Tricyclic compound and medical application thereof

Abstract

The invention relates to a tricyclic compound and medical application thereof, the structure of the tricyclic compound is shown as a formula (I), and particularly relates to a preparation method of the compound, a pharmaceutical composition and application of the compound in cancer treatment. # imgabs0 #

Description

Tricyclic compounds and their medical uses

[0001] This application claims priority to

[0002] This application claims 1) the priority and benefits of Chinese Patent Application No. 202210967635.3 filed with the State Intellectual Property Office of China on August 12, 2022, 2) the priority and benefits of Chinese Patent Application No. 202310200012.8 filed with the State Intellectual Property Office of China on January 16, 2023, 3) the priority and benefits of Chinese Patent Application No. 202310103403.8 filed with the State Intellectual Property Office of China on February 8, 2023, 4) the priority and benefits of Chinese Patent Application No. 202310103403.8 filed with the State Intellectual Property Office of China on February 8, 2023, The disclosures of these applications are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to tricyclic compounds, methods for preparing the same, pharmaceutical compositions containing the same, and uses of the same in treating cancer. Background Art

[0004] The Ras gene is an important proto-oncogene, named after the rat sarcoma virus. The Ras protein it encodes is located on the inner side of the cell membrane. It can bind to GTP / GDP and hydrolyze GTP with the assistance of GTPase-activating protein (GAP). By converting between active (GTP-bound) and inactive (GDP-bound) conformations, the Ras protein controls the "on" and "off" of signal transmission processes such as growth factors and cytokines, playing an important role in life processes such as cell proliferation, differentiation, aging, and apoptosis (Bos JL et al., Cell, 2007, 129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma viral oncogene homolog (HRas), neuroblastoma rat sarcoma viral oncogene homolog (NRas) and Kirsten rat sarcoma viral oncogene homolog (Kras), among which Kras is mainly expressed in the intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8):1177-1195).

[0005] Studies have shown that more than 30% of human tumors have Ras gene mutations, of which Kras mutations account for approximately 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2):201-205). For Kras mutations, mutations at position 12 glycine (G12) account for approximately 80%, and G12D mutations (mutation of position 12 glycine to aspartic acid) are the main form of G12 mutations. (Prior IA et al., Cancer Res, 2012, 72(10):2457-2467). Mutations at G12 reduce the catalytic activity of GAP, ultimately promoting the continued activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.

[0006] Currently, Kras (e.g. Kras G12D ) has become an attractive anticancer target.

[0007] Detailed Description of the Invention

[0008] The present disclosure relates to a compound of formula (I), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] X is selected from -N-, or optionally replaced by R x substituted -CH-;

[0011] R x Selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0012] L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene;

[0013] Each R 1independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0014] R 2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Heteroalkyl, 3-12 membered cycloalkyl-L 2 -, 4-12 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -;

[0015] L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0016] Each R 2a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 Alkylene OC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6 Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0017] R 2c Independently selected from H, deuterium, or C 1-6 alkyl;

[0018] R 2d independently selected from H, deuterium, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0019] Each R 2e independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0020] Each R 2b independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0021] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-12 alkyl)-;

[0022] Each R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0023] R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0024] Each R 3a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-6 Alkylene C(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)R 3d 、-C 1-6 Alkylene NHC(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)OR 3d 、-C 1-6 Alkylene OC(O)R 3d 、-C 1-6 Alkylene C(O)OR 3d 、-C 1-6 Alkylene OC(O)NR 3c R 3d 、-C 1-6 Alkylene SO2R 3d 、-C 1-6 Alkylene OSO2R 3d 、-C 1-6 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0025] R 3c Independently selected from H, deuterium, or C 1-6 alkyl;

[0026] R 3d independently selected from H, deuterium, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0027] Each R 3b independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0028] Each R 3e Independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0029] R 4 Selected from H, deuterium, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0030] Ring A is selected from the group consisting of 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0031] Each R 5 independently selected from deuterium, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12Alkylamino, di-C 1-12 Alkylamino, C 1-12 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl;

[0032] Each R 5a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0033] Each L 1 、L 2 、R 1 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 4 、R 5 、R 5a 、R x , or R z Each is independently optionally substituted with one or more substituents.

[0034] In some embodiments, the compound of formula (I), its stereoisomer, its tautomer, or its pharmaceutically acceptable salt,

[0035] in,

[0036] X is selected from -N-, or optionally replaced by R x substituted -CH-;

[0037] R x Selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0038] L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene;

[0039] Each R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0040] R 2 is selected from H, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Heteroalkyl, 3-12 membered cycloalkyl-L 2 -, 4-12 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -;

[0041] L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0042] Each R 2a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 Alkylene OC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6 Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0043] R 2c Independently selected from H, or C 1-6 alkyl;

[0044] R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0045] Each R 2e independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0046] Each R 2b independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0047] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-12 alkyl)-;

[0048] Each R z are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0049] R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0050] Each R 3a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-6 Alkylene C(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)R 3d 、-C 1-6 Alkylene NHC(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)OR 3d 、-C 1-6 Alkylene OC(O)R 3d 、-C 1-6 Alkylene C(O)OR 3d 、-C 1-6 Alkylene OC(O)NR 3c R 3d 、-C 1-6 Alkylene SO2R 3d 、-C 1-6 Alkylene OSO2R 3d 、-C 1-6 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0051] R 3c Independently selected from H, or C 1-6 alkyl;

[0052] R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0053] Each R 3b independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0054] Each R 3e Independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0055] R 4 Selected from H, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0056] Ring A is selected from the group consisting of 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0057] Each R 5 independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, C 1-12 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl;

[0058] Each R 5a independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0059] Each L 1 、L 2 、R 1 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 4 、R 5 、R 5a 、R x , or R z Each is independently optionally substituted with one or more substituents.

[0060] In some embodiments, the compound of formula (I), its stereoisomer, its tautomer, or its pharmaceutically acceptable salt,

[0061] in,

[0062] X is selected from -N-, or optionally replaced by R x substituted -CH-;

[0063] R x Selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0064] L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene;

[0065] Each R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0066] R 2 is selected from H, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Heteroalkyl, 3-12 membered cycloalkyl-L 2 -, 4-12 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -;

[0067] L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0068] Each R 2aindependently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 Alkylene OC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6 Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6alkylene;

[0069] R 2c Independently selected from H, or C 1-6 alkyl;

[0070] R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0071] Each R 2e independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0072] Each R 2b independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0073] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-12 alkyl)-;

[0074] Each R z are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino;

[0075] R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0076] Each R 3a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-6 Alkylene C(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)R 3d 、-C 1-6 Alkylene NHC(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)OR 3d 、-C 1-6 Alkylene OC(O)R 3d 、-C 1-6 Alkylene C(O)OR 3d 、-C 1-6 Alkylene OC(O)NR 3c R 3d 、-C 1-6 Alkylene SO2R 3d 、-C 1-6 Alkylene OSO2R 3d 、-C1-6 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0077] R 3c Independently selected from H, or C 1-6 alkyl;

[0078] R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0079] Each R 3b independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0080] Each R 3e Independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0081] R 4 Selected from H, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0082] Ring A is selected from the group consisting of 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0083] Each R 5 independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, C 1-12 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl;

[0084] Each R 5a independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0085] Each L 1 , L 2 、R 1 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 4 、R 5 、R 5a 、R x , or R z Each is independently optionally substituted with one or more substituents.

[0086] In some embodiments, the R x Selected from deuterium.

[0087] In some embodiments, the R x Selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 Haloalkylamino.

[0088] In some embodiments, the R x Selected from halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, or C 1-6 Halogenated alkoxy.

[0089] In some embodiments, the R x Selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0090] In some embodiments, the R x Selected from F, Cl, Br, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0091] In some embodiments, the R x is selected from F, Cl, Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy.

[0092] In some embodiments, X is selected from -N-, -CH-, -C(C 1-6 alkyl)-, or -C(C 1-6 haloalkyl)-.

[0093] In some embodiments, X is selected from -N-, -CH-, -C(C 1-3 alkyl)-, or -C(C 1-3 haloalkyl)-.

[0094] In some embodiments, X is selected from -N-.

[0095] In some embodiments, the L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 2-4 Heteroalkenylene.

[0096] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 Heteroalkenylene.

[0097] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 2-3 Heteroalkenylene.

[0098] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, or C 1-3 Heteroalkylene.

[0099] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted with the following groups: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-.

[0100] In some embodiments, the L 1 Selected from -O-, or optionally one or more R 1 Substituted: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-.

[0101] In some embodiments, the L 1 Selected from -O-, -NH-, -N(C 1-3 alkyl)-, or optionally replaced by one or more R 1 Substituted: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-.

[0102] In some embodiments, the L 1 Selected from -O-, -NH-, -N(CH3)-, or optionally one or more R 1 Substituted: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-.

[0103] In some embodiments, the L 1 Selected from optionally one or more R 1 Substituted groups include: -(CH2)3-, -OCH2CH2-, or -NHCH2CH2-.

[0104] In some embodiments, the L 1 Selected from optionally one or more R 1 Substituted -OCH2CH2-.

[0105] In some embodiments, each of said R 1 It can also be selected from deuterium.

[0106] In some embodiments, each of said R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 Haloalkylamino.

[0107] In some embodiments, each of said R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, or C 1-6 Halogenated alkoxy.

[0108] In some embodiments, each of said R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0109] In some embodiments, each of said R 1 Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0110] In some embodiments, each of said R 1 is independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy. In some embodiments, each R 1 Independently selected from -CH2F.

[0111] In some embodiments, each of said R 1 Independently selected from methyl, ethyl, isopropyl, trifluoromethyl, or -CH2F.

[0112] In some embodiments, the R 2 Selected from deuterium.

[0113] In some embodiments, the R2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -.

[0114] In some embodiments, the R 2 is selected from H, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -.

[0115] In some embodiments, the R 2 is selected from H, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocyclic group-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, or benzo 5-6 membered heteroaryl-L 2 -.

[0116] In some embodiments, the R 2 is selected from H, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocyclic group-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, benzo 5-6 membered heterocyclic group-L 2-, or benzo 5-6 membered heteroaryl-L 2 -. In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted 5-6 membered heteroaryl and 5-6 membered cycloalkenyl-L 2 -.

[0117] In some embodiments, the R 2 is selected from H, deuterium, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocycloalkyl-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, benzo 5-6 membered heterocyclic group-L 2 -, benzo 5-6 membered heteroaryl-L 2 -, or 5-6 membered heteroaryl and 5-6 membered cycloalkenyl-L 2 -.

[0118] In some embodiments, the R 2 is selected from H, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocycloalkyl-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, benzo 5-6 membered heterocyclic group-L 2 -, or benzo 5-6 membered heteroaryl-L 2 -. In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted 5-6 membered heteroaryl and 5-6 membered cycloalkenyl-L 2 -.

[0119] In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocyclic group-L 2 -, phenyl-L2 -, or 5-6 membered heteroaryl-L 2 -. In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted with the following groups: C 1-4 Alkyl, or 5-6 membered heteroaryl-L 2 -.

[0120] In some embodiments, the L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 2-6 Heteroalkenylene.

[0121] In some embodiments, the L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, or C 1-6 Heteroalkylene.

[0122] In some embodiments, the L 2 Selected from single bond, -O-, -NH-, -N(C 1-3 Alkyl)-, C 1-4 Alkylene, or C 1-4 Heteroalkylene.

[0123] In some embodiments, the L 2 Selected from single bond, -O-, -NH-, -N(C 1-3 Alkyl)-, C 1-4 Alkylene, -OC 1-4 Alkylene, or -NH-C 1-4 Alkylene.

[0124] In some embodiments, the L 2 is selected from a single bond or a methylene group.

[0125] In some embodiments, the L 2 Selected from -CH(CH3)-.

[0126] In some embodiments, the R 2 is selected from H, deuterium, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, sec-butyl, C 1-4Heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, Oxetane, azetidinyl, pyrrolidinyl, piperidinyl, or pyrazolyl.

[0127] In some embodiments, the R 2 is selected from H, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, C 1-4 Heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, Oxetane, azetidinyl, pyrrolidinyl, piperidinyl, In some embodiments, the R 2 Selected from optionally one or more R 2a In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted: n-butyl, isobutyl, sec-butyl or pyrazolyl.

[0128] In some embodiments, the R 2 Selected from optionally one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, sec-butyl, cyclopropane,

[0129] In some embodiments, the R 2 Selected from optionally one or more R 2a Replaced

[0130] In some embodiments, the R 2a The substituted position is R 2 carbon or nitrogen atoms in the .

[0131] In some embodiments, the R 2a The substituted position is R 2 The carbon atoms in .

[0132] In some embodiments, the R 2a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-3 Alkylene C(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)R 2d 、-C 1-3 Alkylene NHC(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)OR 2d 、-C 1-3 Alkylene OC(O)R 2d 、-C 1-3 Alkylene C(O)OR 2d 、-C 1-3 Alkylene OC(O)NR 2c R 2d 、-C 1-3 Alkyl SO2R 2d 、-C 1-3 Alkylene OSO2R 2d 、-C 1-3 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0133] In some embodiments, the R 2a It can also be selected from deuterium.

[0134] In some embodiments, the R 2a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2cR 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-3 Alkylene C(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)R 2d 、-C 1-3 Alkylene NHC(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)OR 2d 、-C 1-3 Alkylene OC(O)R 2d 、-C 1-3 Alkylene C(O)OR 2d 、-C 1-3 Alkylene OC(O)NR 2c R 2d 、-C 1-3 Alkyl SO2R 2d 、-C 1-3 Alkylene OSO2R 2d 、-C 1-3 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0135] In some embodiments, the R 2aindependently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-C 1-3 Alkylene C(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)R 2d 、-C 1-3 Alkylene NHC(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)OR 2d 、-C 1-3 Alkylene OC(O)R 2d 、-C 1-3 Alkylene C(O)OR 2d 、-C 1-3 Alkylene OC(O)NR 2c R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0136] In some embodiments, the R 2a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-OC(O)R 2d、-C(O)OR 2d 、-C 1-3 Alkylene C(O)NR 2c R 2d 、-C 1-3 Alkylene NR 2c C(O)R 2d 、-C 1-3 Alkylene OC(O)R 2d 、-C 1-3 Alkylene C(O)OR 2d , or optionally one or more R 2b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0137] In some embodiments, the R 2a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、 -OC(O)R 2d 、-C(O)OR 2d , or optionally one or more R 2b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocycloalkyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0138] In some embodiments, the R 2a Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d、-OC(O)R 2d 、-C(O)OR 2d , or optionally one or more R 2b Substituted groups: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, 4-7 membered heterocycloalkyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0139] In some embodiments, the R 2a Independently selected from deuterium, F, -OH, -NH2, methyl, methylamino, dimethylamino, or cyclopropane.

[0140] In some embodiments, the R 2a Independently selected from F, -OH, -NH2, methyl, methylamino, dimethylamino, or cyclopropane.

[0141] In some embodiments, the R 2a Independently selected from -NH2, methyl, methylamino, or cyclopropane.

[0142] In some embodiments, the R 2a Independently selected from F, -OH, or dimethylamino.

[0143] In some embodiments, the R 2a In some embodiments, the R 2a In some embodiments, the R 2a Independently selected from -NH2.

[0144] In some embodiments, the R 2c Independently selected from H, deuterium, or C 1-3 alkyl.

[0145] In some embodiments, the R 2c It can also be selected from deuterium.

[0146] In some embodiments, the R 2c Independently selected from H, or C 1-3 alkyl.

[0147] In some embodiments, the R 2c Independently selected from H, or methyl.

[0148] In some embodiments, the R 2d independently selected from H, deuterium, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-3 Alkylene, 3-10 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0149] In some embodiments, the R 2d It can also be selected from deuterium.

[0150] In some embodiments, the R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-3 Alkylene, 3-10 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0151] In some embodiments, the R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-3 Alkylene, 5-10 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0152] In some embodiments, the R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-4 Alkyl, C 1-4 heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkylC1-3 Alkylene, 3-8 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0153] In some embodiments, the R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-3 Alkyl, C 1-3 heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl C 1-3 Alkylene, 3-8 membered heterocycloalkyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0154] In some embodiments, the R 2e Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.

[0155] In some embodiments, the R 2e It can also be selected from deuterium.

[0156] In some embodiments, the R 2e Independently selected from -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.

[0157] In some embodiments, the R 2e Independently selected from -F, -Cl, -OH, oxo, -NH2, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0158] In some embodiments, the R 2b Independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0159] In some embodiments, the R 2b It can also be selected from deuterium.

[0160] In some embodiments, the R 2bIndependently selected from -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trifluoromethyl, or trifluoromethoxy.

[0161] In some embodiments, the R 2b Independently selected from -F, -Cl, -OH, -NH2, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0162] In some embodiments, the R 2 Selected from H, deuterium, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropane, cyclobutane, cyclopentane,

[0163] In some embodiments, the R 2 Selected from H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropane, cyclobutane, cyclopentane, In some embodiments, the R 2 In some embodiments, the R 2 Selected from In some embodiments, the R 2 Selected from In some embodiments, the R 2 Selected from

[0164] In some embodiments, the R 2 selected from H or optionally one or more R 2a Substituted C 1-4 alkyl.

[0165] In some embodiments, the R 2 Selected from H, methyl, trifluoromethyl,

[0166] In some embodiments, the R 2 Selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,

[0167] In some embodiments, the R 2 Selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,

[0168] In some embodiments, the R 2 Selected from

[0169] In some embodiments, the R 2 isopropyl, tert-butyl, cyclopropane, or

[0170] In some embodiments, when X is selected from -N-, said L 1 Selected from -O-, -S-, -NH-, or -N(C 1-6 alkyl)-, said R 2 is not selected from halogen, -OH, -NH2, or -CN, the L 2 Not selected from -O-, -S-, -NH-, or -N(C 1-6 alkyl)-.

[0171] In some embodiments, Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-6 alkyl)-.

[0172] In some embodiments, each of said R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 Haloalkylamino.

[0173] In some embodiments, the R z It can also be selected from deuterium.

[0174] In some embodiments, each of said R z are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 Haloalkylamino.

[0175] In some embodiments, each of said R z are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, or C 1-6 Halogenated alkoxy.

[0176] In some embodiments, each of said R z are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0177] In some embodiments, each of said R z Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0178] In some embodiments, each of said R z Independently selected from deuterium, F, Cl, Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy.

[0179] In some embodiments, each of said R z Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy.

[0180] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-12 alkyl)-.

[0181] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C1-6 alkyl)-.

[0182] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-.

[0183] In some embodiments, Z is selected from a single bond, -O-, or -N(C 1-3 alkyl)-.

[0184] In some embodiments, Z is selected from a single bond, -O-, or -N(CH3)-.

[0185] In some embodiments, said Z is selected from -O-.

[0186] In some embodiments, Z is selected from a single bond, -O-, -NH-, or -N(CH3)-.

[0187] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene.

[0188] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 3-10 membered heterocyclic group or 3-10 membered heterocyclic group C 1-4 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl C 1-4 Alkylene.

[0189] In some embodiments, the R 3 Selected from deuterium.

[0190] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-4Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 Alkylene.

[0191] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-10 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 3-membered cycloalkyl or 3-membered cycloalkyl C 1-3 Alkylene.

[0192] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 4-10-membered, 4-9-membered, 4-8-membered, or 5-9-membered heterocyclic group C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a substituted 4-10-membered, 4-9-membered, 4-8-membered or 5-9-membered heterocyclic group.

[0193] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 9-membered heterocyclic group C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a substituted 9-membered heterocyclic group.

[0194] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 4-8 membered cycloalkyl C 1-3 Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 In some embodiments, the R 3Selected from optionally one or more R 3a Substituted 3-membered cycloalkyl or 3-membered cycloalkyl C 1-3 Alkylene.

[0195] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocyclic group, 4-8 membered cycloalkyl C 1-3 Alkylene, or 4-8 membered heterocyclic group C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 3-membered cycloalkyl or 3-membered cycloalkyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 5-6 membered heteroaryl C 1-3 Alkylene.

[0196] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocyclic group, 4-8 membered cycloalkyl C 1-3 Alkylene, or 4-8 membered heterocyclic group C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 3-membered cycloalkyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 5-6 membered heteroaryl C 1-3 Alkylene.

[0197] In some embodiments, the heterocyclyl is selected from heterocycloalkyl. In some embodiments, the heterocyclyl is selected from partially unsaturated heterocyclyl.

[0198] In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-6 Alkylene is selected from 3-12 membered heterocycloalkyl C 1-6 Alkylene or benzo 4-6 membered heterocyclic group C 1-6 Alkylene.

[0199] In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-4 Alkylene is selected from 3-10 membered heterocycloalkyl C 1-4 Alkylene or benzo 4-6 membered heterocyclic group C 1-4 Alkylene.

[0200] In some embodiments, the 4-10 membered heterocyclyl is selected from 4-10 membered heterocyclyl or benzo 4-6 membered heterocyclyl. 1-6 Alkylene is selected from 4-10 membered heterocycloalkyl C 1-6 Alkylene or benzo 4-6 membered heterocyclic group C 1-6 In some embodiments, the 4-10 membered heterocyclyl C 1-3 Alkylene is selected from 4-10 membered heterocycloalkyl C 1-3 Alkylene or benzo 4-6 membered heterocyclic group C 1-3 Alkylene.

[0201] In some embodiments, the 4-10 membered, 4-9 membered, 4-8 membered, or 5-9 membered heterocyclyl C 1-3 Alkylene is selected from 4-10 membered, 4-9 membered, 4-8 membered or 5-9 membered heterocycloalkyl C 1-3 In some embodiments, the 4-10 membered, 4-9 membered, 4-8 membered, or 5-9 membered heterocyclyl is selected from 4-10 membered, 4-9 membered, 4-8 membered, or 5-9 membered heterocycloalkyl.

[0202] In some embodiments, the 4-8 membered heterocyclyl is selected from 4-8 membered heterocyclyl. 1-6 Alkylene is selected from 4-8 membered heterocycloalkyl C 1-6 In some embodiments, the 4-8 membered heterocyclyl C 1-3 Alkylene is selected from 4-8 membered heterocycloalkyl C 1-3 Alkylene.

[0203] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocycloalkyl, 4-8 membered cycloalkyl C 1-3 Alkylene, or 4-8 membered heterocycloalkyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted 3-membered cycloalkyl C 1-3 In some embodiments, the R3 Selected from optionally one or more R 3a Substituted 5-6 membered heteroaryl C 1-3 Alkylene.

[0204] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted groups include methyl, ethyl, propyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, cyclopropyl, cyclopropyl C 1-3 Alkylene, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or imidazolyl C 1-3 Alkylene.

[0205] In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted groups include methyl, ethyl, propyl, butyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, or hexahydro-1H-pyrrolizinyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3aSubstituted groups: hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl, or 5-azaspiro[2.4]heptyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted groups: cyclopropyl or cyclopropyl C 1-3 In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted groups: n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or imidazolyl C 1-3 Alkylene.

[0206] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted groups: methyl, piperidinyl, cyclopentyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, or hexahydro-1H-pyrrolizinyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted with the following groups: hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene or 5-azaspiro[2.4]heptyl C 1-3 In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted cyclopropyl C 1-3 In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted groups: ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, morpholinyl C 1-3 Alkylene, imidazolyl C 1-3 Alkylene, tetrahydropyrrolyl, piperazinyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, azetidinyl, cyclobutyl, cyclohexyl, cyclobutyl C 1-3 alkylene, or piperazinyl.

[0207] In some embodiments, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3aSubstituted groups: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0208] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted groups: In some embodiments, the R 3 Selected from optionally one or more R 3a Replaced In some embodiments, the R 3 selected from H or optionally one or more R 3a Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0209] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted hexahydro-1H-pyrrolizinyl C 1-3 Alkylene.

[0210] In some embodiments, the R 3a The substituted position is R 3 In some embodiments, the cyclic portion and / or alkylene portion of R 3a The substituted position is R 3 In some embodiments, the R 3a The substituted position is R 3 The alkylene portion.

[0211] In some embodiments, the R 3a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d、-SO2R 3d 、-NHSO2R 3d 、-C 1-3 Alkylene C(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene C(O)OR 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkyl SO2R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclic group, phenyl, 4-7 membered heterocyclic group C 1-3 Alkylene, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl C 1-3 Alkylene, =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), or =C(C 1-4 Alkyl)2.

[0212] In some embodiments, the R 3a They may also be independently selected from deuterium.

[0213] In some embodiments, the R 3a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3cR 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-3 Alkylene C(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene C(O)OR 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkyl SO2R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, 3-6 membered cycloalkyl, 4-7 membered heterocyclic group, phenyl, 4-7 membered heterocyclic group C 1-3 Alkylene, 5-6 membered heteroaryl, 3-6 membered cycloalkyl C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 In some embodiments, the R 3a independently selected from optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), or =C(C 1-4 Alkyl)2.

[0214] In some embodiments, the R 3a Independently selected from halogen, -OH, oxo, -NH2, -CN, -NR 3c C(O)R 3d 、-OC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 In some embodiments, R 3a independently selected from optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-4 alkyl), or =CH(C 1-4 In some embodiments, the R 3a independently selected from optionally one or more R 3b In some embodiments, the R 3a They may also be independently selected from deuterium.

[0215] In some embodiments, the R 3a Independently selected from deuterium, F, Cl, Br, -OH, oxo, -NH2, -CN, -NR 3c C(O)R 3d 、-OC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted groups such as methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, phenyl, benzyl, pyrazolylmethyl, or oxazolidinonemethyl, =NH, =CH2, or

[0216] In some embodiments, the R 3a Independently selected from F, Cl, Br, -OH, oxo, -NH2, -CN, -NR 3c C(O)R 3d 、-OC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b substituted with methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, phenyl, benzyl, pyrazolylmethyl, or oxazolidinonemethyl. 3a independently selected from optionally one or more R 3b Substituted with the following groups: =NH or =CH2. In some embodiments, the R 3aindependently selected from optionally one or more R 3b Replaced In some embodiments, the R 3a They may also be independently selected from deuterium.

[0217] In some embodiments, the R 3a independently selected from optionally one or more R 3b Substituted =CH2.

[0218] In some embodiments, the R 3a Independently selected from F, -C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d , methyl, methoxy, =CH2, =CH2 substituted by halogen, deuterium, -NH2, dimethylamino, or dimethylaminomethylene.

[0219] In some embodiments, the R 3a Independently selected from F, -C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d , methyl, or methoxy. In some embodiments, the R 3a In some embodiments, the R 3a Independently selected from In some embodiments, the R 3a Independently selected from deuterium, -NH2, dimethylamino, dimethylaminomethylene.

[0220] In some embodiments, the R 3a independently selected from F, -CH2OC(O)R 3d 、-CH2OC(O)NR 3c R 3d , methyl, methoxy, =CH2, =CHF, =CF2, deuterium, -NH2, dimethylamino, or dimethylaminomethylene.

[0221] In some embodiments, the R 3a independently selected from F, -CH2OC(O)R 3d 、-CH2OC(O)NR 3c R 3d , methyl, or methoxy. In some embodiments, the R3a In some embodiments, the R 3a Independently selected from In some embodiments, the R 3a In some embodiments, the R 3a are independently selected from deuterium, F, or methyl.

[0222] In some embodiments, the R 3c are independently selected from H, deuterium, or methyl.

[0223] In some embodiments, the R 3c They may also be independently selected from deuterium.

[0224] In some embodiments, the R 3c Independently selected from H, or methyl.

[0225] In some embodiments, the R 3c Independently selected from H.

[0226] In some embodiments, the R 3d independently selected from H, deuterium, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-3 Alkylene, 5-10 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0227] In some embodiments, the R 3d They may also be independently selected from deuterium.

[0228] In some embodiments, the R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-3 Alkylene, 5-10 membered heterocyclic group C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene.

[0229] In some embodiments, the R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered arylC 1-6 Alkylene, 5-10 membered heteroaryl, or 5-10 membered heteroarylC 1-6 Alkylene.

[0230] In some embodiments, the R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 4-8 membered heterocycloalkyl, phenyl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0231] In some embodiments, the R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy C 1-3 alkylene, phenyl, benzyl, pyrazolyl, pyridinyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, or morpholinyl.

[0232] In some embodiments, the R 3d independently selected from H, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy C 1-3 alkylene, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, or morpholinyl.

[0233] In some embodiments, the R 3d Independently selected from H, C 1-4 Alkyl, or optionally one or more R 3e Substituted: tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0234] In some embodiments, the R 3d independently selected from H, methyl, or optionally substituted by one or more R 3e Substituted: tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0235] In some embodiments, the R 3d are independently selected from H, deuterium, methyl, tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0236] In some embodiments, the R 3d Independently selected from H, methyl, tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0237] In some embodiments, the R 3e Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, methyl, ethyl, trifluoromethyl, or difluoromethyl.

[0238] In some embodiments, the R 3e It can also be selected from deuterium.

[0239] In some embodiments, the R 3e Independently selected from -F, -Cl, -Br, -OH, oxo, methyl, ethyl, trifluoromethyl, or difluoromethyl.

[0240] In some embodiments, the R 3e Independently selected from -F, -Cl, -OH, oxo, methyl, or trifluoromethyl.

[0241] In some embodiments, the R 3b Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0242] In some embodiments, the R 3b They may also be independently selected from deuterium.

[0243] In some embodiments, the R 3b Independently selected from -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0244] In some embodiments, the R 3b Independently selected from -F, -Cl, -NH2, methyl, methoxy, methylamino, or dimethylamino.

[0245] In some embodiments, the R 3 Selected from H, deuterium, methyl,

[0246] In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 Selected from In some embodiments, the R 3 In some embodiments, the R 3 Selected from

[0247] In some embodiments, the R 4 Selected from H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0248] In some embodiments, the R 4 Selected from deuterium.

[0249] In some embodiments, the R 4 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0250] In some embodiments, the R 4 Selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 haloalkoxy, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0251] In some embodiments, the R 4 Selected from H, halogen, -CN, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Halogenated alkoxy.

[0252] In some embodiments, the R 4 Selected from H, -F, -Cl, -Br, -CN, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Haloalkyl, or C 1-2 Halogenated alkoxy.

[0253] In some embodiments, the R 4 Selected from H, -F, -Cl, -Br, C 1-2 Alkyl, C 1-2 Alkoxy, or C 1-2 Fluoroalkyl.

[0254] In some embodiments, the R 4 is selected from H, deuterium, -F, -Cl, -Br, methyl, methoxy, difluoromethyl, or trifluoromethyl.

[0255] In some embodiments, the R 4 is selected from H, -F, -Cl, -Br, methyl, methoxy, difluoromethyl, or trifluoromethyl.

[0256] In some embodiments, the R 4 is selected from H, -F, -Cl, or methyl.

[0257] In some embodiments, the R 4 is selected from H, -F, or -Cl.

[0258] In some embodiments, the ring A is selected from the group consisting of 5 Substituted: 3-6 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0259] In some embodiments, the ring A is selected from the group consisting of 5 Substituted: 6-10 membered aryl, benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, or 5-10 membered heteroaryl.

[0260] In some embodiments, the ring A is selected from the group consisting of 5Substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzopyrimidinyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl.

[0261] In some embodiments, the ring A is selected from the group consisting of 5 substituted with phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, or benzopyrimidinyl. In some embodiments, the ring A is selected from the group consisting of phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, or benzopyrimidinyl. 5 In some embodiments, the ring A is selected from the group consisting of: 5 Substituted: pyridopyrazolyl, or pyridopyrrolyl.

[0262] In some embodiments, the ring A is selected from the group consisting of 5 substituted with phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, or isoquinolinyl. In some embodiments, the ring A is selected from the group consisting of phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, or isoquinolinyl. 5 In some embodiments, the ring A is selected from the group consisting of: 5 Substituted pyrazolyl, pyridopyrazolyl, or pyridopyrrolyl.

[0263] In some embodiments, the ring A is selected from the group consisting of 5 In some embodiments, the ring A is selected from the group consisting of phenyl, naphthyl, pyridyl, benzothiazolyl, or benzothiophenyl. 5 In some embodiments, the ring A is selected from the group consisting of: 5 Substituted: benzopyrazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolinyl, indolyl, or benzimidazolyl.

[0264] In some embodiments, the ring A is selected from the group consisting of 5In some embodiments, the ring A is selected from the group consisting of phenyl, naphthyl, or pyridyl, optionally substituted with one or more R 5 In some embodiments, the ring A is selected from the group consisting of: 5 Substituted benzopyrazolyl, benzothiazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolinyl, indolyl, or benzimidazolyl.

[0265] In some embodiments, the ring A is selected from the group consisting of 5 Substituted as follows: phenyl or naphthyl.

[0266] In some embodiments, each of said R 5 independently selected from deuterium, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl.

[0267] In some embodiments, each of said R 5 It can also be selected from deuterium.

[0268] In some embodiments, each of said R 5 independently selected from halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl.

[0269] In some embodiments, each of said R 5 independently selected from -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R 5asubstituted by: methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, methylamino, dimethylamino, methylthio, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. 5 independently selected from optionally one or more R 5a Substituted propynyl.

[0270] In some embodiments, each of said R 5 Independently selected from -F, -Cl, -OH, -NH2, or optionally replaced by one or more R 5a substituted with methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, methylthio, or cyclopropane. 5 In some embodiments, each of R 5 independently selected from optionally one or more R 5a Substituted propynyl.

[0271] In some embodiments, each of said R 5 R is independently selected from -F, -Cl, -OH, -NH2, methyl, ethyl, isopropyl, vinyl, ethynyl, trifluoromethyl, hydroxymethylene, methoxy, trifluoromethoxy, methylamino, dimethylamino, methylthio, trifluoromethylthio, or cyclopropane optionally substituted with -F, -Cl, -Br, or methyl. In some embodiments, each R 5 In some embodiments, each of R 5 are independently selected from propynyl.

[0272] In some embodiments, each of said R 5 Independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, trifluoromethyl, trifluoromethoxy, methylthio, or methyl-substituted cyclopropane, -CN, methoxy, propynyl, dimethylamino.

[0273] In some embodiments, each of said R 5 In some embodiments, each R is independently selected from -F, -Cl, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, trifluoromethyl, trifluoromethoxy, methylthio, or methyl substituted cyclopropane. 5 In some embodiments, each of R 5 In some embodiments, each of R 5 In some embodiments, each of R 5 Independently selected from dimethylamino.

[0274] In some embodiments, the R 5a Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0275] In some embodiments, the R 5a It can also be selected from deuterium.

[0276] In some embodiments, the R 5a Independently selected from -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino.

[0277] In some embodiments, the R 5a Independently selected from -F, -Cl, -Br, -NH2, methyl, methoxy, methylamino, or dimethylamino.

[0278] In some embodiments, the R 5a Independently selected from -F, -Cl, -Br, or methyl.

[0279] In some embodiments, the ring A is selected from

[0280] In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from In some embodiments, the ring A is selected from

[0281] In some embodiments, the C 1-12 Selected from C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 .

[0282] In some embodiments, the C 1-6 Alkyl is selected from C 1-4 Alkyl, C1-3 Alkyl, or C 1-2 alkyl.

[0283] In some embodiments, the C 1-6 Alkylene is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0284] In some embodiments, the halogen is selected from F, Cl, Br, or I.

[0285] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0286] In some embodiments, the one or more are selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the one or more are selected from 1, 2, 3, 4, or 5. In some embodiments, the one or more are selected from 1, 2, 3, or 4. In some embodiments, the one or more are selected from 1, 2, or 3.

[0287] In some embodiments, the 3-12-membered is selected from 3-10-membered, 3-6-membered, 5-6-membered, 5-8-membered, or 5-10-membered.

[0288] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N, O, or S.

[0289] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N or O.

[0290] In some embodiments, the heteroalkylene group contains 1 N atom and 1 O atom.

[0291] In some embodiments, the heteroalkylene group contains 1 N atom.

[0292] In some embodiments, the heteroalkylene group contains 1 O atom.

[0293] In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0294] In some embodiments, the heterocycloalkyl group contains 1 N atom.

[0295] In some embodiments, the heterocycloalkyl group contains 1 O atom.

[0296] In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.

[0297] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 heteroatoms selected from N, O, or S.

[0298] In some embodiments, the heterocyclyl or heteroaryl group contains 1 or 2 N atoms.

[0299] In some embodiments, the heterocyclyl or heteroaryl group contains 1 N atom and 1 O atom.

[0300] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.

[0301] In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic, spirocyclic, fused, or bridged ring. In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic or spirocyclic ring. In some embodiments, the heterocyclyl or heterocycloalkyl group includes a monocyclic or bridged ring.

[0302] In some embodiments,

[0303] X is selected from -N-, -CH- or -C(C 1-3 alkyl)-;

[0304] L 1 Selected from -S-, -O-, -NH-, -N(C 1-3 alkyl)-, or optionally replaced by one or more R 1 Substituted with the following groups: C 1-4 Alkylene, or C 1-4 heteroalkylene;

[0305] Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 haloalkylamino;

[0306] R 2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl-L 2-, 4-10 membered heterocycloalkyl-L 2 -, 6-10 membered aryl-L 2 -, benzo 4-6 membered heterocyclic group-L 2 -, or 5-10 membered heteroaryl-L 2 -;

[0307] L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0308] Each R 2a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 Alkylene OC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0309] R 2c Independently selected from H, deuterium, or C 1-6 alkyl;

[0310] R 2d independently selected from H, deuterium, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0311] Each R 2e independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0312] Each R 2b independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0313] Z is selected from a single bond, -S-, -O-, -NH-, or -N(C1-3 alkyl)-;

[0314] R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocycloalkyl C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, benzo 4-6 membered heterocyclic group C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 alkylene;

[0315] Each R 3a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-3 Alkylene C(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene C(O)OR 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3Alkylene SO2R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C 1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl C 1-3 Alkylene, optionally oxo-substituted 4-7 membered heterocycloalkyl C 1-3 alkylene;

[0316] R 3c Independently selected from H, deuterium, or C 1-6 alkyl;

[0317] R 3d Independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy C 1-3 Alkylene, or optionally one or more R 3e Substituted groups: phenyl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl, or 4-8 membered heterocycloalkyl;

[0318] Each R 3b independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0319] Each R 3e Independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0320] R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0321] Ring A is selected from the group consisting of 5 Substituted groups include: 6-10 membered aryl, 4-6 membered benzocycloalkenyl, 4-6 membered benzo heterocyclyl, or 5-10 membered heteroaryl;

[0322] Each R 5 independently selected from deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, or optionally substituted by halogen or C 1-3 Alkyl-substituted 3-7 membered cycloalkyl.

[0323] In some embodiments,

[0324] X is selected from -N-, -CH- or -C(C 1-3 alkyl)-;

[0325] L 1 Selected from -S-, -O-, -NH-, -N(C 1-3 alkyl)-, or optionally replaced by one or more R 1 Substituted with the following groups: C 1-4 Alkylene, or C 1-4 heteroalkylene;

[0326] Each R 1 are independently selected from oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 haloalkylamino;

[0327] R 2 is selected from H, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocycloalkyl-L 2 -, 6-10 membered aryl-L 2-, benzo 4-6 membered heterocyclic group-L 2 -, or 5-10 membered heteroaryl-L 2 -;

[0328] L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0329] Each R 2a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 Alkylene OC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6 Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0330] R 2c Independently selected from H, or C 1-6 alkyl;

[0331] R 2d independently selected from H, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene;

[0332] Each R 2e independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0333] Each R 2b independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0334] Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;

[0335] R 3selected from H or optionally one or more R 3a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocycloalkyl C 1-3 Alkylene, 6-10 membered aryl C 1-3 Alkylene, benzo 4-6 membered heterocyclic group C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 alkylene;

[0336] Each R 3a independently selected from halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-3 Alkylene C(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)R 3d 、-C 1-3 Alkylene NHC(O)NR 3c R 3d 、-C 1-3 Alkylene NR 3c C(O)OR 3d 、-C 1-3 Alkylene OC(O)R 3d 、-C 1-3 Alkylene C(O)OR 3d 、-C 1-3 Alkylene OC(O)NR 3c R 3d 、-C 1-3 Alkylene SO2R 3d 、-C 1-3 Alkylene OSO2R 3d 、-C1-3 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, phenyl, 5-6 membered heteroaryl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl C 1-3 Alkylene, optionally oxo-substituted 4-7 membered heterocycloalkyl C 1-3 alkylene;

[0337] R 3c Independently selected from H, or C 1-6 alkyl;

[0338] R 3d Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy C 1-3 Alkylene, or optionally one or more R 3e Substituted groups: phenyl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl, or 4-8 membered heterocycloalkyl;

[0339] Each R 3b independently selected from halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino;

[0340] Each R 3e Independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0341] R 4 Selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy;

[0342] Ring A is selected from the group consisting of 5 Substituted groups include: 6-10 membered aryl, 4-6 membered benzocycloalkenyl, 4-6 membered benzo heterocyclyl, or 5-10 membered heteroaryl;

[0343] Each R 5 independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, or optionally substituted by halogen or C 1-3 Alkyl-substituted 3-7 membered cycloalkyl.

[0344] In some embodiments, the R 3a independently selected from optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), or =C(C 1-4 Alkyl)2.

[0345] The present disclosure relates to compounds of formula (II-1), (II-2), (III), (III-a), (III-b), (III-c), (IV), (IV-a), (IV-b), (IV-c), stereoisomers thereof, tautomers thereof, deuterated compounds thereof, or pharmaceutically acceptable salts thereof,

[0346] Among them, L 1 、R 1 、R 2 、R 3 、R 4 , Z, and Ring A moiety are as defined above; n is selected from 0, 1, 2, 3, 4 or 5.

[0347] In some embodiments, n is selected from 0, 1, 2, or 3.

[0348] In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0349] In some embodiments, "one or more" in the present disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, or three.

[0350] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0351] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0352] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0353] On the other hand, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or (II-1) or (II-2) or (III) or (III-a) or (III-b) or (III-c) or (IV) or (IV-a) or (IV-b) or (IV-c) of the present disclosure, a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0354] On the other hand, the present disclosure relates to a method for treating a mammalian disease, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula (I) or (II-1) or (II-2) or (III) or (III-a) or (III-b) or (III-c) or (IV) or (IV-a) or (IV-b) or (IV-c), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0355] On the other hand, the present disclosure relates to the use of a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), its stereoisomers, its tautomers, its deuterated compounds, or its pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure in the preparation of drugs for treating diseases.

[0356] On the other hand, the present disclosure relates to the use of a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), its stereoisomers, its tautomers, its deuterated compounds, or its pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure in treating diseases.

[0357] On the other hand, the present disclosure relates to a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), a stereoisomer thereof, a deuterated compound thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

[0358] In some embodiments of the present disclosure, the disease is preferably a Kras-related disease.

[0359] On the other hand, the present disclosure relates to a method for treating a Kras-related disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula (I) or (II-1) or (II-2) or (III) or (III-a) or (III-b) or (III-c) or (IV) or (IV-a) or (IV-b) or (IV-c), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0360] On the other hand, the present disclosure relates to the use of a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), its stereoisomers, its tautomers, its deuterated compounds, or its pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure in the preparation of a medicament for treating Kras-related diseases.

[0361] On the other hand, the present disclosure relates to the use of a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), its stereoisomers, its tautomers, its deuterated compounds, or its pharmaceutically acceptable salts, or the pharmaceutical compositions of the present disclosure in treating Kras-related diseases.

[0362] On the other hand, the present disclosure relates to a compound of formula (I) or formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or (III-b) or (III-c) or formula (IV) or (IV-a) or (IV-b) or (IV-c), a stereoisomer thereof, a deuterated compound thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating Kras-related diseases.

[0363] In some embodiments of the present disclosure, the Kras-related disease is preferably a Kras-mutated cancer.

[0364] In some embodiments of the present disclosure, the Kras-associated disease is selected from cancer (eg, pancreatic cancer).

[0365] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12D Related diseases.

[0366] In some embodiments of the present disclosure, the Kras G12D Related diseases are preferably Kras G12D Mutated cancer.

[0367] In some embodiments of the present disclosure, the Kras G12D The related disease is selected from cancer (eg pancreatic cancer).

[0368] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12V Related diseases.

[0369] In some embodiments of the present disclosure, the Kras G12VRelated diseases are preferably Kras G12V Mutated cancer.

[0370] In some embodiments of the present disclosure, the Kras G12V The related disease is selected from cancer (eg pancreatic cancer).

[0371] Technical Effects

[0372] The compounds disclosed herein have high Kras inhibitory activity (e.g., Kras G12D and / or Kras G12V The invention also has the advantages of high activity, such as nucleotide exchange inhibition activity, cell proliferation inhibition activity (such as Aspc-1 cells and / or Capan-1 cells) and in vivo tumor inhibition activity (such as Aspc-1 human pancreatic cancer cell NOD-SCID mouse subcutaneous transplant tumor model), and shows good drugability in in vitro and in vivo pharmacokinetic, bioavailability and / or pharmacodynamic studies.

[0373] definition

[0374] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0375] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0376] Non-limiting examples of “substituents” as described herein include hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkyl, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., wherein the group is optionally Substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0377] The term "substituted" means that a specific atom or group can be replaced by a specified other atom or group. For example, one, two, or three -CH2- in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, etc.

[0378] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0379] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0380] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0381] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0382] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0383] When the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ALZ, the linking group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0384] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0385] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0386] The term "hydroxy" refers to an -OH group.

[0387] The term "cyano" refers to a -CN group.

[0388] The term "mercapto" refers to a -SH group.

[0389] The term "amino" refers to a -NH2 group.

[0390] The term "nitro" refers to a -NO2 group.

[0391] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched chain divalent hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C 1-6"Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0392] Term " heteroalkylene " refers to the alkylene group wherein one or more carbon atoms (and the hydrogen atom connected thereto) are each independently replaced by the same or different heteroatom groups.Unless otherwise indicated, the heteroalkylene group comprises 1, 2 or 3 heteroatom groups, and the heteroatom groups non-limiting examples include O, S, N or NH, typically with 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.For example, term " C1-6 heteroalkylene group " refers to the heteroalkylene group containing 1 to 6 carbon atoms and 1-3 heteroatom groups.The heteroatom groups can be placed in any position (for example, inside or end position) of heteroalkylene group, including the position in which alkylene group is connected to the rest of the molecule.Usually, in the presence of more than a heteroatom group, the heteroatoms are not adjacent to each other. Non-limiting examples of heteroalkylene include, but are not limited to, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2OCH2-, -OCH2O-, -OCH2CH2O-, -OCH2OCH2CH2-, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -CH2SCH2-, -SCH2S-, -SCH2CH2S-, -SCH2SCH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -CH2NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -OCH2NH-, -OCH2CH2NH-, -OCH2NHCH2CH2-, -OCH2N(CH3)CH2-, and the like. The heteroalkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0393] The term "alkyl" refers to a group of the formula C n H 2n+1 The saturated hydrocarbon group typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The alkyl group can be straight or branched and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0394] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms attached thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Heteroalkyl" refers to a heteroalkyl group containing from 1 to 6 carbon atoms and from 1 to 3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal), including the position at which the heteroalkyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0395] The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0396] The term "alkylamino" refers to an -NH-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0397] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0398] The term "alkylsulfonyl" refers to an -SO2-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0399] The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0400] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0401] The term "alkenylene" refers to a divalent form of an alkenyl group. The alkenylene group typically has 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Non-limiting examples of alkenylene groups include, but are not limited to, vinylene, 1-propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, etc. The alkenylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0402] The term "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms (and their associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkenyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4"Heteroalkenyl" refers to a heteroalkenyl group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenyl group (e.g., internal or terminal), including the position at which the heteroalkenyl group is attached to the rest of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenyl groups include, but are not limited to, CH2=N-, alkenyl-O-, alkenyl-NH-, alkenyl-S-, alkenyl-O-alkylene-, alkyl-O-alkenylene-, alkenyl-NH-alkylene-, alkyl-NH-alkenylene-, alkenyl-S-alkylene-, alkyl-S-alkenylene-, Alkenyl-CH=N-, alkenyl-N=CH-, alkyl-CH=N-alkenylene-, alkenyl-CH=N-alkylene-, or alkyl-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenyl group is a carbon-carbon double bond. The heteroalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0403] The term "heteroalkenylene" refers to the divalent form of heteroalkenyl. Unless otherwise indicated, the heteroalkenylene contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, and typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. For example, the term "C 1-4“Heteroalkenylene” refers to a heteroalkenylene group containing 1 to 4 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkenylene group (e.g., internal or terminal), including the position at which the heteroalkenylene group is attached to the remainder of the molecule. Typically, when more than one heteroatom group is present, the heteroatom groups are not adjacent to each other. Exemplary heteroalkenylene groups include, but are not limited to, -alkenylene-O-, -alkenylene-NH-, -alkenylene-S-, -alkenylene-O-alkylene-, -alkylene-O-alkenylene-, -alkenylene-NH-alkylene-, -alkylene-NH-alkenylene-, -alkenylene-S-alkylene-, -alkylene-S-alkenylene -, -alkenylene-CH=N-, -alkenylene-N=CH-, -alkylene-CH=N-alkenylene-, -alkenylene-CH=N-alkylene-, or -alkylene-NH-alkenylene-O-. In some embodiments, the double bond in the heteroalkenylene is a carbon-carbon double bond. The heteroalkenylene is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0404] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0405] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0406] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocycle, bridged ring or spirocycle. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 ring, a 4 to 8 ring, a 5 to 8 ring or a 5 to 6 ring. Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl etc. The cycloalkenyl is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl,-C (O) O-alkyl,-OC (O)-alkyl,-C (O) NH ,-C (O) NH-alkyl,-C (O) N (alkyl) ,-NHC (O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0407] Term " heterocyclic radical " refers to fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can be with monocycle, bridged ring, and ring or spirocyclic non-aromatic ring.Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan of heteroatoms (preferably 1 or 2 heteroatoms) containing 1 to 3 independently selected from sulphur, oxygen, nitrogen, phosphorus, silicon and / or boron.The limiting examples of heterocyclic radical include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N- methylpyrrolidinyl, dihydropyrrolyl, piperidyl, piperazinyl, pyrazolidinyl, 4H- pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)- Alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0408] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3-12-membered, 3-10-membered, 4-8-membered, 5-8-membered, 5-6-membered, 3-7-membered, or 4-6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethanethiol, and aziridinyl groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. The heterocycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O) -alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0409] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0410] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7, or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or a plurality of fused rings containing 5 to 14, especially 5 to 10, ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0411] The group -L in the present disclosure1 -optionally adopts the reading order from left to right, corresponding to the lower side group and the right side group connected to the group in the general formula, for example, when -L 1 When - is -OCH2CH2-, the structure The corresponding

[0412] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0413] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0414] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0415] The term "preventing" or "preventing" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0416] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0417] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0418] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0419] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0420] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0421] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0422] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0423] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0424] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0425] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0426] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0427] The compounds of the present disclosure may have one or more atropisomers. Unless otherwise specified, atropisomers refer to optically active isomers resulting from the obstruction of free rotation between single bonds. The compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation between single bonds of the compounds of the present disclosure containing a chiral axis is sufficiently high, the atropisomers can be isolated in optically pure form.

[0428] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0429] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0430] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0431] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, and the like for oral administration to a patient.

[0432] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0433] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0434] In all administration methods of the compounds of formula I described herein, the daily dosage is 0.01 to 200 mg / kg body weight. 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 synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0435] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0436] The compound of formula (III) disclosed herein can be prepared by those skilled in the art of organic synthesis via route 1, wherein PG is independently selected from a suitable common protecting group, such as tert-butyloxycarbonyl; R 2 、R 3 、R 4 , Z and Ring A moiety are as defined above.

[0437] Each product obtained by the reaction in the above-mentioned route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to, Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this disclosure can be obtained as single isomers or mixtures of isomers using synthetic methods.

[0438] This disclosure uses the following abbreviations:

[0439] TsOH stands for p-toluenesulfonic acid; DMF stands for N,N-dimethylformamide; Boc stands for tert-butyloxycarbonyl; TIPS stands for triisopropylsilyl; MOM stands for methoxymethyl; DMSO stands for dimethyl sulfoxide; TBS stands for tert-butyldimethylsilyl; DIPEA stands for diisopropylethylamine; THF stands for tetrahydrofuran; PMB stands for p-methoxybenzyl; and FA stands for formic acid.

[0440] Commercially available compounds were referred to by their supplier catalog names.

[0441] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail herein and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0442] All reagents used in this disclosure were commercially available and used without further purification. Example

[0443] Example 1

[0444] Step 1:

[0445] Compound SM1 (50 g), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (119.5 g), methanol (450 mL), and H2O (90 mL) were added to the reaction flask. After stirring evenly, the mixture was heated to 45°C and stirred for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 1a was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 8:1) to obtain compound 1a. LC-MS: m / z = 181.01 (M+H) +

[0446] Step 2:

[0447] Compound 1a (60 g), N-iodosuccinimide (90 g), TsOH. H2O (3.2 g) and acetonitrile (600 mL) were stirred evenly, then heated to 70°C and stirred for 4 h. The reaction solution was concentrated to dryness under reduced pressure, and 1 L of ethyl acetate was added to the residue for dissolution. The residue was washed with sodium thiosulfate solution, sodium bicarbonate solution, and brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1b. LC-MS: m / z = 306.84 (M+H) +

[0448] Step 3:

[0449] Compound 1b (100 g), CuCN (45 g), and DMF (1000 mL) were added to the reaction flask, stirred evenly, and then heated to 100°C and stirred for 12 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. 1 L of ethyl acetate was added to the residue, stirred, and filtered. The filtrate was washed with ammonia and brine, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1c. LC-MS: m / z = 206.07 (M+H) +

[0450] Step 4:

[0451] NaOH (19.4 g) and H2O (270 mL) were added to the reaction flask, stirred to dissolve, and then compound 1c (25 g) was added. The temperature was raised to 80°C and stirred for 10 h. The reaction solution was cooled to room temperature and the pH was adjusted to acidic by dropwise addition of concentrated hydrochloric acid in an ice bath. A large amount of solid precipitated, which was filtered and the filter cake was dried under reduced pressure to obtain compound 1d. LC-MS: m / z = 225.07 (M+H) +

[0452] Step 5:

[0453] Compound 1d (10.7 g) and thionyl chloride (100 mL) were added to the reaction flask, stirred evenly, and then heated to 50°C for reaction. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, acetone (90 mL) was added and stirred to dissolve, and the solution was added dropwise to ammonium thiocyanate solution (10.84 g / 150 mL) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:50 to 1:10) to obtain compound 1e. LC-MS: m / z = 264.16 (MH) -

[0454] Step 6:

[0455] Compound 1e (9.3 g), methanol (300 mL), and aqueous sodium hydroxide solution (2.8 g / 30 mL) were added to the reaction flask and stirred until uniform. Methyl iodide (9.9 g) was then added and stirred at room temperature for 6 h. The reaction solution was adjusted to a neutral pH, concentrated to dryness under reduced pressure, and then purified by column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:2) to obtain compound 1f. LC-MS: m / z = 279.97 (M+H) +

[0456] Step 7:

[0457] N-Boc-ethanolamine (13.7 g), lithium hydride (0.68 g), and DMF (21 mL) were added to the reaction flask and reacted at room temperature for 30 minutes. Compound 1f (2.8 g) and DMF (70 mL) were then added. After stirring evenly, the mixture was heated to 60°C and stirred for 4 hours. After addition of 1 L of water, the pH was adjusted to neutral and filtered. The filter cake was purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:3) to obtain compound 1g. LC-MS: m / z = 305.03 (M+H-Boc+H) +

[0458] Step 8:

[0459] Compound 1g (12.3g) and hydrochloric acid ethyl acetate solution (123mL) were added to the reaction flask, stirred evenly, reacted at room temperature overnight, and then filtered. The filter cake was dried under reduced pressure to obtain compound 1h. LC-MS: m / z = 305.03 (M+H) +

[0460] Step 9:

[0461] Compound 1h (6.8 g), benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (12.5 g), triethylamine (10.1 g), and 1,4-dioxane (680 mL) were added to the reaction flask and stirred evenly in an ice-water bath. The mixture was then stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain compound 1i. LC-MS: m / z = 287.03 (M+H) +

[0462] Step 10:

[0463] Compound 1i (524 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.33 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (210 mg), tripotassium phosphate (1160 mg), 1,4-dioxane (100 mL), and purified water (20 mL) were added to the reaction flask. After nitrogen replacement three times, the mixture was stirred at room temperature and heated to 90°C for 10 h. After the reaction, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 1j was purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain compound 1j. LC-MS: m / z = 637.36 (M+H) +

[0464] Step 11:

[0465] Compound 1j (1010 mg), m-chloroperbenzoic acid (800 mg), and dichloromethane (200 mL) were added to a reaction flask and stirred evenly in an ice-water bath. The mixture was then allowed to react at room temperature for 1 h. After the reaction was complete, a 10% aqueous sodium thiosulfate solution (100 mL) was added to the flask, stirred, and separated. The organic phase was collected and concentrated to dryness under reduced pressure. Compound 1k was purified by column chromatography (methanol:dichloromethane = 1:500 to 1:100) to obtain compound 1k. LC-MS: m / z = 669.37 (M+H). +

[0466] Step 12:

[0467] Compound 1k (360 mg), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (420 mg), a 1N tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (2.7 mL), and tetrahydrofuran (150 mL) were added to the reaction flask. The mixture was stirred evenly in an ice-water bath and then allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride (100 mL) was added to the reaction system and stirred to separate the liquids. The organic phase was collected and concentrated to dryness under reduced pressure. Compound 1l was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 11. LC-MS: m / z = 748.44 (M+H) +

[0468] Step 13:

[0469] Compound 11 (150 mg), cesium fluoride (302 mg), and DMF (15 mL) were added to the reaction flask and stirred at room temperature for 2 h. The reaction solution was added to 100 mL of water and 100 mL of ethyl acetate, stirred, and separated. The organic phase was collected and concentrated to dryness under reduced pressure. The compound 1m was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 1m. LC-MS: m / z = 592.26 (M+H) +

[0470] Step 14:

[0471] Compound 1m (133 mg) and ethyl acetate (20 mL) were added to the reaction flask and stirred at 0-5°C for 5 min. Then, a hydrochloric acid-ethyl acetate solution (2 mL) was added dropwise to the reaction system and allowed to react at 0-5°C for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC C18 10 μm 30*250 column; acetonitrile-30 mM ammonium acetate (5%-5%-60% / 0-5-60 min gradient elution). Compound 1 (35 mg, Rt = 36.4 min) was obtained by desalting and purification using a preparative liquid chromatography (YMC C18 10 μm 30*250 column; acetonitrile-0.1% formic acid (10%-10%-70% / 0-5-60 min gradient elution). LC-MS: m / z = 548.24 (M+H). +

[0472] 1 H NMR(500MHz,d-DMSO)δ9.190(s,1H),7.966-7.936(m,1H),7.451(t,1H),7.367(d,1H),7.157(d,1H),5. 288(d,1H),4.495(t,2H),4.122-4.023(m,3H),3.703(t,2H),3.163-3.066(m,3H),2.891-2.831(m,1H), 2.171-2.063(m,2H),2.031-1.962(m,1H),1.910-1.766(m,3H).

[0473] Example 2

[0474] Step 1:

[0475] Compound 11 (150 mg), 2-(dimethylamino) iodoethane hydroiodide (196 mg), cesium carbonate (455 mg), and acetone (15 mL) were added to the reaction flask and stirred at room temperature. The temperature was then raised to 60°C and reacted for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 2a. LC-MS: m / z = 819.52 (M+H) +

[0476] Step 2:

[0477] Compound 2a (164 mg), cesium fluoride (302 mg), and DMF (15 mL) were added to the reaction flask and stirred at room temperature for 2 h. The reaction solution was added to 100 mL of water and 100 mL of ethyl acetate, stirred, and separated. The organic phase was collected, concentrated to dryness under reduced pressure, and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 2b. LC-MS: m / z = 663.35 (M+H) +

[0478] Step 3:

[0479] Compound 2b (133 mg) and ethyl acetate (20 mL) were added to the reaction flask and stirred at 0-5°C for 5 min. Then, a hydrochloric acid-ethyl acetate solution (2 mL) was added dropwise to the reaction system and allowed to react at 0-5°C for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC C18 10 μm 30*250 column; acetonitrile-30 mM ammonium acetate (5%-5%-60% / 0-5-60 min gradient elution). Compound 2 (8 mg, Rt = 33.3 min) was obtained by further preparative liquid chromatography (YMC C18 10 μm 30*250 column; acetonitrile-0.1% formic acid (10%-10%-70% / 0-5-60 min gradient elution). LC-MS: m / z = 619.29 (M+H). +

[0480] Example 3

[0481] Step 1:

[0482] Disperse 1j (318 mg), iodoethane (775 mg), and potassium carbonate (207 mg) in acetone (30 mL), heat to 60°C, and stir for 6 h. Cool the reaction mixture to room temperature, filter, and concentrate the filtrate until no liquid remains to obtain compound 3a. LC-MS: m / z = 665.35 (M+H) + .

[0483] Step 2:

[0484] Disperse 3a (190 mg) in dichloromethane (19 mL), cool to 0-5°C, add m-chloroperbenzoic acid (145 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (200 mL) to the reaction solution, extract with dichloromethane (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is released. Purify by column chromatography (methanol:dichloromethane = 1:500-1:100) to obtain compound 3b. LC-MS: m / z = 697.35 (M+H) + .

[0485] Step 3:

[0486] 3b (195 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (218 mg) were dispersed in tetrahydrofuran (20 mL). Under nitrogen, the temperature was lowered to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 1.4 mL) was added dropwise. The mixture was stirred at this temperature for 30 minutes, then brought to room temperature and stirred overnight. Saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. Compound 3c was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 3c. LC-MS: m / z = 776.45 (M+H). + .

[0487] Step 4:

[0488] Disperse 3c (170 mg) and cesium fluoride (320 mg) in DMF (17 mL) and stir at room temperature for 2 h. Add water (200 mL) and ethyl acetate (200 mL) to the reaction solution, stir, and separate. The organic phase is washed with 5% brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid remains to obtain compound 3d. LC-MS: m / z = 620.31 (M+H) + .

[0489] Step 5:

[0490] Disperse 3d (130 mg) in ethyl acetate (10 mL), cool to 0-5°C, and stir for 5 min. Add hydrogen chloride in ethyl acetate (4N, 1 mL) dropwise to the reaction system, and incubate for 1 h. After the reaction is complete, concentrate the reaction solution to dryness under reduced pressure and purify by column chromatography (methanol:dichloromethane = 1:20) to obtain compound 3. LC-MS: m / z = 576.29 (M+H) + .

[0491] 1 H-NMR(500MHz,DMSO-d6),δ:10.16(br,1H),7.95(dd,1H),7.45(t,1H),7.36(d,1H),7.14(d,1H),5.28(d,1H),4.52(t,2H),4 .14-3.89(m,6H),3.82-3.75(m,1H),3.13-3.00(m,3H),2.87-2.81(m,1H),2.14-1.97(m,3H),1.88-1.74(m,3H),1.25(t,3H).

[0492] Example 4

[0493] Step 1:

[0494] Disperse 1j (318 mg), 2-iodopropane (850 mg), and cesium carbonate (488 mg) in acetone (32 mL), heat to 60°C, and stir for 6 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated until no liquid flowed out. Compound 4a was purified by column chromatography (methanol:dichloromethane = 1:500) to obtain compound 4a. LC-MS: m / z = 679.38 (M+H). + .

[0495] Step 2:

[0496] Disperse 4a (270 mg) in dichloromethane (27 mL), cool to 0-5°C, add m-chloroperbenzoic acid (200 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (200 mL) to the reaction solution, extract with dichloromethane (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is released. Purify by column chromatography (methanol:dichloromethane = 1:500-1:100) to obtain compound 4b. LC-MS: m / z = 711.42 (M+H) + .

[0497] Step 3:

[0498] 4b (300 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (318 mg) were dispersed in tetrahydrofuran (30 mL). Under nitrogen, the temperature was lowered to 0°C, and a 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at this temperature for 30 minutes, then brought to room temperature and stirred for 1 hour. Saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. Compound 4c was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 4c. LC-MS: m / z = 790.48 (M+H). + .

[0499] Step 4:

[0500] Disperse 4c (252 mg) and cesium fluoride (482 mg) in DMF (25 mL) and stir at room temperature for 2 h. Add water (200 mL) and ethyl acetate (200 mL) to the reaction solution, stir and separate the liquids. The organic phase is washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid is discharged to obtain compound 4d. LC-MS: m / z = 634.37 (M+H) + .

[0501] Step 5:

[0502] 4d (203 mg) was dispersed in ethyl acetate (10 mL), cooled to 0-5°C, and stirred for 5 minutes. A 4N solution of hydrogen chloride in ethyl acetate (1 mL) was added dropwise to the reaction system, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 50*250 column; acetonitrile-0.1% formic acid aqueous solution (20%-50% / 0-60 min gradient elution) to afford compound 4. LC-MS: m / z = 590.28 (M+H)+.

[0503] 1 H-NMR(500MHz,DMSO-d6),δ:7.95(dd,1H),7.45(t,1H),7.37(s,1H),7.14(s,1H),5.44-5.38(m,1H),5.28(d,1H),4.54- 4.46(m,2H),4.15-3.72(m,6H),3.13-3.05(m,3H),2.87-2.83(m,1H),2.14-1.97(m,3H),1.88-1.74(m,3H),1.25(t,6H)

[0504] Example 5

[0505] Referring to the preparation process of compound 4 in Example 4, in step 1, 2-iodopropane was replaced with tert-butyl-(2-iodoethoxy)dimethylsilane to prepare compound 5. LC-MS: m / z=592.27 (M+H) + .

[0506] Example 6

[0507] Referring to the preparation process of compound 4 in Example 4, in step 1, (iodomethyl)cyclopropane was used to replace 2-iodopropane to prepare compound 6. LC-MS: m / z=602.29 (M+H) + .

[0508] Example 7

[0509] Referring to the preparation process of compound 4 in Example 4, in step 1, 2-iodopropane was replaced with iodocyclopentane to prepare compound 7. LC-MS: m / z=616.36 (M+H) + .

[0510] Example 8

[0511] Referring to the preparation process of compound 4 in Example 4, in step 1, 2-iodo-1,1,1-trifluoroethane was used instead of 2-iodopropane to prepare compound 8. LC-MS: m / z=630.29 (M+H) + .

[0512] Example 9

[0513] Step 1:

[0514] Disperse 1i (287 mg), iodomethane (1410 mg), and potassium carbonate (414 mg) in acetone (50 mL), heat to 60°C, and stir for 6 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated until no liquid flowed out. Compound 9a was purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain compound 9a. LC-MS: m / z = 301.03 (M+H) + .

[0515] Step 2:

[0516] 9a (301 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.28 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (115 mg), potassium phosphate (636 mg), and water (6 mL) were dispersed in 1,4-dioxane (30 mL) and stirred at 90°C for 10 h under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain compound 9b. LC-MS: m / z = 651.35 (M+H) + .

[0517] Step 3:

[0518] Disperse 9b (415 mg) in dichloromethane (80 mL), cool to 0-5°C, add m-chloroperbenzoic acid (320 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (200 mL) to the reaction solution, extract with dichloromethane (100 mL x 2). Combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is present. Purify by column chromatography (methanol:dichloromethane = 1:500-1:100) to obtain compound 9c. LC-MS: m / z = 683.47 (M+H) + .

[0519] Step 4:

[0520] 9c (437 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (511 mg) were dispersed in tetrahydrofuran (80 mL). Under nitrogen, the temperature was lowered to 0°C, and a 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.3 mL) was added dropwise. The mixture was stirred at this temperature for 30 min, then brought to room temperature and stirred overnight. Saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. The mixture was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to afford compound 9d. LC-MS: m / z = 762.57 (M+H) + .

[0521] Step 5:

[0522] Disperse 9d (360 mg) and cesium fluoride (710 mg) in DMF (36 mL) and stir at room temperature for 2 h. Add water (200 mL) and ethyl acetate (200 mL) to the reaction solution, stir, and separate. The organic phase is washed with 5% brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid remains to obtain compound 9e. LC-MS: m / z = 606.32 (M+H) + .

[0523] Step 6:

[0524] Disperse 9e (121 mg) in ethyl acetate (20 mL), cool to 0-5°C, and stir for 5 min. Add hydrogen chloride in ethyl acetate (4N, 2 mL) dropwise to the reaction system, and incubate for 1 h. After the reaction is complete, concentrate the reaction solution to dryness under reduced pressure and purify by column chromatography (methanol:dichloromethane = 1:20) to obtain compound 9. LC-MS: m / z = 562.26 (M+H) + .

[0525] Example 10

[0526] Step 1:

[0527] 10a (1.15 g), 10b (1 g), and potassium carbonate (2.05 g) were dispersed in DMF (10 mL) and stirred at room temperature for 12 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 10c. LC-MS: m / z = 359.37 (M+H) + .

[0528] Step 2:

[0529] Disperse 1f (5 g) in acetonitrile (100 mL), then add DIPEA (13.8 g) and POCl3 (8.19 g) sequentially. Heat to 80°C under nitrogen and stir for 2 h. After completion, cool the reaction mixture to room temperature, pour into ice water (500 mL), stir and crystallize for 30 min, and filter. The filter cake is dried under vacuum at 55°C for 6 h to yield compound 10d.

[0530] Step 3:

[0531] Compound 10d (1.6 g) was dispersed in THF (10 mL), and compound 10c (1.6 g) and DIPEA (2.3 g) were added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:20) to obtain compound 10e. LC-MS: m / z = 620.32 (M+H) + .

[0532] Step 4:

[0533] 10e (1.1 g) and cesium fluoride (5.4 g) were dispersed in DMF (10 mL), heated to 60°C, and stirred for 3 h. After the reaction was complete, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, stirred, and the liquid separated. The organic phase was washed with 10% brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid flowed out, and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:10) to obtain compound 10f. LC-MS: m / z = 470.24 (M+H) + .

[0534] Step 5:

[0535] 10f (0.8 g), 10g (1.7 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.2 g), potassium phosphate (1 g), and water (6.4 mL) were dispersed in 1,4-dioxane (32 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 2 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain compound 10h. LC-MS: m / z = 820.74 (M+H) + .

[0536] Step 6:

[0537] Disperse 10h (550 mg) in dichloromethane (50 mL), cool to 0-5°C, add m-chloroperbenzoic acid (290 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (200 mL) to the reaction solution, extract with dichloromethane (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out. Purify by column chromatography (methanol:dichloromethane = 1:500-1:100) to obtain compound 10i. LC-MS: m / z = 852.47 (M+H) + .

[0538] Step 7:

[0539] 10i (400 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (220 mg) were dispersed in tetrahydrofuran (5 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 1.2 mL) was added dropwise. The mixture was stirred for 30 min. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. The filtrate was purified by column chromatography (methanol:dichloromethane = 1:200 to 1:50) to obtain compound 10j. LC-MS: m / z = 931.60 (M+H) + .

[0540] Step 8:

[0541] 10j (600 mg) and cesium fluoride (2.16 g) were dispersed in DMF (12 mL) and stirred at room temperature for 2 h. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, stirred, and the mixture separated. The organic phase was washed with 5% brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid remained to obtain compound 10k. LC-MS: m / z = 775.48 (M+H) + .

[0542] Step 9:

[0543] 10k (500 mg) was dispersed in dichloromethane (10 mL), cooled to 0-5°C, and a 4N 1,4-dioxane solution (2 mL) was added dropwise to the reaction system. The mixture was incubated for 1 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 50×250 column; acetonitrile-0.1% formic acid aqueous solution (10%-40% / 0-60 min gradient elution) to obtain compound 10. LC-MS: m / z = 631.39 (M+H)+.

[0544] Example 11

[0545] Step 1:

[0546] 11a (0.57 g), 10b (2.29 g), and potassium carbonate (4.42 g) were dispersed in DMF (60 mL) and stirred at room temperature for 12 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 11b. LC-MS: m / z = 216.23 (M+H) + .

[0547] Step 2:

[0548] Compound 10d (0.6 g) was dispersed in acetonitrile (60 mL), and 11b (1.86 g) and DIPEA (1.03 g) were added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:20) to obtain compound 11c. LC-MS: m / z = 477.18 (M+H) + .

[0549] Step 3:

[0550] 11c (628 mg) and cesium fluoride (2 g) were dispersed in DMF (63 mL), heated to 60°C, and stirred for 3 h. After the reaction was complete, water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, stirred, and the liquids separated. The organic phase was washed with 10% brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was present and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:10) to obtain compound 11d. LC-MS: m / z = 327.12 (M+H) + .

[0551] Step 4:

[0552] 11d (378 mg), 10g (1.2 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (132 mg), potassium phosphate (735 mg), and water (8 mL) were dispersed in 1,4-dioxane (40 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 2 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:1) to obtain compound 11e. LC-MS: m / z = 677.29 (M+H) + .

[0553] Step 5:

[0554] Disperse 11e (540 mg) in dichloromethane (54 mL), cool to 0-5°C, add m-chloroperbenzoic acid (400 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (200 mL) to the reaction solution, extract with dichloromethane (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid outflows. Purify by column chromatography (methanol:dichloromethane = 1:500-1:100) to obtain compound 11f. LC-MS: m / z = 709.32 (M+H) + .

[0555] Step 6:

[0556] 11f (600 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (636 mg) were dispersed in tetrahydrofuran (60 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 4 mL) was added dropwise. The mixture was stirred for 30 min. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. The filtrate was purified by column chromatography (methanol:dichloromethane = 1:500 to 1:100) to obtain compound 11g. LC-MS: m / z = 788.44 (M+H) + .

[0557] Step 7:

[0558] Disperse 11g (330mg) and cesium fluoride (634mg) in DMF (33mL) and stir at room temperature for 3h. Add water (100mL) and ethyl acetate (100mL) to the reaction solution, stir and separate the liquids. Wash the organic phase with 5% brine (80mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is discharged to obtain compound 11h. LC-MS: m / z = 632.32 (M+H) + .

[0559] Step 8:

[0560] Disperse 11h (260 mg) in ethyl acetate (10 mL), cool to 0-5°C, and add hydrogen chloride in ethyl acetate (4N, 1 mL) dropwise to the reaction system. Keep warm for 1 hour. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:20) to obtain compound 11. LC-MS: m / z = 588.28 (M+H) + .

[0561] Example 12

[0562] Referring to the preparation process of compound 11 in Example 11, in step 1, tert-butyl (1S,3S)-3-aminocyclopentylcarbamate was used to replace 11a to prepare compound 12. LC-MS: m / z=631.38 (M+H) + .

[0563] Example 13

[0564] Referring to the preparation process of compound 11 in Example 11, in step 1, tert-butyl (R)-(1-aminopropane-2-yl)carbamate was used to replace 11a to prepare compound 13. LC-MS: m / z=605.37 (M+H) + .

[0565] Example 14

[0566] Referring to the preparation process of compound 11 in Example 11, in step 1, tert-butyl (S)-(1-aminopropane-2-yl)carbamate was used to replace 11a to prepare compound 14. LC-MS: m / z=605.37 (M+H) + .

[0567] Example 15

[0568] Referring to the preparation process of compound 11 in Example 11, in step 1, (1S,3R)-3-aminocyclopentanol hydrochloride was used instead of 11a to prepare compound 15. LC-MS: m / z=632.32 (M+H) + .

[0569] Example 16

[0570] Referring to the preparation process of compound 11 in Example 11, in step 1, tert-butyl [(1S,2S)-2-aminocyclopropyl]carbamate was used to replace 11a to prepare compound 16. LC-MS: m / z=603.23 (M+H) + .

[0571] Example 17

[0572] Referring to the preparation process of compound 11 in Example 11, in step 1, tert-butyl 3-amino-1-cyclobutylcarbamate was used to replace 11a to prepare compound 17. LC-MS: m / z=617.33 (M+H) + .

[0573] Example 18

[0574] Referring to the preparation process of compound 11 in Example 11, in step 1, 4-amino-1-tert-butyloxycarbonylpiperidine was used to replace 11a to prepare compound 18. LC-MS: m / z=631.38 (M+H) + .

[0575] Example 19

[0576] Referring to the preparation process of compound 11 in Example 11, in step 1, 3-amino-1-(tert-butyloxycarbonyl)pyrrolidine was used to replace 11a to prepare compound 19. LC-MS: m / z=617.45 (M+H) + .

[0577] Example 20

[0578] Step 1:

[0579] Compound 10d (1 g) was dispersed in tetrahydrofuran (20 mL), and DIPEA (1.73 g) and 20a (2.8 g) were added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:20) to obtain compound 20b. LC-MS: m / z = 580.17 (M+H) + .

[0580] Step 2:

[0581] 20b (2.62 g) and cesium fluoride (10.33 g) were dispersed in DMF (63 mL) and stirred at room temperature for 3 h. After the reaction was complete, water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, stirred, and the liquid was separated. The organic phase was washed with 10% brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was discharged and purified by column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:10) to obtain compound 20c. LC-MS: m / z = 430.11 (M+H) + .

[0582] Step 3:

[0583] Compound 20c (451 mg) was dispersed in dichloromethane (22.5 mL), cooled to 0-5°C, and m-chloroperbenzoic acid (907 mg) was added. The mixture was stirred for 1 h. After the reaction was complete, 10% sodium thiosulfate solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was present and purified by column chromatography (ethyl acetate:petroleum ether = 1:50-1:10) to obtain compound 20d. LC-MS: m / z = 462.10 (M+H) + .

[0584] Step 4:

[0585] 20d (350 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (604 mg) were dispersed in tetrahydrofuran (9 mL), cooled to 0°C, and a 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3 mL) was added dropwise. The mixture was stirred for 30 min. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was present and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:30) to obtain compound 20e. LC-MS: m / z = 541.21 (M+H) + .

[0586] Step 5:

[0587] 20e (170 mg), 10g (322 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (50 mg), potassium phosphate (200 mg), and water (1.4 mL) were dispersed in 1,4-dioxane (6.8 mL). Under nitrogen protection, the temperature was raised to 90°C and stirred for 5 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:30) to obtain compound 20f. LC-MS: m / z = 891.44 (M+H) + .

[0588] Step 6:

[0589] Disperse 20f (100 mg) and cesium fluoride (171 mg) in DMF (2.5 mL) and stir at room temperature for 1 h. After the reaction is complete, water (50 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (80 mL*2). The organic phases are combined, washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid is discharged to obtain compound 20 g. LC-MS: m / z = 735.31 (M+H) + .

[0590] Step 7:

[0591] Disperse 20 g (100 mg) of the product in dichloromethane (10 mL), cool to 0-5°C, and add a 4 N 1,4-dioxane solution (2 mL) dropwise to the reaction system. Incubate for 0.5 h. After completion, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 50 x 250 column; acetonitrile-0.1% formic acid aqueous solution (5%-35% / 0-60 min gradient elution) to obtain compound 20. LC-MS: m / z = 591.23 (M+H)+.

[0592] Example 21

[0593] Step 1:

[0594] 10d (835 mg) was dispersed in tetrahydrofuran (20 mL), and DIPEA (1.08 g) and 21a (1.45 g) were added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:20) to obtain compound 21b. LC-MS: m / z = 606.19 (M+H) + .

[0595] Step 2:

[0596] 21b (1.49 g) and cesium fluoride (3.75 g) were dispersed in DMF (50 mL) and stirred at room temperature for 3 h. After the reaction was complete, water (100 mL) and ethyl acetate (200 mL) were added to the reaction solution, stirred, and the liquid was separated. The organic phase was washed with 10% brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was discharged and purified by column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:10) to obtain compound 21c. LC-MS: m / z = 456.13 (M+H) + .

[0597] Step 3:

[0598] Disperse 21c (848 mg) in dichloromethane (45 mL), cool to 0-5°C, add m-chloroperbenzoic acid (1.89 g), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (50 mL) to the reaction solution, extract with dichloromethane (80 mL x 2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is released to obtain compound 21d. LC-MS: m / z = 488.12 (M+H) + .

[0599] Step 4:

[0600] 21d (670 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1093 mg) were dispersed in tetrahydrofuran (20 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 5.5 mL) was added dropwise. The mixture was stirred for 30 min. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to a liquid-free state. The filtrate was purified by column chromatography (methanol:dichloromethane = 1:100 to 1:30) to obtain compound 21e. LC-MS: m / z = 567.23 (M+H) + .

[0601] Step 5:

[0602] 21e (700 mg), 10g (2214 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (142 mg), potassium phosphate (786 mg), and water (5.6 mL) were dispersed in 1,4-dioxane (28 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 5 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:30) to obtain compound 21f. LC-MS: m / z = 917.46 (M+H) + .

[0603] Step 6:

[0604] 21f (892 mg) and cesium fluoride (1.5 g) were dispersed in DMF (25 mL) and stirred at room temperature for 1 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL*2). The organic phases were combined, washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was discharged to obtain compound 21g. LC-MS: m / z = 761.33 (M+H) + .

[0605] Step 7:

[0606] Disperse 21g (100mg) of the product in dichloromethane (10mL), cool to 0-5°C, and add a 4N 1,4-dioxane solution (2mL) dropwise to the reaction system. Incubate for 0.5h. After completion, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10μm 50x250 column; acetonitrile-0.1% formic acid aqueous solution (5%-35% / 0-60min gradient elution) to obtain compound 21. LC-MS: m / z = 617.25 (M+H)+.

[0607] Example 22

[0608] Compound 21 (324 mg) was dispersed in methanol (15 mL), and aqueous formaldehyde solution (1.58 g, 40%) and sodium triacetoxyborohydride (446 mg) were added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 50*250 column; acetonitrile-0.1% ammonia solution (20%-60% / 0-60 min gradient elution) to obtain compound 22. LC-MS: m / z = 645.28 (M+H) + .

[0609] Example 23

[0610] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 12 to prepare compound 23. LC-MS: m / z=659.39 (M+H) + .

[0611] Example 24

[0612] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 13 to prepare compound 24. LC-MS: m / z=633.36 (M+H) + .

[0613] Example 25

[0614] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 14 to prepare compound 25. LC-MS: m / z=633.36 (M+H) + .

[0615] Example 26

[0616] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 17 to prepare compound 26. LC-MS: m / z=645.32 (M+H) + .

[0617] Example 27

[0618] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 18 to prepare compound 27. LC-MS: m / z=645.27 (M+H) + .

[0619] Example 28

[0620] Referring to the preparation process of compound 22 in Example 22, compound 21 was replaced with compound 19 to prepare compound 28. LC-MS: m / z=631.30 (M+H) + .

[0621] Example 29

[0622] 21 (455 mg) was dispersed in hexafluoroisopropanol (4.5 mL), and iodomethane (105 mg) was slowly added dropwise. The reaction was stirred at room temperature for 18 h. After the reaction was complete, the reaction solution was purified by preparative liquid chromatography (YMC ODS 10 μm 50*250 column; acetonitrile-30 mM ammonium acetate aqueous solution (10%-50% / 0-60 min gradient elution)) and then desalted (YMC ODS 10 μm 50*250 column; acetonitrile-0.1% formic acid aqueous solution (10%-10%-20%-90% / 0-15-16-60 min)) to obtain compound 29. LC-MS: m / z = 631.26 (M+H) + .

[0623] Example 30

[0624] Step 1:

[0625] 10h (200 mg) was dispersed in DMF (5 mL), cooled to 0-5°C, and NaH (50 mg, 60%) and iodomethane (350 mg) were added. The mixture was stirred and allowed to react for 4 h. After the reaction was complete, saturated ammonium chloride solution (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 30a was purified by column chromatography (methanol:dichloromethane = 1:500 to 1:100) to obtain compound 30a. LC-MS: m / z = 834.55 (M+H) + .

[0626] Step 2:

[0627] Disperse 30a (200 mg) in dichloromethane (2 mL), cool to 0-5°C, add m-chloroperbenzoic acid (103 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (50 mL) to the reaction solution, extract with dichloromethane (80 mL x 2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid is released to obtain compound 30b. LC-MS: m / z = 866.52 (M+H) + .

[0628] Step 3:

[0629] 30b (200 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (112 mg) were dispersed in tetrahydrofuran (5 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 0.6 mL) was added dropwise. The mixture was stirred at room temperature and allowed to react overnight. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 30c. LC-MS: m / z = 945.62 (M+H) + .

[0630] Step 4:

[0631] 30c (390 mg) and cesium fluoride (1.25 g) were dispersed in DMF (15 mL) and stirred at room temperature for 2 h. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL*2). The organic phases were combined, washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was discharged to obtain compound 30d. LC-MS: m / z = 789.40 (M+H)+ .

[0632] Step 5:

[0633] Compound 30d (250 mg) was dispersed in dichloromethane (2.5 mL), cooled to 0-5°C, and a 4N 1,4-dioxane solution (2.5 mL) was added dropwise to the reaction system. The mixture was incubated for 0.5 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC AQ C18 50*250 column; acetonitrile-0.05% acetic acid (10%-70% / 0-60 min gradient elution) to obtain compound 30. LC-MS: m / z = 645.32 (M+H) + .

[0634] Example 31

[0635] Referring to the preparation method of compound 11 in Example 11, in step 1, 11a was replaced with tert-butylamine to prepare compound 31. LC-MS: m / z=604.30 (M+H) + .

[0636] 1 H-NMR (500MHz, DMSO-d6), δ: 7.96 (dd, J=9.2Hz, J=6.0Hz, 1H), 7.46 (t, J=9.0Hz, 1H), 7.37(d,J=2.4Hz,1H),7.15(d,J=2.4Hz,1H),5.30(d,J=54.0Hz,1H),4.61-4.50(m,2H ),4.17(d,J=3.3Hz,1H),4.16-4.06(m,2H),4.01-3.95(m,1H),3.75-3.68(m,1H),3.1 6-3.07(m,3H),2.89-2.84(m,1H),2.17-1.99(m,3H),1.90-1.76(m,3H),1.65(s,9H).

[0637] Example 32 and Example 33

[0638] Step 1:

[0639] 32a (2 g) and imidazole (5.4 g) were dispersed in DMF (40 mL) and stirred at room temperature for 30 min. Tert-butyldimethylsilyl chloride (6 g) was added, and the reaction was stirred for 12 h. Water (100 mL) and ethyl acetate (150 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 5% brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was discharged to obtain compound 32b. LC-MS: m / z = 190.16 (M+H) + .

[0640] Step 2:

[0641] Compound 32b (2 g) was dispersed in DMF (200 mL), and iodoethane (1.47 g) was added dropwise at room temperature. The reaction mixture was stirred for 12 h. Water (200 mL) and ethyl acetate (250 mL) were added to the reaction mixture, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with 5% brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present to obtain compound 32c. LC-MS: m / z = 218.19 (M+H) + .

[0642] Step 3:

[0643] Compound 10d (530 mg) was dispersed in tetrahydrofuran (20 mL), and DIPEA (923 mg) and 32c (774 mg) were slowly added sequentially. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:20) to obtain compound 32d. LC-MS: m / z = 479.13 (M+H) + .

[0644] Step 4:

[0645] 32d (532 mg) and cesium fluoride (2029 mg) were dispersed in DMF (22 mL) and heated to 80°C with stirring for 3 h. After the reaction was complete, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, stirred, and the mixture separated. The organic phase was washed with 10% brine (80 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated until no liquid was present and purified by column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:5) to obtain compound 32e. LC-MS: m / z = 329.06 (M+H) + .

[0646] Step 5:

[0647] 32e (172 mg), 10g (938 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (60.2 mg), potassium phosphate (333 mg), and water (1.72 mL) were dispersed in 1,4-dioxane (8.6 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 5 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:30) to obtain compound 32f. LC-MS: m / z = 679.29 (M+H) + .

[0648] Step 6:

[0649] Disperse 32f (275 mg) in dichloromethane (15 mL), cool to 0-5°C, add m-chloroperbenzoic acid (85%, 412 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 2). The organic phases are combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid is released to obtain compound 32g. LC-MS: m / z = 711.28 (M+H) + .

[0650] Step 7:

[0651] Disperse 32 g (245 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (275 mg) in tetrahydrofuran (8 mL). The temperature was lowered to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 1.4 mL) was added dropwise. The mixture was stirred for 30 min. After the reaction was complete, saturated ammonium chloride solution (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (80 mL*2). The organic phases were combined, washed with 5% brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 32h. LC-MS: m / z = 790.40 (M+H) + .

[0652] Step 8:

[0653] 32h (285 mg) and cesium fluoride (550 mg) were dispersed in DMF (10 mL) and stirred at room temperature for 2 h. Water (50 mL) and ethyl acetate (80 mL) were added to the reaction solution, stirred, and the liquids separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 32i. LC-MS: m / z = 634.26 (M+H) + .

[0654] Step 9:

[0655] Compound 32i (280 mg) was dispersed in dichloromethane (20 mL), cooled to 0-5°C, and a 4N 1,4-dioxane solution (4 mL) was added dropwise to the reaction system. The mixture was allowed to react for 1 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 50*250 column; acetonitrile-0.1% FA (10%-40% / 0-60 min gradient elution) to afford compound 32j. LC-MS: m / z = 590.24 (M+H) + .

[0656] Step 10:

[0657] Compound 32j was purified sequentially by preparative liquid chromatography (YMC Cellulose-SC 10 μm 30*250 column; ethanol-n-hexane (40%-100% / 0-30 min gradient elution) to give compound 32 (Rt 13.1 min, 61 mg) and compound 33 (Rt 15.6 min, 58 mg).

[0658] Compound 32: LC-MS: m / z=590.24 (M+H) + .

[0659] 1 H-NMR(500MHz,DMSO-d6),δ:7.96-7.95(m,1H),7.48-7.43(m,1H),7.37(d, J=2.2Hz,1H),7.20-7.11(m,1H),5.28(d,J=53.6Hz,1H),4.58-4.51(m,1H), 4.35-4.31(m,1H),4.19-4.00(m,5H),3.55-3.47(m,1H),3.12-3.02(m,3H), 2.86-2.81(m,1H),2.14-1.97(m,3H),1.88-1.73(m,3H),1.31-1.27(m,6H).

[0660] Compound 33: LC-MS: m / z=590.24 (M+H) + .

[0661] 1 H-NMR (500MHz, DMSO-d6), δ: 10.11 (s, 1H), 7.95 (dd, J = 9.0Hz, J = 6.0Hz, 1H), 7.48-7 .43(m,1H),7.37-7.36(m,1H),7.20-7.11(m,1H),5.28(d,J=53.8Hz,1H),4.58-4.5 1(m,1H),4.34(d,J=12.9Hz,1H),4.19-4.00(m,5H),3.55-3.47(m,1H),3.13-3.02( m,3H),2.87-2.81(m,1H),2.14-1.96(m,3H),1.88-1.73(m,3H),1.31-1.26(m,6H).

[0662] The retention time of compound 32 in the chiral chromatographic column is shorter than that of compound 33, while the retention time of compound 33 in the chiral chromatographic column is longer than that of compound 32.

[0663] Example 34

[0664] Step 1:

[0665] 34a (7.25 g) and p-methoxybenzyl chloride (26.3 g) were dispersed in DMF (80 mL). Sodium hydroxide (60%, 5.9 g) was added with stirring at room temperature, and the reaction was continued with stirring for 2 h. After the reaction was complete, ammonium chloride solution (20 mL) was added to quench the reaction. Water (100 mL) and ethyl acetate (150 mL) were added, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with 5% brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 34b was purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:10) to obtain compound 34b. LC-MS: m / z = 413.16 (M+H) + .

[0666] Step 2:

[0667] 34b (1.25 g), bis(diphenylphosphine palladium dichloride) (0.21 g), and tributyl(1-ethoxyethylene)tin (3.1 mL) were dispersed in DMF (10 mL) and stirred under nitrogen at 80°C for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, the pH was adjusted to acidic with dilute hydrochloric acid, and water (100 mL) and ethyl acetate (100 mL) were added. The mixture was stirred and separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and washed once with 10% sodium bicarbonate solution (100 mL) and once with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 34c was purified by column chromatography (ethyl acetate:petroleum ether = 1:50 to 1:5) to obtain compound 34c. LC-MS: m / z = 377.26 (M+H) + .

[0668] Step 3:

[0669] 34c (0.7 g), 2-(tert-butyldimethylsilyloxy)ethylamine (1.12 g), and tetraisopropyl titanate (1.2 mL) were dispersed in methanol (14 mL) and heated to 80°C with stirring for 6 h. The reaction solution was cooled to 0°C, sodium borohydride (240 mg) was added, and the mixture was brought to room temperature with stirring for 4 h. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated until no liquid was released. Compound 34d was then purified by column chromatography (ethyl acetate:petroleum ether = 1:20 to 1:2) to obtain compound 34d. LC-MS: m / z = 536.39 (M+H) + .

[0670] Step 4:

[0671] Compound 10d (800 mg), 34d (980 mg), and DIPEA (580 mg) were dispersed in tetrahydrofuran (20 mL) and stirred at room temperature for 1.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:100 to 1:10) to obtain compound 34e. LC-MS: m / z = 797.65 (M+H) + .

[0672] Step 5:

[0673] 34e (809 mg) and cesium fluoride (1.6 g) were dispersed in DMF (16 mL), heated to 60°C, and stirred for 2 h. After the reaction was complete, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, stirred, and the liquids separated. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phase was washed with 10% brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 34f. LC-MS: m / z = 647.28 (M+H) + .

[0674] Step 6:

[0675] Disperse 34f (650 mg) in dichloromethane (30 mL), cool to 0-5°C, add m-chloroperbenzoic acid (85%, 860 mg), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 2). The organic phases are combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid is released to obtain compound 34g. LC-MS: m / z = 679.27 (M+H) + .

[0676] Step 7:

[0677] 34 g (725 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (850 mg) were dispersed in tetrahydrofuran (15 mL). The temperature was lowered to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 4.3 mL) was added dropwise. The mixture was stirred for 1 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction system to quench the reaction. Water (50 mL) and ethyl acetate (80 mL) were added, stirred, and separated. The mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 34h was purified by column chromatography (methanol:dichloromethane = 1:100 to 1:20) to obtain compound 34h. LC-MS: m / z = 758.33 (M+H). + .

[0678] Step 8:

[0679] 34h (200 mg) was dispersed in trifluoroacetic acid (10 mL), cooled to 0°C, and methanesulfonic acid (1 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure until no liquid flowed out. The residue was dissolved in dichloromethane (10 mL), and the pH of the system was adjusted to alkaline with saturated sodium bicarbonate solution under ice bath. Water (50 mL) and dichloromethane (50 mL) were added, stirred, and separated. The mixture was extracted with dichloromethane (50 mL*2). The organic phases were combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 34i. LC-MS: m / z = 518.21 (M+H) + .

[0680] Step 9:

[0681] 34i (166 mg), 10g (327 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (37 mg), potassium phosphate (198 mg), and water (2.4 mL) were dispersed in 1,4-dioxane (12 mL) under nitrogen protection. The temperature was raised to 90°C and stirred for 1 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:100 to 1:15) to obtain compound 34j. LC-MS: m / z = 868.91 (M+H) + .

[0682] Step 10:

[0683] 34j (175 mg) and cesium fluoride (306 mg) were dispersed in DMF (10 mL) and stirred at room temperature for 2 h. Water (50 mL) and ethyl acetate (80 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was discharged to obtain compound 34k. LC-MS: m / z = 712.50 (M+H) + .

[0684] Step 11:

[0685] 34k (168 mg) was dispersed in dichloromethane (10 mL), cooled to 0-5°C, and a 4N 1,4-dioxane solution (2 mL) was added dropwise to the reaction system. The mixture was stirred at this temperature for 1 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC ODS 10 μm 30*250 column; acetonitrile-0.1% FA (5%-5% / 0-60 min gradient elution)) to afford compound 34. LC-MS: m / z = 668.42 (M+H). + .

[0686] Example 35 and Example 36

[0687] Compound 34 was purified by preparative liquid chromatography (YMC Cellulose-SC 10 μm 30*250 column; ethanol-n-hexane (30%-100% / 0-40 min gradient elution)) to give compound 35 (Rt 16.2 min, 44 mg) and compound 36 (Rt 22.3 min, 57 mg).

[0688] Compound 35: LC-MS: m / z=668.40 (M+H) + .

[0689] 1 H-NMR (500MHz, DMSO-d6), δ: 10.15 (br, 1H), 7.99-7.94 (m, 2H), 7.65 (d, J = 6.2Hz, 1H), 7.45 (t, J = 8.6 Hz,1H),7.37(s,1H),7.14(s,1H),6.68(s,1H),6.34(dd,J=29.2Hz,J=5.6Hz,1H),5.79(s,1H),5.72( s,1H),5.30(d,J=54.6Hz,1H),4.47-4.16(m,3H),4.11-3.96(m,2H),3.80-3.65(m,1H),3.47-3.41(m ,1H),3.14-3.03(m,3H),2.86-2.81(m,1H),2.18-1.99(m,3H),1.88-1.75(m,3H),1.62-1.58(m,3H).

[0690] Compound 36: LC-MS: m / z=668.41 (M+H) + .

[0691] 1 H-NMR (500MHz, DMSO-d6), δ: 10.15 (br, 1H), 7.99-7.94 (m, 2H), 7.65 (d, J = 7.4Hz, 1H), 7.46 (t, J = 8.6 Hz,1H),7.37(s,1H),7.15(s,1H),6.68(t,J=5.6Hz,1H),6.39-6.29(m,1H),5.80(s,1H),5.72(s,1H ),5.30(d,J=53.8Hz,1H),4.46-4.21(m,2H),4.16-3.97(m,3H),3.80-3.65(m,1H),3.47-3.42(m,1H ),3.16-3.05(m,3H),2.88-2.82(m,1H),2.20-2.02(m,3H),1.91-1.78(m,3H),1.60(t,J=6.2Hz,3H).

[0692] The retention time of compound 35 in the chiral chromatographic column is shorter than that of compound 36, while the retention time of compound 36 in the chiral chromatographic column is longer than that of compound 35.

[0693] Example 37

[0694] Referring to the preparation process of compound 34 in Example 34, in step 3, DL-aminopropanol was used to replace 2-(tert-butyldimethylsilyloxy)ethylamine to prepare compound 37. LC-MS: m / z=682.42 (M+H) + .

[0695] Example 38

[0696] Referring to the preparation process of compound 34 in Example 34, in step 3, L-aminopropanol was used to replace 2-(tert-butyldimethylsilyloxy)ethylamine to prepare compound 38. LC-MS: m / z=682.42 (M+H) + .

[0697] Example 39 and Example 40

[0698] Compound 38 was purified by liquid chromatography (CHIRALPAK ID 5.0 ​​μm 4.6*250 mm; n-hexane-0.1% ethanolamine / ethanol (50% / isocratic elution 20 min)) to give compound 39 (Rt 11.6 min, LC-MS: m / z=682.42 (M+H) + ) and compound 40 (Rt 14.9 min, LC-MS: m / z=682.42 (M+H) + ).

[0699] Compound 39: 1 H-NMR(500MHz,DMSO-d6),δ:10.30-9.97(m,1H),8.15-7.85(m,2H),7.83-7.60(m,1H),7.59-7.30 (m,2H),7.28-7.04(m,1H),6.83-6.37(m,2H),5.78-5.44(m,2H),5.43-5.15(m,1H),4.64-4.41(m, 1H),4.38-3.72(m,5H),3.21-2.94(m,3H),2.93-2.76(m,1H),2.27-1.96(m,3H),1.95-1.71(m,3H),1.70-1.52(m,3H),0.74-0.44(m,3H).

[0700] Compound 40: 1H-NMR (500MHz, DMSO-d6), δ: 10.30-9.97 (m, 1H), 8.10-7.86 (m, 2H), 7.73 (d, J = 7.2Hz, 1H), 7.56-7.42 (m ,1H),7.41-7.30(m,1H),7.25-7.08(m,1H),6.82-6.62(m,1H),6.60-6.36(m,1H),5.82-5.53(m,2H),5. 43-5.15(m,1H),4.46-4.26(m,1H),4.25-4.15(m,1H),4.14-4.00(m,2H),3.98-3.79(m,2H),3.21-2.98 (m,3H),2.92-2.76(m,1H),2.23-1.95(m,3H),1.93-1.73(m,3H),1.72-1.58(m,3H),1.28-1.17(m,3H).

[0701] The retention time of compound 39 in the chiral chromatographic column is shorter than that of compound 40, while the retention time of compound 40 in the chiral chromatographic column is longer than that of compound 39.

[0702] Example 41

[0703] Referring to the preparation process of compound 34 in Example 34, in step 3, D-aminopropanol was used to replace 2-(tert-butyldimethylsilyloxy)ethylamine to prepare compound 41. LC-MS: m / z=682.42 (M+H) + .

[0704] Example 42 and Example 43

[0705] Compound 41 was purified by liquid chromatography (CHIRALPAK ID 5.0 ​​μm 4.6*250 mm; n-hexane-0.1% ethanolamine / ethanol (50% / isocratic elution 20 min)) to give compound 42 (Rt 13.7 min, LC-MS: m / z=682.42 (M+H) + ) and compound 43 (Rt 16.6 min, LC-MS: m / z=682.42 (M+H) + ).

[0706] Compound 42: 1H-NMR (500MHz, DMSO-d6), δ: 10.16 (br, 1H), 8.10-7.90 (m, 2H), 7.71 (d, J = 7.4Hz, 1H), 7.52-7.42 ( m,1H),7.41-7.32(m,1H),7.26-7.07(m,1H),6.79-6.64(m,1H),6.63-6.41(m,1H),5.80-5.46(m, 2H),5.42-5.14(m,1H),4.69-4.43(m,1H),4.37-4.15(m,2H),4.14-3.75(m,3H),3.20-3.00(m,3H) ),2.90-2.78(m,1H),2.22-1.96(m,3H),1.93-1.73(m,3H),1.69-1.55(m,3H),0.72-0.49(m,3H).

[0707] Compound 43: 1 H-NMR (500MHz, DMSO-d6), δ: 10.15 (br, 1H), 8.10-7.89 (m, 2H), 7.73 (d, J = 7.4Hz, 1H), 7.56-7 .43(m,1H),7.38(d,J=2.4Hz,1H),7.26-7.10(m,1H),6.78-6.63(m,1H),6.61-6.38(m,1H),5. 79-5.56(m,2H),5.42-5.18(m,1H),4.44-4.26(m,1H),4.21-3.79(m,5H),3.20-2.99(m,3H),2 .90-2.77(m,1H),2.22-1.97(m,3H),1.94-1.73(m,3H),1.72-1.57(m,3H),1.27-1.17(m,3H).

[0708] The retention time of compound 42 in the chiral chromatographic column is shorter than that of compound 43, while the retention time of compound 43 in the chiral chromatographic column is longer than that of compound 42.

[0709] Example 44

[0710] Referring to the preparation process of compound 32j in Example 32, in step 2, iodoethane was replaced with iodocyclopropane to prepare compound 44. LC-MS: m / z=602.22 (M+H) + .

[0711] Example 45 and Example 46

[0712] Compound 44 was purified by preparative liquid chromatography (YMC Cellulose-SC 10 μm 30*250 column; ethanol-n-hexane (20%-80% / 0-40 min gradient elution)) to give compound 45 (Rt 15.1 min, LC-MS: m / z=602.22 (M+H) + ) and compound 46 (Rt 22.6 min, LC-MS: m / z=602.22 (M+H) + ).

[0713] The retention time of compound 45 in the chiral chromatographic column is shorter than that of compound 46, while the retention time of compound 46 in the chiral chromatographic column is longer than that of compound 45.

[0714] Example 47 and Example 48

[0715] Referring to the preparation process of compound 34i in Example 34, in step 3, L-aminopropanol was used to replace 2-(tert-butyldimethylsilyloxy)ethylamine to prepare compound 47a. LC-MS: m / z = 532.20 (M+H) + .

[0716] Step 1:

[0717] 47a (160 mg), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (271 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (35 mg), potassium phosphate (190 mg), and water (3 mL) were dispersed in 1,4-dioxane (15 mL) and stirred at 90°C for 2 h under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to obtain compound 47b. LC-MS: m / z = 822.77 (M+H) + .

[0718] Step 2:

[0719] 47b (157 mg) and cesium fluoride (300 mg) were dispersed in DMF (16 mL) and stirred at room temperature for 2 h. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution, stirred, and the mixture separated. The organic phase was washed with 5% brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present to obtain compound 47c. LC-MS: m / z = 666.40 (M+H) + .

[0720] Step 3:

[0721] Compound 47c was purified by preparative liquid chromatography (YMC Cellulose-SB 10 μm 30*250 column; ethanol-n-hexane (10%-90% / 0-40 min gradient elution)) to give compound 47 (Rt 16.3 min, LC-MS: m / z=666.40 (M+H) + ) and compound 48 (Rt 18.4 min, LC-MS: m / z=666.40 (M+H) + ).

[0722] The retention time of compound 47 in the chiral chromatographic column is shorter than that of compound 48, while the retention time of compound 48 in the chiral chromatographic column is longer than that of compound 47.

[0723] Example 49

[0724] Referring to the preparation process of compound 32j in Example 32, in step 2, iodoethane was replaced with 2-iodopropane to prepare compound 49. LC-MS: m / z=604.34 (M+H) + .

[0725] Example 50

[0726] Referring to the preparation process of compound 32j in Example 32, in step 2, 1,1-difluoro-2-iodoethane was used to replace iodoethane to prepare compound 50. LC-MS: m / z=626.30 (M+H) + .

[0727] Example 51

[0728] Referring to the preparation process of compound 34 in Example 34, in step 7, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methane-d2-ol was used to replace ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol to prepare compound 51. LC-MS: m / z = 670.38 (M+H) + .

[0729] Example 52

[0730] Referring to the preparation process of compound 47c in Example 47, in step 1, 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine was used instead of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane to prepare compound 52. LC-MS: m / z=681.32 (M+H) + .

[0731] Example 53 and Example 54

[0732] Compound 52 was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (60%-90% / 0-60 min gradient elution)) to give compound 53 (Rt 22 min, LC-MS: m / z=681.32 (M+H) + ) and compound 54 (Rt 25min, LC-MS: m / z=681.34 (M+H) + ).

[0733] The retention time of compound 53 in the chiral chromatographic column is shorter than that of compound 54, while the retention time of compound 54 in the chiral chromatographic column is longer than that of compound 53.

[0734] Example 55 and Example 56

[0735] Referring to the preparation process of compound 47b in Example 47, in step 1, (3-methyl-2-(trifluoromethyl)phenyl)boronic acid was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 55a.

[0736] Compound 55a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (60%-90% / 0-60 min gradient elution)) to give compound 55 (Rt 25 min, LC-MS: m / z=656.28 (M+H) + ) and compound 56 (Rt 28 min, LC-MS: m / z=656.28 (M+H) + ).

[0737] Compound 55: 1H-NMR (500MHz, DMSO-d6), δ: 7.99 (dd, J=4.8Hz, J=1.6Hz, 1H), 7.69 (d, J=7.6, 1H), 7.67-7.60 (m, 1H), 7.57 (d, J=7 .6Hz,1H),7.30(br,1H),6.69(dd,J=7.4Hz,J=5.0Hz,1H),6.52(q,J=6.6Hz,1H),5.60(s,2H),5.38-5.19(m,1H), 4.52(dd,J=12.6Hz,J=5.2Hz,1H),4.38-4.25(m,1H),4.13(s,2H),4.06-3.98(m,1H),3.14-2.98(m,3H),2.87-2. 79(m,1H),2.57-2.53(m,3H),2.17-1.95(m,3H),1.89-1.74(m,3H),1.60(d,J=6.8Hz,3H),0.54(d,J=6.8Hz,3H).

[0738] Compound 56: 1 H-NMR (500MHz, DMSO-d6), δ: 7.99 (dd, J = 4.8Hz, J = 1.5Hz, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.64 (t, J = 7.6Hz, 1H), 7.57 (d, J =7.6Hz,1H),7.31(br,1H),6.70(dd,J=7.4Hz,J=4.9Hz,1H),6.45(q,J=6.6Hz,1H),5.60(s,2H),5.38-5.20(m,1H),4. 35(dd,J=12.4Hz,J=5.6Hz,1H),4.20(d,J=10.4Hz,1H),4.09-4.00(m,1H),3.95-3.84(m,2H),3.13-2.98(m,3H),2.8 7-2.77(m,1H),2.57-2.53(m,3H),2.17-1.96(m,3H),1.90-1.72(m,3H),1.62(d,J=6.9Hz,3H),1.17(d,J=6.5Hz,3H).

[0739] The retention time of compound 55 in the chiral chromatographic column is shorter than that of compound 56, while the retention time of compound 56 in the chiral chromatographic column is longer than that of compound 55.

[0740] Example 57 and Example 58

[0741] Referring to the preparation process of compound 47b in Example 47, in step 1, 2-(dimethylamino)phenylboronic acid pinacol ester was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 57a.

[0742] Compound 57a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia water (50%-90% / 0-60 min gradient elution)) to give compound 57 (Rt 49 min) and compound 58 (Rt 52 min).

[0743] Compound 57: LC-MS: m / z=617.41 (M+H) + .

[0744] 1 H-NMR (500MHz, DMSO-d6), δ: 7.99 (s, 1H), 7.69 (d, J = 6.8Hz, 1H), 7.36 (t, J = 7.0Hz, 1H), 7.24 (d, J = 7.0Hz, 1H) ,7.09(d,J=8.0Hz,1H),6.99(t,J=7.0Hz,1H),6.72-6.65(m,1H),6.57-6.49(m,1H),5.64(s,2H),5.42-5.17 (m,1H),4.57-4.47(m,1H),4.29(d,J=12.4Hz,1H),4.14(s,2H),4.06-3.97(m,1H),3.16-3.00(m,3H),2.89- 2.79(m,1H),2.53(s,6H),2.21-1.98(m,3H),1.91-1.74(m,3H),1.59(d,J=5.8Hz,3H),0.55(d,J=6.2Hz,3H).

[0745] Compound 58: LC-MS: m / z=617.38 (M+H) + .

[0746] 1H-NMR (500MHz, DMSO-d6), δ: 8.00 (s, 1H), 7.72 (d, J = 5.8Hz, 1H), 7.41-7.30 (m, 1H), 7.25 (d, J = 5.8Hz, 1H), 7 .16-7.04(m,1H),7.03-6.94(m,1H),6.75-6.64(m,1H),6.54-6.41(m,1H),5.62(s,2H),5.42-5.17(m,1H), 4.41-4.27(m,1H),4.20(d,J=9.6Hz,1H),4.06(d,J=9.8Hz,1H),3.90(d,J=10.2Hz,2H),3.16-2.99(m,3H), 2.89-2.77(m,1H),2.54(s,6H),2.21-1.95(m,3H),1.91-1.71(m,3H),1.70-1.53(m,3H),1.27-1.10(m,3H).

[0747] The retention time of compound 57 in the chiral chromatographic column is shorter than that of compound 58, while the retention time of compound 58 in the chiral chromatographic column is longer than that of compound 57.

[0748] Example 59 and Example 60

[0749] Referring to the preparation process of compound 47b in Example 47, in step 1, 1-naphthaleneboronic acid was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 59a.

[0750] Compound 59a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (60%-90% / 0-60 min gradient elution)) to give compound 59 (Rt 49 min, LC-MS: m / z=624.40 (M+H) + ) and compound 60 (Rt 55 min, LC-MS: m / z=624.37 (M+H) + ).

[0751] The retention time of compound 59 in the chiral chromatographic column is shorter than that of compound 60, while the retention time of compound 60 in the chiral chromatographic column is longer than that of compound 59.

[0752] Example 61 and Example 62

[0753] Referring to the preparation process of compound 47b in Example 47, in step 1, 2-(trifluoromethyl)phenylboronic acid was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 61a.

[0754] Compound 61a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (60%-90% / 0-60 min gradient elution)) to give compound 61 (Rt 35 min, LC-MS: m / z=642.34 (M+H) + ) and compound 62 (Rt 40 min, LC-MS: m / z=642.34 (M+H) + ).

[0755] Compound 61: 1 H-NMR (500MHz, DMSO-d6), δ: 7.99 (d, J = 4.2Hz, 1H), 7.89 (d, J = 7.8, 1H), 7.80 (t, J = 7.4Hz, 1H), 7.77 -7.66(m,2H),7.57(d,J=7.4Hz,1H),6.74-6.64(m,1H),6.58-6.46(m,1H),5.59(s,2H),5.38-5.19( m,1H),4.58-4.48(m,1H),4.37-4.27(m,1H),4.14(s,2H),4.08-3.97(m,1H),3.16-2.99(m,3H),2. 88-2.77(m,1H),2.20-1.97(m,3H),1.91-1.72(m,3H),1.60(d,J=6.6Hz,3H),0.54(d,J=6.6Hz,3H).

[0756] Compound 62: 1H-NMR (500MHz, DMSO-d6), δ: 7.99 (dd, J=4.8Hz, J=1.6Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 7.81 (t, J=7.4Hz, 1H), 7.76 -7.69(m,2H),7.58(d,J=7.6Hz,1H),6.70(dd,J=7.4Hz,J=5.0Hz,1H),6.45(q,J=7.0Hz,1H),5.60(s,2H),5.38-5 .20(m,1H),4.35(dd,J=12.6Hz,J=5.6Hz,1H),4.23-4.17(m,1H),4.09-4.03(m,1H),3.95-3.84(m,2H),3.13-2. 99(m,3H),2.87-2.74(m,1H),2.20-1.96(m,3H),1.89-1.72(m,3H),1.62(d,J=6.8Hz,3H),1.17(d,J=6.8Hz,3H).

[0757] The retention time of compound 61 in the chiral chromatographic column is shorter than that of compound 62, while the retention time of compound 62 in the chiral chromatographic column is longer than that of compound 61.

[0758] Example 63 and Example 64

[0759] Referring to the preparation process of compound 47b in Example 47, in step 1, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 63a.

[0760] Compound 63a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (60%-90% / 0-60 min gradient elution)) to give compound 63 (Rt 24 min, LC-MS: m / z=691.23 (M+H) + ) and compound 64 (Rt 27 min, LC-MS: m / z=691.23 (M+H) + ).

[0761] Compound 63: 1H-NMR (500MHz, DMSO-d6), δ: 8.02-7.95 (m, 1H), 7.69 (d, J = 7.4Hz, 1H), 6.89-6.83 (m, 1H), 6.69 ( dd,J=7.4Hz,J=5.0Hz,1H),6.57-6.38(m,2H),6.37-6.19(m,2H),5.59(s,2H),5.38-5.19(m,1H) ,4.56-4.47(m,1H),4.36-4.25(m,1H),4.13(s,2H),4.06-3.98(m,1H),3.14-3.00(m,3H),2.87- 2.79(m,1H),2.19-1.97(m,3H),1.89-1.74(m,3H),1.59(d,J=6.8Hz,3H),0.53(d,J=6.8Hz,3H).

[0762] Compound 64: 1 H-NMR (500MHz, DMSO-d6), δ: 8.02-7.96 (m, 1H), 7.76-7.67 (m, 1H), 6.86 (d, J = 1.9Hz, 1H), 6.70 ( dd,J=7.4Hz,J=4.9Hz,1H),6.56-6.38(m,2H),6.30(br,2H),5.60(s,2H),5.38-5.20(m,1H),4.3 8-4.31(m,1H),4.23-4.16(m,1H),4.09-4.02m,1H),3.98-3.85(m,2H),3.13-3.00(m,3H),2.86- 2.79(m,1H),2.19-1.97(m,3H),1.89-1.72(m,3H),1.62(d,J=6.8Hz,3H),1.16(d,J=6.8Hz,3H).

[0763] The retention time of compound 63 in the chiral chromatographic column is shorter than that of compound 64, while the retention time of compound 64 in the chiral chromatographic column is longer than that of compound 63.

[0764] Example 65 and Example 66

[0765] Referring to the preparation process of compound 34f in Example 34, in step 3, L-aminopropanol was used to replace 2-(tert-butyldimethylsilyloxy)ethylamine to prepare compound 65a. LC-MS: m / z = 661.33 (M+H) + .

[0766] Step 1:

[0767] Disperse 65a (1.5 g) in dichloromethane (30 mL), cool to 0-5°C, add m-chloroperbenzoic acid (80%, 1.82 g), and stir for 1 h. After the reaction is complete, add 10% sodium thiosulfate solution (100 mL) to the reaction solution, extract with dichloromethane (100 mL x 2). The organic phases are combined, washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid is released to obtain compound 65b. LC-MS: m / z = 693.31 (M+H) + .

[0768] Step 2:

[0769] 65b (600 mg) and methanol (83 mg) were dispersed in tetrahydrofuran (10 mL), cooled to 0°C, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1N, 2.6 mL) was added dropwise. The mixture was stirred for 1 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction system to quench the reaction. Water (50 mL) and ethyl acetate (80 mL) were added, stirred, and separated. The mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present. Compound 65c was purified by column chromatography (methanol:dichloromethane = 1:150 to 1:50) to obtain compound 65c. LC-MS: m / z = 645.31 (M+H) + .

[0770] Step 3:

[0771] Compound 65c (500 mg) was dispersed in trifluoroacetic acid (10 mL), cooled to 0°C, and methanesulfonic acid (1 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure until no liquid flowed out. The residue was dissolved in dichloromethane (10 mL), and the pH of the system was adjusted to alkaline with saturated sodium bicarbonate solution under ice bath. Water (50 mL) and dichloromethane (50 mL) were added, stirred, and separated. The mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 65d. LC-MS: m / z = 405.24 (M+H) + .

[0772] Step 4:

[0773] 65d (450 mg), 10g (1.14 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (128 mg), potassium phosphate (706 mg), and water (4 mL) were dispersed in 1,4-dioxane (20 mL) and stirred at 90°C under nitrogen for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:100) to obtain compound 65e. LC-MS: m / z = 755.40 (M+H) + .

[0774] Step 5:

[0775] 65e (550 mg) and cesium fluoride (1.66 g) were dispersed in DMF (20 mL) and stirred at room temperature for 2 h. Water (50 mL) and ethyl acetate (80 mL) were added to the reaction solution, stirred and separated, and the aqueous phase was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 65f. LC-MS: m / z = 599.33 (M+H) + .

[0776] Step 6:

[0777] Disperse 65f (438 mg) in dichloromethane (5 mL), cool to 0-5°C, and add a 4N 1,4-dioxane solution of hydrogen chloride to the reaction system dropwise. Stir and react for 1 h. After the reaction is complete, concentrate the reaction mixture under reduced pressure until no liquid remains, yielding compound 65g. LC-MS: m / z = 555.25 (M+H) + .

[0778] Step 7:

[0779] Compound 65g was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-70% / 0-60 min gradient elution)) to give compound 65 (Rt 28 min, LC-MS: m / z=555.25 (M+H) + ) and compound 66 (Rt 32 min, LC-MS: m / z=555.24 (M+H) + ).

[0780] Compound 65: 1H-NMR (500MHz, DMSO-d6), δ: 10.16 (br, 1H), 8.06-7.89 (m, 2H), 7.71 (d, J= 7.4Hz,1H),7.50-7.42(m,1H),7.40-7.33(m,1H),7.24-7.09(m,1H),6.75 -6.65(m,1H),6.64-6.45(m,1H),5.67-5.48(m,2H),4.59-4.46(m,1H),4. 32-4.17(m,1H),4.10-3.77(m,5H),1.68-1.54(m,3H),0.67-0.52(m,3H).

[0781] Compound 66: 1 H-NMR (500MHz, DMSO-d6), δ: 10.13 (br, 1H), 8.03-7.92 (m, 2H), 7.77-7.70 (m, 1H), 7.49-7.42 (m, 1H), 7.37 (d, J = 2.5Hz, 1H), 7.22-7.12 (m, 1H),6.73-6.66(m,1H),6.58-6.43(m,1H),5.72-5.57(m,2H),4.41-4 .27(m,1H),4.10-3.79(m,6H),1.70-1.59(m,3H),1.27-1.18(m,3H).

[0782] The retention time of compound 65 in the chiral chromatographic column is shorter than that of compound 66, while the retention time of compound 66 in the chiral chromatographic column is longer than that of compound 65.

[0783] Example 67 and Example 68

[0784] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N-methyl-L-prolinol to prepare compound 67a.

[0785] Compound 67a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.05% trifluoroacetic acid aqueous solution (10%-65% / 0-60 min gradient elution)) to give compound 67 (Rt 23.1 min, LC-MS: m / z=638.37 (M+H) + ) and compound 68 (Rt 24.4 min, LC-MS: m / z=638.37 (M+H) + ).

[0786] The retention time of compound 67 in the chiral chromatographic column is shorter than that of compound 68, while the retention time of compound 68 in the chiral chromatographic column is longer than that of compound 67.

[0787] Example 69 and Example 70

[0788] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (1-(morpholinomethyl)cyclopropyl)methanol to prepare compound 69a.

[0789] Compound 69a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.05% trifluoroacetic acid aqueous solution (10%-60% / 0-60 min gradient elution)) to give compound 69 (Rt 24.6 min, LC-MS: m / z = 694.40 (M+H) + ) and compound 70 (Rt 26.5 min, LC-MS: m / z=694.38 (M+H) + ).

[0790] Compound 69: 1 H-NMR (500MHz, DMSO-d6), δ: 10.50-9.46 (m, 1H), 8.28-8.20 (m, 1H), 8.15 (d, J = 6 .2Hz,1H),8.02-7.94(m,1H),7.85-7.56(m,2H),7.51-7.43(m,1H),7.41-7.36( m,1H),7.22-7.04(m,2H),6.63-6.47(m,1H),4.64-4.42(m,3H),4.36-3.91(m,6 H),3.83-3.56(m,4H),3.43-3.02(m,3H),1.77-1.60(m,3H),0.98-0.62(m,7H).

[0791] Compound 70: 1H-NMR (500MHz, DMSO-d6), δ: 10.16-10.08 (m, 1H), 8.03-7.92 (m, 2H), 7.72 (d, J = 7.4Hz, 1H), 7.5 0-7.42(m,1H),7.37(d,J=2.5Hz,1H),7.21-7.10(m,1H),6.75-6.65(m,1H),6.56-6.37(m,1H), 5.77-5.62(m,2H),4.43-4.21(m,3H),4.10-3.82(m,3H),3.70-3.44(m,4H),2.47-2.2 6(m,2H),1.70-1.58(m,3H),1.38-1.14(m,7H),0.72-0.61(m,2H),0.53-0.33(m,2H).

[0792] The retention time of compound 69 in the chiral chromatographic column is shorter than that of compound 70, while the retention time of compound 70 in the chiral chromatographic column is longer than that of compound 69.

[0793] Example 71 and Example 72

[0794] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methane-d2-ol to prepare compound 71a.

[0795] Compound 71a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-80% / 0-60 min gradient elution)) to give compound 71 (Rt 40 min, LC-MS: m / z=684.36 (M+H) + ) and compound 72 (Rt 43 min, LC-MS: m / z=684.37 (M+H) + ).

[0796] Compound 71: 1 H-NMR(500MHz,DMSO-d6),δ:10.36-9.87(m,1H),8.19-7.83(m,2H),7.81-7.59(m,1H),7.57-7.29(m,2H),7.28-7.02(m,1H),6.89 -6.33(m,2H),5.81-5.45(m,2H),5.44-5.09(m,1H),4.72-3.70(m,4H),3.20-2.70(m,3H),2.34-1.46(m,10H),0.85-0.41(m,3H).

[0797] Compound 72: 1 H-NMR (500MHz, DMSO-d6), δ: 10.23-10.11 (m, 1H), 8.06-7.91 (m, 2H), 7.74 (d, J = 7.4Hz, 1H) ,7.51-7.43(m,1H),7.38(d,J=2.4Hz,1H),7.23-7.11(m,1H),6.76-6.67(m,1H),6.54-6.3 7(m,1H),5.87-5.62(m,2H),5.61-5.37(m,1H),4.50-4.31(m,1H),4.14-3.83(m,3H),3.79 -2.96(m,4H),2.47-2.15(m,3H),2.14-1.87(m,3H),1.76-1.57(m,3H),1.33-1.15(m,3H).

[0798] The retention time of compound 71 in the chiral chromatographic column is shorter than that of compound 72, while the retention time of compound 72 in the chiral chromatographic column is longer than that of compound 71.

[0799] Example 73 and Example 74

[0800] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (2S)-2-methoxy-1-propanol to prepare compound 73a.

[0801] Compound 73a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.05% trifluoroacetic acid aqueous solution (20%-80% / 0-40 min gradient elution)) to give compound 73 (Rt 27.1 min, LC-MS: m / z=613.31 (M+H) + ) and compound 74 (Rt 29.3 min, LC-MS: m / z=613.27 (M+H) + ).

[0802] The retention time of compound 73 in the chiral chromatographic column is shorter than that of compound 74, while the retention time of compound 74 in the chiral chromatographic column is longer than that of compound 73.

[0803] Example 75 and Example 76

[0804] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (R)-2-methoxy-1-propanol to prepare compound 75a.

[0805] Compound 75a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-70% / 0-60 min gradient elution)) to give compound 75 (Rt 28 min, LC-MS: m / z=613.33 (M+H) + ) and compound 76 (Rt 31 min, LC-MS: m / z=613.33 (M+H) + ).

[0806] Compound 75: 1 H-NMR (500MHz, DMSO-d6), δ: 10.19 (br, 1H), 8.05-7.91 (m, 2H), 7.71 (d, J = 7.0Hz, 1H), 7.51 -7.42(m,1H),7.41-7.35(m,1H),7.27-7.11(m,1H),6.76-6.66(m,1H),6.62-6.44(m,1H),5 .67-5.47(m,2H),4.60-4.46(m,1H),4.44-4.34(m,2H),4.33-4.21(m,1H),4.12-3.78(m,2H ),3.79-3.70(m,1H),3.34(s,3H),1.72-1.55(m,3H),1.29-1.14(m,3H),0.67-0.63(m,3H).

[0807] Compound 76: 1 H-NMR (500MHz, DMSO-d6), δ: 10.20 (br, 1H), 8.09-7.89 (m, 2H), 7.74 (d, J = 7.4 Hz,1H),7.53-7.42(m,1H),7.39(d,J=2.4Hz,1H),7.26-7.14(m,1H),6.77-6.6 5(m,1H),6.62-6.41(m,1H),5.78-5.52(m,2H),4.46-4.28(m,3H),4.14-3.83 (m,3H),3.79-3.68(m,1H),3.33(s,3H),1.75-1.58(m,3H),1.32-1.14(m,6H).

[0808] The retention time of compound 75 in the chiral chromatographic column is shorter than that of compound 76, while the retention time of compound 76 in the chiral chromatographic column is longer than that of compound 75.

[0809] Example 77 and Example 78

[0810] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 2-methoxy-2-methylpropan-1-ol to prepare compound 77a.

[0811] Compound 77a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-30 mM ammonium acetate (50%-80% / 0-60 min gradient elution)) and then desalted with acetonitrile / 0.1% formic acid to give compound 77 (Rt 21 min, LC-MS: m / z = 627.32 (M+H) + ) and compound 78 (Rt 24 min, LC-MS: m / z=627.33 (M+H) + ).

[0812] Compound 77: 1 H-NMR (500MHz, DMSO-d6), δ: 8.08-7.90 (m, 2H), 7.71 (d, J = 6.9Hz, 1H), 7.54-7.32 (m, 2H), 7.27-7.09 (m, 1H), 6.78-6.41 (m, 2H), 5.72-5.48(m,2H),4.63-4.43(m,1H),4.39-3.76(m,6H),3.19(s,3H),1.73-1.51(m,3H),1.31-1.18(m,6H),0.70-0.48(m,3H).

[0813] Compound 78: 1 H-NMR (500MHz, DMSO-d6), δ: 8.08-7.90 (m, 2H), 7.74 (d, J = 7.0Hz, 1H), 7.54-7.33 (m, 2H), 7.28-7.10 (m, 1H), 6.84-6.6 4(m,1H),6.63-6.39(m,1H),5.80-5.50(m,2H),4.45-3.80(m,7H),3.20(s,3H),1.77-1.59(m,3H),1.33-1.18(m,9H).

[0814] The retention time of compound 77 in the chiral chromatographic column is shorter than that of compound 78, and the retention time of compound 77 in the chiral chromatographic column is longer than that of compound 78.

[0815] Example 79 and Example 80

[0816] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 3-dimethylamino-1-propanol to prepare compound 79a.

[0817] Compound 79a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-80% / 0-60 min gradient elution)) to give compound 79 (Rt 32 min, LC-MS: m / z=626.36 (M+H) + ) and compound 80 (Rt 36 min, LC-MS: m / z=626.36 (M+H) + ).

[0818] Compound 79: 1 H-NMR (500MHz, DMSO-d6), δ: 10.18 (br, 1H), 8.07-7.88 (m, 2H), 7.71 (d, J = 7.4Hz, 1H), 7. 51-7.42(m,1H),7.41-7.34(m,1H),7.26-7.10(m,1H),6.77-6.67(m,1H),6.61-6.43(m, 1H),5.66-5.45(m,2H),4.62-4.38(m,3H),4.34-4.18(m,1H),4.12-3.77(m,2H),2.42-2 .33(m,2H),2.22-2.10(m,6H),1.96-1.87(m,2H),1.69-1.53(m,3H),0.71-0.50(m,3H).

[0819] Compound 80: 1 H-NMR (500MHz, DMSO-d6), δ: 10.17 (br, 1H), 8.07-7.90 (m, 2H), 7.73 (d, J = 7.4Hz, 1 H),7.52-7.42(m,1H),7.38(d,J=2.5Hz,1H),7.24-7.13(m,1H),6.77-6.63(m,1H), 6.58-6.40(m,1H),5.75-5.51(m,2H),4.49-4.25(m,3H),4.13-3.80(m,3H),2.45- 2.35(m,2H),2.17(s,6H),1.97-1.85(m,2H),1.70-1.58(m,3H),1.27-1.17(m,3H).

[0820] The retention time of compound 79 in the chiral chromatographic column is shorter than that of compound 80, while the retention time of compound 80 in the chiral chromatographic column is longer than that of compound 79.

[0821] Example 81

[0822] Referring to the preparation process of compound 47b in Example 47, in step 1, tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-methyl)carbamate was used in place of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 81a. LC-MS: m / z = 788.41 (M+H). + .

[0823] 81a (430 mg) was dispersed in dichloromethane (10 mL), cooled to 0-5°C, trifluoroacetic acid (4 mL) was added, and the mixture was stirred for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure until no liquid flowed out. The residue was dissolved in dichloromethane (10 mL), and the pH of the system was adjusted to alkaline with saturated sodium bicarbonate solution under ice bath. Water (50 mL) and dichloromethane (50 mL) were added, stirred, and separated. The mixture was extracted with dichloromethane (50 mL*2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 81. LC-MS: m / z = 688.30 (M+H) + .

[0824] Example 82 and Example 83

[0825] Compound 81 was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (70%-90% / 0-60 min gradient elution)) to give compound 82 (Rt 23 min, LC-MS: m / z=688.35 (M+H) + ) and compound 83 (Rt 24 min, LC-MS: m / z=688.30 (M+H) + ).

[0826] The retention time of compound 82 in the chiral chromatographic column is shorter than that of compound 83, while the retention time of compound 83 in the chiral chromatographic column is longer than that of compound 82.

[0827] Example 84

[0828] Referring to the preparation process of compound 47b in Example 47, in step 1, 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (synthesized according to WO2022173032A1) was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 84a. LC-MS: m / z = 888.60 (M+H) + .

[0829] Compound 84a (200 mg) was dissolved in methanol (10 mL). p-Toluenesulfonic acid (10 mg) was added at room temperature and the reaction was stirred for 1 h. After the reaction was complete, the reaction solution was purified by preparative liquid chromatography (YMC C18 10 μm 50×250 column; acetonitrile-0.1% ammonia (50%-90% / 0-60 min gradient elution)) to obtain compound 84. LC-MS: m / z = 646.48 (M+H). + .

[0830] Example 85 and Example 86

[0831] Compound 84 was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-90% / 0-60 min gradient elution)) to give compound 85 (Rt 43 min, LC-MS: m / z=646.48 (M+H) + ) and compound 86 (Rt 47 min, LC-MS: m / z=646.48 (M+H) + ).

[0832] Compound 85: 1 H-NMR(500MHz,DMSO-d6),δ:13.18(br,1H),8.00(s,1H),7.86-7.60(m,2H), 7.56-7.33(m,1H),6.88-6.40(m,2H),5.83-5.48(m,2H),5.46-5.15(m,1H), 4.68-4.47(m,1H),4.46-3.90(m,4H),3.19-2.97(m,3H),2.92-2.73(m,1H), 2.31-1.95(m,6H),1.94-1.72(m,3H),1.71-1.50(m,3H),0.77-0.48(m,3H).

[0833] Compound 86: 1H-NMR(500MHz,DMSO-d6),δ:13.18(br,1H),8.09-7.95(m,1H),7.87-7.66(m,2H),7.54-7.4 0(m,1H),6.80-6.68(m,1H),6.58-6.43(m,1H),5.80-5.49(m,2H),5.44-5.17(m,1H),4.46- 4.33(m,1H),4.30-4.19(m,1H),4.14-4.03(m,1H),4.02-3.85(m,2H),3.16-2.99(m,3H),2. 91-2.77(m,1H),2.26-1.94(m,6H),1.92-1.73(m,3H),1.72-1.56(m,3H),1.33-1.15(m,3H).

[0834] The retention time of compound 85 in the chiral chromatographic column is shorter than that of compound 86, while the retention time of compound 86 in the chiral chromatographic column is longer than that of compound 85.

[0835] Example 87 and Example 88

[0836] Referring to the preparation process of compound 65d in Example 65, in step 2, methanol was replaced with N-methyl-L-prolinol to prepare compound 87a. LC-MS: m / z = 488.23 (M+H) + .

[0837] Step 1:

[0838] 87a (132 mg), ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (244 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (31 mg), potassium phosphate (171 mg), and water (3 mL) were dispersed in 1,4-dioxane (15 mL) and stirred at 90°C for 2 h under nitrogen protection. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (ethyl acetate:petroleum ether = 1:10 to 1:2) to give compound 87b. LC-MS: m / z = 778.59 (M+H) + .

[0839] Step 2:

[0840] 87b (130 mg) and cesium fluoride (253 mg) were dispersed in DMF (13 mL) and stirred at room temperature for 2 h. Water (50 mL) and ethyl acetate (80 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phases were washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present to obtain compound 87c. LC-MS: m / z = 622.37 (M+H) + .

[0841] Step 3:

[0842] Compound 87c was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-80% / 0-60 min gradient elution)) to give compound 87 (Rt 32 min, LC-MS: m / z=622.37 (M+H) + ) and compound 88 (Rt 35 min, LC-MS: m / z=622.37 (M+H) + ).

[0843] Compound 87: 1 H-NMR(500MHz,DMSO-d6),δ:8.27-8.12(m,2H),8.05-7.95(m,1H),7.78-7.5 0(m,4H),6.75-6.65(m,1H),6.61-6.43(m,1H),5.69-5.44(m,2H),4.61-4.38 (m,2H),4.34-3.81(m,4H),3.04-2.92(m,1H),2.72-2.58(m,1H),2.38(s,3H) ,2.28-2.16(m,1H),2.05-1.91(m,1H),1.79-1.54(m,6H),0.70-0.48(m,3H).

[0844] Compound 88: 1 H-NMR(500MHz,DMSO-d6),δ:8.44-8.09(m,2H),7.99(s,1H),7.89-7.36(m,4H),6.87-6.40(m,2H),5.64(s,2H),4.70-3.66(m,6H ),3.07-2.86(m,1H),2.73-2.56(m,1H),2.37(s,3H),2.28-2.12(m,1H),2.08-1.89(m,1H),1.83-1.52(m,6H),1.36-1.01(m,3H).

[0845] The retention time of compound 87 in the chiral chromatographic column is shorter than that of compound 88, while the retention time of compound 88 in the chiral chromatographic column is longer than that of compound 87.

[0846] Example 89 and Example 90

[0847] Step 1:

[0848] Compound 65b (600 mg) and ethanol (10 mL) were dispersed in dichloromethane (10 mL), cooled to 0°C, and sodium borohydride (65 mg) was slowly added. The mixture was allowed to stir at room temperature for 1 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction system to quench the reaction. Water (50 mL) and ethyl acetate (80 mL) were added, stirred, and separated. The mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with 5% brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was released to obtain compound 89a. LC-MS: m / z = 615.30 (M+H) + .

[0849] Step 2:

[0850] 89a (420 mg) was dispersed in trifluoroacetic acid (10 mL), cooled to 0°C, and methanesulfonic acid (1 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure until no liquid outflowed. The residue was dissolved in dichloromethane (10 mL), and the pH of the system was adjusted to alkaline with saturated sodium bicarbonate solution under ice bath. Water (50 mL) and dichloromethane (50 mL) were added, stirred, and separated. The mixture was extracted with dichloromethane (50 mL*2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid outflowed to obtain compound 89b. LC-MS: m / z = 375.25 (M+H) + .

[0851] Step 3:

[0852] 89b (180 mg), 10g (492 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine(2-amino-1,1'-biphenyl-2-yl)palladium(II) (55 mg), potassium phosphate (305 mg), and water (3 mL) were dispersed in 1,4-dioxane (15 mL) and stirred at 90°C under nitrogen for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (methanol:dichloromethane = 1:200 to 1:100) to obtain compound 89c. LC-MS: m / z = 725.35 (M+H) + .

[0853] Step 4:

[0854] 89c (220 mg) and cesium fluoride (592 mg) were dispersed in DMF (5 mL) and stirred at room temperature for 2 h. Water (50 mL) and ethyl acetate (80 mL) were added to the reaction solution, stirred, and the mixture separated. The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phases were washed with 5% brine (80 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid was present to obtain compound 89d. LC-MS: m / z = 569.25 (M+H) + .

[0855] Step 5:

[0856] Disperse 89d (220 mg) in dichloromethane (5 mL), cool to 0-5°C, and add a 4N 1,4-dioxane solution of hydrogen chloride to the reaction system dropwise. Stir and react for 1 h. After the reaction is complete, concentrate the reaction mixture under reduced pressure until no liquid remains, yielding compound 89e. LC-MS: m / z = 525.20 (M+H). + .

[0857] Step 6:

[0858] Compound 89e was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (55%-85% / 0-60 min gradient elution)) to give compound 89 (Rt 21 min, LC-MS: m / z=525.20 (M+H) + ) and compound 90 (Rt 24 min, LC-MS: m / z=525.22 (M+H) + ).

[0859] Compound 89: 1 H-NMR(500MHz,DMSO-d6),δ:10.24-10.00(m,1H),8.77-8.71(m,1H),8.03-7.9 4(m,2H),7.76-7.70(m,1H),7.50-7.43(m,1H),7.41-7.36(m,1H),7.25-7.13(m ,1H),6.74-6.60(m,2H),5.64-5.45(m,2H),4.60-4.50(m,1H),4.39-4.24(m,1 H),4.12-4.04(m,1H),4.03-3.81(m,1H),1.69-1.55(m,3H),0.67-0.52(m,3H).

[0860] Compound 90: 1H-NMR (500MHz, DMSO-d6), δ: 10.13 (br, 1H), 8.73 (s, 2H), 8.04-7.93 (m, 2H), 7.79-7.72 (m, 1H), 7.50-7.42 (m, 1H), 7.38 (d, J=2.5Hz, 1H ),7.24-7.14(m,1H),6.75-6.60(m,2H),5.70-5.58(m,1H),4.43-4.29(m,1H),4.06-3.80(m,3H),1.72-1.59(m,3H),1.28-1.16(m,3H).

[0861] The retention time of compound 89 in the chiral chromatographic column is shorter than that of compound 90, while the retention time of compound 90 in the chiral chromatographic column is longer than that of compound 89.

[0862] Example 91 and Example 92

[0863] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (R)-(4-methylmorpholin-3-yl)methanol to prepare compound 91a.

[0864] Compound 91a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-70% / 0-60 min gradient elution)) to give compound 91 (Rt 28 min, LC-MS: m / z=654.34 (M+H) + ) and compound 92 (Rt 30 min, LC-MS: m / z=654.35 (M+H) + ).

[0865] The retention time of compound 91 in the chiral chromatographic column is shorter than that of compound 92, while the retention time of compound 92 in the chiral chromatographic column is longer than that of compound 91.

[0866] Example 93 and Example 94

[0867] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-methyl-2-hydroxymethyl-1H-imidazole to prepare compound 93a.

[0868] Compound 93a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (35%-65% / 0-60 min gradient elution)) to give compound 93 (Rt 26 min, LC-MS: m / z=635.35 (M+H) +) and compound 94 (Rt 30 min, LC-MS: m / z=635.33 (M+H) + ).

[0869] The retention time of compound 93 in the chiral chromatographic column is shorter than that of compound 94, while the retention time of compound 94 in the chiral chromatographic column is longer than that of compound 93.

[0870] Example 95 and Example 96

[0871] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N,N-dimethylethanolamine to prepare compound 95a.

[0872] Compound 95a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-70% / 0-60 min gradient elution)) to give compound 95 (Rt 25 min, LC-MS: m / z=612.34 (M+H) + ) and compound 96 (Rt 28 min, LC-MS: m / z=612.34 (M+H) + ).

[0873] The retention time of compound 95 in the chiral chromatographic column is shorter than that of compound 96, while the retention time of compound 96 in the chiral chromatographic column is longer than that of compound 95.

[0874] Example 97 and Example 98

[0875] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (hexahydro-1H-pyrrolidine-7a-yl)methanol to prepare compound 97a.

[0876] Compound 97a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-70%-90% / 0-20-60 min gradient elution)) to give compound 97 (Rt 33 min, LC-MS: m / z=664.36 (M+H) + ) and compound 98 (Rt 36 min, LC-MS: m / z=664.36 (M+H) + ).

[0877] The retention time of compound 97 in the chiral chromatographic column is shorter than that of compound 98, while the retention time of compound 98 in the chiral chromatographic column is longer than that of compound 97.

[0878] Example 99 and Example 100

[0879] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-(tert-butoxycarbonylamino)cyclopropylmethanol to prepare compound 99a.

[0880] Compound 99a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (40%-90% / 0-60 min gradient elution)) to give compound 99 (Rt 34 min, LC-MS: m / z=610.32 (M+H) + ) and compound 100 (Rt 39 min, LC-MS: m / z=610.32 (M+H) + ).

[0881] The retention time of compound 99 in the chiral chromatographic column is shorter than that of compound 100, while the retention time of compound 100 in the chiral chromatographic column is longer than that of compound 99.

[0882] Example 101 and Example 102

[0883] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (R)-(1-methylpyrrolidin-3-yl)methanol to prepare compound 101a.

[0884] Compound 101a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; methanol-0.1% ammonia (40%-70% / 0-60 min gradient elution)) to give compound 101 (Rt 54 min, LC-MS: m / z=638.37 (M+H) + ) and compound 102 (Rt 58 min, LC-MS: m / z=638.40 (M+H) + ).

[0885] The retention time of compound 101 in the chiral chromatographic column is shorter than that of compound 102, while the retention time of compound 102 in the chiral chromatographic column is longer than that of compound 101.

[0886] Example 103 and Example 104

[0887] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (3S)-1-methylpyrrolidin-3-ol to prepare compound 103a.

[0888] Compound 103a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 103 (Rt 28.0 min, LC-MS: m / z=624.36 (M+H) + ) and compound 104 (Rt 29.9 min, LC-MS: m / z=624.36 (M+H) + ).

[0889] The retention time of compound 103 in the chiral chromatographic column is shorter than that of compound 104, while the retention time of compound 104 in the chiral chromatographic column is longer than that of compound 103.

[0890] Example 105 and Example 106

[0891] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol to prepare compound 105a.

[0892] Compound 105a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-70% / 0-60 min gradient elution)) to give compound 105 (Rt 37.2 min, LC-MS: m / z=656.33 (M+H) + ) and compound 106 (Rt 47.1 min, LC-MS: m / z=656.33 (M+H) + ).

[0893] The retention time of compound 105 in the chiral chromatographic column is shorter than that of compound 106, while the retention time of compound 106 in the chiral chromatographic column is longer than that of compound 105.

[0894] Example 107 and Example 108

[0895] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S)-1-((S)-1-methylpyrrolidin-2-yl)ethanol to prepare compound 107a.

[0896] Compound 107a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 107 (Rt 31.8 min, LC-MS: m / z=652.36 (M+H) + ) and compound 108 (Rt 34.8 min, LC-MS: m / z=652.36 (M+H) + ).

[0897] The retention time of compound 107 in the chiral chromatographic column is shorter than that of compound 108, while the retention time of compound 108 in the chiral chromatographic column is longer than that of compound 107.

[0898] Example 109 and Example 110

[0899] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S)-(1,4-dimethylpiperazin-2-yl)methanol to prepare compound 109a.

[0900] Compound 109a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-90% / 0-60 min gradient elution)) to give compound 109 (Rt 32.4 min, LC-MS: m / z=667.35 (M+H) + ) and compound 110 (Rt 37.1 min, LC-MS: m / z=667.35 (M+H) + ).

[0901] The retention time of compound 109 in the chiral chromatographic column is shorter than that of compound 110, while the retention time of compound 110 in the chiral chromatographic column is longer than that of compound 109.

[0902] Example 111 and Example 112

[0903] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S)-2-(dimethylamino)propanol to prepare compound 111a.

[0904] Compound 111a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 111 (Rt 25.0 min, LC-MS: m / z=626.43 (M+H)+ ) and compound 112 (Rt 27.1 min, LC-MS: m / z=626.43 (M+H) + ).

[0905] Compound 111: 1 H-NMR (500MHz, DMSO-d6), δ: 8.07-7.91 (m, 2H), 7.71 (d, J = 7.4Hz, 1H), 7.50-7 .41(m,1H),7.40-7.34(m,1H),7.25-7.10(m,1H),6.75-6.67(m,1H),6.60-6.4 4(m,1H),5.64-5.47(m,2H),4.60-4.43(m,2H),4.35-3.76(m,5H),3.02-2.93 (m,1H),2.24(s,6H),1.68-1.57(m,3H),1.09-1.00(m,3H),0.66-0.52(m,3H).

[0906] Compound 112: 1 H-NMR(500MHz,DMSO-d6),δ:8.06-7.88(m,2H),7.78-7.69(m,1H),7.50-7.42 (m,1H),7.37(d,J=2.5Hz,1H),7.23-7.12(m,1H),6.75-6.67(m,1H),6.59-6.4 1(m,1H),5.71-5.55(m,2H),4.55-4.17(m,3H),4.11-3.81(m,4H),3.01-2.91 (m,1H),2.24(s,6H),1.70-1.60(m,3H),1.26-1.21(m,3H),1.07-1.00(m,3H).

[0907] The retention time of compound 111 in the chiral chromatographic column is shorter than that of compound 112, while the retention time of compound 112 in the chiral chromatographic column is longer than that of compound 111.

[0908] Example 113 and Example 114

[0909] Referring to the preparation process of compound 65f in Example 65, in step 2, methanol was replaced with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methane-d2-ol; in step 4, 10 g was replaced with ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 113a.

[0910] Compound 113a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (60%-90% / 0-60 min gradient elution)) to give compound 113 (Rt 35.1 min, LC-MS: m / z=668.39 (M+H) + ) and compound 114 (Rt 37.1 min, LC-MS: m / z=668.35 (M+H) + ).

[0911] Compound 113: 1 H-NMR(500MHz,DMSO-d6),δ:8.39-8.12(m,2H),8.09-7.92(m,1H),7.81-7.51(m,4H ),6.80-6.64(m,1H),6.62-6.38(m,1H),5.73-5.52(m,2H),5.43-5.16(m,1H),4.69 -4.42(m,1H),4.38-4.20(m,1H),4.19-3.84(m,2H),3.16-2.96(m,3H),2.92-2.76( m,1H),2.25-1.96(m,3H),1.92-1.71(m,3H),1.70-1.53(m,3H),0.71-0.47(m,3H).

[0912] Compound 114: 1 H-NMR(500MHz,DMSO-d6),δ:8.32-8.09(m,2H),8.08-7.94(m,1H),7.82-7.50( m,4H),6.80-6.63(m,1H),6.62-6.35(m,1H),5.83-5.53(m,2H),5.45-5.17(m, 1H),4.44-4.27(m,1H),4.21-3.78(m,3H),3.18-2.99(m,3H),2.92-2.75(m,1H ),2.22-1.96(m,3H),1.92-1.72(m,3H),1.72-1.57(m,3H),1.32-1.15(m,3H).

[0913] The retention time of compound 113 in the chiral chromatographic column is shorter than that of compound 114, while the retention time of compound 114 in the chiral chromatographic column is longer than that of compound 113.

[0914] Example 115

[0915] Referring to the preparation process of compound 47b in Example 47, in step 1, 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was substituted for ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 115. LC-MS: m / z=658.32 (M+H) + .

[0916] Example 116 and Example 117

[0917] Referring to the preparation process of compound 47b in Example 47, in step 1, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was replaced with (2-amino-7-fluorobenzo[d]thiazol-4-yl)boronic acid to prepare compound 116a.

[0918] Compound 116a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-70%-90% / 0-20-60 min gradient elution)) to give compound 116 (Rt 41 min, LC-MS: m / z=664.34 (M+H) + ) and compound 117 (Rt 44 min, LC-MS: m / z=664.33 (M+H) + ).

[0919] The retention time of compound 116 in the chiral chromatographic column is shorter than that of compound 117, while the retention time of compound 117 in the chiral chromatographic column is longer than that of compound 116.

[0920] Example 118 and Example 119

[0921] Referring to the preparation process of compound 47b in Example 47, in step 1, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 118a.

[0922] Compound 118a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-70%-90% / 0-20-60 min gradient elution)) to give compound 118 (Rt 34 min, LC-MS: m / z=640.40 (M+H) + ) and compound 119 (Rt 39 min, LC-MS: m / z=640.41 (M+H) + ).

[0923] The retention time of compound 118 in the chiral chromatographic column is shorter than that of compound 119, while the retention time of compound 119 in the chiral chromatographic column is longer than that of compound 118.

[0924] Example 120 and Example 121

[0925] Referring to the preparation process of compound 47b in Example 47, in step 1, 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 120a.

[0926] Compound 120a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia (50%-70%-90% / 0-20-60 min gradient elution)) to give compound 120 (Rt 43 min, LC-MS: m / z=660.35 (M+H) + ) and compound 121 (Rt 47 min, LC-MS: m / z=660.35 (M+H) + ).

[0927] Compound 120: 1 H-NMR(500MHz,DMSO-d6),δ:8.31-8.11(m,1H),8.10-7.90(m,2H),7.90-7.43(m,4H),6.98-6.34(m,2H),5.88 -5.50(m,2H),5.46-5.15(m,1H),4.81-3.86(m,5H),3.24-2.74(m,4H),2.26-1.51(m,9H),0.78-0.40(m,3H).

[0928] Compound 121: 1H-NMR(500MHz,DMSO-d6),δ:8.30-7.90(m,3H),7.89-7.44(m,4H),6.79-6.42(m,2H),5.76-5.50(m, 2H),5.44-5.16(m,1H),4.49-3.84(m,5H),3.20-2.73(m,4H),2.27-1.54(m,9H),1.36-1.11(m,3H).

[0929] The retention time of compound 120 in the chiral chromatographic column is shorter than that of compound 121, while the retention time of compound 121 in the chiral chromatographic column is longer than that of compound 120.

[0930] Example 122 and Example 123

[0931] Compound 47 (30 mg) and Pd / C (10%, 24 mg) were dispersed in methanol (6 mL), replaced with hydrogen three times, and stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered and purified by preparative liquid chromatography (YMC C18 10 μm 50×250 column; acetonitrile-0.1% formic acid aqueous solution (5%-35% / 0-60 min gradient elution)) to afford compound 122. LC-MS: m / z = 670.38 (M+H) + .

[0932] Referring to the preparation process of compound 122, compound 48 was used to replace compound 47 to prepare compound 123. LC-MS: m / z=670.38 (M+H) + .

[0933] All chiral carbon atom configurations of compound 122 are the same as those of compound 47. All chiral carbon atom configurations of compound 123 are the same as those of compound 48.

[0934] Example 124 and Example 125

[0935] Referring to the preparation process of compound 47b in Example 47, in step 1, 2-(8-chloro-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 124a.

[0936] Compound 124a was purified by preparative liquid chromatography (YMC-TA-C18, 10 μm, 50*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-50 min gradient elution)) to give compound 125 (Rt 39 min, LC-MS: m / z=676.30 (M+H) + ); purified by preparative liquid chromatography (YMC-TA-C18, 10 μm, 50*250 column; methanol-0.1% ammonia aqueous solution (50%-100% / 0-40 min gradient elution)) to give compound 124 (Rt 28 min, LC-MS: m / z=676.32 (M+H) + ).

[0937] Example 126 and Example 127

[0938] Referring to the preparation process of compound 47b in Example 47, in step 1, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was replaced with (2-(dimethylamino)-3-fluorophenyl)boronic acid to prepare compound 126a.

[0939] Compound 126a was purified by preparative liquid chromatography (YMC-AQ-C18, 10 μm, 50*250 column; acetonitrile-0.1% TFA aqueous solution (10%-70% / 0-60 min gradient elution)) to give compound 126 (Rt 22 min, LC-MS: m / z=635.40 (M+H) + ); purified by preparative liquid chromatography (YMC-AQ-C18, 10 μm, 50*250 column; methanol-0.1TFA% aqueous solution (10%-70% / 0-60 min gradient elution)) to give compound 127 (Rt 43 min, LC-MS: m / z=635.40 (M+H) + ).

[0940] Example 128 and Example 129

[0941] Referring to the preparation process of compound 47b in Example 47, in step 1, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was replaced with (2-(dimethylamino)-3-methylphenyl)boronic acid to prepare compound 128a.

[0942] Compound 128a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 128 (Rt 29.5 min, LC-MS: m / z=631.45 (M+H) + ) and compound 129 (Rt 33.4 min, LC-MS: m / z=631.46 (M+H) + ).

[0943] The retention time of compound 128 in the chiral chromatographic column is shorter than that of compound 129, while the retention time of compound 129 in the chiral chromatographic column is longer than that of compound 128.

[0944] Example 130 and Example 131

[0945] Referring to the preparation process of compound 47c in Example 47, in step 1, triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 130a.

[0946] Compound 130a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% formic acid aqueous solution (20%-80% / 0-60 min gradient elution)) to give compound 130 (Rt 16.9 min, LC-MS: m / z=648.36 (M+H) + ) and compound 131 (Rt 18.0 min, LC-MS: m / z=648.36 (M+H) + ).

[0947] The retention time of compound 130 in the chiral chromatographic column is shorter than that of compound 131, while the retention time of compound 131 in the chiral chromatographic column is longer than that of compound 130.

[0948] Example 132 and Example 133

[0949] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 3-(1-pyrrolidinyl)-1-propanol to prepare compound 132a.

[0950] Compound 132a was purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; methanol-0.1% ammonia aqueous solution (40%-90% / 0-60min gradient elution)) and further purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; acetonitrile-0.1% acetic acid aqueous solution (15%-45% / 0-60min gradient elution)) to give compound 132 (Rt 40min, LC-MS: m / z=652.37 (M+H) + ) and compound 133 (Rt 38 min, LC-MS: m / z=652.36 (M+H) + ).

[0951] The retention time of compound 133 in the chiral chromatographic column is shorter than that of compound 132, while the retention time of compound 132 in the chiral chromatographic column is longer than that of compound 133.

[0952] Example 134 and Example 135

[0953] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 2-(azetidin-1-yl)ethanol to prepare compound 134a.

[0954] Compound 134a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 134 (Rt 31.56 min, LC-MS: m / z=624.33 (M+H) + ) and compound 135 (Rt 35.48 min, LC-MS: m / z=624.33 (M+H) + ).

[0955] The retention time of compound 134 in the chiral chromatographic column is shorter than that of compound 135, while the retention time of compound 135 in the chiral chromatographic column is longer than that of compound 134.

[0956] Example 136 and Example 137

[0957] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 2-morpholinoethanol to prepare compound 136a.

[0958] Compound 136a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (30%-90% / 0-60 min gradient elution)) to give compound 136 (Rt 29 min, LC-MS: m / z=654.34 (M+H) + ) and compound 137 (Rt 33 min, LC-MS: m / z=654.34 (M+H) + ).

[0959] The retention time of compound 136 in the chiral chromatographic column is shorter than that of compound 137, while the retention time of compound 137 in the chiral chromatographic column is longer than that of compound 136.

[0960] Example 138 and Example 139

[0961] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-(2-hydroxyethyl)pyrrolidine to prepare compound 138a.

[0962] Compound 138a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (50%-80% / 0-60 min gradient elution)) to give compound 138 (Rt 26.21 min, LC-MS: m / z=638.38 (M+H) + ) and compound 139 (Rt 38.27 min, LC-MS: m / z=638.39 (M+H) + ).

[0963] The retention time of compound 138 in the chiral chromatographic column is shorter than that of compound 139, while the retention time of compound 139 in the chiral chromatographic column is longer than that of compound 138.

[0964] Example 140 and Example 141

[0965] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-tert-butyloxycarbonyl-4-(3-hydroxypropane)piperazine to prepare compound 140a.

[0966] Compound 140a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (35%-65%-65% / 0-60-70 min gradient elution)) to give compound 140 (Rt 56.35 min, LC-MS: m / z=667.38 (M+H) +) and compound 141 (Rt 62.30 min, LC-MS: m / z=667.36 (M+H) + ).

[0967] The retention time of compound 140 in the chiral chromatographic column is shorter than that of compound 141, while the retention time of compound 141 in the chiral chromatographic column is longer than that of compound 140.

[0968] Example 142 and Example 143

[0969] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-piperidinol to prepare compound 142a.

[0970] Compound 142a was purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; methanol-0.1% ammonia aqueous solution (45%-85% / 0-60min gradient elution)) and then purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; acetonitrile-0.1% acetic acid aqueous solution (15%-45% / 0-60min gradient elution)) to give compound 142 (Rt 28min, LC-MS: m / z=666.38 (M+H) + ) and compound 143 (Rt 29 min, LC-MS: m / z=666.40 (M+H) + ).

[0971] The retention time of compound 142 in the chiral chromatographic column is shorter than that of compound 143, while the retention time of compound 143 in the chiral chromatographic column is longer than that of compound 142.

[0972] Example 144 and Example 145

[0973] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 3-(dimethylamino)-2-methyl-1-propanol to prepare compound 144a.

[0974] Compound 144a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-70% / 0-60 min gradient elution)) to give compound 144 (Rt 36.54 min, LC-MS: m / z=640.38 (M+H) + ) and compound 145 (Rt 47.57 min, LC-MS: m / z=640.38 (M+H) + ).

[0975] The retention time of compound 144 in the chiral chromatographic column is shorter than that of compound 145, while the retention time of compound 145 in the chiral chromatographic column is longer than that of compound 144.

[0976] Example 146 and Example 147

[0977] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol to prepare compound 146a.

[0978] Compound 146a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-70% / 0-60 min gradient elution)) to give compound 146 (Rt 35.37 min, LC-MS: m / z=656.32 (M+H) + ) and compound 147 (Rt 42.08 min, LC-MS: m / z=656.33 (M+H) + ).

[0979] The retention time of compound 146 in the chiral chromatographic column is shorter than that of compound 147, while the retention time of compound 147 in the chiral chromatographic column is longer than that of compound 146.

[0980] Example 148 and Example 149

[0981] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol to prepare compound 148a.

[0982] Compound 148a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-70% / 0-60 min gradient elution)) to give compound 148 (Rt 30.18 min, LC-MS: m / z=674.32 (M+H) + ) and compound 149 (Rt 49.50 min, LC-MS: m / z=674.32 (M+H) + ).

[0983] The retention time of compound 148 in the chiral chromatographic column is shorter than that of compound 149, while the retention time of compound 149 in the chiral chromatographic column is longer than that of compound 148.

[0984] Example 150 and Example 151

[0985] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (1-((dimethylamino)methyl)cyclopropyl)methanol to prepare compound 150a.

[0986] Compound 150a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 150 (Rt 37 min, LC-MS: m / z=652.36 (M+H) + ) and compound 151 (Rt 38 min, LC-MS: m / z=652.34 (M+H) + ).

[0987] The retention time of compound 150 in the chiral chromatographic column is shorter than that of compound 151, while the retention time of compound 151 in the chiral chromatographic column is longer than that of compound 150.

[0988] Example 152 and Example 153

[0989] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (R)-2-(dimethylamino)propanol to prepare compound 152a.

[0990] Compound 152a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% formic acid aqueous solution (20%-80% / 0-60 min gradient elution)) to give compound 152 (Rt 13.9 min, LC-MS: m / z=626.33 (M+H) + ) and compound 153 (Rt 16.7 min, LC-MS: m / z=626.33 (M+H) + ).

[0991] The retention time of compound 152 in the chiral chromatographic column is shorter than that of compound 153, while the retention time of compound 153 in the chiral chromatographic column is longer than that of compound 152.

[0992] Example 154 and Example 155

[0993] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 3-(4-morpholino)-1-propanol to prepare compound 154a.

[0994] Compound 154a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% formic acid aqueous solution (20%-80% / 0-60 min gradient elution)) to give compound 154 (Rt 13.8 min, LC-MS: m / z=668.34 (M+H) + ) and compound 155 (Rt 15.4 min, LC-MS: m / z=668.32 (M+H) + ).

[0995] The retention time of compound 154 in the chiral chromatographic column is shorter than that of compound 155, while the retention time of compound 155 in the chiral chromatographic column is longer than that of compound 154.

[0996] Example 156 and Example 157

[0997] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N,N,3-trimethylazetidin-3-amine dihydrochloride to prepare compound 156a.

[0998] Compound 156a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% acetic acid aqueous solution (5%-45% / 0-80 min gradient elution)) to give compound 156 (Rt 55.26 min, LC-MS: m / z=637.38 (M+H) + ) and compound 157 (Rt 63.01 min, LC-MS: m / z=637.39 (M+H) + ).

[0999] The retention time of compound 156 in the chiral chromatographic column is shorter than that of compound 157, while the retention time of compound 157 in the chiral chromatographic column is longer than that of compound 156.

[1000] Example 158 and Example 159

[1001] Referring to the preparation process of compound 87b in Example 87, in step 1, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was replaced with tert-butyl(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-methyl)carbamate to prepare compound 158a.

[1002] Compound 158a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% acetic acid aqueous solution (10%-45% / 0-80 min gradient elution)) to give compound 158 (Rt 54.7 min, LC-MS: m / z=644.34 (M+H) + ) and compound 159 (Rt 59.37 min, LC-MS: m / z=644.36 (M+H) + ).

[1003] The retention time of compound 158 in the chiral chromatographic column is shorter than that of compound 159, while the retention time of compound 159 in the chiral chromatographic column is longer than that of compound 158.

[1004] Example 160 and Example 161

[1005] Referring to the preparation process of compound 87b in Example 87, in step 1, ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was replaced with (3-methyl-2-(trifluoromethyl)phenyl)boronic acid to prepare compound 160a.

[1006] Compound 160a was purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; methanol-0.1% acetic acid aqueous solution (20%-50% / 0-60min gradient elution)) to give compound 160 (Rt 45min, LC-MS: m / z=612.34 (M+H) + ) and compound 161 (Rt 48 min, LC-MS: m / z=612.33 (M+H) + ).

[1007] The retention time of compound 160 in the chiral chromatographic column is shorter than that of compound 161, while the retention time of compound 161 in the chiral chromatographic column is longer than that of compound 160.

[1008] Example 162 and Example 163

[1009] Referring to the preparation process of compound 87b in Example 87, in step 1, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was used to replace ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 162a.

[1010] Compound 162a was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (50%-70%-100% / 0-20-60 min gradient elution)) to give compound 162 (Rt 36.12 min, LC-MS: m / z=647.27 (M+H) + ) and compound 163 (Rt 39.01 min, LC-MS: m / z=647.27 (M+H) + ).

[1011] The retention time of compound 162 in the chiral chromatographic column is shorter than that of compound 163, while the retention time of compound 163 in the chiral chromatographic column is longer than that of compound 162.

[1012] Example 164 and Example 165

[1013] Refer to the preparation process of compound 65f in Example 65. In step 2, methanol is replaced with (hexahydro-1H-pyrrolidine-7a-yl)methanol; in step 4, 10 g is replaced with 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine to prepare compound 164a.

[1014] Compound 164a was purified by preparative liquid chromatography (YMC-AQ-C18, 10 μm, 50*250 column; methanol-0.1% acetic acid aqueous solution (10%-70% / 0-60 min gradient elution)) to give compound 164 (Rt 27.34 min, LC-MS: m / z=663.37 (M+H) + ) and compound 165 (Rt 32.16 min, LC-MS: m / z=663.38 (M+H) + ).

[1015] The retention time of compound 164 in the chiral chromatographic column is shorter than that of compound 165, while the retention time of compound 165 in the chiral chromatographic column is longer than that of compound 164.

[1016] Example 166 and Example 167

[1017] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N-hydroxyethylpiperidine to prepare compound 166a.

[1018] Compound 166a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 166 (Rt 34.34 min, LC-MS: m / z=652.35 (M+H) + ) and compound 167 (Rt 38.08 min, LC-MS: m / z=652.36 (M+H) + ).

[1019] The retention time of compound 166 in the chiral chromatographic column is shorter than that of compound 167, while the retention time of compound 167 in the chiral chromatographic column is longer than that of compound 166.

[1020] Example 168 and Example 169

[1021] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-hydroxyethyl-4-methylpiperazine to prepare compound 168a.

[1022] Compound 168a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 168 (Rt 28.56 min, LC-MS: m / z=667.37 (M+H) + ) and compound 169 (Rt 32.12 min, LC-MS: m / z=667.37 (M+H) + ).

[1023] The retention time of compound 168 in the chiral chromatographic column is shorter than that of compound 169, while the retention time of compound 169 in the chiral chromatographic column is longer than that of compound 168.

[1024] Example 170 and Example 171

[1025] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 1-(3-hydroxypropyl)-4-methylpiperazine to prepare compound 170a.

[1026] Compound 170a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 170 (Rt 27.54 min, LC-MS: m / z=681.39 (M+H)+ ) and compound 171 (Rt 31.58 min, LC-MS: m / z=681.37 (M+H) + ).

[1027] The retention time of compound 170 in the chiral chromatographic column is shorter than that of compound 171, while the retention time of compound 171 in the chiral chromatographic column is longer than that of compound 170.

[1028] Example 172 and Example 173

[1029] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with 2-(3-fluoroazetidin-1-yl)ethanol to prepare compound 172a.

[1030] Compound 172a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 172 (Rt 24.14 min, LC-MS: m / z=642.34 (M+H) + ) and compound 173 (Rt 28.07 min, LC-MS: m / z=642.35 (M+H) + ).

[1031] The retention time of compound 172 in the chiral chromatographic column is shorter than that of compound 173, while the retention time of compound 173 in the chiral chromatographic column is longer than that of compound 172.

[1032] Example 174 and Example 175

[1033] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (R)-2-(azetidin-1-yl)propanol to prepare compound 174a.

[1034] Compound 174a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (40%-60%-90% / 0-15-60 min gradient elution)) to give compound 174 (Rt 33.57 min, LC-MS: m / z=638.38 (M+H) + ) and compound 175 (Rt 37.53 min, LC-MS: m / z=638.26 (M+H) + ).

[1035] The retention time of compound 174 in the chiral chromatographic column is shorter than that of compound 175, while the retention time of compound 175 in the chiral chromatographic column is longer than that of compound 174.

[1036] Example 176 and Example 177

[1037] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol to prepare compound 176a.

[1038] Compound 176a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% acetic acid aqueous solution (30%-90% / 0-60 min gradient elution)) to give compound 176 (Rt 19.34 min, LC-MS: m / z=694.36 (M+H) + ) and compound 177 (Rt 24.16 min, LC-MS: m / z=694.35 (M+H) + ).

[1039] The retention time of compound 176 in the chiral chromatographic column is shorter than that of compound 177, while the retention time of compound 177 in the chiral chromatographic column is longer than that of compound 176.

[1040] Example 178 and Example 179

[1041] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with (S)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol to prepare compound 178a.

[1042] Compound 178a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% acetic acid aqueous solution (20%-80% / 0-60 min gradient elution)) to give compound 178 (Rt 26.35 min, LC-MS: m / z = 676.30 (M+H) + ) and compound 179 (Rt 34.01 min, LC-MS: m / z=676.32 (M+H) + ).

[1043] The retention time of compound 178 in the chiral chromatographic column is shorter than that of compound 179, while the retention time of compound 179 in the chiral chromatographic column is longer than that of compound 178.

[1044] Example 180 to Example 425

[1045] With reference to Route 1 and Examples 1-179 of this application, the following compounds were prepared:

[1046] Experimental Example 1 Nucleotide Exchange Experimental Method

[1047] 1. Reagents: His-KRAS G12D (1-169); SOS1 cat (564-1049); GDP (purchased from Sigma); Anti-6HIS-Cryptate (purchased from Cisbio); EDA-GTP-DY-647P1 (purchased from Jena Bioscience)

[1048] 2. Prepare buffer solution:

[1049] 1) Assay buffer: HEPES pH 7.4, NaCl, MgCl2, DTT, BSA, Igepal;

[1050] 2) KRAS G12D working solution: Prepare KRAS G12D working solution containing 100 nM His-KRAS G12D and 2 nM Anti-6HIS-Cryptate in assay buffer;

[1051] 3) SOS1 cat Working solution: Prepared with assay buffer containing 20 nM SOS1 cat and 200 nM EDA-GTP-DY-647P1 SOS1 cat Working fluid;

[1052] 4) Blank control working solution: Prepare a blank control solution containing 2 nM Anti-6HIS-Cryptate using assay buffer.

[1053] 3. Testing process:

[1054] The entire experimental process was completed at room temperature. Using a black bottom transparent 384-well plate, 5 μL of KRAS G12D working solution was added to each well of the experimental group and the negative group. At the same time, 5 μL of blank control working solution was added to each well of the blank group and incubated at room temperature for 10 minutes. Then, an ultra-micropipette was used to add a compound with a starting concentration of 100 μM and 8 concentration gradients of continuous 1:2 dilution to the experimental group and incubated at room temperature for 30 minutes. Finally, 5 μL of SOS1 was added to each well. cat The working solution was incubated at room temperature for 15 minutes, and the signal values ​​at 665 nm / 620 nm were measured using a PerkinElmer Envision HTS multi-label reader. The inhibition rate was calculated as: inhibition rate (%) = (average value of negative control group - average value of experimental group) / (average value of negative control group - average value of blank group) × 100%. The logarithm of compound concentration was used as the horizontal axis, and the inhibition rate was used as the vertical axis. A four-parameter logistic model was used to fit the curve and calculate the IC 50 value.

[1055] Test Example 2 AsPc-1 cell proliferation inhibitory activity assay

[1056] Take AsPc-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 Cells were inoculated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 5000 nM to 0.31 nM in duplicate wells. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 3 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[1057] Test Example 3 Capan-1 cell proliferation inhibitory activity assay

[1058] Take Capan-1 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1.5×10 4 Cells were plated at 100 μL / mL in a 96-well plate (100 μL / well). Compounds were added using a nanoliter pipette to a final concentration of 20,000 nM to 9.1 nM in duplicate wells. A control was also set up. After 5 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[1059] The test results of some compounds disclosed in the present invention are shown in Table 1.

[1060] Table 1 Test results of some compounds Note: A stands for IC 50 ≤100nM; B represents 100nM<IC 50 ≤500nM; C represents 500nM<IC 50 ≤999nM; ——represents IC 50 Value not detected.

[1061] Test Example 4: In vitro liver microsome stability

[1062] Liver microsomal incubation samples (species: human, monkey, rat, and mouse) were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. The sample was added to acetonitrile containing an internal standard for protein precipitation, and the supernatant was prepared. The supernatant was diluted and analyzed by LC / MS / MS. The results are shown in Table 2.

[1063] Table 2. In vitro liver microsome metabolic stability results

[1064] Experimental Example 5: Pharmacokinetic Evaluation in Mice

[1065] ICR mice weighing 20-24 g were acclimated for 3-5 days and then randomly divided into groups of 9 mice each. The experimental compound was orally administered at a dose of 10 mg / kg.

[1066] The test animals (ICR mice) were fasted for 12 h before administration and given food 4 h after administration. They had free access to water before, during and after the experiment.

[1067] After oral administration, blood samples were collected from the eye sockets of three mice at three to four time points: 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h after oral administration. Blood samples were collected from three mice at each time point. Approximately 0.1 mL of blood was collected from the eye sockets. After anticoagulation with EDTA-K2, the blood was transferred to 4°C and centrifuged at 4000 rpm for 10 min within 30 min to separate plasma. All collected plasma was immediately stored at -20°C until testing.

[1068] Pipette 20 μL of the plasma sample to be tested and the standard sample, add 400 μL of acetonitrile solution containing the internal standard (20 ng / mL), shake and mix for 10 minutes, centrifuge at 13000 rpm for 10 minutes, take 50 μL of the supernatant, add 100 μL of ultrapure water to dilute, mix, and take 0.5 μL for LC / MS / MS determination, and record the chromatogram.

[1069] The oral exposure of the compound of the present invention was evaluated by in vivo pharmacokinetic experiments in mice. The experimental results are shown in Table 3.

[1070] Table 3 a The gavage parameters were fitted to 6 h.

[1071] Test Example 6: Pharmacokinetic evaluation in rats

[1072] SD rats, weighing 180-220 g, were randomly divided into three groups after acclimation for 3-5 days, with three rats in each group, and the compound was orally administered at a dose of 10 mg / kg.

[1073] The test animals (SD rats) were fasted for 12 h before administration and given food 4 h after administration. They had free access to water before, during and after the experiment.

[1074] After oral administration, approximately 0.2 mL of blood was collected from the eye socket at 0 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. After anticoagulation with EDTA-K2, the blood was transferred to 4°C within 30 min and centrifuged at 4000 rpm for 10 min to separate plasma. All collected plasma was immediately stored at -20°C until testing.

[1075] Pipette 50 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing the internal standard (diazepam 20 mg / mL), shake and mix for 5 minutes, centrifuge at 13000 rpm for 10 minutes, take 75 μL of the supernatant, add 75 μL of ultrapure water to dilute, mix, and take 2 μL for LC / MS / MS determination, and record the chromatogram.

[1076] Experimental Example 7: Pharmacodynamic Evaluation of Aspc-1 Human Pancreatic Cancer Cell Subcutaneous Transplantation Model in NOD-SCID Mice

[1077] SPF female NOD-SCID mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.) were subcutaneously inoculated with 1×107 Aspc-1 human pancreatic cancer cells per mouse in the right axilla. When the average tumor volume reached approximately 200 mm3, the animals were divided into groups.

[1078] The day of grouping was designated Day 0. Starting from Day 1, drugs were administered intraperitoneally once daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[1079] The detection indicators and calculation formulas are as follows:

[1080] Tumor volume, TV (mm3) = 1 / 2 × (a × b2); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[1081] Relative tumor volume, RTV=TVt / TV0; TV0 is the tumor volume on day 0, and TVt is the tumor volume at each measurement.

[1082] Relative tumor growth rate, T / C (%) = TRTV / CRTV × 100%; where TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.

[1083] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[1084] Body weight change rate, WCR (%) = (Wtt-Wt0) / Wt0×100%; wherein Wt0 is the weight of the mouse on day 0, and Wtt is the weight of the mouse at each measurement.

Claims

1. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in, X is selected from -N-, or optionally replaced by R x substituted -CH-; R x Selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino; L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 1-4 heteroalkenylene; Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino; R 2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-12 Alkyl, C 1-12 Heteroalkyl, 3-12 membered cycloalkyl-L 2 -, 4-12 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -; L 2 Selected from single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, or C 1-6 heteroalkenylene; Each R 2a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 2c R 2d 、-NR 2c C(O)R 2d 、-NHC(O)NR 2c R 2d 、-NR 2c C(O)OR 2d 、-OC(O)R 2d 、-C(O)OR 2d 、-OC(O)OR 2d 、-OC(O)NR 2c R 2d 、-SO2R 2d 、-NHSO2R 2d 、-C 1-6 Alkylene C(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)R 2d 、-C 1-6 Alkylene NHC(O)NR 2c R 2d 、-C 1-6 Alkylene NR 2c C(O)OR 2d 、-C 1-6 AlkyleneOC(O)R 2d 、-C 1-6 Alkylene C(O)OR 2d 、-C 1-6 Alkylene OC(O)NR 2c R 2d 、-C 1-6 Alkylene SO2R 2d 、-C 1-6 Alkylene OSO2R 2d 、-C 1-6 Alkylene NHSO2R 2d , or optionally one or more R 2b Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene; R 2c Independently selected from H, deuterium, or C 1-6 alkyl; R 2d independently selected from H, deuterium, or optionally substituted by one or more R 2e Substituted with the following groups: C 1-6 Alkyl, C 1-6 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene; Each R 2e independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; Each R 2b independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-12 alkyl)-; Each R z independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 haloalkylamino; R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-12 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene; Each R 3a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, -C(O)NR 3c R 3d 、-NR 3c C(O)R 3d 、-NHC(O)NR 3c R 3d 、-NR 3c C(O)OR 3d 、-OC(O)R 3d 、-C(O)OR 3d 、-OC(O)OR 3d 、-OC(O)NR 3c R 3d 、-SO2R 3d 、-NHSO2R 3d 、-C 1-6 Alkylene C(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)R 3d 、-C 1-6 Alkylene NHC(O)NR 3c R 3d 、-C 1-6 Alkylene NR 3c C(O)OR 3d 、-C 1-6 AlkyleneOC(O)R 3d 、-C 1-6 Alkylene C(O)OR 3d 、-C 1-6 Alkylene OC(O)NR 3c R 3d 、-C 1-6 Alkylene SO2R 3d 、-C 1-6 Alkylene OSO2R 3d 、-C 1-6 Alkylene NHSO2R 3d , or optionally one or more R 3b Substituted groups: =NH, =CH2, =N(C 1-6 alkyl), =CH(C 1-6 alkyl), =C(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl C 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene; R 3c Independently selected from H, deuterium, or C 1-6 alkyl; R 3d independently selected from H, deuterium, or optionally substituted by one or more R 3e Substituted with the following groups: C 1-12 Alkyl, C 1-12 heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 alkylene; Each R 3b independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Each R 3e Independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 alkyl halide; R 4 Selected from H, deuterium, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Halogenated alkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Ring A is selected from the group consisting of 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Each R 5 independently selected from deuterium, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, C 1-12 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl; Each R 5a independently selected from deuterium, halogen, -OH, oxo, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, or di-C 1-4 Alkylamino; Each L 1 、L 2 、R 1 、R 2 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 3 、R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 4 、R 5 、R 5a 、R x , or R z Each is independently optionally substituted with one or more substituents.

2. The compound of formula (I) according to claim 1, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The R x Selected from deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 haloalkylamino; Alternatively, the R x Selected from deuterium, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Alternatively, the R x Selected from deuterium, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; Alternatively, the R x Selected from deuterium, F, Cl, Br, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; Alternatively, the R x is selected from deuterium, F, Cl, Br, -OH, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy; Alternatively, the X is selected from -N-, -CH-, -C(C 1-6 alkyl)-, or -C(C 1-6 haloalkyl)-; Alternatively, the X is selected from -N-, -CH-, -C(C 1-3 alkyl)-, or -C(C 1-3 haloalkyl)-; Alternatively, said X is selected from -N-.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The L 1 Selected from -O-, -S-, or optionally one or more R 1 Substituted groups: -NH-, C 1-5 Alkylene, C 1-4 Heteroalkylene, C 2-5 Alkenylene, or C 2-4 heteroalkenylene; Alternatively, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 1-3 heteroalkenylene; Alternatively, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, C 1-3 Heteroalkylene, C 2-4 Alkenylene, or C 2-3 heteroalkenylene; Alternatively, the L 1 Selected from -O-, or optionally one or more R 1 Substituted groups: -NH-, C 2-4 Alkylene, or C 1-3 heteroalkylene; Alternatively, the L 1 Selected from -O-, or optionally one or more R 1 Substituted as follows: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, -CH2CH2O-, -O(CH2)3-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2CH2O-, -NHCH2-, -NHCH2CH2-, -CH2NHCH2-, -CH2CH2NH-, -NH(CH2)3-, -CH2NHCH2CH2-, -CH2CH2NHCH2-, or -CH2CH2CH2NH-; Alternatively, the L 1 Selected from -O-, or optionally one or more R 1 Substituted as follows: -NH-, -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-; Alternatively, the L 1 Selected from -O-, -NH-, -N(C 1-3 alkyl)-, or optionally substituted by one or more R 1 Substituted as follows: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-; Alternatively, the L 1 Selected from -O-, -NH-, -N(CH3)-, or optionally one or more R 1 Substituted as follows: -CH2CH2-, -(CH2)3-, -(CH2)4-, -OCH2-, -OCH2CH2-, -O(CH2)3-, -NHCH2-, -NHCH2CH2-, or -NH(CH2)3-; Alternatively, the L 1 Selected from optionally one or more R 1 Substituted with the following groups: -(CH2)3-, -OCH2CH2-, or -NHCH2CH2-; Alternatively, the L 1 Selected from optionally one or more R 1 Substituted -OCH2CH2-.

4. The compound of formula (I) according to any one of claims 1 to 3, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: Each R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 haloalkylamino; Alternatively, each of the R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Haloalkyl, or C 1-6 haloalkoxy; Alternatively, each of the R 1 independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, di-C 1-3 Alkylamino, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; Alternatively, each of the R 1 independently selected from deuterium, F, Cl, Br, -OH, oxo, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, or C 1-3 haloalkoxy; Alternatively, each of the R 1 independently selected from deuterium, F, Cl, Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, , trifluoromethoxy, or -CH2F; Alternatively, each of the R 1 Independently selected from deuterium, methyl, ethyl, isopropyl, trifluoromethyl, or -CH2F.

5. The compound of formula (I) according to any one of claims 1 to 4, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The R 2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocyclic group-L 2 -, 6-10 membered aryl-L 2 -, or 5-10 membered heteroaryl-L 2 -; Alternatively, the R 2 is selected from H, deuterium, halogen, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-10 membered cycloalkyl-L 2 -, 4-10 membered heterocyclic group-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, or benzo 5-6 membered heteroaryl-L 2 -; Alternatively, the R 2 is selected from H, deuterium, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocyclic group-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, benzo 5-6 membered heterocyclic group-L 2 -, benzo 5-6 membered heteroaryl-L 2 -, or 5-6 membered heteroaryl and 5-6 membered cycloalkenyl-L 2 -; Alternatively, the R 2 is selected from H, deuterium, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted with the following groups: C 1-4 Alkyl, C 1-4 Heteroalkyl, 3-8 membered cycloalkyl-L 2 -, 4-8 membered heterocycloalkyl-L 2 -, phenyl-L 2 -, naphthyl-L 2 -, 5-6 membered heteroaryl-L 2 -, benzo 5-6 membered heterocyclic group-L 2 -, benzo 5-6 membered heteroaryl-L 2 -, or 5-6 membered heteroaryl and 5-6 membered cycloalkenyl-L 2 -; Alternatively, the R 2 is selected from H, deuterium, F, Cl, Br, -OH, -NH2, -CN, or optionally substituted by one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, Oxetane, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolyl, Alternatively, the R 2 is selected from H, deuterium, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, 6. The compound of formula (I) according to any one of claims 1 to 5, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted groups: -NH-, or -N(C 1-6 alkyl)-; Alternatively, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-12 alkyl)-; Alternatively, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-6 alkyl)-; Alternatively, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-; Alternatively, Z is selected from a single bond, -O-, or -N(C 1-3 alkyl)-; Alternatively, Z is selected from a single bond, -O-, -NH-, or -N(CH3)-; Alternatively, Z is selected from a single bond, -O-, or -N(CH3)-; Alternatively, said Z is selected from -O-.

7. The compound of formula (I) according to any one of claims 1 to 6, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-6 Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl C 1-4 Alkylene, 3-10 membered heterocyclic group C 1-4 Alkylene, 6-10 membered aryl C 1-4 Alkylene, or 5-10 membered heteroaryl C 1-4 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-10 membered cycloalkyl C 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocyclic group, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocycloalkyl, 3-8 membered cycloalkyl C 1-3 Alkylene, 4-8 membered heterocycloalkyl C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted groups include methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, hexahydro-1H-pyrrolazinyl, cyclopropyl C 1-3 Alkylene, cyclobutyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, cyclohexyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene, tetrahydropyrrolyl C 1-3 Alkylene, morpholinyl C 1-3 Alkylene, piperidinyl C 1-3 Alkylene, piperazinyl C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or imidazolyl C 1-3 alkylene; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted groups: methyl, piperidinyl, cyclopropyl C 1-3 Alkylene, cyclopentyl C 1-3 Alkylene, tetrahydropyrrole C 1-3 Alkylene, hexahydro-1H-pyrrolizinyl C 1-3 Alkylene, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl C 1-3 Alkylene, 5-azaspiro[2.4]heptyl C 1-3 Alkylene, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, morpholinyl C 1-3 Alkylene, imidazolyl C 1-3 Alkylene, tetrahydropyrrolyl, piperazinyl C 1-3 Alkylene, azetidinyl C 1-3 Alkylene C-piperidinyl 1-3 Alkylene, azetidinyl, cyclobutyl, cyclohexyl, cyclobutyl C 1-3 Alkylene, or piperazinyl; Alternatively, the R 3 selected from H, deuterium, or optionally substituted by one or more R 3a Substituted groups: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Alternatively, the R 3 Selected from H, deuterium, methyl, 8. The compound of formula (I) according to any one of claims 1 to 7, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The R 4 Selected from H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 haloalkoxy, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Alternatively, the R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 haloalkoxy; Alternatively, the R 4 Selected from H, deuterium, -F, -Cl, -Br, -CN, C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Haloalkyl, or C 1-2 haloalkoxy; Alternatively, the R 4 Selected from H, deuterium, -F, -Cl, -Br, C 1-2 Alkyl, C 1-2 Alkoxy, or C 1-2 Fluorinated alkyl; Alternatively, the R 4 is selected from H, deuterium, -F, -Cl, -Br, methyl, methoxy, difluoromethyl, or trifluoromethyl; Alternatively, the R 4 is selected from H, deuterium, -F, -Cl, or methyl; Alternatively, the R 4 is selected from H, deuterium, -F, or -Cl.

9. The compound of formula (I) according to any one of claims 1 to 8, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The ring A is selected from the group consisting of 5 Substituted: 3-6 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Alternatively, the ring A is selected from the group consisting of 5 Substituted groups include: 6-10 membered aryl, 4-6 membered benzocycloalkenyl, 4-6 membered benzo heterocyclyl, or 5-10 membered heteroaryl; Alternatively, the ring A is selected from the group consisting of 5 substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzopyrimidinyl, benzothienyl, pyridopyrazolyl, or pyridopyrrolyl; Alternatively, the ring A is selected from the group consisting of 5 Substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, pyrazolyl, pyridopyrazolyl, or pyridopyrrolyl; Alternatively, the ring A is selected from the group consisting of 5 Substituted phenyl, naphthyl, pyridyl, benzothiazolyl, benzothiophenyl, isoquinolinyl, benzopyrazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolinyl, indolyl, or benzimidazolyl; Alternatively, the ring A is selected from the group consisting of 5 Substituted phenyl, naphthyl, pyridyl, isoquinolyl, benzopyrazolyl, benzothiazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolyl, indolyl, or benzimidazolyl; Alternatively, the ring A is selected from 10. The compound of formula (I) according to any one of claims 1 to 9, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: Each R 5 independently selected from deuterium, halogen, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl; Alternatively, each of the R 5 independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted groups include methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylamino, dimethylamino, methylthio, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl; Alternatively, each of the R 5 independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted groups such as methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylthio, or cyclopropane; Alternatively, each of the R 5 independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, trifluoromethyl, hydroxymethylene, methoxy, trifluoromethoxy, methylamino, dimethylamino, methylthio, trifluoromethylthio, or cyclopropane optionally substituted with -F, -Cl, -Br, or methyl; Alternatively, each of the R 5 Independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, propynyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, or methyl-substituted cyclopropane.

11. A compound of formula (I) according to any one of claims 1 to 10, a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula (II-1) or formula (II-2) or formula (III) or formula (III-a) or formula (III-b) or formula (III-c) or formula (IV) or formula (IV-a) or formula (IV-b) or formula (IV-c), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in, L 1 、R 1 、R 2 、R 3 、R 4 , Z, and ring A moiety are as defined in any one of claims 1-10; n is selected from 0, 1, 2, 3, 4 or 5.

12. The compound of formula (I) according to any one of claims 1 to 11, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, which is selected from: Alternatively, it is selected from: Alternatively, it is selected from:

13. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 12, its stereoisomers, its tautomers, its deuterated compounds, or pharmaceutically acceptable salts thereof; optionally, further comprising a pharmaceutically acceptable excipient.

14. Use of the compound of formula (I) according to any one of claims 1 to 12, its stereoisomers, its tautomers, its deuterated compounds, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease.

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