),1.51-1.38(m,1H),0.88-0.73(m,4H).

实施例104Embodiment 104

4-氯-6-(3-((1R,3S)-3-(甲氧基甲基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1R,3S)-3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(3-((1S,3R)-3-(甲氧基甲基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
4-Chloro-6-(3-((1S,3R)-3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在0℃条件下，氮气保护，氮气保护，将化合物(甲氧基甲基)三苯基氯化鏻(1.4g,3.9mmol)溶于四氢呋喃(6.6mL)中。随后，向上述溶液中加入氢化钠(157mg,6.5mmol)，搅拌1小时。然后再加入化合物3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-酮(400mg,1.3mmol)，继续搅拌1小时。Step A: Dissolve (methoxymethyl)triphenylphosphonium chloride (1.4 g, 3.9 mmol) in tetrahydrofuran (6.6 mL) under nitrogen protection at 0°C. Then, add sodium hydride (157 mg, 6.5 mmol) to the solution and stir for 1 hour. Then add 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one (400 mg, 1.3 mmol) and continue stirring for 1 hour.

LCMS监测显示原料消失后，向反应液中加冰水(10mL)淬灭，用1M稀盐酸调节至pH＝6。混合液用二氯甲烷(20mL×2次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化，得到123mg 3-(1-(3-溴苯基)-3-(甲氧基亚甲基)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, ice water (10 mL) was added to the reaction solution to quench, and the pH was adjusted to 6 with 1M dilute hydrochloric acid. The mixed solution was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 123 mg 3-(1-(3-bromophenyl)-3-(methoxymethylene)cyclobutyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:334.1[M+H]⁺.MS (ESI) M/Z: 334.1 [M+H] ⁺ .

步骤B：在室温条件下，氢气气氛，将化合物3-(1-(3-溴苯基)-3-(甲氧基亚甲基)环丁基)-4-甲基-4H-1,2,4-三唑(123mg,0.4mol)溶于甲醇(0.2mL)中。随后，向上述溶液中加入10％wt钯碳(120mg)。然后该反应体系继续搅拌5分钟。Step B: Under room temperature and hydrogen atmosphere, compound 3-(1-(3-bromophenyl)-3-(methoxymethylene)cyclobutyl)-4-methyl-4H-1,2,4-triazole (123 mg, 0.4 mol) was dissolved in methanol (0.2 mL). Subsequently, 10% wt palladium on carbon (120 mg) was added to the above solution. The reaction system was then stirred for 5 minutes.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(8mL×2次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到73mg 3-(1-(3-溴苯基)-3-(甲氧基甲基)环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (8 mL × 2 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 73 mg 3-(1-(3-bromophenyl)-3-(methoxymethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole was obtained.

MS(ESI)M/Z:336.1[M+H]⁺.MS (ESI) M/Z: 336.1 [M+H] ⁺ .

步骤C：在室温条件下，氮气保护，将化合物3-(1-(3-溴苯基)-3-(甲氧基甲基)环丁基)-4-甲基-4H-1,2,4-三唑(73mg,0.2mmol)溶于二甲亚砜(1.1mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(85mg,0.2mmol)、碘化亚铜(40mg,0.2mmol)、N,N'-二甲基乙二胺(22mg,0.3mmol)和碳酸钾(57mg,0.4mmol)。然后该反应体系在150°С条件下搅拌3小时。Step C: Under nitrogen protection at room temperature, compound 3-(1-(3-bromophenyl)-3-(methoxymethyl)cyclobutyl)-4-methyl-4H-1,2,4-triazole (73 mg, 0.2 mmol) was dissolved in dimethyl sulfoxide (1.1 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (85 mg, 0.2 mmol), cuprous iodide (40 mg, 0.2 mmol), N,N'-dimethylethylenediamine (22 mg, 0.3 mmol) and potassium carbonate (57 mg, 0.4 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到50mg(S)-4-氯-6-(3-(甲氧基甲基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of (S)-4-chloro-6-(3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:665.2[M+H]⁺.MS (ESI) M/Z: 665.2 [M+H] ⁺ .

步骤D：在室温条件下，将化合物(S)-4-氯-6-(3-(甲氧基甲基)-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(50mg,0.08mmol)溶于二氯甲烷(0.8mL)。随后，向上述溶液中滴加三氟乙酸(0.8mL)。然后该反应体系在室温条件下搅拌2小时。Step D: Compound (S)-4-chloro-6-(3-(methoxymethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50 mg, 0.08 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Subsequently, trifluoroacetic acid (0.8 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，继续搅拌30分钟。随后，向上述溶液中加水(15mL)稀释，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备型高效液相色谱纯化。然后经手性柱拆分(色谱柱：Daicel AS-3；流动相:CO₂/MeOH[0.2％NH₃(7M in MeOH)]＝85/15)，得到化合物104-P1(保留时间：1.671min)和化合物104-P2(保留时间：1.913min)。After LCMS monitoring showed that the starting material disappeared, ammonia water was added dropwise to the reaction solution to adjust the pH to 8, and stirring was continued for 30 minutes. Subsequently, water (15 mL) was added to dilute the above solution, and the mixed solution was extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. Then, it was separated by chiral column (chromatographic column: Daicel AS-3; mobile phase: CO ₂ /MeOH [0.2% NH ₃ (7M in MeOH)] = 85/15) to obtain compound 104-P1 (retention time: 1.671 min) and compound 104-P2 (retention time: 1.913 min).

化合物104-P1：Compound 104-P1:

MS(ESI)M/Z:535.3[M+H]⁺.MS (ESI) M/Z: 535.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),8.31(s,1H),7.55-7.40(m,3H),7.38-7.29(m,2H),6.28(s,1H),3.61(s,1H),3.32-3.29(m,2H),3.25(s,3H),3.22(s,3H),2.86-2.68(m,6H),2.57-2.53(m,1H),1.98-1.80(m,1H),1.71-1.40(m,5H),0.92-0.76(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),8.31(s,1H),7.55-7.40(m,3H),7.38-7.29(m,2H),6.28(s,1H),3.61(s,1H),3.32 -3.29(m,2H),3.2 5(s,3H),3.22(s,3H),2.86-2.68(m,6H),2.57-2.53(m,1H),1.98-1.80(m,1H),1.71-1.40(m,5H), 0.92-0.76(m,4H).

化合物104-P2：Compound 104-P2:

MS(ESI)M/Z:535.4[M+H]⁺.MS (ESI) M/Z: 535.4 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.37(s,1H),8.38(s,1H),7.47(t,J＝8.2Hz,1H),7.42(s,1H),7.36-7.26(m,2H),7.16(d,J＝8Hz,1H),6.26(s,1H),3.60(s,2H),3.31-3.33(m,2H),3.30(s,3H),3.23(s,3H),3.09-2.96(m,2H),2.83-2.72(m,2H),2.56-2.53(m,1H),2.48-2.43(m,2H),1.97-1.84(m,1H),1.68-1.53(m,4H),1.52-1.38(m,1H),0.89-0.74(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.37(s,1H),8.38(s,1H),7.47(t,J＝8.2Hz,1H),7.42(s,1H),7.36-7.26(m,2H ),7.16(d,J=8Hz,1H),6.26(s,1H),3.60(s,2H),3.31-3.33(m,2H),3.30(s,3H),3 .23(s,3H),3.09-2.96(m,2H),2.83-2.72(m,2H),2.56-2.53(m,1H),2.48-2.43(m ,2H),1.97-1.84(m,1H),1.68-1.53(m,4H),1.52-1.38(m,1H),0.89-0.74(m,4H).

实施例105Embodiment 105

反应路线:
Reaction route:

操作步骤：Steps:

MS(ESI)M/Z:676.3[M+H]⁺.MS (ESI) M/Z: 676.3 [M + H] ⁺ .

步骤B：在室温条件下，将化合物4-氯-6-(6-环丙基-4-((1R,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(80mg,0.12mmol)溶于二氯甲烷(2.2mL)中。随后，向上述溶液中滴加三氟乙酸(2.2mL)，继续搅拌2小时。LCMS监测显示原料消失后，向反应液中滴加氨水(5.0mL)至碱性，继续搅拌4小时。Step B: At room temperature, compound 4-chloro-6-(6-cyclopropyl-4-((1R,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (80 mg, 0.12 mmol) was dissolved in dichloromethane (2.2 mL). Subsequently, trifluoroacetic acid (2.2 mL) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia (5.0 mL) was added dropwise to the reaction solution until it was alkaline and stirring was continued for 4 hours.

MS(ESI)M/Z:546.2[M+H]⁺.MS (ESI) M/Z: 546.2 [M + H] ⁺ .

实施例106Embodiment 106

4-氯-6-(6-乙氧基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
4-Chloro-6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，氮气保护，将化合物2-溴-6-氯-4-甲基吡啶(7g,34.1mmol)溶于乙醇(70mL)中。随后，向上述溶液中加入乙醇钠(3.5g,51.2mmol)。然后该反应体系在90℃条件下搅拌4小时。Step A: Under nitrogen protection at room temperature, compound 2-bromo-6-chloro-4-methylpyridine (7 g, 34.1 mmol) was dissolved in ethanol (70 mL). Then, sodium ethoxide (3.5 g, 51.2 mmol) was added to the above solution. The reaction system was then stirred at 90°C for 4 hours.

LCMS监测显示原料消失后，反应液先浓缩，然后向反应液中加水(50mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到6.0g 2-氯-6-乙氧基-4-甲基吡啶。After LCMS monitoring showed that the raw material disappeared, the reaction solution was concentrated first, and then water (50 mL) was added to the reaction solution to quench it. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6.0 g 2-chloro-6-ethoxy-4-methylpyridine.

MS(ESI)M/Z:172.0[M+H]⁺.MS (ESI) M/Z: 172.0 [M+H] ⁺ .

步骤B：在-78℃条件下，氮气保护，将化合物2-氯-6-乙氧基-4-甲基吡啶(5.5g,32.2mmol)溶于四氢呋喃(55mL)中。随后，向上述溶液中滴加2M二异丙基氨基锂的四氢呋喃/正庚烷溶液(40.2mL,80.5mmol)，搅拌1小时后，加入碳酸二甲酯(4.3g,48.3mmol)。然后该反应体系在0℃条件下搅拌2小时。Step B: Under nitrogen protection at -78°C, the compound 2-chloro-6-ethoxy-4-methylpyridine (5.5 g, 32.2 mmol) was dissolved in tetrahydrofuran (55 mL). Subsequently, a 2M tetrahydrofuran/n-heptane solution of lithium diisopropylamide (40.2 mL, 80.5 mmol) was added dropwise to the above solution. After stirring for 1 hour, dimethyl carbonate (4.3 g, 48.3 mmol) was added. The reaction system was then stirred at 0°C for 2 hours.

LCMS监测显示原料消失后，向反应液中先加入饱和氯化铵水溶液(20mL)淬灭，再加水(50mL)稀释，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.9g 2-(2-氯-6-乙氧基吡啶-4-基)乙酸甲酯。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to quench, and then water (50 mL) was added to dilute, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.9 g methyl 2-(2-chloro-6-ethoxypyridin-4-yl)acetate.

MS(ESI)M/Z:230.0[M+H]⁺.MS (ESI) M/Z: 230.0 [M+H] ⁺ .

步骤C：在0℃条件下，氮气保护，将化合物2-(2-氯-6-乙氧基吡啶-4-基)乙酸甲酯(2.4g,10.4mmol)和1,3-二溴-2-甲基丙烷(2.7g,12.5mmol)溶于N,N-二甲基甲酰胺(24mL)中。随后，向上述溶液中缓慢加入60％wt氢化钠(832mg,20.8mmol)。然后该反应体系在室温条件下搅拌2小时。Step C: Under nitrogen protection at 0°C, compound 2-(2-chloro-6-ethoxypyridin-4-yl)acetic acid methyl ester (2.4 g, 10.4 mmol) and 1,3-dibromo-2-methylpropane (2.7 g, 12.5 mmol) were dissolved in N,N-dimethylformamide (24 mL). Subsequently, 60% wt sodium hydride (832 mg, 20.8 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加入饱和氯化铵水溶液(20mL)淬灭，再加水(50mL)稀释，混合液用乙酸乙酯(40mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.8g 1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羧酸甲酯。After LCMS monitoring showed that the raw material disappeared, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to quench, and then water (50 mL) was added to dilute, and the mixed solution was extracted with ethyl acetate (40 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g 1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarboxylic acid methyl ester.

MS(ESI)M/Z:284.0[M+H]⁺.MS (ESI) M/Z: 284.0 [M+H] ⁺ .

步骤D：在室温条件下，将化合物1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羧酸甲酯(1.8g,6.34mmol)溶于甲醇(5mL)和四氢呋喃(15mL)的混合溶液中。随后，向上述溶液中加入氢氧化锂(456mg,19.0mmol)的水溶液(10mL)。然后该反应体系在室温条件下搅拌2小时。Step D: Compound 1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarboxylic acid methyl ester (1.8 g, 6.34 mmol) was dissolved in a mixed solution of methanol (5 mL) and tetrahydrofuran (15 mL) at room temperature. Subsequently, an aqueous solution (10 mL) of lithium hydroxide (456 mg, 19.0 mmol) was added to the above solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，先将上述反应液浓缩去除有机溶剂，再用2M的稀盐酸调至pH＝3，然后用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩得到1.4g 1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羧酸。After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated to remove the organic solvent, and then adjusted to pH = 3 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL x 3 times), the organic phases were combined, washed with saturated brine (30 mL x 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.4 g of 1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarboxylic acid.

MS(ESI)M/Z:270.0[M+H]⁺.MS (ESI) M/Z: 270.0 [M+H] ⁺ .

步骤E：在室温条件下，将化合物1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羧酸(1.4g,5.18mmol)溶于N,N-二甲基甲酰胺(14mL)中。随后，向上述溶液中依次加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.9g,7.77mmol)和N,N-二异丙基乙胺(2.0g,15.54mmol)，搅拌10分钟后，加入4-甲基氨基硫脲(816mg,7.77mmol)。然后该反应体系在室温条件下搅拌1小时。Step E: Dissolve the compound 1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarboxylic acid (1.4 g, 5.18 mmol) in N,N-dimethylformamide (14 mL) at room temperature. Then, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.9 g, 7.77 mmol) and N,N-diisopropylethylamine (2.0 g, 15.54 mmol) to the above solution in sequence. After stirring for 10 minutes, add 4-methylthiosemicarbazide (816 mg, 7.77 mmol). Then, stir the reaction system at room temperature for 1 hour.

LCMS监测显示原料消失后，向上述反应液中加入水(50mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。粗品用石油醚/乙酸乙酯(20mL/6mL)打浆得到1.2g 2-(1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羰基)-N-甲基肼甲硫酰胺。After LCMS monitoring showed that the raw material disappeared, water (50 mL) was added to the above reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with petroleum ether/ethyl acetate (20 mL/6 mL) to obtain 1.2 g 2-(1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarbonyl)-N-methylhydrazine methylthioamide.

MS(ESI)M/Z:357.1[M+H]⁺.MS (ESI) M/Z: 357.1 [M+H] ⁺ .

步骤F：在室温条件下，将化合物2-(1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁烷羰基)-N-甲基肼甲硫酰胺(1.2g,3.35mmol)溶于四氢呋喃(12mL)中。随后，向上述溶液中加入氢氧化钠(1.3g,33.5mmol)的水溶液(6mL)。然后该反应体系在80℃条件下搅拌5小时。Step F: Dissolve the compound 2-(1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutanecarbonyl)-N-methylhydrazine methylthioamide (1.2 g, 3.35 mmol) in tetrahydrofuran (12 mL) at room temperature. Then, add an aqueous solution (6 mL) of sodium hydroxide (1.3 g, 33.5 mmol) to the solution. Then, stir the reaction system at 80°C for 5 hours.

LCMS监测显示原料消失后，反应液用2M稀盐酸调至pH＝5，再用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩得到粗产品1.0g 5-(1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the raw material disappeared, the reaction solution was adjusted to pH = 5 with 2M dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 1.0 g 5-(1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol.

MS(ESI)M/Z:339.0[M+H]⁺.MS (ESI) M/Z: 339.0 [M+H] ⁺ .

步骤G：在0℃条件下，将化合物5-(1-(2-氯-6-乙氧基吡啶-4-基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑-3-硫醇(1.0g,2.95mmol)溶于二氯甲烷(15mL)和乙酸(2.5mL)的混合溶液中。随后，向上述溶液中缓慢滴加30％双氧水(2.5mL)。然后该反应体系在室温条件下搅拌1小时。Step G: Compound 5-(1-(2-chloro-6-ethoxypyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (1.0 g, 2.95 mmol) was dissolved in a mixed solution of dichloromethane (15 mL) and acetic acid (2.5 mL) at 0°C. Subsequently, 30% hydrogen peroxide (2.5 mL) was slowly added dropwise to the solution. The reaction system was then stirred at room temperature for 1 hour.

LCMS监测显示原料消失后，将反应液倒入冰水(30mL)中淬灭，混合液用二氯甲烷(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到600mg 2-氯-6-乙氧基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶。After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water (30 mL) to quench, the mixed solution was extracted with dichloromethane (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 600 mg 2-chloro-6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine.

MS(ESI)M/Z:307.1[M+H]⁺.MS (ESI) M/Z: 307.1 [M+H] ⁺ .

步骤H：化合物2-氯-6-乙氧基-4-(3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(300mg,0.98mmol)经制备型高效液相色谱纯化，得到180mg化合物2-氯-6-乙氧基-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(A1)Step H: Compound 2-chloro-6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (300 mg, 0.98 mmol) was purified by preparative high performance liquid chromatography to obtain 180 mg of compound 2-chloro-6-ethoxy-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (A1)

¹H NMR(400MHz,CDCl₃)δ8.04(s,1H),6.79(d,J＝1.2Hz,1H),6.62(d,J＝1.2Hz,1H),4.37(dd,J₁＝7.0Hz,J₂＝14.2Hz,2H),3.23(s,3H),2.79-2.78(m,2H),2.66-2.64(m,3H),1.39(t,J＝7.2Hz,3H),1.14(d,J＝4.8Hz,3H). ¹ H NMR (400MHz, CDCl ₃ ) δ8.04 (s, 1H), 6.79 (d, J = 1.2Hz, 1H), 6.62 (d, J = 1.2Hz, 1H), 4.37 (dd, J ₁ = 7.0 Hz,J ₂ ＝14.2Hz,2H),3.23(s,3H),2.79-2.78(m,2H),2.66-2.64(m,3H),1.39(t,J＝7.2Hz,3H),1.14(d,J＝ 4.8Hz,3H).

和40mg化合物2-氯-6-乙氧基-4-((1R,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(A2)。and 40 mg of the compound 2-chloro-6-ethoxy-4-((1R,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (A2).

¹H NMR(400MHz,CDCl₃)δ8.08(s,1H),6.67(d,J＝1.2Hz,1H),6.48(d,J＝1.2Hz,1H),4.36(dd,J₁＝6.8Hz,J₂＝14.0Hz,2H),3.28(s,3H),3.13-3.07(m,2H),2.61-2.51(m,1H),2.26-2.20(m,2H),1.39(t,J＝7.2Hz,3H),1.13(d,J＝6.8Hz,3H) ¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 6.67 (d, J = 1.2Hz, 1H), 6.48 (d, J = 1.2Hz, 1H), 4.36 (dd, J ₁ = 6.8 Hz,J ₂ ＝14.0Hz,2H),3.28(s,3H),3.13-3.07(m,2H),2.61-2.51(m,1H),2.26-2.20(m,2H),1.39(t,J＝7.2Hz, 3H),1.13(d,J＝6.8Hz,3H)

步骤I：在室温条件下，氮气保护，将化合物(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(98mg,0.24mmol)、2-氯-6-乙氧基-4-((1S,3S)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(80mg,0.26mmol)、N,N'-二甲基乙二胺(21mg,0.24mmol)、碘化亚铜(46mg,0.24mmol)和碳酸钾(66mg,0.48mmol)溶于二甲基亚砜(0.8mL)中。然后该反应体系在150℃条件下搅拌3小时。Step I: Compound (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (98 mg, 0.24 mmol), 2-chloro-6-ethoxy-4-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (80 mg, 0.26 mmol), N,N'-dimethylethylenediamine (21 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol) and potassium carbonate (66 mg, 0.48 mmol) were dissolved in dimethyl sulfoxide (0.8 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(10mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(10mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到100mg 4-氯-6-(6-乙氧基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (10 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg 4-chloro-6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:680.3[M+H]⁺.MS (ESI) M/Z: 680.3 [M + H] ⁺ .

步骤J:在0℃条件下，将化合物4-氯-6-(6-乙氧基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((S)-3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(100mg,0.15mmol)溶于二氯甲烷(2mL)中。随后，向上述溶液中滴加三氟乙酸(1.5mL)，然后该反应体系在室温条件下搅拌2小时。LCMS监测显示原料消失后，向反应液中加氨水至碱性，继续搅拌 1小时。Step J: At 0°C, compound 4-chloro-6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((S)-3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (100 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). Subsequently, trifluoroacetic acid (1.5 mL) was added dropwise to the above solution, and the reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, ammonia water was added to the reaction solution until it was alkaline and stirring was continued. 1 hour.

LCMS监测显示中间体消失后，向反应液中加水(10mL)淬灭，混合液用二氯甲烷(10mL×3次)萃取，合并有机相。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到42.82mg 4-氯-6-(6-乙氧基-4-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。After LCMS monitoring showed that the intermediate disappeared, water (10 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (10 mL × 3 times), and the organic phases were combined. Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 42.82 mg 4-chloro-6-(6-ethoxy-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one.

MS(ESI)M/Z:550.2[M+H]⁺.MS (ESI) M/Z: 550.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.43(s,1H),8.34(s,1H),7.69(s,1H),7.27(d,J＝1.2Hz,1H),6.77(d,J＝1.2Hz,1H),6.26(s,1H),4.32(dd,J₁＝7.2Hz,J₂＝14.4Hz,2H),3.59(s,2H),3.27(s,3H),2.90-2.82(m,2H),2.80-2.69(m,2H),2.63-2.52(m,3H),1.94-1.82(m,1H),1.67-1.52(m,4H),1.52-1.38(m,1H),1.33(t,J＝7.0Hz,3H),1.07(d,J＝6.0Hz,3H),0.88-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.43 (s, 1H), 8.34 (s, 1H), 7.69 (s, 1H), 7.27 (d, J = 1.2Hz, 1H), 6.77 (d, J＝1.2Hz,1H),6.26(s,1H),4.32(dd,J ₁ =7.2Hz,J ₂ ＝14.4Hz,2H),3.59(s,2H),3.27(s,3H),2.90-2.82(m,2H),2.80-2.69(m,2H),2.63-2.52(m,3H),1.94- 1.82( m,1H),1.67-1.52(m,4H),1.52-1.38(m,1H),1.33(t,J＝7.0Hz,3H),1.07(d,J＝6.0Hz,3H),0.88-0.72 (m,4H).

实施例107Embodiment 107

反应路线:
Reaction route:

操作步骤：Steps:

MS(ESI)M/Z:680.3[M+H]⁺.MS (ESI) M/Z: 680.3 [M + H] ⁺ .

MS(ESI)M/Z:550.2[M+H]⁺.MS (ESI) M/Z: 550.2 [M+H] ⁺ .

实施例125和126Examples 125 and 126

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，将化合物4-溴-7-甲氧基-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯(2g,4.66mmol)溶于1,4-二氧六环(23mL)和水(4mL)中。随后，向上述溶液中依次加入乙烯基三氟硼酸钾(1.25g,9.32mmol)、碳酸钾(1.29g,9.32mmol)、2-二环己基膦-2′,6′-二甲氧基-联苯(287mg,0.70mmol)和醋酸钯(157mg,0.70mmol)。然后该反应体系在90℃条件下搅拌4小时。Step A: Dissolve the compound 4-bromo-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (2 g, 4.66 mmol) in 1,4-dioxane (23 mL) and water (4 mL) at room temperature. Then, potassium vinyl trifluoroborate (1.25 g, 9.32 mmol), potassium carbonate (1.29 g, 9.32 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (287 mg, 0.70 mmol) and palladium acetate (157 mg, 0.70 mmol) were added to the above solution in sequence. The reaction system was then stirred at 90°C for 4 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.6g 7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4-乙烯基-1H-吡咯并 [2,3-c]吡啶-2-羧酸乙酯。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.6 g of 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrrolo[ ... [2,3-c]pyridine-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:377.2[M+H]⁺.MS (ESI) M/Z: 377.2 [M+H] ⁺ .

LCMS监测显示原料消失后，减压浓缩，所得粗品经高效液相色谱纯化，得到1.2g 4-甲酰基-7-甲氧基-1-(2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-羧酸乙酯。After LCMS monitoring showed the disappearance of the starting material, the reaction was concentrated under reduced pressure and the crude product was purified by HPLC to obtain 1.2 g of 4-formyl-7-methoxy-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester.

MS(ESI)M/Z:379.3[M+H]⁺.MS (ESI) M/Z: 379.3 [M + H] ⁺ .

MS(ESI)M/Z:401.2[M+H]⁺.MS (ESI) M/Z: 401.2 [M + H] ⁺ .

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到390mg(4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶-2-基)甲醇。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 390 mg (4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol.

MS(ESI)M/Z:359.2[M+H]⁺.MS (ESI) M/Z: 359.2 [M+H] ⁺ .

LCMS监测显示原料消失后，将上述反应液减压浓缩，得到390mg 2-(氯甲基)-4-(二氟甲基)-7-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-c]吡啶。After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 390 mg 2-(chloromethyl)-4-(difluoromethyl)-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine.

MS(ESI)M/Z:377.2[M+H]⁺.MS (ESI) M/Z: 377.2 [M+H] ⁺ .

MS(ESI)M/Z:440.2[M+H]⁺.MS (ESI) M/Z: 440.2 [M+H] ⁺ .

MS(ESI)M/Z:426.2[M+H]⁺.MS (ESI) M/Z: 426.2 [M+H] ⁺ .

步骤H:在室温条件下，氧气气氛中，将化合物(S)-4-(二氟甲基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(110mg,0.22mmol)、4-甲基-3-((1s，3s)-3-甲基-1-(3-(4,4,5,5-四甲基-1,3,2-二恶硼烷-2-基)苯基)环丁基)-4H-12,4-三唑(272mg,0.77mmol)、碳酸氢钠(26mg,0.44mmol)和醋酸铜(131mg,0.66mmol)溶于二甲基亚砜(3mL)中。然后该反应体系在90℃条件下搅拌3小时。Step H: At room temperature, in an oxygen atmosphere, compound (S)-4-(difluoromethyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.22 mmol), 4-methyl-3-((1s, 3s)-3-methyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-12,4-triazole (272 mg, 0.77 mmol), sodium bicarbonate (26 mg, 0.44 mmol) and copper acetate (131 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction system was then stirred at 90 ° C for 3 hours.

MS(ESI)M/Z:651.3[M+H]⁺.MS (ESI) M/Z: 651.3 [M + H] ⁺ .

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到粗品。所得粗品经制备型高效液相色谱纯化得到4.5mg 4-(二氟甲基)-6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(化合物125)和3.3mg 6-(3-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-甲醛(化合物126)。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a crude product. The crude product was purified by preparative HPLC to give 4.5 mg of 4-(difluoromethyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Compound 125) and 3.3 mg of 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde (Compound 126).

化合物125Compound 125

MS(ESI)M/Z:521.2[M+H]⁺.MS (ESI) M/Z: 521.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.27(s,1H),8.29(s,1H),7.62(s,1H),7.56-7.45(m,2H),7.38-7.30(m,2H),6.94(t,J＝14.6Hz,1H),6.33(s,1H),3.61(s,2H),3.25(s,3H),2.92-2.83(m,2H),2.82-2.72(m,2H),2.61-2.53(m,3H),1.99-1.83(m,1H),1.69-1.54(m,4H),1.52-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.86-0.74(m,4H). ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.27(s,1H),8.29(s,1H),7.62(s,1H),7.56-7.45(m,2H),7.38-7.30(m ,2H),6.94(t,J＝14.6Hz,1H),6.33(s,1H),3.61(s,2H),3.25(s,3H),2.92- 2.83(m,2H),2.82-2.72(m,2H),2.61-2.53(m,3H),1.99-1.83(m,1H),1.69 -1.54(m,4H),1.52-1.40(m,1H),1.07(d,J＝5.2Hz,3H),0.86-0.74(m,4H).

化合物126Compound 126

MS(ESI)M/Z:499.3[M+H]⁺.MS (ESI) M/Z: 499.3 [M + H] ⁺ .

实施例127Embodiment 127

(S)-4-氯-6-(3-(6-(4-甲基-4H-1,2,4-三唑-3-基)-2-氧杂螺[3.3]庚烷-6-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
(S)-4-Chloro-6-(3-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-2-oxaspiro[3.3]heptane-6-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤： Steps:

步骤A:在0°С条件下，氮气保护，将化合物2-(3-溴苯基)乙酸甲酯(3.5g,15.4mmol)和3,3-双(溴甲基)氧杂环丁烷(3.7g,15.3mmol)溶于N,N-二甲基甲酰胺(77mL)中。随后，向上述溶液中缓慢加入60％wt氢化钠(1.4g,54.8mmol)。然后该反应体系在室温条件下搅拌3小时。Step A: Under nitrogen protection at 0°С, compound 2-(3-bromophenyl)acetic acid methyl ester (3.5 g, 15.4 mmol) and 3,3-bis(bromomethyl)oxetane (3.7 g, 15.3 mmol) were dissolved in N,N-dimethylformamide (77 mL). Subsequently, 60%wt sodium hydride (1.4 g, 54.8 mmol) was slowly added to the above solution. The reaction system was then stirred at room temperature for 3 hours.

LCMS监测显示原料消失后，将上述反应液滴加到冰水(40mL)中淬灭，混合液用二氯甲烷(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(40mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩得到3g 6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-羧酸甲酯。After LCMS monitoring showed that the raw material disappeared, the reaction solution was added dropwise to ice water (40 mL) to quench, the mixed solution was extracted with dichloromethane (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (40 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3 g of 6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-carboxylic acid methyl ester.

MS(ESI)M/Z:311.2[M+H]⁺.MS (ESI) M/Z: 311.2 [M+H] ⁺ .

步骤B:在室温条件下，将化合物6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-羧酸甲酯(3mg,9.7mmol)溶于乙醇(14mL)中。随后，向上述溶液中加入水合肼(2.4g,48mmol)。然后该反应体系在80°С条件下搅拌48小时。Step B: Dissolve the compound 6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-carboxylic acid methyl ester (3 mg, 9.7 mmol) in ethanol (14 mL) at room temperature. Then, add hydrazine hydrate (2.4 g, 48 mmol) to the solution. Then, stir the reaction system at 80°C for 48 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.9g 6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-碳酰肼。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.9 g 6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-carbohydrazide.

MS(ESI)M/Z:311.2[M+H]⁺.MS (ESI) M/Z: 311.2 [M+H] ⁺ .

步骤C:在室温条件下，将化合物6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-碳酰肼(2.9g,9.4mmol)溶于四氢呋喃(24.3mL)中。随后，向上述溶液中加入异硫氰酸甲酯(1.4mg,18.7mmol)，升温至80℃，搅拌2小时。然后将反应液降到0℃，依次加入氢氧化钾(2.6mg,46.4mmol)和水(7.8mL)，再升温至85℃，继续搅拌16小时。Step C: Dissolve the compound 6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-carbohydrazide (2.9 g, 9.4 mmol) in tetrahydrofuran (24.3 mL) at room temperature. Then, add methyl isothiocyanate (1.4 mg, 18.7 mmol) to the above solution, heat to 80°C, and stir for 2 hours. Then cool the reaction solution to 0°C, add potassium hydroxide (2.6 mg, 46.4 mmol) and water (7.8 mL) in sequence, heat to 85°C, and continue stirring for 16 hours.

LCMS监测显示原料消失后，向反应液中加入冰水(20mL)淬灭。混合液用乙酸乙酯(30mL×3)次萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。得到3.9g 5-(6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-基)-4-甲基-4H-1,2,4-三唑-3-硫醇。After LCMS monitoring showed that the raw material disappeared, ice water (20 mL) was added to the reaction solution to quench. The mixed solution was extracted with ethyl acetate (30 mL × 3) times, the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 3.9 g of 5-(6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-yl)-4-methyl-4H-1,2,4-triazole-3-thiol was obtained.

MS(ESI)M/Z:366.0[M+H]⁺.MS (ESI) M/Z: 366.0 [M+H] ⁺ .

步骤D:在0°С条件下，将化合物5-(6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-基)-4-甲基-4H-1,2,4-三唑-3-硫醇(3.4g,9.35mmol)溶于二氯甲烷(24mL)中。随后，向上述溶液中依次加入乙酸(10.6mL)和过氧化氢(5.3g,47mmol)。然后该反应体系继续搅拌30分钟。Step D: Compound 5-(6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-yl)-4-methyl-4H-1,2,4-triazole-3-thiol (3.4 g, 9.35 mmol) was dissolved in dichloromethane (24 mL) at 0°C. Acetic acid (10.6 mL) and hydrogen peroxide (5.3 g, 47 mmol) were then added to the solution. The reaction system was then stirred for 30 minutes.

LCMS监测显示原料消失后，向反应液中加入冰水(20mL)淬灭。混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(30mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.2g 3-(6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, ice water (20 mL) was added to the reaction solution to quench. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.2 g 3-(6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-yl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:334.0[M+H]⁺.MS (ESI) M/Z: 334.0 [M+H] ⁺ .

步骤E:在室温条件下，氮气保护，将化合物3-(6-(3-溴苯基)-2-氧杂螺[3.3]庚烷-6-基)-4-甲基-4H-1,2,4-三唑(100mg,0.3mmol)溶于二甲亚砜(1mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(60mg,0.2mmol)、碘化亚铜(41mg,0.2mmol)、N,N'-二甲基乙二胺(19mg,0.2mmol)和碳酸钾(59mg,0.4mmol)。然后该反应体系在150°С条件下搅拌3小时。Step E: Under nitrogen protection at room temperature, compound 3-(6-(3-bromophenyl)-2-oxaspiro[3.3]heptane-6-yl)-4-methyl-4H-1,2,4-triazole (100 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (1 mL). Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (60 mg, 0.2 mmol), cuprous iodide (41 mg, 0.2 mmol), N,N'-dimethylethylenediamine (19 mg, 0.2 mmol) and potassium carbonate (59 mg, 0.4 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加入水(20mL)淬灭，混合液用乙酸乙酯(20mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化。收集产品。得到18.97mg化合物(S)-4-氯-6-(3-(6-(4-甲基-4H-1,2,4-三唑-3-基)-2-氧杂螺[3.3]庚烷-6-基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (20 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. The product was collected. 18.97 mg of compound (S)-4-chloro-6-(3-(6-(4-methyl-4H-1,2,4-triazol-3-yl)-2-oxaspiro[3.3]heptane-6-yl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one was obtained.

MS(ESI)M/Z:533.2[M+H]⁺.MS (ESI) M/Z: 533.2 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.35(s,1H),7.47(t,J＝8.0Hz,1H),7.42(s,1H),7.37(s,1H),7.35-7.30(m,1H),7.16(d,J＝8.0Hz,1H),6.26(s,1H),4.54(s,2H),4.46(s,2H),3.60(s,2H),3.27(s,3H),3.22(d,J＝12.8Hz,2H),2.95(d,J＝12.8Hz,2H),2.84-2.70(m,2H),1.96-1.84(m,1H),1.68-1.53(m,4H),1.52-1.40(m,1H),0.88-0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.35(s,1H),7.47(t,J＝8.0Hz,1H),7.42(s,1H),7.37(s,1H),7.3 5-7.30(m,1H),7.16(d,J＝8.0Hz,1H),6.26(s,1H),4.54(s,2H),4.46(s,2H),3.60 (s,2H),3.27(s,3H),3.22(d,J＝12.8Hz,2H),2.95(d,J＝12.8Hz,2H),2.84-2.70(m ,2H),1.96-1.84(m,1H),1.68-1.53(m,4H),1.52-1.40(m,1H),0.88-0.73(m,4H).

实施例128Embodiment 128

(S)-4-氯-6-(3-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-氧代环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
(S)-4-Chloro-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-oxocyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物3-(3-溴苯基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁烷-1-酮(100mg,0.33mmol)和(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(148mg,0.36mmol)溶于二甲基亚砜(1.7mL)中。随后，向上述溶液中依次加入N,N'-二甲基乙二胺(29mg,0.33mmol)、碘化亚铜(63mg,0.33mmol)和碳酸钾(91mg,0.66mmol)。然后该反应体系在150℃条件下搅拌3小时。Step A: Under nitrogen protection at room temperature, compound 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one (100 mg, 0.33 mmol) and (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (148 mg, 0.36 mmol) were dissolved in dimethyl sulfoxide (1.7 mL). Subsequently, N,N'-dimethylethylenediamine (29 mg, 0.33 mmol), cuprous iodide (63 mg, 0.33 mmol) and potassium carbonate (91 mg, 0.66 mmol) were added to the above solution in sequence. The reaction system was then stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(25mL)淬灭，混合液用乙酸乙酯(10mL×3次)萃取，合并有机相，有机相用饱和食盐水(20mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到45mg(S)-4-氯-6-(3-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-氧代环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (25 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (10 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 45 mg of (S)-4-chloro-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-oxocyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:635.3[M+H]⁺.MS (ESI) M/Z: 635.3 [M + H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物(S)-4-氯-6-(3-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-氧代环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(45mg,0.07mmol)溶于二氯甲烷(0.7mL)中。随后，向上述溶液中滴加三氟乙酸(0.7mL)，搅拌2小时。然后在0℃条件下，向上述溶液中滴加氨水(5.0mL)调节至pH＝8，升至室温，继续搅拌2小时。Step B: Under nitrogen protection at room temperature, compound (S)-4-chloro-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-oxocyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (45 mg, 0.07 mmol) was dissolved in dichloromethane (0.7 mL). Subsequently, trifluoroacetic acid (0.7 mL) was added dropwise to the above solution and stirred for 2 hours. Then, ammonia water (5.0 mL) was added dropwise to the above solution at 0°C to adjust the pH to 8, and the mixture was heated to room temperature and stirred for 2 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经制备型高效液相色谱纯化，得到11.17mg(S)-4-氯-6-(3-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-氧代环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with dichloromethane (15 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain 11.17 mg (S)-4-chloro-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-oxocyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:505.3[M+H]⁺.MS (ESI) M/Z: 505.3 [M + H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),8.46(s,1H),7.60-7.49(m,2H),7.47(s,1H),7.43-7.38(m,1H),7.31(d,J＝8.4Hz,1H),6.27(s,1H),4.20-4.08(m,2H),3.99-3.86(m,2H),3.61(s,2H),3.37(s,3H),2.84-2.71(m,2H),1.97-1.82(m,1H),1.67-1.52(m,4H),1.50-1.39(m,1H),0.88-0.72(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.39(s,1H),8.46(s,1H),7.60-7.49(m,2H),7.47(s,1H),7.43-7.38(m,1H),7.31(d,J＝8.4Hz ,1H),6.27(s,1H),4.20-4.08(m,2H),3. 99-3.86(m,2H),3.61(s,2H),3.37(s,3H),2.84-2.71(m,2H),1.97-1 .82(m,1H),1.67-1.52(m,4H),1.50-1.39(m,1H),0.88-0.72(m,4H).

实施例131Embodiment 131

6-(6-环丙基-4-((1r,3S)-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-乙基-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
6-(6-cyclopropyl-4-((1r,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-ethyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A:在室温条件下，将化合物2,6-二氯-4-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-亚甲基环丁基)吡啶(2.64g,8.94mmol)溶于甲苯(50mL)中，向反应液中依次添加环丙基硼酸(1.15g,13.41mmol)、1,1'-双(二苯膦基)二茂铁合氯化钯(0.65g,0.89mmol)、磷酸钾(3.80g,17.88mmol)。在95℃条件下搅拌6小时。Step A: Dissolve the compound 2,6-dichloro-4-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-methylenecyclobutyl)pyridine (2.64 g, 8.94 mmol) in toluene (50 mL) at room temperature, and add cyclopropylboric acid (1.15 g, 13.41 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (0.65 g, 0.89 mmol), and potassium phosphate (3.80 g, 17.88 mmol) to the reaction solution in sequence. Stir at 95°C for 6 hours.

LCMS监测显示原料消失后，向反应液中加水(55mL)淬灭，混合液用二氯甲烷和甲醇(150mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到1.2g 2-氯-6-环丙基-4-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-亚甲基环丁基)吡啶。After LCMS monitoring showed that the raw material disappeared, water (55 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol (150 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.2 g 2-chloro-6-cyclopropyl-4-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-methylenecyclobutyl)pyridine.

MS(ESI)M/Z:301.2[M+H]⁺.MS (ESI) M/Z: 301.2 [M+H] ⁺ .

步骤B：在室温条件下，将化合物2-氯-6-环丙基-4-(1-(4-甲基-4H-1,2,4-三唑-3-基)-3-亚甲基环丁基)吡啶(1.08g,3.59mmol)溶于乙腈(65mL)和水(11mL)的混合溶液中，依次向混合溶液中添加三氯化铑(0.074g,0.36mmol)、高碘酸钠(1.54g,7.18mmol)。在0℃条件下加入高碘酸钠(1.54g,7.18mmol)，在20℃条件下搅拌3小时。Step B: At room temperature, the compound 2-chloro-6-cyclopropyl-4-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-methylenecyclobutyl)pyridine (1.08 g, 3.59 mmol) was dissolved in a mixed solution of acetonitrile (65 mL) and water (11 mL), and rhodium trichloride (0.074 g, 0.36 mmol) and sodium periodate (1.54 g, 7.18 mmol) were added to the mixed solution in sequence. Sodium periodate (1.54 g, 7.18 mmol) was added at 0°C and stirred at 20°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加碳酸氢钠水溶液(55mL)淬灭，混合液用二氯甲烷(150mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到0.6g 3-(2-氯-6-环丙基吡啶-4-基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁-1-酮。After LCMS monitoring showed that the raw material disappeared, sodium bicarbonate aqueous solution (55 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (150 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.6 g 3-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-one.

MS(ESI)M/Z:303.2[M+H]⁺.MS (ESI) M/Z: 303.2 [M + H] ⁺ .

步骤C:在0℃条件下，氮气保护，将化合物3-(2-氯-6-环丙基吡啶-4-基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁-1-酮(600mg,1.98mmol)溶于甲醇(10mL)中。随后，向上述溶液中硼氢化钠(0.11g,2.97mmol)。然后该反应体系在25℃条件下搅拌2小时。Step C: Under nitrogen protection at 0°C, compound 3-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-one (600 mg, 1.98 mmol) was dissolved in methanol (10 mL). Then, sodium borohydride (0.11 g, 2.97 mmol) was added to the above solution. The reaction system was then stirred at 25°C for 2 hours.

LCMS监测显示原料消失后，将冰水(1mL)倒入反应液中淬灭。混合液用二氯甲烷和甲醇10：1(5mL×2次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩，得到370mg 3-(2-氯-6-环丙基吡啶-4-基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁-1-醇。After LCMS monitoring showed that the raw material disappeared, ice water (1 mL) was poured into the reaction solution to quench. The mixed solution was extracted with dichloromethane and methanol 10:1 (5 mL × 2 times), and the organic phases were combined and washed with saturated brine (2 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 370 mg 3-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol.

MS(ESI)M/Z:MS 305.1[M+H]⁺.MS(ESI)M/Z:MS 305.1[M+H] ⁺ .

步骤D:在室温条件下，将化合物3-(2-氯-6-环丙基吡啶-4-基)-3-(4-甲基-4H-1,2,4-三唑-3-基)环丁-1-醇(0.37g,1.21mmol)溶于二氯甲烷((10mL)中。在零下78℃条件下加入二乙胺基三氟化硫(3.90g,24.2mmol)，在20℃条件下搅拌16小时。Step D: Dissolve the compound 3-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol (0.37 g, 1.21 mmol) in dichloromethane (10 mL) at room temperature. Add diethylaminosulfur trifluoride (3.90 g, 24.2 mmol) at -78°C and stir at 20°C for 16 hours.

LCMS监测显示原料消失后，向反应液中加饱和碳酸氢钠水(5mL)淬灭，混合液用二氯甲烷甲醇10：1(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到80mg 2-氯-6-环丙基-4-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶。After LCMS monitoring showed that the raw material disappeared, saturated sodium bicarbonate water (5 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane methanol 10:1 (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (5 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg 2-chloro-6-cyclopropyl-4-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine.

MS(ESI)M/Z:MS 307.0[M+H]⁺.MS(ESI)M/Z:MS 307.0[M+H] ⁺ .

步骤E：在室温条件下，氮气保护，将(S)-4-乙基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(0.035g,0.087mmol)、2-溴-6-环丙基-4-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(0.031g,0.087mmol)、碘化亚铜(0.017g,0.087mmol)、N,N,N',N'-四甲基乙二胺(0.012g,0.10mmol)和碳酸钾(0.036g,0.26mmol)溶于二甲基亚砜(0.5mL)中。然后该反应体系在180℃条件下搅拌8小时。Step E: At room temperature, under nitrogen protection, (S)-4-ethyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.035 g, 0.087 mmol), 2-bromo-6-cyclopropyl-4-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (0.031 g, 0.087 mmol), cuprous iodide (0.017 g, 0.087 mmol), N,N,N',N'-tetramethylethylenediamine (0.012 g, 0.10 mmol) and potassium carbonate (0.036 g, 0.26 mmol) were dissolved in dimethyl sulfoxide (0.5 mL). The reaction system was then stirred at 180°C for 8 hours.

LCMS监测显示原料消失后，向反应液中加水(1mL)淬灭，混合液用二氯甲烷和甲醇10：1(4mL×2次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到30mg(S)-6-(6-环丙基-4-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-乙基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (1 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (4 mL×2 times), and the organic phases were combined and washed with saturated brine (2 mL×2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of (S)-6-(6-cyclopropyl-4-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-ethyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl ester)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:MS 674.4[M+H]⁺.MS(ESI)M/Z:MS 674.4[M+H] ⁺ .

步骤F：在室温条件下，将(S)-6-(6-环丙基-4-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-乙基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲酯)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(R0,30.33mg,0.045mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(0.77g,6.73mmol)，继续搅拌2小时。LCMS监测显示原料消失后，室温将反应液旋干，向反应液中滴加胺的甲醇溶液(1mL)至碱性，继续搅拌16小时。Step F: (S)-6-(6-cyclopropyl-4-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-ethyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (R0, 30.33 mg, 0.045 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, trifluoroacetic acid (0.77 g, 6.73 mmol) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was spin-dried at room temperature, and a methanol solution of amine (1 mL) was added dropwise to the reaction solution until it was alkaline and stirring was continued for 16 hours.

LCMS监测显示中间体消失后，反应液减压浓缩。所得残余物用硅胶柱层析纯化得到15mg产物。送手性高效液相色谱(色谱柱：Daicel OD,流动相：CO₂/MeOH[0.2％NH₃(7M in MeOH)]＝75/25,流速： 100mL/min])得到4.44mg化合物6-(6-环丙基-4-((1r,3S)-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-乙基-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(保留时间1.735min)。After LCMS monitoring showed that the intermediate disappeared, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 15 mg of the product. The product was subjected to chiral high performance liquid chromatography (chromatographic column: Daicel OD, mobile phase: CO ₂ /MeOH _{[0.2% NH 3} (7M in MeOH)] = 75/25, flow rate: 100 mL/min]) to give 4.44 mg of compound 6-(6-cyclopropyl-4-((1r,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-ethyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (retention time 1.735 min).

MS(ESI)M/Z:544.2[M+H]⁺.MS (ESI) M/Z: 544.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.00(s,1H),8.43(s,1H),7.33(s,1H),7.24(s,1H),7.17(s,1H),6.25(s,1H),5.19–5.11(m,0.5H),5.05–4.97(m,0.5H),3.62–3.44(m,4H),3.36(s,3H),2.95–2.82(m,2H),2.80–2.70(m,2H),2.60(q,J＝7.5Hz,2H),2.23–2.14(m,1H),1.95–1.83(m,1H),1.66–1.51(m,4H),1.50–1.41(m,1H),1.20(t,J＝7.5Hz,3H),1.02–0.91(m,4H),0.89–0.65(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.00(s,1H),8.43(s,1H),7.33(s,1H),7.24(s,1H),7.17(s,1H),6.25(s,1H),5.19– 5.11(m,0.5H),5.05–4.97(m,0.5H),3.62–3.44(m,4H),3.36(s,3H),2.95–2.82(m,2H),2 .80–2.70(m,2H),2.60(q,J＝7.5Hz,2H),2.23–2.14(m,1H),1.95–1.83(m,1H),1.66–1.5 1(m,4H),1.50–1.41(m,1H),1.20(t,J＝7.5Hz,3H),1.02–0.91(m,4H),0.89–0.65(m,4H).

实施例132Embodiment 132

6-(6-环丙基-4-((1r,3S)-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-异丙基-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮
6-(6-cyclopropyl-4-((1r,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-isopropyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将(S)-4-异丙基-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(0.035g,0.087mmol)、3-(1-(3-溴苯基)-3-氟环丁基)-4-甲基-4H-1,2,4-三唑(0.031g,0.087mmol)、碘化亚铜(0.017g,0.087mmol)、N,N,N',N'-四甲基乙二胺(0.012g,0.10mmol)和碳酸钾(0.036g,0.26mmol)溶于二甲基亚砜(0.5mL)中。然后该反应体系在180℃条件下搅拌8小时。Step A: (S)-4-isopropyl-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.035 g, 0.087 mmol), 3-(1-(3-bromophenyl)-3-fluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (0.031 g, 0.087 mmol), cuprous iodide (0.017 g, 0.087 mmol), N,N,N',N'-tetramethylethylenediamine (0.012 g, 0.10 mmol) and potassium carbonate (0.036 g, 0.26 mmol) were dissolved in dimethyl sulfoxide (0.5 mL) under nitrogen protection at room temperature. The reaction system was then stirred at 180°C for 8 hours.

LCMS监测显示原料消失后，向反应液中加水(1mL)淬灭，混合液用二氯甲烷和甲醇10：1(4mL×2次)萃取，合并有机相，有机相用饱和食盐水(2mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到32mg(S)-4-异丙基-6-(3-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (1 mL) was added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane and methanol 10:1 (4 mL×2 times), and the organic phases were combined and washed with saturated brine (2 mL×2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 32 mg of (S)-4-isopropyl-6-(3-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:MS 688.4[M+H]⁺.MS(ESI)M/Z:MS 688.4[M+H] ⁺ .

步骤B：在室温条件下，将(S)-4-异丙基-6-(3-(3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(30.33mg,0.045mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(0.77g,6.73mmol)，继续搅拌2小时。LCMS监测显示原料消失后，室温将反应液旋干，向反应液中滴加胺的甲醇溶液(1mL)至碱性，继续搅拌16小时。Step B: (S)-4-isopropyl-6-(3-(3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30.33 mg, 0.045 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. Subsequently, trifluoroacetic acid (0.77 g, 6.73 mmol) was added dropwise to the above solution and stirring was continued for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was spin-dried at room temperature, and a methanol solution of amine (1 mL) was added dropwise to the reaction solution until it was alkaline and stirring was continued for 16 hours.

LCMS监测显示中间体消失后，反应液减压浓缩。所得残余物用硅胶柱层析纯化得到15mg产物。送手性高效液相色谱(色谱柱：Daicel OD,流动相：CO₂/EtOH[0.5％NH₃(7M in MeOH)]＝75/25,流速：100mL/min])得到4.44mg化合物6-(6-环丙基-4-((1r,3S)-3-氟-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-4-异丙基-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(保留时间2.453min)。After LCMS monitoring showed that the intermediate disappeared, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 15 mg of the product. Chiral high performance liquid chromatography (chromatographic column: Daicel OD, mobile phase: CO ₂ /EtOH [0.5% NH ₃ (7M in MeOH)] = 75/25, flow rate: 100 mL/min]) was performed to obtain 4.44 mg of compound 6-(6-cyclopropyl-4-((1r,3S)-3-fluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-4-isopropyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (retention time 2.453 min).

MS(ESI)M/Z:558.2[M+H]⁺.MS (ESI) M/Z: 558.2 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.00(s,1H),8.43(s,1H),7.36(s,1H),7.24(s,1H),7.18(s,1H),6.29(s,1H),5.18–5.11(m,0.5H),5.04–4.98(m,0.5H),3.60–3.44(m,4H),3.36(s,3H),3.00–2.83(m,3H),2.79–2.71(m,2H),2.22–2.16(m,1H),1.93–1.84(m,1H),1.65–1.54(m,4H),1.50–1.41(m,1H),1.26(d,J＝6.9Hz,6H),1.01–0.92(m,4H),0.84–0.75(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.00(s,1H),8.43(s,1H),7.36(s,1H),7.24(s,1H),7.18(s,1H),6.29(s,1H), 5.18–5.11(m,0.5H),5.04–4.98(m,0.5H),3.60–3.44(m,4H),3.36(s,3H),3.00–2. 83(m,3H),2.79–2.71(m,2H),2.22–2.16(m,1H),1.93–1.84(m,1H),1.65–1.54(m,4 H),1.50–1.41(m,1H),1.26(d,J=6.9Hz,6H),1.01–0.92(m,4H),0.84–0.75(m,4H).

实施例133Embodiment 133

4-氯-6-(6-(环戊氧基)-4-((1s,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclopentyloxy)-4-((1s,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(6-(环戊氧基)-4-((1r,3S)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclopentyloxy)-4-((1r,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在0℃条件下，氮气保护，将化合物环戊醇(0.098g,1.14mmol)溶于N,N-二甲基甲酰胺(2mL)中。随后，向上述反应液中加氢化钠(0.020g,0.49mmol,60％)。继续搅拌半小时，随后向反应液中加2,6-二氯-4-(3-甲氧基-1-(4-甲基l-4H-1,2,4-三唑-3-基)环丁基)吡啶(0.12g,0.38mmol)。将反应体系升至室温继续搅拌6小时。Step A: Under nitrogen protection at 0°C, dissolve the compound cyclopentanol (0.098 g, 1.14 mmol) in N,N-dimethylformamide (2 mL). Then, add sodium hydride (0.020 g, 0.49 mmol, 60%) to the above reaction solution. Continue stirring for half an hour, then add 2,6-dichloro-4-(3-methoxy-1-(4-methyl l-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (0.12 g, 0.38 mmol) to the reaction solution. Warm the reaction system to room temperature and continue stirring for 6 hours.

LCMS监测显示原料转化为产物后，向反应液中加入水(0.1mL)淬灭。所得粗品用反相柱层析纯化得到0.1g化合物2-氯-6-(环戊氧基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶。After LCMS monitoring showed that the raw material was converted into the product, water (0.1 mL) was added to the reaction solution to quench. The crude product was purified by reverse phase column chromatography to obtain 0.1 g of compound 2-chloro-6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine.

MS(ESI)M/Z:363.2[M+H]⁺。MS (ESI) M/Z: 363.2 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物2-氯-6-(环戊氧基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶(0.081g,0.22mmol)、4-氯-2-{[(3S)-3-甲基哌啶-1-基]甲基}-1-[(2-(三甲基甲硅烷基)乙氧基)甲基]-1H,6H,7H-吡咯[2,3-c]吡啶-7-酮(0.064g,0.16mmol),碘化亚铜(0.030g,0.16mmol)、N,N'-二甲基-1,2-乙二胺(0.014g,0.16mmol)和碳酸钾(0.044g,0.32mmol)溶于N-甲基吡咯烷酮(1mL)中。该反应体系升至180度，继续搅拌6小时。Step B: At room temperature, under nitrogen protection, compound 2-chloro-6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (0.081 g, 0.22 mmol), 4-chloro-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.064 g, 0.16 mmol), cuprous iodide (0.030 g, 0.16 mmol), N,N'-dimethyl-1,2-ethylenediamine (0.014 g, 0.16 mmol) and potassium carbonate (0.044 g, 0.32 mmol) were dissolved in N-methylpyrrolidone (1 mL). The reaction system was heated to 180 degrees and stirred for 6 hours.

LCMS监测显示原料转化为产物后。所得粗品用反相柱层析纯化得到0.028g化合物4-氯-6-(6-(环戊氧基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-{[(3S)-3-甲基哌啶-1-基)甲基]}-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material was converted into the product, the crude product was purified by reverse phase column chromatography to obtain 0.028 g of compound 4-chloro-6-(6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-{[(3S)-3-methylpiperidin-1-yl)methyl]}-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:736.3[M+H]⁺。MS (ESI) M/Z: 736.3 [M+H] ⁺ .

步骤C：在0℃条件下，将化合物4-氯-6-(6-(环戊氧基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-{[(3S)-3-甲基哌啶-1-基)甲基]}-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮(0.025g,0.034mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(0.77g,6.73mmol)，升至室温继续搅拌2小时。 Step C: Dissolve the compound 4-chloro-6-(6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-{[(3S)-3-methylpiperidin-1-yl)methyl]}-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.025 g, 0.034 mmol) in dichloromethane (0.5 mL) at 0°C. Then, add trifluoroacetic acid (0.77 g, 6.73 mmol) dropwise to the solution, warm to room temperature and continue stirring for 2 hours.

LCMS监测显示原料消失后，将混合液减压浓缩，然后缓慢滴加氨水(5.0mL)调节至pH＝8，升至室温，继续搅拌2小时。然后混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经过硅胶柱层析纯化，再通过手性高效液相色谱(色谱柱：Daicel OD；流动相:CO₂/IPA[0.5％NH₃(7M in MeOH)]＝65/35,)纯化得到11mg化合物133-P1(保留时间1.628min)和4mg化合物133-P2(保留时间1.977min)。After LCMS monitoring showed that the raw material disappeared, the mixed solution was concentrated under reduced pressure, and then ammonia water (5.0 mL) was slowly added dropwise to adjust to pH = 8, warmed to room temperature, and stirred for 2 hours. The mixed solution was then extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and then purified by chiral high performance liquid chromatography (chromatographic column: Daicel OD; mobile phase: CO ₂ /IPA [0.5% NH ₃ (7M in MeOH)] = 65/35,) to obtain 11 mg of compound 133-P1 (retention time 1.628 min) and 4 mg of compound 133-P2 (retention time 1.977 min).

化合物133-P1：Compound 133-P1:

MS(ESI)M/Z:606.3[M+H]⁺。MS (ESI) M/Z: 606.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.48(s,1H),8.36(s,1H),7.68(s,1H),7.22(s,1H),6.72(s,1H),6.29(s,1H),5.40–5.21(m,1H),4.20–4.03(m,1H),3.79–3.43(m,2H),3.16(s,2H),3.12–3.02(m,2H),2.87–2.72(m,3H),2.06–1.81(m,3H),1.81–1.66(m,4H),1.67–1.40(m,6H),0.95–0.65(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.48(s,1H),8.36(s,1H),7.68(s,1H),7.22(s,1H),6.72(s,1H),6.29(s,1H),5.40–5.21(m ,1H),4.20–4.03(m,1H),3.79–3.43(m ,2H),3.16(s,2H),3.12–3.02(m,2H),2.87–2.72(m,3H),2.06–1.81(m,3H),1.81–1.66(m,4H),1.67–1.40 (m,6H),0.95–0.65(m,4H).

化合物133-P2：Compound 133-P2:

MS(ESI)M/Z:606.3[M+H]⁺。MS (ESI) M/Z: 606.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.48(s,1H),8.43(s,1H),7.68(s,1H),7.13(s,1H),6.59(s,1H),6.30(s,1H),5.36–5.26(m,1H),3.92–3.80(m,1H),3.62(s,2H),3.33(s,3H),3.32(s,3H),3.31–3.27(m,2H),3.17(s,2H),2.79(s,2H),2.56–2.52(m,1H),2.03–1.80(m,3H),1.78–1.49(m,10H),0.92–0.71(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.48(s,1H),8.43(s,1H),7.68(s,1H),7.13(s,1H),6.59(s,1H),6 .30(s,1H),5.36–5.26(m,1H),3.92–3.80(m,1H),3.62(s,2H),3.33(s ,3H),3.32(s,3H),3.31–3.27(m,2H),3.17(s,2H),2.79(s,2H),2.56– 2.52(m,1H),2.03–1.80(m,3H),1.78–1.49(m,10H),0.92–0.71(m,4H).

实施例134Embodiment 134

4-氯-6-(6-(环戊氨基)-4-((1s,3R)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclopentylamino)-4-((1s,3R)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

4-氯-6-(6-(环戊氨基)-4-((1r,3S)-3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮
4-Chloro-6-(6-(cyclopentylamino)-4-((1r,3S)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在室温条件下，氮气保护，将化合物2,6-二氯-4-(3-甲氧基-1-(4-甲基l-4H-1,2,4-三唑-3-基)环丁基)吡啶(0.12g,0.38mmol)和环戊胺(0.32g,3.8mmol)溶于二甲基亚砜(1mL)中。该反应体系升至130度，继续搅拌4小时。Step A: Under nitrogen protection at room temperature, compound 2,6-dichloro-4-(3-methoxy-1-(4-methyl-1-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine (0.12 g, 0.38 mmol) and cyclopentylamine (0.32 g, 3.8 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction system was heated to 130 degrees and stirred for 4 hours.

LCMS监测显示原料转化为产物后。粗品直接用反相柱层析纯化得到0.09g化合物6-氯-N-环戊基-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-氨基。After LCMS monitoring showed that the raw material was converted into the product, the crude product was directly purified by reverse phase column chromatography to obtain 0.09 g of compound 6-chloro-N-cyclopentyl-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amino.

MS(ESI)M/Z:362.2[M+H]⁺。MS (ESI) M/Z: 362.2 [M+H] ⁺ .

步骤B：在室温条件下，氮气保护，将化合物6-氯-N-环戊基-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-氨基(0.081g,0.22mmol)、4-氯-2-{[(3S)-3-甲基哌啶-1-基]甲基}-1-[(2-(三甲基甲硅烷基)乙氧基)甲基]-1H,6H,7H-吡咯[2,3-c]吡啶-7-酮(0.064g,0.16mmol)、碘化亚铜(0.030g,0.16mmol)、N,N'-二甲基-1,2-乙二胺(0.017g,0.19mmol)和碳酸钾(0.044g,0.32mmol)溶于N-甲基吡咯烷酮(1mL)中。该反应体系升至180度，继续搅拌6小时。Step B: At room temperature, under nitrogen protection, compound 6-chloro-N-cyclopentyl-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amino (0.081 g, 0.22 mmol), 4-chloro-2-{[(3S)-3-methylpiperidin-1-yl]methyl}-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one (0.064 g, 0.16 mmol), cuprous iodide (0.030 g, 0.16 mmol), N,N'-dimethyl-1,2-ethylenediamine (0.017 g, 0.19 mmol) and potassium carbonate (0.044 g, 0.32 mmol) were dissolved in N-methylpyrrolidone (1 mL). The reaction system was heated to 180 degrees and stirred for 6 hours.

LCMS监测显示原料转化为产物后。所得粗品直接用反相柱层析纯化得到0.045g化合物(S)-4-氯-6-(6-(环戊氨基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the raw material was converted into the product, the crude product was directly purified by reverse phase column chromatography to obtain 0.045 g of compound (S)-4-chloro-6-(6-(cyclopentylamino)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:735.3[M+H]⁺。MS (ESI) M/Z: 735.3 [M+H] ⁺ .

步骤C：在0℃条件下，将化合物(S)-4-氯-6-(6-(环戊氨基)-4-(3-甲氧基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)吡啶-2-基)-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮(0.045g，0.06mmol)溶于二氯甲烷(0.5mL)中。随后，向上述溶液中滴加三氟乙酸(1.38g,12.08mmol)，升至室温继续搅拌2小时。Step C: Compound (S)-4-chloro-6-(6-(cyclopentylamino)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.045 g, 0.06 mmol) was dissolved in dichloromethane (0.5 mL) at 0°C. Trifluoroacetic acid (1.38 g, 12.08 mmol) was then added dropwise to the solution and stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，将混合液减压浓缩，然后缓慢滴加氨水(5.0mL)调节至pH＝8，升至室温，继续搅拌2小时。然后混合液用二氯甲烷(15mL×3次)萃取，合并有机相，有机相用饱和食盐水(25mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得粗品经过硅胶柱层析纯化，再通过手性高效液相色谱(色谱柱：Daicel ID-3；流动相:CO₂/EtOH[1.0％NH₃(7M in MeOH)]＝45/55,流速:100ml/min,)纯化得到13mg化合物134-P1(保留时间2.256min)和7mg化合物134-P2(保留时间2.933min)。After LCMS monitoring showed that the raw material disappeared, the mixed solution was concentrated under reduced pressure, and then ammonia water (5.0 mL) was slowly added dropwise to adjust to pH = 8, warmed to room temperature, and stirred for 2 hours. The mixed solution was then extracted with dichloromethane (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (25 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and then purified by chiral high performance liquid chromatography (chromatographic column: Daicel ID-3; mobile phase: CO ₂ /EtOH [1.0% NH ₃ (7M in MeOH)] = 45/55, flow rate: 100 ml/min) to obtain 13 mg of compound 134-P1 (retention time 2.256 min) and 7 mg of compound 134-P2 (retention time 2.933 min).

化合物134-P1Compound 134-P1

MS(ESI)M/Z:605.3[M+H]⁺。MS (ESI) M/Z: 605.3 [M+H] ⁺ .

¹H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.35(s,1H),7.62(s,1H),6.90(d,J＝6.5Hz,1H),6.81(s,1H),6.31(s,1H),6.25(s,1H),4.14–3.96(m,2H),3.59(s,2H),3.32(s,3H),3.16(s,3H),3.02–2.93(m,2H),2.86–2.69(m,4H),1.97–1.81(m,3H),1.70–1.39(m,11H),0.91–0.73(m,4H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.35(s,1H),7.62(s,1H),6.90(d,J＝6.5Hz,1H),6.81(s,1H),6.31(s,1H), 6.25(s,1H),4.14–3.96(m,2H),3.59( s,2H),3.32(s,3H),3.16(s,3H),3.02–2.93(m,2H),2.86–2.69(m,4H),1.97–1.81(m,3H),1.70–1.39( m,11H),0.91–0.73(m,4H).

化合物134-P2Compound 134-P2

实施例135Embodiment 135

(S)-2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)丙腈
(S)-2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)propionitrile

(R)-2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1,7-二氢-6-吡咯并[2,3-c]吡啶-6-基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)丙腈
(R)-2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1,7-dihydro-6-pyrrolo[2,3-c]pyridin-6-yl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)propionitrile

反应路线:
Reaction route:

操作步骤：Steps:

步骤A：在0℃条件下，将化合物3-溴-5-羟基苯甲醛(10.0g,49.8mmol)溶于N,N-二甲基甲酰胺(250.0mL)中。随后，向上述溶液中依次加入碳酸钾(17.2g,124.5mmol)和溴化苄(12.8g,74.7mmol)。然后该反应体系在室温条件下搅拌12小时。Step A: Dissolve 3-bromo-5-hydroxybenzaldehyde (10.0 g, 49.8 mmol) in N,N-dimethylformamide (250.0 mL) at 0°C. Then, add potassium carbonate (17.2 g, 124.5 mmol) and benzyl bromide (12.8 g, 74.7 mmol) to the solution. Then stir the reaction system at room temperature for 12 hours.

LCMS监测显示原料消失后，向反应液中加水(750mL)淬灭，混合液用乙酸乙酯(200mL×3次)萃取，合并有机相，有机相用饱和食盐水(100mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到12.1g 3-(苄氧基)-5-溴苯甲醛。After LCMS monitoring showed that the raw material disappeared, water (750 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 12.1 g 3-(benzyloxy)-5-bromobenzaldehyde.

步骤B:在-30℃条件下，氮气保护，将化合物3-(苄氧基)-5-溴苯甲醛(3.6g,12.4mmol)和4-甲基-4H-1,2,4-三唑(1.1g,13.6mmol)溶于无水乙二醇二甲醚62.0mL)中。随后，向上述溶液中缓慢滴加2.5M正丁基锂(7.4mL,18.6mmol)。然后该反应体系在-20℃条件下搅拌3小时。Step B: Under nitrogen protection at -30°C, compound 3-(benzyloxy)-5-bromobenzaldehyde (3.6 g, 12.4 mmol) and 4-methyl-4H-1,2,4-triazole (1.1 g, 13.6 mmol) were dissolved in anhydrous ethylene glycol dimethyl ether (62.0 mL). Subsequently, 2.5 M n-butyl lithium (7.4 mL, 18.6 mmol) was slowly added dropwise to the above solution. The reaction system was then stirred at -20°C for 3 hours.

LCMS监测显示原料消失后，向反应液中缓慢滴加冰水(50mL)淬灭，混合液用二氯甲烷(100mL×3次)萃取，合并有机相，有机相用饱和食盐水(50mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.5g(3-(苄氧基)-5-溴苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇。After LCMS monitoring showed that the raw material disappeared, ice water (50 mL) was slowly added dropwise to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.5 g (3-(benzyloxy)-5-bromophenyl) (4-methyl-4H-1,2,4-triazol-3-yl) methanol.

MS(ESI)M/Z:374.0[M+H]⁺.MS (ESI) M/Z: 374.0 [M+H] ⁺ .

步骤C：在0℃条件下，将化合物(3-(苄氧基)-5-溴苯基)(4-甲基-4H-1,2,4-三唑-3-基)甲醇(2.5g,6.7mmol)溶于四氢呋喃(67.0mL)中。随后，向上述溶液中依次加入咪唑(2.3g,33.5mmol)、碘单质(6.0g,23.5mmol)和三苯基膦(6.1g,23.5mmol)。然后该反应体系80℃条件下搅拌4小时。Step C: Dissolve the compound (3-(benzyloxy)-5-bromophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methanol (2.5 g, 6.7 mmol) in tetrahydrofuran (67.0 mL) at 0°C. Then, add imidazole (2.3 g, 33.5 mmol), iodine (6.0 g, 23.5 mmol) and triphenylphosphine (6.1 g, 23.5 mmol) to the solution. Then stir the reaction system at 80°C for 4 hours.

LCMS监测显示原料消失后，向反应液中缓慢滴加冰的饱和硫代硫酸钠水溶液(60mL)淬灭，混合液用二氯甲烷(80mL×3次)萃取，合并有机相，有机相用饱和食盐水(100mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到2.3g 3-(3-(苄氧基)-5-溴苄基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, ice-cold saturated sodium thiosulfate aqueous solution (60 mL) was slowly added to the reaction solution to quench, and the mixed solution was extracted with dichloromethane (80 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). Then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.3 g 3-(3-(benzyloxy)-5-bromobenzyl)-4-methyl-4H-1,2,4-triazole.

MS(ESI)M/Z:358.0[M+H]⁺.MS (ESI) M/Z: 358.0 [M+H] ⁺ .

步骤D：在0℃条件下，将化合物3-(3-(苄氧基)-5-溴苄基)-4-甲基-4H-1,2,4-三唑(2.3g,6.4mmol)和1,3-二溴-2-甲基丙烷(1.5g,7.1mmol)溶于N,N-二甲基甲酰胺(32.0mL)中。随后，向上述溶液中滴加1M二(三甲基硅基)氨基锂的四氢呋喃溶液(14.7mL,14.7mmol)。然后该反应体系在室温条件下继续搅拌2小时。Step D: Compound 3-(3-(benzyloxy)-5-bromobenzyl)-4-methyl-4H-1,2,4-triazole (2.3 g, 6.4 mmol) and 1,3-dibromo-2-methylpropane (1.5 g, 7.1 mmol) were dissolved in N,N-dimethylformamide (32.0 mL) at 0°C. Subsequently, a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (14.7 mL, 14.7 mmol) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中加入冰水(150mL)淬灭，混合液用乙酸乙酯(30mL×3次)萃取，合并有机相，有机相用饱和食盐水(100mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用制备柱纯化得到410mg 3-((1S,3S)-1-(3-(苄氧基)-5-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑。After LCMS monitoring showed that the raw material disappeared, ice water (150 mL) was added to the reaction solution to quench, and the mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative column to obtain 410 mg 3-((1S, 3S)-1-(3-(benzyloxy)-5-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole.

¹H NMR(400MHz,CDCl₃)δ8.05(s,1H),7.41-7.28(m,5H),7.12(t,J＝1.6Hz,1H),7.04(t,J＝2.0Hz,1H),6.76(t,J＝2.2Hz,1H),4.99(s,2H),3.12(s,3H),2.83-2.69(m,2H),2.67-2.53(m,3H),1.12(d,J＝5.6Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ8.05(s,1H),7.41-7.28(m,5H),7.12(t,J＝1.6Hz,1H),7.04(t,J＝2.0Hz,1H),6.76(t,J＝2.2 Hz,1H),4.99(s,2H),3.12(s,3H),2.83-2.69(m,2H),2.67-2.53(m,3H),1.12(d,J＝5.6Hz,3H).

步骤E：在0℃条件下，氮气保护，将化合物3-((1S,3S)-1-(3-(苄氧基)-5-溴苯基)-3-甲基环丁基)-4-甲基-4H-1,2,4-三唑(410.0mg,1.0mmol)溶于二甲基亚砜(5.0mL)中。随后，向上述溶液中依次加入(S)-4-氯-2-((3-甲基哌啶-1-基)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯[2,3-c]吡啶-7-酮(410.0mg,1.00mmol)、N,N'-二甲基乙二胺(88.0mg,1.0mmol)、碳酸钾(414.0mg,3.0mmol)和碘化亚铜(190.0mg,1.0mmol)。然后该反应体系在150℃条件下搅拌3小时。Step E: Compound 3-((1S,3S)-1-(3-(benzyloxy)-5-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (410.0 mg, 1.0 mmol) was dissolved in dimethyl sulfoxide (5.0 mL) at 0°C under nitrogen protection. Subsequently, (S)-4-chloro-2-((3-methylpiperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (410.0 mg, 1.00 mmol), N,N'-dimethylethylenediamine (88.0 mg, 1.0 mmol), potassium carbonate (414.0 mg, 3.0 mmol) and cuprous iodide (190.0 mg, 1.0 mmol) were added to the above solution in sequence. Then the reaction system was stirred at 150°C for 3 hours.

LCMS监测显示原料消失后，向反应液中加水(20mL)淬灭，混合液用乙酸乙酯(5mL×3次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到470.0mg 6-(3-(苄氧基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-(2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (5 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 470.0 mg 6-(3-(benzyloxy)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one.

MS(ESI)M/Z:741.3[M+H]⁺.MS (ESI) M/Z: 741.3 [M + H] ⁺ .

步骤F：在室温条件下，将化合物6-(3-(苄氧基)-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-1-(2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮(470.0mg,0.63mmol)溶于甲醇(20.0mL)中。随后，向上述溶液中加入钯/碳(230.0mg)。然后该反应体系在氢气气氛、30℃条件下搅拌16小时。Step F: Compound 6-(3-(benzyloxy)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (470.0 mg, 0.63 mmol) was dissolved in methanol (20.0 mL) at room temperature. Palladium/carbon (230.0 mg) was then added to the solution. The reaction system was then stirred at 30° C. under a hydrogen atmosphere for 16 hours.

LCMS监测显示原料消失后，将反应液过滤，收集滤液，减压浓缩。所得残余物用硅胶柱层析纯化得到180.0mg 4-氯-6-(3-羟基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-(2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c吡啶-7-酮。After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered, the filtrate was collected, and it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 180.0 mg of 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-c-pyridin-7-one.

MS(ESI)M/Z:651.3[M+H]⁺.MS (ESI) M/Z: 651.3 [M + H] ⁺ .

步骤G：在0℃条件下，将化合物4-氯-6-(3-羟基-5-((1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯基)-2-(((S)-3-甲基哌啶-1-基)甲基)-1-(2-(三甲基硅基)乙氧基)甲基)-1,6-二氢-7H-吡咯并[2,3-c吡啶-7-酮(180.0mg,0.28mmol)溶于N,N-二甲基甲酰胺(1.5mL)中。随后，向上述溶液中加入氢化钠(14.6mg,0.36mmol)，搅拌0.5小时。随后，向上述溶液中加入2-溴丙腈(37.3mg,0.28mmol)，升温至室温，继续搅拌1小时。Step G: At 0°C, compound 4-chloro-6-(3-hydroxy-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrrolo[2,3-cpyridin-7-one (180.0 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). Subsequently, sodium hydride (14.6 mg, 0.36 mmol) was added to the above solution and stirred for 0.5 hours. Subsequently, 2-bromopropionitrile (37.3 mg, 0.28 mmol) was added to the above solution, the temperature was raised to room temperature, and stirring was continued for 1 hour.

LCMS监测显示原料消失后，向反应液中加入冰水(10mL)淬灭，混合液用乙酸乙酯(3mL×3次)萃取，合并有机相，有机相用饱和食盐水(5mL×2次)洗涤。然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化得到140.0mg 2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-(2-(三甲基硅基乙氧基)甲基)-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-5-(1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)丙腈。After LCMS monitoring showed that the starting material disappeared, ice water (10 mL) was added to the reaction solution to quench, the mixed solution was extracted with ethyl acetate (3 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (5 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 140.0 mg 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilylethoxy)methyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-(1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)propionitrile.

MS(ESI)M/Z:704.3[M+H]⁺.MS (ESI) M/Z: 704.3 [M + H] ⁺ .

步骤H:在0℃条件下，将化合物2-(3-(4-氯-2-(((S)-3-甲基哌啶-1-基)甲基)-7-氧代-1-(2-(三甲基硅基乙氧基)甲基)-1,7-二氢-6H-吡咯[2,3-c]吡啶-6-基)-5-(1S,3R)-3-甲基-1-(4-甲基-4H-1,2,4-三唑-3-基)环丁基)苯氧基)丙腈(105.0mg,0.15mmol)溶于二氯甲烷(1.0mL)中。随后，向上述溶液中滴加三氟乙酸(0.5mL)。然后该反应体系在室温条件下搅拌2小时。Step H: Compound 2-(3-(4-chloro-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-1-(2-(trimethylsilylethoxy)methyl)-1,7-dihydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-5-(1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenoxy)propionitrile (105.0 mg, 0.15 mmol) was dissolved in dichloromethane (1.0 mL) at 0°C. Subsequently, trifluoroacetic acid (0.5 mL) was added dropwise to the solution. The reaction system was then stirred at room temperature for 2 hours.

LCMS监测显示原料消失后，向反应液中滴加氨水调节至pH＝8，减压浓缩，所得残余物经手性拆分(手性柱：Daicel IC-3(4.6*100mm,3.0um)；流动相:CO₂/MeOH[0.2％NH₃(7M in MeOH)]＝45/55；流速：3mL/min)纯化，得到16.28mg化合物135-P1(保留时间2.128min)和9.77mg化合物135-P2(保留时间3.127min)。After LCMS monitoring showed that the starting material disappeared, aqueous ammonia was added dropwise to the reaction solution to adjust the pH to 8, and the solution was concentrated under reduced pressure. The residue was purified by chiral separation (chiral column: Daicel IC-3 (4.6*100 mm, 3.0 um); mobile phase: CO ₂ /MeOH [0.2% NH ₃ (7M in MeOH)]=45/55; flow rate: 3 mL/min) to obtain 16.28 mg of compound 135-P1 (retention time 2.128 min) and 9.77 mg of compound 135-P2 (retention time 3.127 min).

化合物135-P1：Compound 135-P1:

MS(ESI)M/Z:574.2[M+H]⁺.MS (ESI) M/Z: 574.2 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.29(s,1H),7.44(s,1H),7.14(d,J＝1.6Hz,2H),7.00(s,1H),6.26(s,1H),5.53(q,J＝6.8Hz,1H),3.59(s,2H),3.26(s,3H),2.96-2.83(m,2H),2.82-2.70(m,2H),2.63-2.53(m,3H),1.95-1.83(m,1H),1.69(d,J＝6.4Hz,3H),1.65-1.53(m,4H),1.51-1.39(m,1H),1.07(d,J＝5.2Hz,3H),0.87-0.72(m,4H).1H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.29(s,1H),7.44(s,1H),7.14(d,J＝1.6Hz,2H),7.00(s,1H),6 .26(s,1H),5.53(q,J＝6.8Hz,1H),3.59(s,2H),3.26(s,3H),2.96-2.83(m,2H), 2.82-2.70(m,2H),2.63-2.53(m,3H),1.95-1.83(m,1H),1.69(d,J＝6.4Hz,3H), 1.65-1.53(m,4H),1.51-1.39(m,1H),1.07(d,J＝5.2Hz,3H),0.87-0.72(m,4H).

化合物135-P2：Compound 135-P2:

MS(ESI)M/Z:574.2[M+H]⁺.MS (ESI) M/Z: 574.2 [M+H] ⁺ .

1H NMR(400MHz,DMSO-d₆)δ12.38(s,1H),8.29(s,1H),7.44(s,1H),7.14(d,J＝2.0Hz,2H),7.00(s,1H),6.26(s,1H),5.53(q,J＝6.8Hz,1H),3.59(s,2H),3.26(s,3H),2.94-2.83(m,2H),2.80-2.71(m,2H),2.58-2.52(m,3H),1.93-1.83(m,1H),1.69(d,J＝7.2Hz,3H),1.66-1.52(m,4H),1.51-1.38(m,1H),1.07(d,J＝5.2Hz,3H),0.86-0.72(m,4H).1H NMR (400MHz, DMSO-d ₆ )δ12.38(s,1H),8.29(s,1H),7.44(s,1H),7.14(d,J＝2.0Hz,2H),7.00(s,1H),6 .26(s,1H),5.53(q,J＝6.8Hz,1H),3.59(s,2H),3.26(s,3H),2.94-2.83(m,2H), 2.80-2.71(m,2H),2.58-2.52(m,3H),1.93-1.83(m,1H),1.69(d,J＝7.2Hz,3H), 1.66-1.52(m,4H),1.51-1.38(m,1H),1.07(d,J=5.2Hz,3H),0.86-0.72(m,4H).

生物活性Biological Activity

测试例1CBL-B活性实验实验目的：测试在候选化合物存在的情况下，检测CBL-B与荧光团标记探针配体的相互作用实验方法：150nL 3倍稀释化合物(终浓度选自10μM-0.5nM，起始终浓度选自10μM，进行3倍稀释，10个点，第10个点是0.5nM)与5μL 72nM GST-Cbl-b蛋白(Bioduro)室温孵育1小时，反应缓冲液选自50mM HEPES PH7.5(Sigma)，50mM(Sigma)50mM NaCl(Sigma)，0.01％ Brij-35(Sigma)，0.05mM DTT(Sigma),100μg/mL BSA(Sigma)。在反应板中加入5μL终浓度选自346.5nM荧光团标记探针配体(Bioduro)。在反应板中加入5μL 100倍稀释的Streptavidin-Tb抗体(Cisbio)。室温，摇床孵育1个小时，在Envision(Perkin Elmer)上读取TR-FRET 520/615。Test Example 1 CBL-B Activity Experiment Experimental Purpose: To test the interaction between CBL-B and fluorophore-labeled probe ligands in the presence of candidate compounds Experimental method: 150nL of 3-fold diluted compound (final concentration selected from 10μM-0.5nM, starting and ending concentration selected from 10μM, 3-fold dilution, 10 points, the 10th point is 0.5nM) was incubated with 5μL 72nM GST-Cbl-b protein (Bioduro) at room temperature for 1 hour, the reaction buffer was selected from 50mM HEPES PH7.5 (Sigma), 50mM (Sigma) 50mM NaCl (Sigma), 0.01% Brij-35 (Sigma), 0.05mM DTT (Sigma), 100μg/mL BSA (Sigma). 5μL of fluorophore labeled probe ligand (Bioduro) with a final concentration selected from 346.5nM was added to the reaction plate. 5μL of 100-fold diluted Streptavidin-Tb antibody (Cisbio) was added to the reaction plate. The mixture was incubated at room temperature for 1 hour on a shaking platform and TR-FRET 520/615 was read on Envision (Perkin Elmer).

经测定，本公开化合物对CBL-B有很好的抑制作用，其IC₅₀值一般低于1微摩尔；部分本公开化合物的IC₅₀值低于0.5微摩尔，更为优异的本公开化合物的IC₅₀值低于0.3微摩尔，甚至低于0.1微摩尔。本公开部分化合物对CBL-B的抑制结果见表1。It has been determined that the compounds disclosed herein have a good inhibitory effect on CBL-B, and their IC ₅₀ values are generally less than 1 micromolar; the IC ₅₀ values of some of the compounds disclosed herein are less than 0.5 micromolar, and the IC ₅₀ values of more excellent compounds disclosed herein are less than 0.3 micromolar, or even less than 0.1 micromolar. The inhibition results of some of the compounds disclosed herein on CBL-B are shown in Table 1.

表1酶学抑制结果

Table 1 Enzyme inhibition results

结论：本公开化合物对CBL-B有很好的抑制作用。Conclusion: The disclosed compounds have a good inhibitory effect on CBL-B.

测试例2：Jurkat T激活实验Test Example 2: Jurkat T Activation Experiment

实验目的：测试化合物对Jurkat T细胞IL2释放激活作用实验方法：96孔细胞板(Corning)用100μL 5ug/mL抗人CD3(BD)抗体稀释液4℃过夜包被，PBS洗涤一次后，去除上清，加入100uL 4μg/mL抗人CD28(BD)抗体稀释液，混合均匀。5倍梯度稀释化合物(终浓度选自1μM-0.32nM，起始浓度选自1μM，进行5倍稀释，6个点，第6个点是0.32nM)，与2x 106/mL的Jurkat T细胞悬液(ATCC)以1：1比例预混合后37℃孵育1小时，转移100μL化合物和细胞的混合液至已预处理的板孔中，37℃细胞培养24小时收上清，使用IL2-TR FRET试剂盒(bioauxilium)检测IL2的释放量。使用Prism分析EC₅₀。Experimental purpose: To test the effect of compounds on the activation of IL2 release from Jurkat T cells. Experimental method: 96-well cell plates (Corning) were coated with 100 μL 5ug/mL anti-human CD3 (BD) antibody diluent at 4°C overnight, washed once with PBS, the supernatant was removed, 100 μL 4μg/mL anti-human CD28 (BD) antibody diluent was added, and mixed evenly. Compounds were diluted 5-fold (final concentration was selected from 1μM-0.32nM, starting concentration was selected from 1μM, 5-fold dilution, 6 points, the 6th point was 0.32nM), pre-mixed with 2x 106/mL Jurkat T cell suspension (ATCC) at a ratio of 1:1, and incubated at 37°C for 1 hour. 100 μL of the mixture of compounds and cells was transferred to the pre-treated plate wells, and the cells were cultured at 37°C for 24 hours. The supernatant was collected and the IL2 release was detected using the IL2-TR FRET kit (bioauxilium). EC ₅₀ was analyzed using Prism.

对照化合物1：NX-1607结构式如下：
Reference compound 1: NX-1607 has the following structural formula:

对照化合物2结构式如下：
The structural formula of reference compound 2 is as follows:

对照化合物来源：对照化合物1参考专利WO2020264398制备；对照化合物2参考专利WO2024020034制备。Source of control compounds: Control compound 1 was prepared according to patent WO2020264398; Control compound 2 was prepared according to patent WO2024020034.

表2.本发明化合物对Jurkat T细胞IL2释放激活活性

Table 2. Activation activity of the compounds of the present invention on IL2 release of Jurkat T cells

通过表2所示实验数据，与对照组NX-1607相比，本发明示例化合物51对Jurkat T细胞IL2释放激活活性明显更强。According to the experimental data shown in Table 2, compared with the control group NX-1607, the exemplary compound 51 of the present invention has significantly stronger IL2 release activation activity on Jurkat T cells.

测试例3：对CYP3A的抑制试验Test Example 3: Inhibition test of CYP3A

实验目的：测试化合物对CYP3酶的抑制能力Experimental purpose: To test the inhibitory ability of compounds on CYP3 enzyme

实验材料：混合的人肝微粒体、NADPH、酮康唑、米达唑仑和睾酮Experimental Materials: Mixed human liver microsomes, NADPH, ketoconazole, midazolam, and testosterone

实验方法：Experimental methods:

称取所需量的测试化合物或对照化合物粉末并添加相应体积的DMSO配制成30mM的储备液。然后进行连续稀释，得到每种化合物的DMSO标称浓度为20000、6000、2000、600、200和60μM的溶液。测定中化合物的最终浓度为100、30、10、3、1和0.3μM，测试化合物或阳性对照抑制剂引入的有机溶剂的最终百分比为0.5％。阳性对照抑制剂的最终浓度0,0.0015,0.005,0.015,0.05,0.15,0.5μM。特异性底物米达唑仑和睾酮的最终浓度为1和40μM，混合的人肝微粒体溶液最终蛋白浓度为0.2mg/mL。Weigh the required amount of test compound or control compound powder and add the corresponding volume of DMSO to prepare a 30mM stock solution. Then serial dilutions were performed to obtain solutions with nominal DMSO concentrations of 20000, 6000, 2000, 600, 200 and 60μM for each compound. The final concentrations of the compounds in the assay were 100, 30, 10, 3, 1 and 0.3μM, and the final percentage of organic solvent introduced by the test compound or positive control inhibitor was 0.5%. The final concentrations of the positive control inhibitor were 0, 0.0015, 0.005, 0.015, 0.05, 0.15, 0.5μM. The final concentrations of the specific substrates midazolam and testosterone were 1 and 40μM, and the final protein concentration of the mixed human liver microsome solution was 0.2mg/mL.

孵育在96深孔板中进行，在孵育板的每个孔中加入169uL微粒体和1μL多个浓度的测试化合物或阳性对照化合物(DMSO)。将孵育板放入水浴锅中37℃预孵育5分钟。然后向孵育板中加入10μL稀释的底物溶液，在旋涡混合器上混合孵育15秒，再加入20μL 10mM的NADPH溶液，最终浓度为1mM时开始反应。Incubations were performed in 96-deep-well plates, with 169uL of microsomes and 1μL of test compound or positive control compound (DMSO) at multiple concentrations added to each well of the incubation plate. The incubation plate was pre-incubated at 37°C in a water bath for 5 minutes. Then 10μL of diluted substrate solution was added to the incubation plate, mixed and incubated on a vortex mixer for 15 seconds, and then 20μL of 10mM NADPH solution was added to start the reaction at a final concentration of 1mM.

在预定时间点，加入300μL的淬灭液(冷乙腈加3％甲酸、200nM阿普唑仑、200nM盐酸拉贝洛尔、200nM甲苯磺叮脲)淬灭反应。以3220g离心40分钟。将150μL上清液转移到新板上。上清液可用150μL纯水稀释。混合均匀，用LC/MS/MS测定底物代谢产物的含量。At the predetermined time point, add 300 μL of quenching solution (cold acetonitrile plus 3% formic acid, 200 nM alprazolam, 200 nM labetalol hydrochloride, 200 nM tolbutamide) to quench the reaction. Centrifuge at 3220 g for 40 minutes. Transfer 150 μL of supernatant to a new plate. The supernatant can be diluted with 150 μL of pure water. Mix well and determine the content of substrate metabolites by LC/MS/MS.

对所有样本进行自动峰值积分区域检查。分析峰面积和内标准峰面积导出到excel电子表格。人肝微粒体中CYP 3A活性的抑制是通过与非抑制对照(＝100％活性)相比，标志代谢物形成活性下降的百分比来测量的。以剩余活性(％)和抑制剂浓度的对数计算IC₅₀值。Automatic peak integration area check was performed on all samples. Analytical peak areas and internal standard peak areas were exported to excel spreadsheets. Inhibition of CYP 3A activity in human liver microsomes was measured as the percentage decrease in activity of marker metabolite formation compared to non-inhibited controls (=100% activity). _IC50 values were calculated as residual activity (%) and logarithm of inhibitor concentration.

计算剩余活性的百分比如下:Calculate the percentage of remaining activity as follows:

面积比＝被分析物峰面积/内标物峰面积Area ratio = analyte peak area / internal standard peak area

剩余活性(％)＝面积比_待测药/面积比_空白对照*100％Remaining activity (%) = area ratio of _{the drug to be tested} / area ratio of _{the blank control} * 100%

利用Excel XLfit 5.5.1.3计算IC₅₀值，结果如表3所示。The _IC50 values were calculated using Excel XLfit 5.5.1.3. The results are shown in Table 3.

表3.本发明化合物对CYP3酶的抑制活性
Table 3. Inhibitory activity of the compounds of the present invention on CYP3 enzymes

细胞色素P4503A(CYP3A)是人体最重要的药物代谢酶之一，其参与大约50％已上市药物的代谢清除。与对照组化合物1和对照化合物2相比，本发明示例化合物51对CYP3A具有显著更弱的抑制活性，可显著降低药物联用时产生的药物-药物相互作用(DDI)风险。Cytochrome P4503A (CYP3A) is one of the most important drug metabolizing enzymes in the human body, and is involved in the metabolic clearance of approximately 50% of marketed drugs. Compared with control compound 1 and control compound 2, the exemplary compound 51 of the present invention has significantly weaker inhibitory activity against CYP3A, which can significantly reduce the risk of drug-drug interaction (DDI) when the drugs are used in combination.

测试例4：体外评估本化合物的双向渗透性试验Test Example 4: In vitro evaluation of the bidirectional permeability of the compound

实验目的：通过检测受试物在Caco-2细胞模型的渗透系数，考察其在可能的渗透和吸收情况。Experimental purpose: To investigate the possible permeation and absorption of the test substance by detecting its permeability coefficient in the Caco-2 cell model.

实验材料：Caco-2细胞购自美国典型菌种保藏中心(ATCC)。Experimental materials: Caco-2 cells were purchased from the American Type Culture Collection (ATCC).

供试品：对照化合物2和本发明化合物51。Test samples: reference compound 2 and compound 51 of the present invention.

实验方法：Experimental methods:

1.1溶液配制：1)配制1L HBSS(10mM HEPES，pH 7.4)；1.1 Solution preparation: 1) Prepare 1L HBSS (10mM HEPES, pH 7.4);

2)配制受试物的高浓度DMSO储备液，并用DMSO稀释到1mM储备液。之后相应地用HBSS稀释得到测试浓度为5μM；2) Prepare a high concentration DMSO stock solution of the test substance and dilute it to 1 mM stock solution with DMSO. Then dilute it with HBSS accordingly to obtain a test concentration of 5 μM;

3)配制对照药地高辛和美托洛尔的高浓度DMSO储备液，并用DMSO稀释到2mM储备液。之后相应地用HBSS(10mM HEPES,pH 7.4)稀释得到测试浓度为10μM。3) Prepare high concentration DMSO stock solutions of control drugs digoxin and metoprolol, and dilute them to 2 mM stock solution with DMSO. Then dilute them accordingly with HBSS (10 mM HEPES, pH 7.4) to obtain a test concentration of 10 μM.

2.1药物穿透试验：1)从培养箱中取出Transwell培养板。使用HBSS(10mM HEPES,pH 7.4)缓冲液润洗细胞单层膜两次，37℃条件下孵育30分钟；2.1 Drug penetration test: 1) Take out the Transwell culture plate from the incubator. Rinse the cell monolayer twice with HBSS (10 mM HEPES, pH 7.4) buffer and incubate at 37°C for 30 minutes;

2)测定化合物由顶端到基底端的转运速率。向上层小室(顶端)每孔加入125μL给药端溶液，然后转移50 μL样品加到200μL含内标的乙腈作为经过Transwell培养板顶端0分钟给药样品进行检测。下层小室(基底端)每孔加入235μL接收端溶液；2) Determine the transport rate of the compound from the top to the base. Add 125 μL of the dosing solution to each well of the upper chamber (top), and then transfer 50 μL sample was added to 200 μL acetonitrile containing internal standard as the 0-minute dosing sample through the top of the Transwell culture plate for detection. 235 μL of receiving end solution was added to each well of the lower chamber (basal end);

3)测定化合物由基底端到顶端的转运速率。向上层小室(顶端)每孔加入75μL接收端溶液，下层小室(基底端)每孔加入285μL给药端溶液。然后转移50μL样品加到200μL含内标的乙腈作为经过Transwell培养板基底端0分钟给药样品进行检测；3) Determine the transport rate of the compound from the base to the top. Add 75 μL of the receiving end solution to each well of the upper chamber (top), and add 285 μL of the dosing end solution to each well of the lower chamber (base). Then transfer 50 μL of the sample and add it to 200 μL of acetonitrile containing the internal standard as the 0-minute dosing sample at the base of the Transwell culture plate for detection;

4)将上下的转运装置合并后，37℃条件下孵育2小时；4) Combine the upper and lower transport devices and incubate at 37°C for 2 hours;

5)从工作液配制板中转移50μL样品加到200μL含内标的乙腈作为0分钟给药样品进行检测；5) Transfer 50 μL of sample from the working solution preparation plate and add it to 200 μL of acetonitrile containing internal standard as the 0-minute dosing sample for detection;

6)孵育完成后，分别从Transwell培养板上室和下室每孔取样50μL加入到新的样品管中。向样品管内加入200μL含内标的乙腈，涡旋10分钟后，于3220g离心30分钟。吸取上清液150μL，与等体积水稀释之后进行LC-MS/MS分析。所有样品进行双平行制备；6) After incubation, take 50 μL of sample from each well of the upper and lower chambers of the Transwell culture plate and add them to new sample tubes. Add 200 μL of acetonitrile containing internal standard to the sample tube, vortex for 10 minutes, and centrifuge at 3220g for 30 minutes. Take 150 μL of the supernatant and dilute it with an equal volume of water for LC-MS/MS analysis. All samples were prepared in duplicate;

7)用荧光黄的渗漏评价孵育2小时后细胞单层膜的完整性，使用HBSS(10mM HEPES,pH 7.4)稀释荧光黄储备液至最终浓度100μM。在上侧的Transwell插板的每个孔中加入荧光黄溶液100μL，下侧接收板的每个孔中加300μL HBSS(10mM HEPES,pH 7.4)。37℃下孵育30分钟后，分别从每孔上下层吸出80μL溶液至一个新的96孔板中。使用酶标仪，激发波长485nm和发射波长530nm条件下进行荧光测定。通过接收端和给药端的具体浓度计算化合物在Caco-2细胞中的表观渗透系数(Papp，单位：cm/s)用以下公式计算得出：
7) The integrity of the cell monolayer membrane after 2 hours of incubation was evaluated by leakage of fluorescent yellow. The fluorescent yellow stock solution was diluted to a final concentration of 100 μM using HBSS (10 mM HEPES, pH 7.4). 100 μL of fluorescent yellow solution was added to each well of the upper Transwell insert, and 300 μL of HBSS (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using an ELISA reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The apparent permeability coefficient (Papp, unit: cm/s) of the compound in Caco-2 cells was calculated using the following formula based on the specific concentrations at the receiving end and the administration end:

公式中：VA为接收端溶液的体积(由顶端到基底端是0.235mL，基底端到顶端是0.075mL)，Area为Transwell-96孔板膜面积(0.143cm²)；time为孵育时间In the formula: VA is the volume of the receiving end solution (0.235 mL from the top to the base, 0.075 mL from the base to the top), Area is the Transwell-96 plate membrane area (0.143 cm ² ); time is the incubation time

(单位：s)。(Unit: s).

外排率使用以下的公式计算得出：
The efflux rate is calculated using the following formula:

公式中：Papp(B-A)为由基底端到顶端的表观渗透系数；In the formula: Papp(B-A) is the apparent permeability coefficient from the base end to the top end;

Papp(A-B)为由顶端到基底端的表观渗透系数。Papp(A-B) is the apparent permeability from the apical end to the basal end.

2.实验结果与分析2. Experimental results and analysis

该渗透性实验参数如下表4所示。The permeability test parameters are shown in Table 4 below.

表4.本发明化合物在Caco-2细胞模型的渗透性
Table 4. Permeability of the compounds of the present invention in the Caco-2 cell model

通过表4所示实验数据，与对照化合物2相比，本发明示例化合物51对具有更低的外排率，表明该化合物口服吸收较更好，口服生物利用度更高。According to the experimental data shown in Table 4, compared with the control compound 2, the exemplary compound 51 of the present invention has a lower efflux rate, indicating that the compound has better oral absorption and higher oral bioavailability.

测试例5：本发明化合物在比格犬的体内药代动力学实验以雄性比格犬为受试动物，研究本发明化合物在剂量为1mg/kg时经注射给药后的体内药代动力学行为。Test Example 5: In vivo pharmacokinetic study of the compound of the present invention in beagle dogs Male beagle dogs were used as test animals to study the in vivo pharmacokinetic behavior of the compound of the present invention at a dose of 1 mg/kg after injection.

1.试验方案1. Experimental plan

1.1供试品：1.1 Test sample:

对照化合物1、对照化合物2和本发明化合物51。Control compound 1, control compound 2 and compound 51 of the present invention.

1.2试验动物1.2 Experimental animals

动物基本信息Basic information about animals

种属：雄性比格犬(3只/组)Species: Male beagle dogs (3/group)

体重：约8～10kgWeight: about 8-10kg

来源：江苏玛斯生物技术有限公司Source: Jiangsu Masi Biotechnology Co., Ltd.

1.3给药： 1.3 Administration:

雄比格犬注射给予对照化合物1、对照化合物2和本发明化合物51，给药剂量为1mg/kg，给药体积为1mL/kg。Male beagle dogs were injected with control compound 1, control compound 2 and compound 51 of the present invention at a dosage of 1 mg/kg and an administration volume of 1 mL/kg.

供试品溶液的配制：供试品采用溶媒(10％ DMSO+10％ Kolliphor HS15+80％ Saline)溶解，配制时依次加入DMSO、Kolliphor HS15、Saline。Preparation of test sample solution: The test sample was dissolved in solvent (10% DMSO + 10% Kolliphor HS15 + 80% Saline). DMSO, Kolliphor HS15 and Saline were added in sequence during preparation.

对照组：对照化合物1、对照化合物2，结构同上。Control group: control compound 1 and control compound 2, the structures are the same as above.

实验组：本发明化合物51。Experimental group: Compound 51 of the present invention.

1.4样品采集：1.4 Sample collection:

分别采集药前0、药后5min、15min、0.5h、1h、2h、4h、8h、24h，The data were collected at 0 min before medication, 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after medication.

采血0.5mL置于EDTA-2K抗凝管中。上下轻柔颠倒使抗凝剂(EDTA-2K)与血液充分混合后，立即置于湿冰中，并于采血后15分钟内离心分离血浆，离心条件设置为4℃、3000g、5分钟。离心后分离血浆，进行样品分析。0.5 mL of blood was collected and placed in an EDTA-2K anticoagulant tube. After gently inverting the tube upside down to fully mix the anticoagulant (EDTA-2K) and the blood, the tube was immediately placed in wet ice and centrifuged within 15 minutes after blood collection to separate the plasma. The centrifugation conditions were set at 4°C, 3000g, and 5 minutes. After centrifugation, the plasma was separated and the sample was analyzed.

2.实验结果与分析2. Experimental results and analysis

药代动力学参数参见如下表5。本发明犬体内药代结果显示：与对照组化合物1和对照化合物2相比，本发明化合物51具有更慢的体内清除速度、更长的半衰期、组织分布较高以及更高的血浆暴露量。The pharmacokinetic parameters are shown in Table 5. The pharmacokinetic results of the present invention in dogs show that compared with the control group compound 1 and the control compound 2, the present compound 51 has a slower in vivo clearance rate, a longer half-life, a higher tissue distribution and a higher plasma exposure.

表5比格犬静脉给药的药代动力学参数
Table 5 Pharmacokinetic parameters of intravenous administration in beagle dogs

从前述中可以理解，尽管为了示例性说明的目的描述了本公开的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或修改。特别地，在一个实施方案中描述的一个或多个技术特征可以与另一个实施方案中描述的一个或多个技术特征相结合，只要这样的结合不违背本公开的主旨即可。这样的变形、修改或组合都应落入本公开所附权利要求的范围内。 It can be understood from the foregoing that although specific embodiments of the present disclosure are described for illustrative purposes, various variations or modifications may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. In particular, one or more technical features described in one embodiment may be combined with one or more technical features described in another embodiment, as long as such combination does not violate the purport of the present disclosure. Such variations, modifications or combinations shall all fall within the scope of the claims appended to the present disclosure.

Claims

A compound represented by formula (II), its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate,

in,

Ring A is selected from 6-10 membered aryl, 5-6 membered heteroaryl;

The bond "--" between _X1 and _X2 represents a single bond or a double bond;

_X1 is selected _from -C(= _CH2 ), _CRa1Ra2 , N, NH, _CRa3 ;

_Ra1 , _Ra2 , _Ra3 are each independently selected from hydrogen, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkylamino, nitro, substituted or unsubstituted _C2-4 alkenyl, substituted or _{unsubstituted} _C3-6 cycloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy _, _C1-4 alkylene- _OC1-4 alkyl, _-NRe1Re2 , _-CORe3 , _-SO2CH3 ;

Re ₁ , Re ₂ , and Re ₃ are each independently hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, -NH ₂ , or -NH-C _1-4 alkyl;

_X2 is selected from CR _b1 R _b2 , CR _b3 ;

R _b1 and R _b2 are each independently selected from hydrogen, halogen, C _1-4 alkyl, or said R _a1 and R _b1 , or R _a1 and R _b2 , or R _a2 and R _b1 , or R _a2 and R _b2 , together with the carbon atom to which they are linked, form a substituted or unsubstituted C _3-6 cycloalkyl;

R _b3 is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, -WC _3-6 cycloalkyl;

R ₁ is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyano, nitro, substituted or unsubstituted C _3-6 cycloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, deuterium, C _1-4 deuterated alkyl, C _1-4 deuterated alkoxy; or R ₁ and X ₁ are combined to form a substituted or unsubstituted 5-6 membered heterocyclic group;

L ₁ is selected from C _1-4 alkylene, C _1-4 deuterated alkylene, -NH-C _1-4 alkylene, C _3-6 cycloalkylene;

Ring B is selected from C _3-6 cycloalkyl, 5-10 membered heterocyclyl;

_R2 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 alkyl- _OC1-4 alkyl, deuterium, _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, NH=;

m is selected from 0, 1, 2, 3, 4. When there are multiple R ₂ , adjacent R ₂ and the atoms to which they are connected optionally form a substituted or unsubstituted C _3-6 cycloalkyl group;

Y ₁ and Y ₂ are each independently selected from CH, N, and CR _c , wherein R _c is selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkylamino, C _3-6 cycloalkylamino, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, -NH ₂ , -NH-C _1-4 alkyl, -NH-C _1-4 alkylene-C _1-4 haloalkyl, -NH-C _1-4 alkylene-CONH ₂ , -OC _1-4 alkylene _- CN, -OC _3-6 cycloalkylene-CN, -W-C _3-6 cycloalkyl, -W-(3-6 membered heterocyclyl), C _2-6 alkenyl-CN, cyano, and -CO-NH-C _1-4 alkyl; the C _3-6 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted by halogen, C _1-4 alkyl, cyano, C _1-4 alkylene-CN substitution;

W is selected from O, NH, S;

Z is selected from CR _d1 R _d2 , O, S, N, wherein R _d1 and R _d2 are independently hydrogen, halogen, C _1-4 alkyl, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 alkyl-C _1-4 haloalkyl, C _{1-4 alkyl-cyano, C 1-4} _alkyl -C _1-4 alkoxy, C _1-4 deuterated alkoxy, C 1-4 haloalkoxy, C _2-4 alkenyl, OC _1-4 haloalkyl, oxo, or R _d1 and R _d2 form a substituted or unsubstituted C _3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are linked _together ;

_R3 is selected from hydrogen, halogen, _C1-4 alkyl, _C1-4 deuterated alkyl, _C1-4 haloalkyl, _C1-4 alkoxy.

The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that ring A is selected from phenyl, Preferably, ring A is selected from phenyl, or

_Ra1 , _Ra2 , and _Ra3 are each independently selected from -F, -Cl, -Br, -I, _-CH3 , _-CF3 , _-CHF2 , -NH- _CH3 , -CH= _CH2 , -C( _CH3 )= _CH2 , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCF ₃ , -OCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CONH ₂ , -SO ₂ CH ₃ , -CHO, -CONHCH ₃ ; or

R _b1 and R _b2 are each independently selected from H, -CH ₃ ; or

R _b3 is selected from

The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate, characterized in that R ₁ is selected from H, -Br, -F, -Cl, -CF ₃ , -CH ₃ , -C ₂ H ₅ , -CH ₂ -CF ₃ , -CHF ₂ .

The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that the structural unit Selected from

The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that _L1 is selected from _-CH2- , -CH( _CH3 )-, _-CD2- , -NH- _CH2- ,

The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that ring B is selected from

The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that R ₂ is selected from -F, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -(CH ₂ ) ₂ OCH ₃ , deuterium, and NH＝.

The compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that the structural unit Selected from

The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that R _c is selected from -CF ₃ , cyclopropyl, methylamino, cyclopropylamino, -OC ₂ H ₅ , -OCF ₃ , -NH ₂ , -NH-C ₂ H ₅ , -NH-CH ₂ -CHF ₂ , -NH-CH ₂ -CONH ₂ , -OCH ₂ -CN, _-OCH2F , CN, or

R _d1 and R _d2 are selected from hydrogen, -F, -CH ₃ , -CN, -OCH ₃ , -CH ₂ F, -CHF ₂ , -CH ₂ -CHF ₂ , -CH ₂ -CN, -CH ₂ -OCH _3. -OCD ₃ , -OCHF ₂ , -CH＝CH ₂ , OCF ₃ , C ₂ H ₅ , CH ₂ CH ₂ F; or

R _d1 , R _d2 and the carbon atoms that are linked together form

The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that the structural unit Selected from

The compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate, characterized in that R ₃ is selected from -CH ₃ and -CD ₃ .

The compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, and its hydrate are selected from:

wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , Ring B, Z, and m are as defined in any one of claims 1 to 11;

wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , Ring B, Z, m, R _d1 , and R _d2 are as defined in any one of claims 1 to 11;

wherein X ₁ , X ₂ , Y ₂ , R ₁ , R ₂ , R ₃ , L ₁ , Ring B, m, R _d1 and R _d2 are as defined in any one of claims 1-11.

Compound, its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate,

A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer, its isotope-labeled substance, its solvate, its hydrate and a pharmaceutically acceptable carrier.

The compound according to any one of claims 1 to 13, its pharmaceutically acceptable salt, its stereoisomer, its isotope label, its solvate, its hydrate or the pharmaceutical composition according to claim 14 for treating CBL-B target-mediated related diseases, preferably wherein the CBL-B target-mediated related diseases are CBL-B-mediated cancers, such as urogenital tract cancer, uterine cancer, cervical cancer, ovarian cancer, breast cancer, gastrointestinal cancer, bone tumor, myeloma, skin cancer, head and neck cancer, liver cancer, gallbladder cancer, bile duct cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain tumor, ganglion cancer, central nervous system tumor, peripheral nervous system tumor, hematopoietic system tumor and immune system tumor.