Tricyclic compound and medical application thereof

Abstract

The invention belongs to the field of medical chemistry, and relates to a tricyclic compound and medical application thereof, the structure of the tricyclic compound is shown as a formula (III-c), in particular to a preparation method of the compound, a pharmaceutical composition of the compound and application of the compound in cancer treatment. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to tricyclic compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof in treating cancer. Background Art

[0002] Ras gene is an important proto-oncogene, named after the discovery of rat sarcoma virus. The encoded Ras protein is located on the inner side of the cell membrane, 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, Ras protein controls the "on" and "off" of signal transmission processes such as growth factors and cytokines, and plays 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).

[0003] Studies have shown that more than 30% of human tumors have Ras gene mutations, of which Kras mutations account for about 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2): 201-205). For Kras mutations, mutations at glycine 12 (G12) account for about 80%, and G12D mutations (mutation of glycine 12 to aspartic acid) are the main mutation forms of G12 mutations. (Prior IA et al., Cancer Res, 2012, 72(10): 2457-2467). Mutations at G12 reduce the catalytic activity of GAP, ultimately leading to the continuous activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.

[0004] Currently, Kras (such as Kras G12D ) has become an attractive anticancer target. DETAILED DESCRIPTION OF THE INVENTION

[0006] The present disclosure relates to a compound of formula (III-c), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in,

[0009] 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 -;

[0010] L 2 Selected from single bonds, -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;

[0011] 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 AlkyleneNHC(O)NR 2c R 2d , -C 1-6 Alkylene NR 2c C(O)OR 2d , -C 1-6 Alkylene OC(O)R 2d , -C1-6 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 AlkyleneNHSO2R 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 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;

[0012] R 2c independently selected from H, deuterium, or C 1-6 alkyl;

[0013] 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 cycloalkyl 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;

[0014] 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;

[0015] Each R 2b independently selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4Alkoxy, C 1-4 Alkylamino, di-C 1-4 Alkylamino, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0016] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-12 alkyl)-;

[0017] 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 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino;

[0018] R 3 is selected from H, deuterium, 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 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 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 、-SO2R3d 、-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 AlkyleneNHC(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 AlkyleneNHSO2R 3d , or optionally one or more R 3b Substituted with the following 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 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;

[0020] R 3c independently selected from H, deuterium, or C 1-6 alkyl;

[0021] 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 1-12heteroalkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl 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;

[0022] 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;

[0023] Each R 3e independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0024] R 4 Selected from H, deuterium, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0025] Ring A is selected from optionally substituted with one or more R 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0026] 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, -P(O)(C 1-12 Alkyl)2, -P(O)HC 1-12 Alkyl, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl;

[0027] Each R 5aindependently 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 L 2 , 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 , or R z Each is independently optionally substituted with one or more substituents.

[0029] In some embodiments, the compound of formula (III-c), its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt,

[0030] in,

[0031] 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 -;

[0032] L 2 Selected from single bonds, -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;

[0033] 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 AlkyleneNHC(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 AlkyleneNHSO2R 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 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;

[0034] R 2c independently selected from H, deuterium, or C1-6 alkyl;

[0035] 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 cycloalkyl 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;

[0036] 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;

[0037] 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;

[0038] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-12 alkyl)-;

[0039] 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 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino;

[0040] R 3is selected from H, deuterium, 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 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;

[0041] 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 AlkyleneNHC(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 AlkyleneNHSO2R 3d, or optionally one or more R 3b Substituted with the following 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 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;

[0042] R 3c independently selected from H, deuterium, or C 1-6 alkyl;

[0043] 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 cycloalkyl 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;

[0044] 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;

[0045] Each R 3e independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0046] R 4 Selected from H, deuterium, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0047] Ring A is selected from optionally substituted with one or more R 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0048] 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;

[0049] 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;

[0050] Each L 2 , 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 , or R z Each is independently optionally substituted with one or more substituents.

[0051] In some embodiments, the compound of formula (III-c), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0052] in,

[0053] R 2is 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 -;

[0054] L 2 Selected from single bonds, -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;

[0055] 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 AlkyleneNHC(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 1-6Alkylene OC(O)NR 2c R 2d , -C 1-6 Alkylene SO2R 2d , -C 1-6 Alkylene OSO2R 2d , -C 1-6 AlkyleneNHSO2R 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 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;

[0056] R 2c Independently selected from H, or C 1-6 alkyl;

[0057] R 2d independently selected from H, or optionally 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 cycloalkyl 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;

[0058] 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;

[0059] 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 1-4Haloalkyl, or C 1-4 Haloalkoxy;

[0060] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-12 alkyl)-;

[0061] 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 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino;

[0062] 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 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;

[0063] 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)NR3c R 3d , -C 1-6 Alkylene NR 3c C(O)R 3d , -C 1-6 AlkyleneNHC(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 AlkyleneNHSO2R 3d , or optionally one or more R 3b Substituted with the following 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 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;

[0064] R 3c Independently selected from H, or C 1-6 alkyl;

[0065] R 3d independently selected from H, or optionally 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 cycloalkyl 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C1-6 Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene;

[0066] 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;

[0067] Each R 3e are independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0068] R 4 Selected from H, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0069] Ring A is selected from optionally substituted with one or more R 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0070] 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;

[0071] 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;

[0072] Each L 2 , R 2 , R2a , 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 , or R z Each is independently optionally substituted with one or more substituents.

[0073] In some embodiments, the compound of formula (III-c), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof,

[0074] in,

[0075] 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 -;

[0076] L 2 Selected from single bonds, -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;

[0077] 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 AlkyleneNHC(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 AlkyleneNHSO2R 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 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;

[0078] R 2c Independently selected from H, or C 1-6 alkyl;

[0079] R 2d independently selected from H, or optionally 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 cycloalkyl1-6 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;

[0080] 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;

[0081] 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;

[0082] Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-12 alkyl)-;

[0083] 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 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino;

[0084] 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 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;

[0085] 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 AlkyleneNHC(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 AlkyleneNHSO2R 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 1-6 Alkylene, 3-12 membered heterocyclic group C 1-6 Alkylene, 6-10 membered aryl C 1-6Alkylene, or 5-10 membered heteroaryl C 1-6 Alkylene;

[0086] R 3c Independently selected from H, or C 1-6 alkyl;

[0087] R 3d independently selected from H, or optionally 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 cycloalkyl 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;

[0088] 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;

[0089] Each R 3e are independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0090] R 4 Selected from H, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0091] Ring A is selected from optionally substituted with one or more R 5 Substituted: 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0092] 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 1-12Alkoxy, 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;

[0093] 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;

[0094] Each L 2 , 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 , or R z Each is independently optionally substituted with one or more substituents.

[0095] In some embodiments, 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 -.

[0096] In some embodiments, 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 -.

[0097] In some embodiments, the R 2 is selected from H, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally with 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 -.

[0098] In some embodiments, the R 2 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally with 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 -.

[0099] 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-L 2 -, or 5-6 membered heteroaryl-L 2 -. In some embodiments, the R2 Selected from optionally one or more R 2a Substituted with the following groups: C 1-4 Alkyl, or 5-6 membered heteroaryl-L 2 -.

[0100] In some embodiments, the L 2 Selected from single bonds, -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.

[0101] In some embodiments, the L 2 Selected from single bonds, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, or C 1-6 Heteroalkylene.

[0102] In some embodiments, the L 2 Selected from single bonds, -O-, -NH-, -N(C 1-3 Alkyl)-, C 1-4 Alkylene, or C 1-4 Heteroalkylene.

[0103] In some embodiments, the L 2 Selected from single bonds, -O-, -NH-, -N(C 1-3 Alkyl)-, C 1-4 Alkylene, -OC 1-4 Alkylene, or -NH-C 1-4 Alkylene.

[0104] In some embodiments, the L 2 is selected from a single bond or a methylene group.

[0105] In some embodiments, the L 2 Selected from -CH(CH3)-.

[0106] In some embodiments, the R 2 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or optionally with one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 heteroalkyl, cyclopropane, cyclobutane, cyclopentane, Oxetane, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolyl,

[0107] 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,

[0108] In some embodiments, the R 2 Selected from optionally one or more R 2a Replaced

[0109] In some embodiments, the R 2a The substituted position is R 2 The carbon or nitrogen atoms in the

[0110] In some embodiments, the R 2a The substituted position is R 2 The carbon atoms in .

[0111] 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 、-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 AlkyleneNHC(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 Alkyl substituent OSO2R 2d , -C 1-3 AlkyleneNHSO2R 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.

[0112] 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 、-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 AlkyleneNHC(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.

[0113] 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 、-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.

[0114] In some embodiments, the R 2aindependently selected from deuterium, 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.

[0115] In some embodiments, the R 2a independently selected from deuterium, -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, isopropoxy, 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.

[0116] In some embodiments, the R 2a Independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, methylamino, dimethylamino, or cyclopropane.

[0117] In some embodiments, the R 2a Independently selected from deuterium, -NH2, methyl, methylamino, or cyclopropane.

[0118] In some embodiments, the R 2aIndependently selected from deuterium, -F, -OH, or dimethylamino.

[0119] In some embodiments, the R 2a is independently selected from deuterium, -F, -NH2, or methyl. 2a In some embodiments, R 2a are independently selected from -NH2.

[0120] In some embodiments, the R 2c independently selected from H, deuterium, or C 1-3 alkyl.

[0121] In some embodiments, the R 2c are independently selected from H, deuterium, or methyl.

[0122] 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 cycloalkyl 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.

[0123] 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 cycloalkyl 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.

[0124] 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 1-4 Alkyl, C 1-4heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkylC 1-3 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.

[0125] 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 1-3 Alkyl, C 1-3 heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkylC 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.

[0126] In some embodiments, the R 2e Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, -NH2, -CN, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.

[0127] In some embodiments, the R 2e Independently selected from deuterium, -F, -Cl, -OH, oxo, -NH2, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

[0128] 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.

[0129] In some embodiments, the R 2b Independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

[0130] In some embodiments, the R 2 is selected from H, deuterium, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropane, cyclobutane, cyclopentane,

[0131]

[0132] In some embodiments, the R 2 Selected from

[0133] In some embodiments, the R 2 Selected from H or optionally one or more R 2a Substituted C 1-4 alkyl.

[0134] In some embodiments, the R 2 Selected from H, methyl, trifluoromethyl,

[0135] In some embodiments, the R 2 is selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,

[0136] In some embodiments, the R 2 is selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl,

[0137] In some embodiments, the R 2 Selected from

[0138] In some embodiments, the R 2 is selected from isopropyl, tert-butyl, cyclopropane, or

[0139] In some embodiments, Z is selected from a single bond, -S-, -O-, or optionally substituted by one or more R z Substituted with the following groups: -NH-, or -N(C 1-6 alkyl)-.

[0140] In some embodiments, each 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 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Halogenated alkylthio, C 1-3 Haloalkylamino, or di-C 1-3 Haloalkylamino.

[0141] In some embodiments, 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 Haloalkyl, or C 1-6 Halogenated alkoxy.

[0142] In some embodiments, each 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 Haloalkyl, or C 1-3 Halogenated alkoxy.

[0143] In some embodiments, each R z 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 Halogenated alkoxy.

[0144] In some embodiments, each R z Independently selected from deuterium, F, Cl, Br, -OH, oxo, -NH2, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy.

[0145] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-12 alkyl)-.

[0146] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-6 alkyl)-.

[0147] In some embodiments, Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-.

[0148] In some embodiments, Z is selected from a single bond, -O-, or -N(C 1-3 alkyl)-.

[0149] In some embodiments, Z is selected from a single bond, -O-, or -N(CH3)-.

[0150] In some embodiments, said Z is selected from -O-.

[0151] In some embodiments, Z is selected from a single bond, -O-, -NH-, or -N(CH3)-.

[0152] In some embodiments, the R 3 is selected from H, deuterium, 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 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.

[0153] In some embodiments, the R 3 is selected from H, deuterium, or optionally 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 1-3 Alkylene, 4-10 membered heterocyclic group C 1-3 Alkylene, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl C 1-3 Alkylene.

[0154] In some embodiments, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 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.

[0155] In some embodiments, the R 3 is selected from H, deuterium, or optionally 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 1-3Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0156] In some embodiments, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocyclic group, 3-8 membered cycloalkyl group C 1-3 Alkylene, 4-8 membered heterocyclic group C 1-3 Alkylene, or 5-6 membered heteroaryl C 1-3 Alkylene.

[0157] In some embodiments, the R 3 is selected from H, deuterium, or optionally 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.

[0158] 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.

[0159] 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.

[0160] 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 A substituted 9-membered heterocyclic group.

[0161] In some embodiments, the heterocyclyl is selected from heterocycloalkyl. In some embodiments, the heterocyclyl is selected from partially unsaturated heterocyclyl.

[0162] In some embodiments, the 3-12 membered heterocyclyl is selected from a 3-12 membered heterocyclyl or a benzo 4-6 membered heterocyclyl. 1-6 The alkylene group is selected from 3-12 membered heterocycloalkyl C 1-6 Alkylene or benzo 4-6 membered heterocyclic group C 1-6 Alkylene.

[0163] In some embodiments, the 3-10 membered heterocyclyl is selected from a 3-10 membered heterocyclyl or a benzo 4-6 membered heterocyclyl. 1-4 The alkylene group is selected from 3-10 membered heterocycloalkyl C 1-4 Alkylene or benzo 4-6 membered heterocyclic group C 1-4 Alkylene.

[0164] In some embodiments, the 4-10 membered heterocyclyl is selected from a 4-10 membered heterocyclyl or a benzo 4-6 membered heterocyclyl. 1-6 The alkylene group 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 group C 1-3 The alkylene group is selected from 4-10 membered heterocycloalkyl C 1-3 Alkylene or benzo 4-6 membered heterocyclic group C 1-3 Alkylene.

[0165] In some embodiments, the 4-10 membered, 4-9 membered, 4-8 membered, or 5-9 membered heterocyclyl C 1-3 The alkylene group 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.

[0166] In some embodiments, the 4-8 membered heterocyclyl is selected from 4-8 membered heterocyclyl. 1-6 The alkylene group is selected from 4-8 membered heterocycloalkyl C 1-6 In some embodiments, the 4-8 membered heterocyclyl group C 1-3 The alkylene group is selected from 4-8 membered heterocycloalkyl C 1-3Alkylene.

[0167] In some embodiments, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted groups: 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, piperazine 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]heptylC 1-3 Alkylene, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or imidazolyl C 1-3 Alkylene.

[0168] In some embodiments, the R 3 selected from H, deuterium, optionally substituted by one or more R 3a Substituted groups: methyl, piperidinyl, cyclopentyl 1-3 Alkylene, tetrahydropyrrolyl 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, cyclopropyl 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, piperidinyl C 1-3 Alkylene, azetidinyl, cyclobutyl, cyclohexyl, cyclobutyl C 1-3 Alkylene, or piperazinyl.

[0169] In some embodiments, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,

[0170] In some embodiments, the R 3 Selected from optionally one or more R 3a Substituted hexahydro-1H-pyrrolizinyl C 1-3 Alkylene.

[0171] In some embodiments, the R 3a The substituted position is R 3 In some embodiments, the R 3a The substituted position is R 3 In some embodiments, the R 3a The substituted position is R 3 The alkylene portion of

[0172] 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 AlkyleneNHC(O)NR 3c R 3d , -C 1-3 Alkylene NR 3c C(O)OR3d , -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 Alkyl substituent OSO2R 3d , -C 1-3 AlkyleneNHSO2R 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 heterocyclyl, phenyl, 4-7 membered heterocyclyl 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.

[0173] In some embodiments, the R 3a independently selected from deuterium, 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 AlkyleneNHC(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 AlkyleneNHSO2R3d , 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, benzyl, pyrazolyl, pyrazolylmethyl, tetrahydropyrrolylmethyl, oxazolidinonemethyl, =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), morpholinemethyl.

[0174] 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 1-3 AlkyleneNHC(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 AlkyleneNHSO2R 3d , or optionally one or more R 3b Substituted groups: methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, phenyl, benzyl, pyrazolylmethyl, oxazolidinonemethyl, =NH, =CH2, or

[0175] In some embodiments, the R 3a independently selected from optionally one or more R 3b Substituted =CH2.

[0176] In some embodiments, the R 3a independently selected from deuterium, 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, -NH2, dimethylamino, or dimethylaminomethylene.

[0177] In some embodiments, the R 3a independently selected from deuterium, F, -CH2OC(O)R 3d 、-CH2OC(O)NR 3c R 3d , methyl, methoxy, =CH2, =CHF, =CF2, deuterium, -NH2, dimethylamino, or dimethylaminomethylene.

[0178] In some embodiments, the R 3c are independently selected from H, deuterium, or methyl.

[0179] In some embodiments, the R 3c Independently selected from H.

[0180] 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.

[0181] 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 1-12 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.

[0182] 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, 4-8 membered heterocycloalkyl, phenyl, phenyl C 1-3Alkylene, 5-6 membered heteroaryl, or 5-6 membered heteroarylC 1-3 Alkylene.

[0183] 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 1-4 Alkyl, C 1-4 Alkoxy C 1-3 alkylene, phenyl, benzyl, pyrazolyl, pyridinyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, or morpholinyl.

[0184] 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 1-4 Alkyl, C 1-4 Alkoxy C 1-3 alkylene, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, or morpholinyl.

[0185] In some embodiments, the R 3d independently selected from H, deuterium, C 1-4 Alkyl, or optionally with one or more R 3e Substituted: tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0186] In some embodiments, the R 3d independently selected from H, deuterium, methyl, or optionally substituted by one or more R 3e Substituted: tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0187] In some embodiments, the R 3d are independently selected from H, deuterium, methyl, tetrahydropyrrolyl, piperidinyl, or morpholinyl.

[0188] In some embodiments, the R 3e Independently selected from deuterium, -F, -Cl, -Br, -OH, oxo, methyl, ethyl, trifluoromethyl, or difluoromethyl.

[0189] In some embodiments, the R 3e Independently selected from -F, -Cl, -OH, oxo, methyl, or trifluoromethyl.

[0190] 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.

[0191] In some embodiments, the R 3b Independently selected from -F, -Cl, -NH2, methyl, methoxy, methylamino, or dimethylamino.

[0192] In some embodiments, the R 3 Selected from H, deuterium, methyl,

[0193]

[0194] In some embodiments, the R 3 Selected from

[0195] In some embodiments, the R 4 Selected from H, deuterium, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0196] In some embodiments, the R 4 Selected from H, deuterium, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 haloalkoxy, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.

[0197] In some embodiments, 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 Halogenated alkoxy.

[0198] In some embodiments, 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 Halogenated alkoxy.

[0199] In some embodiments, the R 4 Selected from H, deuterium, -F, -Cl, -Br, C 1-2 Alkyl, C1-2 Alkoxy, or C 1-2 Fluorinated alkyl.

[0200] In some embodiments, the R 4 is selected from H, deuterium, -F, -Cl, -Br, methyl, methoxy, difluoromethyl, or trifluoromethyl.

[0201] In some embodiments, the R 4 is selected from H, deuterium, -F, -Cl, or methyl.

[0202] In some embodiments, the R 4 is selected from H, deuterium, -F, or -Cl.

[0203] 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.

[0204] 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.

[0205] In some embodiments, the ring A is selected from the group consisting of 5 Substituted: 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.

[0206] In some embodiments, the ring A is selected from the group consisting of 5 Substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzothiophenyl, pyrazolyl, pyridopyrazolyl, or pyridopyrrolyl.

[0207] In some embodiments, the ring A is selected from the group consisting of 5 Substituted: phenyl, naphthyl, pyridyl, benzothiazolyl, benzothiophenyl, isoquinolyl, benzopyrazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolyl, indolyl, or benzimidazolyl.

[0208] In some embodiments, 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.

[0209] In some embodiments, the ring A is selected from the group consisting of 5 Substituted as follows: phenyl or naphthyl.

[0210] In some embodiments, 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 In some embodiments, each R 5 independently selected from optionally one or more R 5a Substituted groups: -P(O)(C 1-6 Alkyl)2 or -P(O)HC 1-6 alkyl.

[0211] In some embodiments, each R 5 independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R 5a substituted with: methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, methylamino, dimethylamino, methylthio, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, or propynyl. 5 independently selected from optionally one or more R 5a Substituted groups: -P(O)(C 1-3 Alkyl)2 or -P(O)HC 1-3 alkyl.

[0212] In some embodiments, each R 5 independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, or optionally substituted by one or more R 5asubstituted with: methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, methylamino, dimethylamino, methylthio, cyclopropane, or propynyl. 5 independently selected from optionally one or more R 5a Substituted with the following groups:

[0213] In some embodiments, each R 5 R is independently selected from deuterium, -F, -Cl, -CN, -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, or propynyl. In some embodiments, each R 5 Independently selected from

[0214] In some embodiments, each R 5 is independently selected from deuterium, -F, -Cl, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, trifluoromethyl, trifluoromethoxy, methylthio, or methyl-substituted cyclopropane, -CN, methoxy, propynyl, dimethylamino. In some embodiments, each R 5 Independently selected from methylamino or

[0215] 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.

[0216] In some embodiments, the R 5a Independently selected from deuterium, -F, -Cl, -Br, -NH2, methyl, methoxy, methylamino, or dimethylamino.

[0217] In some embodiments, the R 5a are independently selected from deuterium, -F, -Cl, -Br, or methyl.

[0218] In some embodiments, the ring A is selected from

[0219]

[0220] In some embodiments, the ring A is selected from

[0221] 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 .

[0222] In some embodiments, the C 1-6 The alkyl group is selected from C 1-4 Alkyl, C 1-3 Alkyl, or C 1-2 alkyl.

[0223] In some embodiments, the C 1-6 The alkylene group is selected from C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 Alkylene.

[0224] In some embodiments, the halogen is selected from F, Cl, Br, or I.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N, O, or S.

[0229] In some embodiments, the heteroalkylene group contains 1 or 2 heteroatoms selected from N or O.

[0230] In some embodiments, the heteroalkylene contains 1 N atom and 1 O atom.

[0231] In some embodiments, the heteroalkylene contains 1 N atom.

[0232] In some embodiments, the heteroalkylene contains 1 O atom.

[0233] In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.

[0234] In some embodiments, the heterocycloalkyl contains 1 N atom.

[0235] In some embodiments, the heterocycloalkyl contains 1 O atom.

[0236] In some embodiments, the heterocycloalkyl contains 1 N atom and 1 O atom.

[0237] In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 heteroatoms selected from N, O, or S.

[0238] In some embodiments, the heterocyclyl or heteroaryl contains 1 or 2 N atoms.

[0239] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 O atom.

[0240] In some embodiments, the heterocyclyl or heteroaryl contains 1 N atom and 1 S atom.

[0241] In some embodiments, the heterocyclyl or heterocycloalkyl includes a monocyclic, spirocyclic, fused or bridged ring. In some embodiments, the heterocyclyl or heterocycloalkyl includes a monocyclic or spirocyclic ring. In some embodiments, the heterocyclyl or heterocycloalkyl includes a monocyclic or bridged ring.

[0242] In some embodiments,

[0243] 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 -;

[0244] L 2 Selected from single bonds, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, C2-6 Alkenylene, or C 1-6 heteroalkenylene;

[0245] 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 AlkyleneNHC(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 AlkyleneNHSO2R 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 1-6Alkylene, 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;

[0246] R 2c independently selected from H, deuterium, or C 1-6 alkyl;

[0247] 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 cycloalkyl 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;

[0248] 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;

[0249] 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;

[0250] Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;

[0251] R 3 is selected from H, deuterium, 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 1-3 Alkylene, 4-10 membered heterocycloalkyl C 1-3 Alkylene, 6-10 membered aryl C1-3 Alkylene, benzo 4-6 membered heterocyclic group C 1-3 Alkylene, or 5-10 membered heteroaryl C 1-3 Alkylene;

[0252] 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 AlkyleneNHC(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 , -C 1-3 AlkyleneNHSO2R 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 C1-3 Alkylene, optionally oxo-substituted 4-7 membered heterocycloalkyl C 1-3 Alkylene;

[0253] R 3c independently selected from H, deuterium, or C 1-6 alkyl;

[0254] 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 with the following groups: phenyl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl, or 4-8 membered heterocycloalkyl;

[0255] 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;

[0256] Each R 3e independently selected from deuterium, halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0257] 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;

[0258] Ring A is selected from optionally substituted with one or more R 5 Substituted groups: 6-10 membered aryl, benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, or 5-10 membered heteroaryl;

[0259] 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 1-6Alkylthio, C 1-6 haloalkylthio, or optionally substituted by halogen or C 1-3 Alkyl-substituted 3-7 membered cycloalkyl.

[0260] In some embodiments,

[0261] 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 -;

[0262] L 2 Selected from single bonds, -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;

[0263] 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 AlkyleneNHC(O)NR 2c R2d , -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 AlkyleneNHSO2R 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 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;

[0264] R 2c Independently selected from H, or C 1-6 alkyl;

[0265] R 2d independently selected from H, or optionally 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 cycloalkyl 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;

[0266] 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 1-4Haloalkoxy;

[0267] 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;

[0268] Z is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;

[0269] 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, 4-10 membered heterocycloalkyl, 6-10 membered aryl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl 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;

[0270] 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 AlkyleneNHC(O)NR3c 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 , -C 1-3 AlkyleneNHSO2R 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;

[0271] R 3c Independently selected from H, or C 1-6 alkyl;

[0272] 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 with the following groups: phenyl, phenyl C 1-3 Alkylene, 5-6 membered heteroaryl, or 4-8 membered heterocycloalkyl;

[0273] 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;

[0274] Each R 3e are independently selected from halogen, -OH, formaldehyde, oxo, C 1-4 Alkyl, or C 1-4 Haloalkyl;

[0275] R4 Selected from H, halogen, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0276] Ring A is selected from optionally substituted with one or more R 5 Substituted groups: 6-10 membered aryl, benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, or 5-10 membered heteroaryl;

[0277] Each R 5 independently selected from 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 haloalkylthio, or optionally substituted by halogen or C 1-3 Alkyl-substituted 3-7 membered cycloalkyl.

[0278] In some embodiments, the R 3a independently selected from optionally one or more R 3b Substituted with the following groups: =NH, =CH2, =N(C 1-4 alkyl), =CH(C 1-4 alkyl), or =C(C 1-4 Alkyl)2.

[0279] The present disclosure relates to a compound of formula (III-b), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof,

[0280]

[0281] Among them, R 2 , R 3 , R 4 , Z, and Ring A moieties are as defined above. In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

[0282] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0283]

[0284]

[0285]

[0286]

[0287]

[0288] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296] The present disclosure also relates to the following compounds, their stereoisomers, their tautomers, their deuterated compounds, or their pharmaceutically acceptable salts:

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound 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.

[0315] In another aspect, the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of a compound of the present disclosure, a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.

[0316] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.

[0317] In another aspect, the present disclosure relates to use of the compound of the present disclosure, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure in treating a disease.

[0318] In another aspect, the present disclosure relates to a compound of the present disclosure, 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.

[0319] In some embodiments of the present disclosure, the disease is preferably a Kras-associated disease.

[0320] In some embodiments of the present disclosure, the Kras-related disease is preferably a Kras-mutated cancer.

[0321] In some embodiments of the present disclosure, the Kras-associated disease is selected from cancer (eg, pancreatic cancer).

[0322] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12D Related diseases.

[0323] In some embodiments of the present disclosure, the Kras G12D Related diseases are preferably Kras G12D Mutation cancer.

[0324] In some embodiments of the present disclosure, the Kras G12D The related disease is selected from cancer (eg pancreatic cancer).

[0325] In some embodiments of the present disclosure, the Kras-related disease is preferably Kras G12V Related diseases.

[0326] In some embodiments of the present disclosure, the Kras G12V Related diseases are preferably Kras G12V Mutation cancer.

[0327] In some embodiments of the present disclosure, the Kras G12V The related disease is selected from cancer (eg pancreatic cancer).

[0328] Technical Effects

[0329] 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.

[0330] definition

[0331] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0332] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced 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 oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0333] Non-limiting examples of “substituents” as described herein include hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, 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, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroarylalkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group, a heterocyclic group, a heterocyclic group, a heterocyclic groupoxy group, a heterocyclic groupthio group, a heterocyclic groupalkylene group, a heterocyclic groupalkoxy group, a heterocyclic groupalkylthio group, an acyl group, an acyloxy group, a carbamate group, an amide group, a urea group, an epoxy group, and an ester group, and the like, wherein the 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, carboxy, -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.

[0334] The term "replaced" 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.

[0335] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. 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 appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0336] 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.

[0337] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0338] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0339] 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.

[0340] When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, in ALZ, the connection

[0341] The group L is -MW-, which means that the structure can be AMWZ or AWMZ.

[0342] 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.

[0343] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0344] The term "hydroxy" refers to an -OH group.

[0345] The term "cyano" refers to a -CN group.

[0346] The term "mercapto" refers to a -SH group.

[0347] The term "amino" refers to a -NH2 group.

[0348] The term "nitro" refers to a -NO2 group.

[0349] The term "alkylene" refers to a group of the formula C n H 2n A saturated straight or branched 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.

[0350] The term "heteroalkylene" refers to an alkylene 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 heteroalkylene 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"Heteroalkylene" refers to a heteroalkylene group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkylene group (e.g., internal or terminal positions), including the position that connects the alkylene group to the rest of the molecule. Typically, when more than one heteroatom group is present, 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-, -SC H2SCH2CH2-, -NHCH2-, -NHCH2CH2-, -NHCH2CH2CH2-, -CH2NHCH2-, -N(CH3)CH2-, -CH2N(CH3)-, -OCH2NH-, -OCH2CH2NH-, -OCH2NHCH2CH2-, -OCH2N(CH3)CH2-, etc. The heteroalkylene 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.

[0351] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched, 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 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, heterocyclylalkyl, heterocyclylalkyloxy, 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.

[0352] 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 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position of the heteroalkyl group (e.g., internal or terminal position), including the position that connects the heteroalkyl group 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 following: 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.

[0353] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0354] The term "alkylamino" refers to -NH-alkyl groups, 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0355] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0356] The term "alkylsulfonyl" refers to -SO2-alkyl, 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0357] 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, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0358] The term "alkenyl" refers to a linear 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, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl 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.

[0359] The term "alkenylene" refers to the divalent form of alkenyl. The alkenylene 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 include but are not limited to vinylene, 1-propenylene, 2-propenylene, 1-butenylene, isobutenylene, 1,3-butadienylene, etc. The alkenylene is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0360] The term "heteroalkenyl" refers to an alkenyl 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 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 position), including the position that connects the heteroalkenyl group 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 is a carbon-carbon double bond. The heteroalkenyl 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.

[0361] 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 that connects the heteroalkenylene group 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 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 following: 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.

[0362] The term "alkynyl" refers to a linear 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), etc. The alkynyl is optionally substituted with one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

[0363] 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, 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.

[0364] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic ring with at least one double bond and which can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 10 rings, 4 to 8 rings, 5 to 8 rings or 5 to 6 rings. 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 following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, 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.

[0365] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, and ring or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring 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 sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron. The non-limiting examples of heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted by 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.

[0366] 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 to 12-membered, 3 to 10-membered, 4 to 8-membered, 5 to 8-membered, 5 to 6-membered, 3 to 7-membered or 4 to 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, thioethane, and cyclonitriles; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. The heterocycloalkyl radical 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.

[0367] The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring 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, etc. The aryl group is optionally substituted with one or more substituents selected from the group consisting of 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, heterocyclylalkyl, heterocyclylalkylene, heterocyclyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0368] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, and the remaining ring atoms are 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 ring, especially a 5 to 6 ring, or multiple fused rings containing 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, 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, 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, heterocyclylalkyl, heterocyclylalkylene, heterocyclyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0369] The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0370] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0371] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0372] The term "prevention" 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.

[0373] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular 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 the present disclosure.

[0374] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are 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.

[0375] 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.

[0376] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0377] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0378] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0379] 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 an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0380] 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 may be incorporated into 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.

[0381] 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. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18F 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.

[0382] 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.

[0383] 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 form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

[0384]

[0385] The compounds of the present disclosure may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The compounds containing chiral axes of the present disclosure can be separated in racemic form. When the energy barrier for free rotation of single bonds of the compounds containing chiral axes of the present disclosure is high enough, the atropisomers thereof can be separated in an optically pure form.

[0386] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they 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, etc.

[0387] 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, intravenous administration.

[0388] 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.

[0389] 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, etc., for oral administration to patients.

[0390] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0391] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0392] 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 synthesis 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

[0393] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

[0394] The compound of formula (III) disclosed herein can be prepared by a person skilled in the art of organic synthesis via route 1, wherein PG is independently selected from a suitable common protecting group, such as tert-butyldimethyl; R 2 , R 3 , R 4 , Z and Ring A moiety are as defined above.

[0395]

[0396] Each product obtained by the reaction in the above route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, 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 the present disclosure can be used to obtain a single isomer or a mixture of isomers using synthetic methods.

[0397] This disclosure uses the following abbreviations:

[0398] 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-butyldimethyl; DIPEA stands for diisopropylethylamine; THF stands for tetrahydrofuran; PMB stands for p-methoxybenzyl; and FA stands for formic acid.

[0399] Commercially available compounds were given by their supplier catalog names.

[0400] For the sake of clarity, the present invention is further described with 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.

[0401] All reagents used in this disclosure were commercially available and used without further purification. Example

[0402] Example 1

[0403]

[0404]

[0405] Step 1:

[0406] 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, stirred evenly, and then heated to 45°C and stirred for 24 hours, filtered, and the filtrate was concentrated under reduced pressure and 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) +

[0407] Step 2:

[0408] Compound 1a (60 g), N-iodosuccinimide (90 g), TsOH . H2O (3.2 g) and acetonitrile (600 mL) were stirred evenly and then heated to 70°C for 4 h. The reaction solution was concentrated to dryness under reduced pressure, 1 L of ethyl acetate was added to the residue to dissolve, and 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) +

[0409] Step 3:

[0410] 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, and the filtrate was concentrated to dryness under reduced pressure. 1 L of ethyl acetate was added to the residue and stirred, filtered, and the filtrate was washed with ammonia water 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) +

[0411] Step 4:

[0412] NaOH (19.4 g) and H2O (270 mL) were added to the reaction flask, and compound 1c (25 g) was added after stirring until dissolved. The temperature was raised to 80°C and stirred for 10 h. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise under ice bath to adjust the pH to acidic. A large amount of solid was precipitated, filtered, and the filter cake was dried under reduced pressure to obtain compound 1d. LC-MS: m / z=225.07 (M+H) +

[0413] Step 5:

[0414] 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 stirring. 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 then 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) -

[0415] Step 6:

[0416] Compound 1e (9.3 g), methanol (300 mL) and sodium hydroxide aqueous solution (2.8 g / 30 mL) were added to the reaction flask, and iodomethane (9.9 g) was added after stirring evenly, 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) +

[0417] Step 7:

[0418] N-Boc-ethanolamine (13.7 g), lithium hydride (0.68 g), and DMF (21 mL) were added to the reaction flask. After reacting at room temperature for 30 minutes, compound 1f (2.8 g) and DMF (70 mL) were added. After stirring evenly, the temperature was raised to 60° C. and stirred for 4 hours. After that, 1 L of water was added to adjust the pH 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) +

[0419] Step 8:

[0420] Compound 1g (12.3 g) and hydrochloric acid ethyl acetate solution (123 mL) were added to the reaction flask, stirred evenly, reacted at room temperature overnight, filtered, and the filter cake was dried under reduced pressure to obtain compound 1h. LC-MS: m / z=305.03 (M+H) +

[0421] Step 9:

[0422] 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, stirred evenly in an ice-water bath, and 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) +

[0423] Step 10:

[0424] 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 evenly at room temperature, heated to 90°C for 10 h, and the reaction solution was filtered after the reaction was completed. 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 1j. LC-MS: m / z = 637.36 (M+H) +

[0425] Step 11:

[0426] Compound 1j (1010 mg), m-chloroperbenzoic acid (800 mg), and dichloromethane (200 mL) were added to the reaction flask, stirred evenly in an ice-water bath, and then reacted at room temperature for 1 h. After the reaction was complete, sodium thiosulfate (10%) aqueous solution (100 mL) was added to the reaction flask, stirred and separated, and the organic phase was collected and concentrated to dryness under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 1k. LC-MS: m / z = 669.37 (M+H) +

[0427] Step 12:

[0428] Compound 1k (360 mg), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (420 mg), bis(trimethylsilyl)amide lithium (1N) tetrahydrofuran solution (2.7 mL), tetrahydrofuran (150 mL) were added to the reaction flask, stirred evenly in an ice-water bath and then reacted at room temperature overnight. After the reaction was completed, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction system and stirred for separation. The organic phase was collected and concentrated to dryness under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 1:200-1:50) to obtain compound 1l. LC-MS: m / z = 748.44 (M+H) +

[0429] Step 13:

[0430] Compound 11 (150 mg), cesium fluoride (302 mg), and DMF (15 mL) were added to the reaction flask, and the mixture was 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, and purified by column chromatography (methanol: dichloromethane = 1:200 to 1:50) to obtain compound 1m. LC-MS: m / z = 592.26 (M+H) +

[0431] Step 14:

[0432] Compound 1m (133 mg) and ethyl acetate (20 mL) were added to the reaction flask, stirred at 0-5°C for 5 min, and then hydrochloric acid ethyl acetate solution (2 mL) was added dropwise to the reaction system, and reacted at 0-5°C for 1 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, purified by preparative liquid phase (YMC C18 10 μm 30*250 column; acetonitrile-30 mM ammonium acetate (5%-5%-60% / 0-5-60min gradient elution), and then desalted and purified by preparative liquid phase (YMC C18 10 μm 30*250 column; acetonitrile-0.1% formic acid (10%-10%-70% / 0-5-60min gradient elution) to obtain compound 1 (35 mg, Rt=36.4 min). LC-MS: m / z=548.24 (M+H) +

[0433] 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).

[0434] Example 2

[0435]

[0436] Step 1:

[0437] 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 evenly at room temperature, then heated to 60°C for 6 h, cooled to room temperature, filtered, and 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) +

[0438] Step 2:

[0439] 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 and stirred for separation. The organic phase was collected and concentrated to dryness under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 1:200-1:50) to obtain compound 2b. LC-MS: m / z = 663.35 (M+H) +

[0440] Step 3:

[0441] Compound 2b (133 mg) and ethyl acetate (20 mL) were added to the reaction flask, stirred at 0-5°C for 5 min, and then hydrochloric acid ethyl acetate solution (2 mL) was added dropwise to the reaction system, and reacted at 0-5°C for 1 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, purified by preparative liquid phase (YMC C18 10 μm 30*250 column; acetonitrile-30 mM ammonium acetate (5%-5%-60% / 0-5-60 min gradient elution), and then purified by preparative liquid phase (YMC C18 10 μm 30*250 column; acetonitrile-0.1% formic acid (10%-10%-70% / 0-5-60 min gradient elution) to obtain compound 2 (8 mg, Rt=33.3 min). LC-MS: m / z=619.29 (M+H) +

[0442] Example 3

[0443]

[0444]

[0445] Step 1:

[0446] Disperse 1j (318 mg), iodoethane (775 mg), and potassium carbonate (207 mg) in acetone (30 mL), heat to 60°C, and stir to react for 6 h. Cool the reaction solution to room temperature, filter, and concentrate the filtrate until no liquid flows out to obtain compound 3a. LC-MS: m / z=665.35 (M+H) + .

[0447] Step 2:

[0448] 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 with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 3b. LC-MS: m / z = 697.35 (M+H) + .

[0449] Step 3:

[0450] Disperse 3b (195 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (218 mg) in tetrahydrofuran (20 mL), protect with nitrogen, cool to 0°C, add dropwise a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 1.4 mL), keep warm and stir for 30 min, move to room temperature and stir overnight. Add saturated ammonium chloride solution (100 mL) to the reaction system, extract with dichloromethane (50 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:50) to obtain compound 3c. LC-MS: m / z = 776.45 (M+H) + .

[0451] Step 4:

[0452] 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, wash the organic phase with 5% brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 3d. LC-MS: m / z=620.31 (M+H) + .

[0453] Step 5:

[0454] Disperse 3d (130 mg) in ethyl acetate (10 mL), cool to 0-5°C and stir for 5 min, add hydrogen chloride ethyl acetate solution (4N, 1 mL) dropwise to the reaction system, and keep warm for 1 h. 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 3. LC-MS: m / z = 576.29 (M+H) + .

[0455] 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).

[0456] Example 4

[0457]

[0458]

[0459] Step 1:

[0460] Disperse 1j (318 mg), 2-iodopropane (850 mg), and cesium carbonate (488 mg) in acetone (32 mL), heat to 60°C, and stir to react for 6 h. The reaction solution 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). LC-MS: m / z = 679.38 (M+H) + .

[0461] Step 2:

[0462] 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 with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 4b. LC-MS: m / z = 711.42 (M+H) + .

[0463] Step 3:

[0464] Disperse 4b (300 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (318 mg) in tetrahydrofuran (30 mL), protect with nitrogen, cool to 0°C, add dropwise a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 2 mL), keep warm and stir for 30 min, move to room temperature and stir for 1 h. Add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:50) to obtain compound 4c. LC-MS: m / z = 790.48 (M+H) + .

[0465] Step 4:

[0466] 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, wash the organic phase with saturated brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 4d. LC-MS: m / z=634.37 (M+H) + .

[0467] Step 5:

[0468] Disperse 4d (203 mg) in ethyl acetate (10 mL), cool to 0-5°C and stir for 5 min, add hydrogen chloride ethyl acetate solution (4N, 1 mL) dropwise to the reaction system, and stir and react for 1 h. After the reaction is complete, the reaction solution is 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% / 0-60min gradient elution) to obtain compound 4. LC-MS: m / z=590.28 (M+H)+.

[0469] 1H-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)

[0470] Example 5

[0471]

[0472] 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) + .

[0473] Example 6

[0474]

[0475] Referring to the preparation process of compound 4 in Example 4, in step 1, 2-iodopropane was replaced with (iodomethyl)cyclopropane to prepare compound 6. LC-MS: m / z=602.29 (M+H) + .

[0476] Example 7

[0477]

[0478] Referring to the preparation process of compound 4 in Example 4, in step 1, iodocyclopentane was used to replace 2-iodopropane to prepare compound 7. LC-MS: m / z=616.36 (M+H) + .

[0479] Example 8

[0480]

[0481] Referring to the preparation process of compound 4 in Example 4, in step 1, 2-iodo-1,1,1-trifluoroethane was used to replace 2-iodopropane to prepare compound 8. LC-MS: m / z=630.29 (M+H) + .

[0482] Example 9

[0483]

[0484] Step 1:

[0485] Disperse 1i (287 mg), iodomethane (1410 mg), and potassium carbonate (414 mg) in acetone (50 mL), heat to 60°C, and stir to react for 6 h. The reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated until no liquid flows out. Purify by column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:2) to obtain compound 9a. LC-MS: m / z = 301.03 (M+H) + .

[0486] Step 2:

[0487] 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 the mixture was protected by nitrogen. The mixture was heated to 90° C. and stirred for 10 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The compound 9b was purified by column chromatography (ethyl acetate: petroleum ether=1:10-1:2). LC-MS: m / z=651.35 (M+H) + .

[0488] Step 3:

[0489] 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*2), combine the organic phases, wash with 5% brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 9c. LC-MS: m / z = 683.47 (M+H) + .

[0490] Step 4:

[0491] Disperse 9c (437 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (511 mg) in tetrahydrofuran (80 mL), protect with nitrogen, cool to 0°C, add dropwise a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 3.3 mL), keep warm and stir for 30 min, move to room temperature and stir overnight. Add saturated ammonium chloride solution (100 mL) to the reaction system, extract with dichloromethane (50 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:50) to obtain compound 9d. LC-MS: m / z = 762.57 (M+H) + .

[0492] Step 5:

[0493] 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, wash the organic phase with 5% brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 9e. LC-MS: m / z=606.32 (M+H) + .

[0494] Step 6:

[0495] Disperse 9e (121 mg) in ethyl acetate (20 mL), cool to 0-5°C and stir for 5 min, add hydrogen chloride ethyl acetate solution (4N, 2 mL) dropwise to the reaction system, and keep warm for 1 h. 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 9. LC-MS: m / z = 562.26 (M+H) + .

[0496] Example 10

[0497]

[0498]

[0499] Step 1:

[0500] 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 separated, the aqueous phase was extracted with ethyl acetate (50 mL*2), the organic phases were combined, the organic phases were washed with 5% brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 10c. LC-MS: m / z=359.37 (M+H) + .

[0501] Step 2:

[0502] 1f (5 g) was dispersed in acetonitrile (100 mL), and DIPEA (13.8 g) and POCl3 (8.19 g) were added in sequence. The mixture was heated to 80°C and stirred for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, poured into ice water (500 mL), stirred for crystallization for 30 min, and filtered. The filter cake was dried in vacuo at 55°C for 6 h to obtain compound 10d.

[0503] Step 3:

[0504] 10d (1.6 g) was dispersed in THF (10 mL), and 10c (1.6 g) and DIPEA (2.3 g) were added in sequence, and 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) + .

[0505] Step 4:

[0506] Disperse 10e (1.1 g) and cesium fluoride (5.4 g) in DMF (10 mL), heat to 60 ° C and stir to react for 3 h. After the reaction is complete, add water (100 mL) and ethyl acetate (100 mL) to the reaction solution, stir and separate, wash the organic phase with 10% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:100 to 1:10) to obtain compound 10f. LC-MS: m / z = 470.24 (M+H) + .

[0507] Step 5:

[0508] 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), protected by nitrogen, and heated to 90°C with stirring for 2 h. The reaction solution was cooled to room temperature, filtered, and 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) + .

[0509] Step 6:

[0510] 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 with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 10i. LC-MS: m / z = 852.47 (M+H) + .

[0511] Step 7:

[0512] Disperse 10i (400 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (220 mg) in tetrahydrofuran (5 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 1.2 mL) dropwise, and stir for 30 min. After the reaction is complete, add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:50) to obtain compound 10j. LC-MS: m / z = 931.60 (M+H) + .

[0513] Step 8:

[0514] Disperse 10j (600 mg) and cesium fluoride (2.16 g) in DMF (12 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, wash the organic phase with 5% brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 10k. LC-MS: m / z=775.48 (M+H) + .

[0515] Step 9:

[0516] Disperse 10k (500 mg) in dichloromethane (10 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 2 mL) dropwise to the reaction system, and keep warm for 1 hour. After the reaction is complete, the reaction solution is 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% / 0-60min gradient elution) to obtain compound 10. LC-MS: m / z=631.39 (M+H)+.

[0517] Embodiment 11

[0518]

[0519] Step 1:

[0520] Disperse 11a (0.57 g), 10b (2.29 g), and potassium carbonate (4.42 g) in DMF (60 mL), and stir at room temperature for 12 h. Add water (50 mL) and ethyl acetate (50 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (50 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 11b. LC-MS: m / z=216.23 (M+H) + .

[0521] Step 2:

[0522] Disperse 10d (0.6 g) in acetonitrile (60 mL), add 11b (1.86 g) and DIPEA (1.03 g) in sequence, and stir at room temperature for 1 h. After the reaction is complete, the reaction solution is 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) + .

[0523] Step 3:

[0524] 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 separated, 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 flowed out, and purified by column chromatography (methanol: dichloromethane = 1:100 to 1:10) to obtain compound 11d. LC-MS: m / z = 327.12 (M+H) + .

[0525] Step 4:

[0526] 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), and the mixture was protected by nitrogen. The mixture was heated 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) + .

[0527] Step 5:

[0528] 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 with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 11f. LC-MS: m / z = 709.32 (M+H) + .

[0529] Step 6:

[0530] Disperse 11f (600 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (636 mg) in tetrahydrofuran (60 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 4 mL) dropwise, and stir for 30 min. After the reaction is complete, add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500 to 1:100) to obtain compound 11g. LC-MS: m / z = 788.44 (M+H) + .

[0531] Step 7:

[0532] Disperse 11g (330mg) and cesium fluoride (634mg) in DMF (33mL), stir and react at room temperature for 3h. Add water (100mL) and ethyl acetate (100mL) to the reaction solution, stir and separate, wash the organic phase with 5% brine (80mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 11h. LC-MS: m / z=632.32 (M+H) + .

[0533] Step 8:

[0534] Disperse 11h (260 mg) in ethyl acetate (10 mL), cool to 0-5°C, add hydrogen chloride ethyl acetate solution (4N, 1 mL) dropwise to the reaction system, and 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) + .

[0535] Example 12

[0536]

[0537] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with (1S, 3S)-3-aminocyclopentylcarbamic acid tert-butyl ester to prepare compound 12. LC-MS: m / z=631.38 (M+H) + .

[0538] Example 13

[0539]

[0540] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with (R)-(1-aminopropane-2-yl)carbamic acid tert-butyl ester to prepare compound 13. LC-MS: m / z=605.37 (M+H) + .

[0541] Embodiment 14

[0542]

[0543] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with (S)-(1-aminopropane-2-yl)carbamic acid tert-butyl ester to prepare compound 14. LC-MS: m / z=605.37 (M+H) + .

[0544] Embodiment 15

[0545]

[0546] Referring to the preparation process of compound 11 in Example 11, in step 1, (1S, 3R)-3-aminocyclopentanol hydrochloride was used to replace 11a to prepare compound 15. LC-MS: m / z=632.32 (M+H) + .

[0547] Example 16

[0548]

[0549] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with tert-butyl [(1S,2S)-2-aminocyclopropyl]carbamate to prepare compound 16. LC-MS: m / z=603.23 (M+H) + .

[0550] Embodiment 17

[0551]

[0552] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with tert-butyl 3-amino-1-cyclobutylcarbamate to prepare compound 17. LC-MS: m / z=617.33 (M+H) + .

[0553] Embodiment 18

[0554]

[0555] Referring to the preparation process of compound 11 in Example 11, in step 1, 11a was replaced with 4-amino-1-tert-butyloxycarbonylpiperidine to prepare compound 18. LC-MS: m / z=631.38 (M+H) + .

[0556] Embodiment 19

[0557]

[0558] 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) + .

[0559] Embodiment 20

[0560]

[0561] Step 1:

[0562] Disperse 10d (1 g) in tetrahydrofuran (20 mL), add DIPEA (1.73 g) and 20a (2.8 g) in turn, and stir at room temperature for 1 h. After the reaction is complete, the reaction solution is 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) + .

[0563] Step 2:

[0564] Disperse 20b (2.62 g) and cesium fluoride (10.33 g) in DMF (63 mL) and stir at room temperature for 3 h. After the reaction is complete, add water (200 mL) and ethyl acetate (200 mL) to the reaction solution, stir and separate, wash the organic phase with 10% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:10) to obtain compound 20c. LC-MS: m / z = 430.11 (M+H) + .

[0565] Step 3:

[0566] Disperse 20c (451 mg) in dichloromethane (22.5 mL), cool to 0-5°C, add m-chloroperbenzoic acid (907 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*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (ethyl acetate: petroleum ether = 1:50-1:10) to obtain compound 20d. LC-MS: m / z = 462.10 (M+H) + .

[0567] Step 4:

[0568] Disperse 20d (350 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (604 mg) in tetrahydrofuran (9 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 3 mL) dropwise, and stir for 30 min. After the reaction is complete, add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:100 to 1:30) to obtain compound 20e. LC-MS: m / z = 541.21 (M+H) + .

[0569] Step 5:

[0570] 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), and the mixture was stirred at 90°C under nitrogen protection for 5 h. The reaction solution was cooled to room temperature, filtered, and 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) + .

[0571] Step 6:

[0572] 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, add water (50 mL) to the reaction solution, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 20 g. LC-MS: m / z=735.31 (M+H) + .

[0573] Step 7:

[0574] Disperse 20g (100mg) in dichloromethane (10mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 2mL) dropwise to the reaction system, and keep warm for 0.5h. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure and purified by preparative liquid phase (YMC ODS 10μm 50*250 column; acetonitrile-0.1% formic acid aqueous solution (5%-35% / 0-60min gradient elution) to obtain compound 20. LC-MS: m / z=591.23 (M+H)+.

[0575] Embodiment 21

[0576]

[0577]

[0578] Step 1:

[0579] 10d (835 mg) was dispersed in tetrahydrofuran (20 mL), and DIPEA (1.08 g) and 21a (1.45 g) were added in sequence. 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) + .

[0580] Step 2:

[0581] 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 separated, 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 flowed out. Compound 21c was purified by column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:10). LC-MS: m / z = 456.13 (M+H) + .

[0582] Step 3:

[0583] 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*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 to obtain compound 21d. LC-MS: m / z=488.12 (M+H) + .

[0584] Step 4:

[0585] Disperse 21d (670 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (1093 mg) in tetrahydrofuran (20 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 5.5 mL) dropwise, and stir for 30 min. After the reaction is complete, add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (100 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:100 to 1:30) to obtain compound 21e. LC-MS: m / z = 567.23 (M+H) + .

[0586] Step 5:

[0587] 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), and the mixture was protected by nitrogen. The mixture was heated to 90°C and stirred for 5 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The compound 21f was purified by column chromatography (methanol: dichloromethane = 1:100 to 1:30) to obtain compound 21f. LC-MS: m / z = 917.46 (M+H) + .

[0588] Step 6:

[0589] Disperse 21f (892 mg) and cesium fluoride (1.5 g) in DMF (25 mL) and stir at room temperature for 1 h. After the reaction is complete, add water (50 mL) to the reaction solution, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 21g. LC-MS: m / z=761.33 (M+H) + .

[0590] Step 7:

[0591] Disperse 21g (100mg) in dichloromethane (10mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 2mL) dropwise to the reaction system, and keep warm for 0.5h. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure and purified by preparative liquid phase (YMC ODS 10μm 50*250 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)+.

[0592] Embodiment 22

[0593]

[0594] 21 (324 mg) was dispersed in methanol (15 mL), and aqueous formaldehyde solution (1.58 g, 40%) and sodium triacetoxyborohydride (446 mg) were added in sequence, and 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) + .

[0595] Embodiment 23

[0596]

[0597] 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) + .

[0598] Embodiment 24

[0599]

[0600] 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) + .

[0601] Embodiment 25

[0602]

[0603] 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) + .

[0604] Embodiment 26

[0605]

[0606] 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) + .

[0607] Embodiment 27

[0608]

[0609] 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) + .

[0610] Embodiment 28

[0611]

[0612] 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) + .

[0613] Embodiment 29

[0614]

[0615] 21 (455 mg) was dispersed in hexafluoroisopropanol (4.5 mL), iodomethane (105 mg) was slowly added dropwise, and the reaction was stirred at room temperature for 18 h. After the reaction was complete, the reaction solution was purified by preparative liquid phase (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 water (10%-10%-20%-90% / 0-15-16-60 min)) to obtain compound 29. LC-MS: m / z=631.26 (M+H) + .

[0616] Embodiment 30

[0617]

[0618] Step 1:

[0619] Disperse 10h (200 mg) in DMF (5 mL), cool to 0-5°C, add NaH (50 mg, 60%) and iodomethane (350 mg), and stir for 4 h. After the reaction is complete, add saturated ammonium chloride solution (30 mL) to the reaction system, extract with ethyl acetate (50 mL*2), combine the organic phases, wash with 5% brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:100) to obtain compound 30a. LC-MS: m / z = 834.55 (M+H) + .

[0620] Step 2:

[0621] 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*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 to obtain compound 30b. LC-MS: m / z=866.52 (M+H) + .

[0622] Step 3:

[0623] Disperse 30b (200 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (112 mg) in tetrahydrofuran (5 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 0.6 mL) dropwise, move to room temperature and stir to react overnight. After the reaction is complete, add saturated ammonium chloride solution (100 mL) to the reaction system, extract with ethyl acetate (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 to obtain compound 30c. LC-MS: m / z=945.62 (M+H) + .

[0624] Step 4:

[0625] 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 ethyl acetate (80 mL*2) was used for extraction. 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 flowed out to obtain compound 30d. LC-MS: m / z=789.40 (M+H) + .

[0626] Step 5:

[0627] Disperse 30d (250 mg) in dichloromethane (2.5 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 2.5 mL) dropwise to the reaction system, and keep warm for 0.5 h. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC AQ C1850*250 column; acetonitrile-0.05% acetic acid (10%-70% / 0-60min gradient elution) to obtain compound 30. LC-MS: m / z=645.32 (M+H) + .

[0628] Embodiment 31

[0629]

[0630] 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) + .

[0631] 1H-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).

[0632] Example 32 and Example 33

[0633]

[0634] Step 1:

[0635] Disperse 32a (2 g) and imidazole (5.4 g) in DMF (40 mL), stir at room temperature for 30 min, add tert-butyldimethylsilyl chloride (6 g), and continue stirring and reacting for 12 h. Add water (100 mL) and ethyl acetate (150 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (100 mL*2), combine the organic phases, wash the organic phases with 5% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 32b. LC-MS: m / z=190.16 (M+H) + .

[0636] Step 2:

[0637] 32b (2 g) was dispersed in DMF (200 mL), iodoethane (1.47 g) was added dropwise at room temperature, and the reaction was stirred for 12 h. Water (200 mL) and ethyl acetate (250 mL) were added to the reaction solution, and the mixture was stirred to separate the liquids. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined, washed with 5% brine (150 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 32c. LC-MS: m / z=218.19 (M+H) + .

[0638] Step 3:

[0639] Disperse 10d (530 mg) in tetrahydrofuran (20 mL), slowly add DIPEA (923 mg) and 32c (774 mg) in sequence, and stir at room temperature for 1 h. After the reaction is complete, the reaction solution is 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) + .

[0640] Step 4:

[0641] 32d (532 mg) and cesium fluoride (2029 mg) were dispersed in DMF (22 mL), heated to 80°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 separated, the organic phase was washed with 10% brine (80 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out. Compound 32e was purified by column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:5). LC-MS: m / z = 329.06 (M+H) + .

[0642] Step 5:

[0643] 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), and the mixture was heated to 90°C and stirred for 5 h under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and 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) + .

[0644] Step 6:

[0645] 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*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 to obtain compound 32g. LC-MS: m / z=711.28 (M+H) + .

[0646] Step 7:

[0647] Disperse 32g (245mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (275mg) in tetrahydrofuran (8mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 1.4mL) dropwise, and stir for 30min. After the reaction is complete, add saturated ammonium chloride solution (50mL) to the reaction system, extract with ethyl acetate (80mL*2), combine the organic phases, wash with 5% brine (80mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 32h. LC-MS: m / z=790.40 (M+H) + .

[0648] Step 8:

[0649] Disperse 32h (285 mg) and cesium fluoride (550 mg) in DMF (10 mL), stir and react at room temperature for 2 h. Add water (50 mL) and ethyl acetate (80 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 32i. LC-MS: m / z=634.26 (M+H) + .

[0650] Step 9:

[0651] Disperse 32i (280 mg) in dichloromethane (20 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 4 mL) dropwise to the reaction system, and keep warm for 1 h. After the reaction is complete, the reaction solution is concentrated to dryness under reduced pressure and purified by preparative liquid phase (YMC ODS 10 μm 50*250 column; acetonitrile-0.1% FA (10%-40% / 0-60 min gradient elution) to obtain compound 32j. LC-MS: m / z=590.24 (M+H) + .

[0652] Step 10:

[0653] Compound 32j was purified by preparative liquid chromatography (YMC Cellulose-SC 10 μm 30*250 column; ethanol-n-hexane (40%-100% / 0-30 min gradient elution) to obtain compound 32 (Rt 13.1 min, 61 mg) and compound 33 (Rt 15.6 min, 58 mg).

[0654] Compound 32: LC-MS: m / z=590.24 (M+H) + .

[0655] 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).

[0656] Compound 33: LC-MS: m / z=590.24 (M+H) + .

[0657] 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).

[0658] 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.

[0659] Embodiment 34

[0660]

[0661] Step 1:

[0662] 34a (7.25 g) and p-methoxybenzyl chloride (26.3 g) were dispersed in DMF (80 mL), and sodium hydrogen (60%, 5.9 g) was added under stirring at room temperature, and the reaction was continued under stirring for 2 h. After the reaction was complete, ammonium chloride solution (20 mL) was added to quench the reaction, and water (100 mL) and ethyl acetate (150 mL) were added and stirred to separate the liquids. The aqueous phase was extracted with ethyl acetate (100 mL*2), and 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 flowed out. Compound 34b was purified by column chromatography (ethyl acetate: petroleum ether = 1:100 to 1:10). LC-MS: m / z = 413.16 (M+H)+.

[0663] Step 2:

[0664] 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 the mixture was heated to 80°C and stirred for 8 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, the pH was adjusted to acidic with dilute hydrochloric acid, water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined. The organic phases were washed once with 10% sodium bicarbonate solution (100 mL) and 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out. Compound 34c was purified by column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:5). LC-MS: m / z = 377.26 (M+H)+.

[0665] Step 3:

[0666] Disperse 34c (0.7 g), 2-(tert-butyldimethylsilyloxy)ethylamine (1.12 g), and tetraisopropyl titanate (1.2 mL) in methanol (14 mL), heat to 80°C and stir for 6 h. The reaction solution was cooled to 0°C, sodium borohydride (240 mg) was added, and the mixture was stirred at room temperature for 4 h. After the reaction, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated until no liquid flowed out. Compound 34d was purified by column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:2). LC-MS: m / z = 536.39 (M+H)+.

[0667] Step 4:

[0668] 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)+.

[0669] Step 5:

[0670] Disperse 34e (809 mg) and cesium fluoride (1.6 g) in DMF (16 mL), heat to 60°C and stir to react for 2 h. After the reaction is complete, add water (100 mL) and ethyl acetate (100 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (100 mL*2), wash the organic phase with 10% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 34f. LC-MS: m / z=647.28(M+H)+.

[0671] Step 6:

[0672] 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*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 to obtain compound 34g. LC-MS: m / z=679.27 (M+H)+.

[0673] Step 7:

[0674] Disperse 34g (725 mg) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (850 mg) in tetrahydrofuran (15 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 4.3 mL) dropwise, and stir for 1 h. After the reaction is complete, add saturated ammonium chloride solution (20 mL) to the reaction system to quench the reaction, add water (50 mL) and ethyl acetate (80 mL) to stir and separate, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:100 to 1:20) to obtain compound 34h. LC-MS: m / z = 758.33 (M+H)+.

[0675] Step 8:

[0676] Disperse 34h (200 mg) in trifluoroacetic acid (10 mL), cool to 0°C, add methanesulfonic acid (1 mL) dropwise, move to room temperature and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (10 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (50 mL) and dichloromethane (50 mL) are added and stirred to separate the liquids, and dichloromethane (50 mL*2) is used for extraction, the organic phases are combined, the organic phases are washed with 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 34i. LC-MS: m / z=518.21(M+H)+.

[0677] Step 9:

[0678] 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), protected by nitrogen, and heated to 90°C with stirring 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)+.

[0679] Step 10:

[0680] Disperse 34j (175 mg) and cesium fluoride (306 mg) in DMF (10 mL) and stir at room temperature for 2 h. Add water (50 mL) and ethyl acetate (80 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 34k. LC-MS: m / z=712.50 (M+H) + .

[0681] Step 11:

[0682] Disperse 34k (168 mg) in dichloromethane (10 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 2 mL) dropwise to the reaction system, and stir and react for 1 h. After the reaction is complete, the reaction solution is 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 obtain compound 34. LC-MS: m / z=668.42 (M+H) + .

[0683] Example 35 and Example 36

[0684]

[0685] 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).

[0686] Compound 35: LC-MS: m / z=668.40 (M+H) + .

[0687] 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).

[0688] Compound 36: LC-MS: m / z=668.41 (M+H) + .

[0689] 1H-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).

[0690] 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.

[0691] Embodiment 37

[0692]

[0693] 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) + .

[0694] Embodiment 38

[0695]

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

[0697] Example 39 and Example 40

[0698]

[0699] Compound 38 was purified by liquid phase (CHIRALPAKID 5.0 ​​μm 4.6*250 mm; n-hexane-0.1% ethanolamine / ethanol (50% / isocratic elution 20 min)) to obtain 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) + ).

[0700] 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,1 H),7.59-7.30(m,2H),7.28-7.04(m,1H),6.83-6.37(m,2H),5.78-5.44(m,2H),5.4 3-5.15(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).

[0701] Compound 40: 1 H-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).

[0702] 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.

[0703] Embodiment 41

[0704]

[0705] 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) + .

[0706] Example 42 and Example 43

[0707]

[0708] Compound 41 was purified by liquid phase (CHIRALPAKID 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) + ).

[0709] Compound 42: 1 H-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).

[0710] Compound 43: 1H-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).

[0711] 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.

[0712] Embodiment 44

[0713]

[0714] 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) + .

[0715] Example 45 and Example 46

[0716]

[0717] 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) + ).

[0718] 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.

[0719] Example 47 and Example 48

[0720]

[0721]

[0722] Referring to the preparation process of compound 34i in Example 34, in step 3, 2-(tert-butyldimethylsilyloxy)ethylamine was replaced with L-aminopropanol to prepare compound 47a. LC-MS: m / z=532.20 (M+H) + .

[0723] Step 1:

[0724] 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 the mixture was protected by nitrogen. The mixture was heated to 90° C. and stirred for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 47b was purified by column chromatography (ethyl acetate: petroleum ether=1:10-1:2) to obtain compound 47b. LC-MS: m / z=822.77 (M+H) + .

[0725] Step 2:

[0726] Disperse 47b (157 mg) and cesium fluoride (300 mg) in DMF (16 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, wash the organic phase with 5% brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 47c. LC-MS: m / z=666.40 (M+H) + .

[0727] Step 3:

[0728] 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) + ).

[0729] 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.

[0730] Compound 47: 1 H-NMR(500MHz,DMSO-d6),δ:8.30-8.10(m,2H),8.06-7.95(m,1H),7.80-7.49( m,4H),6.80-6.65(m,1H),6.62-6.44(m,1H),5.77-5.47(m,2H),5.42-5.17(m, 1H),4.63-4.44(m,1H),4.33-3.87(m,5H),3.17-2.98(m,3H),2.92-2.77(m,1H ),2.22-1.98(m,3H),1.92-1.72(m,3H),1.71-1.52(m,3H),0.72-0.47(m,3H).

[0731] Embodiment 49

[0732]

[0733] 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) + .

[0734] Embodiment 50

[0735]

[0736] 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) + .

[0737] Embodiment 51

[0738]

[0739] Referring to the preparation process of compound 34 in Example 34, in step 7, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methane-d2-ol was used to replace ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to prepare compound 51. LC-MS: m / z=670.38 (M+H) + .

[0740] Embodiment 52

[0741]

[0742] 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 to replace ((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) + .

[0743] Example 53 and Example 54

[0744]

[0745] 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) + ).

[0746] 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.

[0747] Example 55 and Example 56

[0748]

[0749] 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 (3-methyl-2-(trifluoromethyl)phenyl)boric acid to prepare compound 55a.

[0750] 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 28min, LC-MS: m / z=656.28 (M+H) + ).

[0751] Compound 55: 1 H-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).

[0752] 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).

[0753] 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.

[0754] Example 57 and Example 58

[0755]

[0756] 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)phenylboronic acid pinacol ester to prepare compound 57a.

[0757] 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 obtain compound 57 (Rt 49 min) and compound 58 (Rt 52 min).

[0758] Compound 57: LC-MS: m / z=617.41 (M+H) + .

[0759] 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).

[0760] Compound 58: LC-MS: m / z=617.38 (M+H) + .

[0761] 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).

[0762] 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.

[0763] Example 59 and Example 60

[0764]

[0765] 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 1-naphthaleneboronic acid to prepare compound 59a.

[0766] 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 55min, LC-MS: m / z=624.37 (M+H) + ).

[0767] 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.

[0768] Example 61 and Example 62

[0769]

[0770]

[0771] 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-(trifluoromethyl)phenylboronic acid to prepare compound 61a.

[0772] Compound 61a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia water (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 40min, LC-MS: m / z=642.34 (M+H) + ).

[0773] 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).

[0774] 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).

[0775] 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.

[0776] Example 63 and Example 64

[0777]

[0778] 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.

[0779] Compound 63a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia water (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 27min, LC-MS: m / z=691.23 (M+H) + ).

[0780] 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).

[0781] 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).

[0782] 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.

[0783] Example 65 and Example 66

[0784]

[0785] Referring to the preparation process of compound 34f in Example 34, in step 3, 2-(tert-butyldimethylsilyloxy)ethylamine was replaced with L-aminopropanol to prepare compound 65a. LC-MS: m / z=661.33 (M+H) + .

[0786] Step 1:

[0787] 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*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 to obtain compound 65b. LC-MS: m / z=693.31 (M+H) + .

[0788] Step 2:

[0789] Disperse 65b (600 mg) and methanol (83 mg) in tetrahydrofuran (10 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 2.6 mL) dropwise, and stir for 1 h. After the reaction is complete, add saturated ammonium chloride solution (20 mL) to the reaction system to quench the reaction, add water (50 mL) and ethyl acetate (80 mL) to stir and separate, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:150 to 1:50) to obtain compound 65c. LC-MS: m / z = 645.31 (M+H) + .

[0790] Step 3:

[0791] Disperse 65c (500 mg) in trifluoroacetic acid (10 mL), cool to 0°C, add methanesulfonic acid (1 mL) dropwise, move to room temperature and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (10 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (50 mL) and dichloromethane (50 mL) are added and stirred to separate the liquids, and dichloromethane (50 mL*2) is used for extraction, the organic phases are combined, the organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 65d. LC-MS: m / z=405.24 (M+H) + .

[0792] Step 4:

[0793] 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 the mixture was protected by nitrogen. The mixture was heated to 90°C and stirred for 3 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 65e was purified by column chromatography (methanol: dichloromethane = 1:200 to 1:100) to obtain compound 65e. LC-MS: m / z = 755.40 (M+H) + .

[0794] Step 5:

[0795] Disperse 65e (550 mg) and cesium fluoride (1.66 g) in DMF (20 mL) and stir at room temperature for 2 h. Add water (50 mL) and ethyl acetate (80 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 65f. LC-MS: m / z=599.33 (M+H) + .

[0796] Step 6:

[0797] Disperse 65f (438 mg) in dichloromethane (5 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 1 mL) dropwise to the reaction system, and stir to react for 1 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, to obtain compound 65g. LC-MS: m / z=555.25 (M+H) + .

[0798] Step 7:

[0799] 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 32min, LC-MS: m / z=555.24 (M+H) + ).

[0800] 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).

[0801] 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).

[0802] 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.

[0803] Example 67 and Example 68

[0804]

[0805] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by N-methyl-L-prolinol to prepare compound 67a.

[0806] 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 24.4min, LC-MS: m / z=638.37(M+H) + ).

[0807] 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.

[0808] Example 69 and Example 70

[0809]

[0810] 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.

[0811] 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 26.5min, LC-MS: m / z=694.38 (M+H) + ).

[0812] 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).

[0813] 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) ,7.50-7.42(m,1H),7.37(d,J=2.5Hz,1H),7.21-7.10(m,1H),6.75-6.65(m,1H),6.56-6.3 7(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 -2.26(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).

[0814] 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.

[0815] Example 71 and Example 72

[0816]

[0817]

[0818] Referring to the preparation process of compound 65g in Example 65, in step 22, methanol is replaced by ((2R,7aS)-2-fluorotetrahydro-1HH-pyrrolizin-7a(5H)-yl)methane-d2-ol to prepare compound 71a.

[0819] 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 43min, LC-MS: m / z=684.37 (M+H) + ).

[0820] Compound 71: 1H-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).

[0821] 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).

[0822] 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.

[0823] Example 73 and Example 74

[0824]

[0825] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by (2S)-2-methoxy-1-propanol to prepare compound 73a.

[0826] 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 29.3min, LC-MS: m / z=613.27 (M+H)+ ).

[0827] 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.

[0828] Example 75 and Example 76

[0829]

[0830]

[0831] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol is replaced by (R)-2-methoxy-1-propanol to prepare compound 75a.

[0832] 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 31min, LC-MS: m / z=613.33 (M+H) + ).

[0833] 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).

[0834] Compound 76: 1H-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).

[0835] 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.

[0836] Example 77 and Example 78

[0837]

[0838] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 2-methoxy-2-methylpropane-1-ol to prepare compound 77a.

[0839] 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 by acetonitrile / 0.1% formic acid to obtain compound 77 (Rt 21 min, LC-MS: m / z = 627.32 (M+H) + ) and compound 78 (Rt 24min, LC-MS: m / z=627.33 (M+H) + ).

[0840] 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).

[0841] 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).

[0842] 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.

[0843] Example 79 and Example 80

[0844]

[0845] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 3-dimethylamino-1-propanol to prepare compound 79a.

[0846] 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 36min, LC-MS: m / z=626.36 (M+H) + ).

[0847] 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).

[0848] 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).

[0849] 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.

[0850] Embodiment 81

[0851]

[0852] 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-dioxybenzofuran-2-yl)benzo[b]thiophene-2-methyl)carbamate 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 81a. LC-MS: m / z=788.41 (M+H) + .

[0853] Disperse 81a (430 mg) in dichloromethane (10 mL), cool to 0-5°C, add trifluoroacetic acid (4 mL), and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (10 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (50 mL) and dichloromethane (50 mL) are added, stirred and separated, and extracted with dichloromethane (50 mL*2), the organic phases are combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 81. LC-MS: m / z=688.30 (M+H) + .

[0854] Example 82 and Example 83

[0855]

[0856] Compound 81 was purified by preparative liquid chromatography (YMCC18 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 24min, LC-MS: m / z=688.30 (M+H) + ).

[0857] 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.

[0858] Embodiment 84

[0859]

[0860] 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 with reference 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) + .

[0861] 84a (200 mg) was dispersed in methanol (10 mL), p-toluenesulfonic acid (10 mg) was added at room temperature, and the reaction was continued with stirring 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 water (50%-90% / 0-60 min gradient elution)) to obtain compound 84. LC-MS: m / z=646.48 (M+H) + .

[0862] Example 85 and Example 86

[0863]

[0864] 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 47min, LC-MS: m / z=646.48 (M+H) + ).

[0865] 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).

[0866] Compound 86: 1 H-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).

[0867] 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.

[0868] Example 87 and Example 88

[0869]

[0870] 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) + .

[0871] Step 1:

[0872] 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 the mixture was protected by nitrogen. The mixture was heated to 90°C and stirred for 2 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The compound 87b was purified by column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:2). LC-MS: m / z = 778.59 (M+H) + .

[0873] Step 2:

[0874] Disperse 87b (130 mg) and cesium fluoride (253 mg) in DMF (13 mL) and stir at room temperature for 2 h. Add water (50 mL) and ethyl acetate (80 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 87c. LC-MS: m / z=622.37 (M+H) + .

[0875] Step 3:

[0876] 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 35min, LC-MS: m / z=622.37 (M+H) + ).

[0877] Compound 87: 1H-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).

[0878] 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).

[0879] 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.

[0880] Example 89 and Example 90

[0881]

[0882] Step 1:

[0883] Disperse 65b (600 mg) and ethanol (10 mL) in dichloromethane (10 mL), cool to 0°C, slowly add sodium borohydride (65 mg), move to room temperature and stir to react for 1 h. After the reaction is complete, add saturated ammonium chloride solution (20 mL) to the reaction system to quench the reaction, add water (50 mL) and ethyl acetate (80 mL) to stir and separate, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 89a. LC-MS: m / z=615.30 (M+H) + .

[0884] Step 2:

[0885] Disperse 89a (420 mg) in trifluoroacetic acid (10 mL), cool to 0°C, add methanesulfonic acid (1 mL) dropwise, move to room temperature and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (10 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (50 mL) and dichloromethane (50 mL) are added and stirred to separate the liquids, and dichloromethane (50 mL*2) is used for extraction, the organic phases are combined, the organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 89b. LC-MS: m / z=375.25 (M+H) + .

[0886] Step 3:

[0887] 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 the mixture was protected by nitrogen. The mixture was heated to 90°C and stirred for 3 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 89c was purified by column chromatography (methanol: dichloromethane = 1:200 to 1:100) to obtain compound 89c. LC-MS: m / z = 725.35 (M+H) + .

[0888] Step 4:

[0889] Disperse 89c (220 mg) and cesium fluoride (592 mg) in DMF (5 mL) and stir at room temperature for 2 h. Add water (50 mL) and ethyl acetate (80 mL) to the reaction solution, stir and separate, extract the aqueous phase with ethyl acetate (50 mL*2), combine the organic phases, wash the organic phases with 5% brine (80 mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 89d. LC-MS: m / z=569.25 (M+H) + .

[0890] Step 5:

[0891] Disperse 89d (220 mg) in dichloromethane (5 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 1 mL) dropwise to the reaction system, and stir to react for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure until no liquid flows out to obtain compound 89e. LC-MS: m / z=525.20 (M+H) + .

[0892] Step 6:

[0893] 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 24min, LC-MS: m / z=525.22 (M+H) + ).

[0894] 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).

[0895] Compound 90: 1 H-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).

[0896] 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.

[0897] Example 91 and Example 92

[0898]

[0899] 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.

[0900] 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 30min, LC-MS: m / z=654.35 (M+H) + ).

[0901] 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.

[0902] Example 93 and Example 94

[0903]

[0904] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol is replaced by 1-methyl-2-hydroxymethyl-1H-imidazole to prepare compound 93a.

[0905] 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 30min, LC-MS: m / z=635.33 (M+H) + ).

[0906] 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.

[0907] Example 95 and Example 96

[0908]

[0909] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by N,N-dimethylethanolamine to prepare compound 95a.

[0910] 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 28min, LC-MS: m / z=612.34 (M+H) + ).

[0911] 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.

[0912] Example 97 and Example 98

[0913]

[0914]

[0915] 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.

[0916] Compound 97a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia water (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 36min, LC-MS: m / z=664.36 (M+H) + ).

[0917] 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.

[0918] Example 99 and Example 100

[0919]

[0920] 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.

[0921] 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 39min, LC-MS: m / z=610.32 (M+H) + ).

[0922] 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.

[0923] Example 101 and Example 102

[0924]

[0925] 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.

[0926] 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 58min, LC-MS: m / z=638.40 (M+H) + ).

[0927] 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.

[0928] Example 103 and Example 104

[0929]

[0930] 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.

[0931] 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) + ).

[0932] 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.

[0933] Example 105 and Example 106

[0934]

[0935] 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.

[0936] 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) + ).

[0937] 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.

[0938] Example 107 and Example 108

[0939]

[0940] 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.

[0941] 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 34.8min, LC-MS: m / z=652.36 (M+H) + ).

[0942] 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.

[0943] Example 109 and Example 110

[0944]

[0945] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by (S)-(1,4-dimethylpiperazin-2-yl)methanol to prepare compound 109a.

[0946] 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) + ).

[0947] 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.

[0948] Example 111 and Example 112

[0949]

[0950] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by (S)-2-(dimethylamino)propanol to prepare compound 111a.

[0951] 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) + ).

[0952] 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).

[0953] 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).

[0954] 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.

[0955] Example 113 and Example 114

[0956]

[0957] Referring to the preparation process of compound 65f in Example 65, in step 2, methanol is replaced with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methane-d2-ol; in step 4, 10 g is 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.

[0958] 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) + ).

[0959] 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).

[0960] 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).

[0961] 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.

[0962] Embodiment 115

[0963]

[0964] 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 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 115. LC-MS: m / z=658.32 (M+H) + .

[0965] Example 116 and Example 117

[0966]

[0967] 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.

[0968] Compound 116a was purified by preparative liquid chromatography (YMC C18 10 μm 50*250 column; acetonitrile-0.1% ammonia water (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 44min, LC-MS: m / z=664.33 (M+H) + ).

[0969] 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.

[0970] Example 118 and Example 119

[0971]

[0972] 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.

[0973] 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 39min, LC-MS: m / z=640.41 (M+H) + ).

[0974] 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.

[0975] Example 120 and Example 121

[0976]

[0977] 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.

[0978] 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 47min, LC-MS: m / z=660.35 (M+H) + ).

[0979] Compound 120: 1H-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).

[0980] Compound 121: 1 H-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).

[0981] 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.

[0982] Example 122 and Example 123

[0983]

[0984] 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 under hydrogen atmosphere for overnight reaction. After the reaction was complete, the mixture was filtered, and the reaction solution was 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 obtain compound 122. LC-MS: m / z=670.38 (M+H) + .

[0985] 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) + .

[0986] The chiral carbon atom configurations of compound 122 are the same as those of compound 47. The chiral carbon atom configurations of compound 123 are the same as those of compound 48.

[0987] Example 124 and Example 125

[0988]

[0989] 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.

[0990] 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% / 0-40min gradient elution)) to give compound 124 (Rt 28min, LC-MS: m / z=676.32 (M+H) + ).

[0991] Example 126 and Example 127

[0992]

[0993]

[0994] 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.

[0995] 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 phase (YMC-AQ-C18, 10 μm, 50*250 column; methanol-0.1 TFA% aqueous solution (10%-70% / 0-60min gradient elution)) to give compound 127 (Rt 43min, LC-MS: m / z=635.40 (M+H) + ).

[0996] Example 128 and Example 129

[0997]

[0998] 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.

[0999] 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) + ).

[1000] 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.

[1001] Example 130 and Example 131

[1002]

[1003] 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.

[1004] 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) + ).

[1005] 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.

[1006] Example 132 and Example 133

[1007]

[1008] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 3-(1-pyrrolidinyl)-1-propanol to prepare compound 132a.

[1009] Compound 132a was purified by preparative liquid phase (Novasep C18 250*50mm, 10μm column; methanol-0.1% ammonia aqueous solution (40%-90% / 0-60min gradient elution)), and then purified by preparative liquid phase (Novasep C18 250*50mm, 10μm column; acetonitrile-0.1% acetic acid aqueous solution (15%-45% / 0-60min gradient elution)) to obtain compound 132 (Rt 40min, LC-MS: m / z=652.37 (M+H) + ) and compound 133 (Rt 38min, LC-MS: m / z=652.36 (M+H) + ).

[1010] 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.

[1011] Example 134 and Example 135

[1012]

[1013] 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.

[1014] 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) + ).

[1015] 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.

[1016] Example 136 and Example 137

[1017]

[1018] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 2-morpholinoethanol to prepare compound 136a.

[1019] 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 33min, LC-MS: m / z=654.34 (M+H) + ).

[1020] 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.

[1021] Example 138 and Example 139

[1022]

[1023] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 1-(2-hydroxyethyl)pyrrolidine to prepare compound 138a.

[1024] 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) + ).

[1025] 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.

[1026] Example 140 and Example 141

[1027]

[1028] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 1-tert-butyloxycarbonyl-4-(3-hydroxypropane)piperazine to prepare compound 140a.

[1029] 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 62.30min, LC-MS: m / z=667.36 (M+H) + ).

[1030] 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.

[1031] Example 142 and Example 143

[1032]

[1033] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 1-piperidinylpropanol to prepare compound 142a.

[1034] Compound 142a was purified by preparative liquid phase (Novasep C18 250*50mm, 10μm column; methanol-0.1% ammonia aqueous solution (45%-85% / 0-60min gradient elution)), and then purified by preparative liquid phase (Novasep C18 250*50mm, 10μm column; acetonitrile-0.1% acetic acid aqueous solution (15%-45% / 0-60min gradient elution)) to obtain compound 142 (Rt 28min, LC-MS: m / z=666.38 (M+H) + ) and compound 143 (Rt 29min, LC-MS: m / z=666.40 (M+H) + ).

[1035] 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.

[1036] Example 144 and Example 145

[1037]

[1038]

[1039] 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.

[1040] 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) + ).

[1041] 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.

[1042] Example 146 and Example 147

[1043]

[1044] 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.

[1045] 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 42.08min, LC-MS: m / z=656.33 (M+H) + ).

[1046] 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.

[1047] Example 148 and Example 149

[1048]

[1049] 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.

[1050] 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 49.50min, LC-MS: m / z=674.32 (M+H) + ).

[1051] 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.

[1052] Example 150 and Example 151

[1053]

[1054] 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.

[1055] 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 38min, LC-MS: m / z=652.34 (M+H) + ).

[1056] 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.

[1057] Example 152 and Example 153

[1058]

[1059] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by (R)-2-(dimethylamino)propanol to prepare compound 152a.

[1060] 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) + ).

[1061] 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.

[1062] Example 154 and Example 155

[1063]

[1064] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 3-(4-morpholine)-1-propanol to prepare compound 154a.

[1065] 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) + ).

[1066] 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.

[1067] Example 156 and Example 157

[1068]

[1069] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N,N,3-trimethylazetidine-3-amine dihydrochloride to prepare compound 156a.

[1070] 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) + ).

[1071] 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.

[1072] Example 158 and Example 159

[1073]

[1074] 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-dioxybenzofuran-2-yl)benzo[b]thiophene-2-methyl)carbamate to prepare compound 158a.

[1075] 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) + ).

[1076] 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.

[1077] Example 160 and Example 161

[1078]

[1079] Referring to the preparation process of compound 87b in Example 87, in step 1, (3-methyl-2-(trifluoromethyl)phenyl)boronic acid is 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 160a.

[1080] 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 48min, LC-MS: m / z=612.33 (M+H) + ).

[1081] 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.

[1082] Example 162 and Example 163

[1083]

[1084] 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.

[1085] 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) + ).

[1086] 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.

[1087] Example 164 and Example 165

[1088]

[1089] Referring 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.

[1090] 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) + ).

[1091] 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.

[1092] Example 166 and Example 167

[1093]

[1094] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced with N-hydroxyethylpiperidine to prepare compound 166a.

[1095] 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) + ).

[1096] 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.

[1097] Example 168 and Example 169

[1098]

[1099] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 1-hydroxyethyl-4-methylpiperazine to prepare compound 168a.

[1100] 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) + ).

[1101] 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.

[1102] Example 170 and Example 171

[1103]

[1104]

[1105] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by 1-(3-hydroxypropyl)-4-methylpiperazine to prepare compound 170a.

[1106] 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) + ).

[1107] 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.

[1108] Example 172 and Example 173

[1109]

[1110] 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.

[1111] 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) + ).

[1112] 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.

[1113] Example 174 and Example 175

[1114]

[1115] 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.

[1116] 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 37.53min, LC-MS: m / z=638.26(M+H) + ).

[1117] 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.

[1118] Example 176 and Example 177

[1119]

[1120] 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.

[1121] 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) + ).

[1122] 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.

[1123] Example 178 and Example 179

[1124]

[1125] Referring to the preparation process of compound 65g in Example 65, in step 2, methanol was replaced by (S)-(2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol to prepare compound 178a.

[1126] 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) + ).

[1127] 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.

[1128] Embodiment 180 to Embodiment 425

[1129] With reference to route 1 and examples 1-179 of the present application, the following compounds were prepared:

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144] Example 426 and Example 427

[1145]

[1146]

[1147] Step 1:

[1148] Disperse 426a (7.25 g) and p-methoxybenzyl chloride (26.3 g) in DMF (80 mL), add sodium hydrogen sulfide (60%, 5.9 g) under stirring at room temperature, and continue stirring to react for 2 h. After the reaction is complete, add ammonium chloride solution (20 mL) to quench the reaction, add water (100 mL) and ethyl acetate (150 mL) and stir to separate the liquids, extract the aqueous phase with ethyl acetate (100 mL*2), combine the organic phases, wash the organic phases with 5% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (ethyl acetate: petroleum ether = 1:100 to 1:10) to obtain compound 426b. LC-MS: m / z = 413.16 (M+H) + .

[1149] Step 2:

[1150] 426b (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 the mixture was heated to 80°C and stirred for 8 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, and the pH was adjusted to acidic with dilute hydrochloric acid. Water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined. The organic phases were washed once with 10% sodium bicarbonate solution (100 mL) and 5% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out. Compound 426c was purified by column chromatography (ethyl acetate: petroleum ether = 1:50 to 1:5). LC-MS: m / z = 377.26 (M+H) + .

[1151] Step 3:

[1152] Disperse 426c (1.4 g), L-aminopropanol (0.84 g), and tetraisopropyl titanate (4.5 g) in methanol (28 mL), heat to 80°C, and stir to react for 16 h. Cool the reaction solution to 0°C, add sodium borohydride (280 mg), and move to room temperature and stir to react for 4 h. After the reaction, filter the reaction solution through diatomaceous earth, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:10) to obtain compound 426d. LC-MS: m / z = 436.40 (M+H) + .

[1153] Step 4:

[1154] Disperse 426e (5 g) in acetonitrile (100 mL), add DIPEA (13.8 g) and phosphorus oxychloride (8.19 g) in sequence, and heat to 80°C under nitrogen protection and stir for 2 h. After the reaction is complete, cool the reaction solution to room temperature, pour into ice water (500 mL), stir and crystallize for 30 min, and filter. The filter cake is dried in vacuo at 55°C for 6 h to obtain compound 426f.

[1155] Step 5:

[1156] Disperse 426f (1.4 g), 426d (700 mg), and DIPEA (630 mg) in tetrahydrofuran (45 mL) and stir to react overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:5) to obtain compound 426g. LC-MS: m / z = 697.31 (M+H) + Step 6:

[1157] Disperse 426g (1.5g) and cesium fluoride (3.3g) in DMF (150mL), heat to 60°C and stir to react for 2h. After the reaction is complete, the reaction solution is concentrated until no liquid flows out, ethyl acetate (100mL) is used to dissolve the residue, water (100mL) is added and stirred to separate the liquids, the aqueous phase is extracted with ethyl acetate (100mL*2), the organic phases are combined, the organic phases are washed with 10% brine (100mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 426h. LC-MS: m / z=661.33 (M+H) + .

[1158] Step 7:

[1159] Disperse 426h (2.78 g) in dichloromethane (110 mL), cool to 0-5°C, add m-chloroperbenzoic acid (85%, 3.6 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*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 to obtain compound 426i. LC-MS: m / z=693.28 (M+H) + .

[1160] Step 8:

[1161] Disperse 426i (700 mg) and 426j (500 mg) in tetrahydrofuran (15 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 3 mL) dropwise, and stir for 1 h. After the reaction is complete, add saturated ammonium chloride solution (20 mL) to the reaction system to quench the reaction, add water (50 mL) and ethyl acetate (80 mL) to stir and separate, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200-1:30) to obtain compound 426k. LC-MS: m / z = 772.33 (M+H) + .

[1162] Step 9:

[1163] Disperse 426k (2.83 g) in trifluoroacetic acid (30 mL), cool to 0°C, add methanesulfonic acid (6 mL) dropwise, move to room temperature and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (200 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (100 mL) and dichloromethane (100 mL) are added and stirred to separate the liquids, and dichloromethane (100 mL*2) is used for extraction, the organic phases are combined, the organic phases are washed with 10% brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated until no liquid flows out to obtain compound 426l. LC-MS: m / z=532.21 (M+H) + .

[1164] Step 10:

[1165] 426l (3.6 g), 426m (6.9 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1'-biphenyl-2-yl)palladium (II) (777 mg), potassium phosphate (4.3 g), and water (10.8 mL) were dispersed in 1,4-dioxane (54 mL), protected by nitrogen, and heated to 90°C with stirring 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 = 1:200 to 1:10) to obtain compound 426n. LC-MS: m / z = 882.56 (M+H) + .

[1166] Step 11:

[1167] Disperse 426n (250 mg) and N-chlorosuccinimide (114 mg) in acetonitrile (25 mL), heat to 60°C and stir to react for 5 h. Add saturated sodium sulfite solution (100 mL) and dichloromethane (100 mL) to the reaction solution, stir and separate, extract the aqueous phase with dichloromethane (100 mL*2), combine the organic phases, wash the organic phases with saturated sodium bicarbonate solution (100 mL*2) and 10% brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 426o. LC-MS: m / z=916.54 (M+H) + .

[1168] Step 12:

[1169] Disperse 426o (280 mg) and cesium fluoride (465 mg) in DMF (14 mL) and stir at room temperature for 1 h. The reaction solution was concentrated under reduced pressure until no liquid flowed out, and the residue was dissolved in dichloromethane (100 mL). Water (100 mL) was added and stirred to separate the liquids. The aqueous phase was extracted with dichloromethane (60 mL*2), and the organic phases were combined. The organic phases were washed with 10% brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound 426p. LC-MS: m / z=760.31 (M+H) + .

[1170] Step 13:

[1171] Disperse 426p (248 mg) in dichloromethane (10 mL), cool to 0-5°C, add hydrogen chloride 1,4-dioxane solution (4N, 1 mL) dropwise to the reaction system, and stir to react for 1 h. After the reaction is complete, concentrate the reaction solution under reduced pressure until no liquid flows out to obtain compound 426q. LC-MS: m / z=716.27 (M+H) + .

[1172] Step 14:

[1173] Compound 426q was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (70%-100% / 0-60 min gradient elution)) to give compound 426 (Rt 54.0 min, LC-MS: m / z=716.27 (M+H) + ) and compound 427 (Rt 57.4 min, LC-MS: m / z=716.27 (M+H) + ).

[1174] Example 428 and Example 429

[1175]

[1176] Referring to the preparation process of compound 426n in Example 426, in step 10, compound 426m is replaced with 6-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-amine to prepare compound 428a.

[1177] Referring to the preparation process of compound 426p in Example 426, in step 12, compound 428o was replaced with 428a to prepare compound 428b.

[1178] Compound 428b was purified by preparative liquid chromatography (YMC TAC18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-60 min gradient elution)) to give compound 428 (Rt 47 min, LC-MS: m / z=695.34 (M+H) + ) and compound 429 (Rt 51min, LC-MS: m / z=695.34 (M+H) + ).

[1179] Example 430 and Example 431

[1180]

[1181] Referring to the preparation process of compound 426n in Example 426, in step 10, compound 426m was replaced with 2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to prepare compound 430a.

[1182] Compound 430a was purified by preparative liquid chromatography (YMC TA C18 10 μm 50*250 column; methanol-0.1% ammonia aqueous solution (50%-90% / 0-60 min gradient elution)) to give compound 430 (Rt 46.5 min, LC-MS: m / z=689.33 (M+H) + ) and compound 431 (Rt 51.1 min, LC-MS: m / z=689.35 (M+H) + ).

[1183] Example 432 and Example 433

[1184]

[1185] Referring to the preparation process of compound 426n in Example 426, in step 8, compound 426j is replaced with (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-yl)methanol; in step 10, compound 426m is replaced with ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to prepare compound 432a.

[1186] Referring to the preparation process of compound 426p in Example 426, in step 12, compound 432o was replaced with 432a to prepare compound 432b.

[1187] Compound 432b was purified by preparative liquid chromatography (Novasep C18 250*50mm, 10μm column; methanol-0.1% ammonia solution (60%-85% / 0-60min gradient elution)) to give compound 432 (Rt 38min, LC-MS: m / z=678.32 (M+H) + ) and compound 433 (Rt 40min, LC-MS: m / z=678.32 (M+H) + ).

[1188] Example 434 and Example 435

[1189]

[1190] Step 1:

[1191] Disperse 434a (1.0 g) in acetonitrile (50 mL), cool to 0-5°C, drop 6N hydrochloric acid solution (3.6 mL) and sodium nitrite solution (225 mg / 5 mL) in sequence, and stir to react at room temperature for 1 h. Cool the reaction system to 0-5°C, drop 6N hydrochloric acid solution of cuprous chloride (1.1 g / 5 mL), and stir to react at room temperature for 1 h. Pour the reaction solution into ice water (400 mL), add ethyl acetate (50 mL), stir and separate, collect the organic phase, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography (petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 434b. LC-MS: m / z = 405.32 (M+H) + .

[1192] Step 2:

[1193] 426l (300 mg), 434b (470 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1'-biphenyl-2-yl)palladium (II) (66 mg), potassium phosphate (365 mg), and water (5 mL) were dispersed in 1,4-dioxane (25 mL), and the mixture was protected by nitrogen. The mixture was heated to 90°C and stirred for 4 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 (dichloromethane:methanol=400:1-40:1) to obtain compound 434c. LC-MS: m / z=856.58 (M+H) + .

[1194] Step 3:

[1195] Disperse 434c (150 mg) and cesium fluoride (530 mg) in DMF (8 mL) and stir at room temperature for 2 h. Add water (60 mL) and ethyl acetate (50 mL) to the reaction solution, stir and separate, wash the organic phase with 5% brine (100 mL*4), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate until no liquid flows out to obtain compound 434d. LC-MS: m / z=700.25 (M+H) + .

[1196] Step 4:

[1197] Compound 434d was purified by preparative HPLC (YMC TAC18 10 μm 30*250 column; methanol-0.05% TFA (10%-10%-30%-70% / 0-5-10-90 min gradient elution) to give 434 (Rt 48 min, LC-MS: m / z=700.25 (M+H) + ) and compound 435 (Rt 53min, LC-MS: m / z=700.25 (M+H) + ).

[1198] Example 436 and Example 437

[1199]

[1200] Referring to the preparation process of compound 426k in Example 426, in step 8, (S)-(1,2-dimethylpyrrolidin-2-yl)methanol was used to replace compound 426j to prepare compound 436a;

[1201] Referring to the preparation process of compound 34 in Example 34, in step 9, compound 436d was prepared by replacing compound 34i with 436a.

[1202] Compound 436d was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (40%-100% / 0-50 min gradient elution)) to give compound 436 (Rt 22.2 min, LC-MS: m / z=652.36 (M+H) + ); purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; methanol-0.1% formic acid aqueous solution (20%-80% / 0-60min gradient elution)) to give compound 437 (Rt 15min, LC-MS: m / z=652.34 (M+H) + ).

[1203] Embodiment 438

[1204]

[1205] Step 1:

[1206] 426h (10 g) was purified by preparative SFC (YMC-SA 10 μm 30*150 column; ethanol-CO2 (50%-50%, 0-15 min isocratic elution)) to give 438a (Rt 10 min, LC-MS: m / z=661.33 (M+H) + ).

[1207] Step 2:

[1208] Disperse 438a (6.3 g) in dichloromethane (252 mL), cool to 0-5°C, add m-chloroperbenzoic acid (75%, 8.2 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*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 to obtain compound 438b. LC-MS: m / z=693.28 (M+H) + .

[1209] Step 3:

[1210] Disperse 438b (6.3 g) and 426j (4.34 g) in tetrahydrofuran (12 mL), cool to 0°C, add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1N, 13.6 mL) dropwise, and stir for 1 h. After the reaction is complete, add saturated ammonium chloride solution (50 mL) to the reaction system to quench the reaction, add water (50 mL) and ethyl acetate (100 mL) to stir and separate, extract with ethyl acetate (80 mL*2), combine the organic phases, wash with 5% brine (80 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200 to 1:30) to obtain compound 438c. LC-MS: m / z = 772.38 (M+H) + .

[1211] Step 4:

[1212] Disperse 438c (8.8 g) in trifluoroacetic acid (88 mL), cool to 0°C, add methanesulfonic acid (13.2 mL) dropwise, move to room temperature and stir to react for 2 h. After the reaction is complete, the reaction solution is concentrated under reduced pressure until no liquid flows out, the residue is dissolved with dichloromethane (200 mL), the pH of the system is adjusted to alkaline with saturated sodium bicarbonate solution under ice bath, water (100 mL) and dichloromethane (100 mL) are added and stirred to separate the liquids, and dichloromethane (100 mL*2) is used for extraction, the organic phases are combined, the organic phases are washed with 10% brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated until no liquid flows out, and purified by column chromatography (methanol: dichloromethane = 1:200 to 1:10) to obtain compound 438d. LC-MS: m / z = 532.21 (M+H) + .

[1213] Step 5:

[1214] Dissolve 438d (1g) and DIPEA (490mg) in dichloromethane (80mL), cool to 0°C, and add 2-trimethylsilylethoxycarbonyl chloride in dichloromethane (690mg / 10mL) and 4-dimethylaminopyridine in dichloromethane (115mg / 10mL) dropwise in sequence. After the addition, keep warm and react for 3h. Pour the reaction solution into 10% sodium bicarbonate solution (100mL), extract with ethyl acetate (200mL*2), collect the organic phase, concentrate to dryness under reduced pressure, and purify by column chromatography (dichloromethane: methanol = 150:1 to 30:1) to obtain compound 438e. LC-MS: m / z = 676.31 (M+H) + .

[1215] Step 6:

[1216] 438e (920 mg), 438f (1.3 g), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1'-biphenyl-2-yl) palladium (II) (156 mg), potassium phosphate (866 mg), and water (18 mL) were dispersed in 1,4-dioxane (90 mL), protected by nitrogen, and heated to 80°C with stirring 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 (methanol: dichloromethane = 1:100 to 1:15) to obtain compound 438g. LC-MS: m / z = 981.56 (M+H) + .

[1217] Step 7:

[1218] Disperse 438g (820mg) in acetonitrile (65mL), add hydroiodic acid (57%, 2.2g) and sodium nitrite aqueous solution (120mg / 8mL) dropwise in an ice bath, stir and react for 1h; add potassium iodide aqueous solution (280mg / 4mL) to the reaction system, move to room temperature and stir and react for 2h. Drop the reaction solution into ice water, extract with dichloromethane (100mL*2), wash the organic phase with saturated sodium bicarbonate solution (100mL) and sodium thiosulfate solution (100mL), collect the organic phase, concentrate under reduced pressure until no liquid flows out, and purify compound 438h by column chromatography (methanol: dichloromethane = 1:200~1:50). LC-MS: m / z = 1092.45 (M+H) + .

[1219] Step 8:

[1220] Disperse 438h (360 mg), dimethylphosphine (72 mg), DIPEA (200 mg), palladium acetate (20 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg) in 1,4-dioxane (35 mL), protect with nitrogen, heat to 90°C and stir for 3 h. The reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 1:100 to 1:20) to obtain compound 438i. LC-MS: m / z = 898.51 (M+H) + .

[1221] Step 9:

[1222] 438i (150 mg) and cesium fluoride (510 mg) were dispersed in DMF (7 mL) and stirred at room temperature for 4 h. The reaction solution was purified by preparative liquid chromatography (YMC TA C18 10 μm 30*250 column; acetonitrile-0.1% acetic acid aqueous solution (5%-50% / 0-45 min gradient elution)) to obtain compound 13. LC-MS: m / z=742.33 (M+H) + .

[1223] Embodiment 439

[1224]

[1225] Step 1:

[1226] Disperse 439a (10 g), dimethylphosphine (6.5 g), DIPEA (20 g), palladium acetate (1.7 g), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.6 g) in 1,4-dioxane (300 mL), protect with nitrogen, heat to 90°C and stir to react for 3 h. The reaction solution is cooled to room temperature, concentrated to dryness under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 1:600 ​​to 1:20) to obtain compound 439b. LC-MS: m / z = 215.10 (M+H) + .

[1227] Step 2:

[1228] Disperse 439b (6 g) and N-bromosuccinimide (5.5 g) in DMF (100 mL) and stir at room temperature to react overnight. Pour the reaction solution into water (500 mL), extract with dichloromethane (200 mL*2), combine the organic phases, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:200-1:30) to obtain compound 439c. LC-MS: m / z = 292.92 (M+H) + .

[1229] Step 3:

[1230] Disperse 439c (4 g) in acetonitrile (100 mL), add dilute sulfuric acid (50%, 22 mL) and sodium nitrite aqueous solution (2 g / 5 mL) dropwise in an ice bath, and stir to react for 1 h; add potassium iodide aqueous solution (8 g / 10 mL) to the reaction system, move to room temperature and stir to react for 2 h. Drop the reaction solution into ice water, extract with dichloromethane (100 mL*2), wash the organic phase with saturated sodium bicarbonate solution (100 mL) and sodium thiosulfate solution (100 mL), collect the organic phase, concentrate under reduced pressure until no liquid flows out, and purify compound 439d by column chromatography (methanol: dichloromethane = 1:400 ~ 1:75). LC-MS: m / z = 403.97 (M+H) + .

[1231] Step 4:

[1232] Disperse 439d (1 g), cuprous iodide (1.2 g), and methyl fluorosulfonyl difluoroacetate (965 mg) in DMF (50 mL), protect with nitrogen, and heat to 80°C for 3 h. Filter the reaction solution, drop the filtrate into water (100 mL), extract with ethyl acetate (200 mL*2), collect the organic phase, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:200) to obtain compound 439e. LC-MS: m / z = 345.98 (M+H) + .

[1233] Step 5:

[1234] Disperse 439e (730 mg), ammonium chloride (570 mg), reduced iron powder (950 mg), and ethanol (10 mL) in water (20 mL), heat to 75°C, and stir to react for 1 h. Filter the reaction solution, concentrate the filtrate under reduced pressure to remove ethanol, adjust the pH of the residue to 9-10 with sodium carbonate solution, extract with ethyl acetate (80 mL*2), collect the organic phase, concentrate under reduced pressure until no liquid flows out, and purify by column chromatography (methanol: dichloromethane = 1:500-1:50) to obtain compound 439f. LC-MS: m / z = 316.01 (M+H) + .

[1235] Step 6:

[1236] Disperse 439f (520 mg), bipyralidin (2.1 g), potassium acetate (500 mg), and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (136 mg) in 1,4-dioxane (25 mL), protect with nitrogen, and heat to 90°C for 5 h. Filter the reaction solution, and concentrate the filtrate under reduced pressure until no liquid flows out. Purify the compound 439g by column chromatography (methanol: dichloromethane = 1:500 to 1:50). LC-MS: m / z = 364.25 (M+H) + .

[1237] Step 7:

[1238] 438d (230 mg), 439g (540 mg), chloro[(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2-amino-1,1'-biphenyl-2-yl)palladium (II) (51 mg), potassium phosphate (285 mg), and water (2.4 mL) were dispersed in 1,4-dioxane (12 mL), protected by nitrogen, and heated to 90°C and stirred for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by preparative liquid chromatography (YMC TAC18 10 μm 30*250 column; methanol-0.1% ammonia aqueous solution (30%-80% / 0-60 min gradient elution)) to obtain compound 439. LC-MS: m / z=733.27 (M+H) + .

[1239] Embodiment 440

[1240]

[1241]

[1242] Step 1:

[1243] Disperse 440a (400 mg), iodomethane (900 mg), and potassium carbonate (355 mg) in DMF (40 mL), heat to 60 ° C, stir and react for 5 h. The reaction solution was cooled to room temperature, and water (100 mL) and ethyl acetate (150 mL) were added and stirred to separate the liquids. The aqueous phase was extracted with ethyl acetate (50 mL*2), and the organic phases were combined. The organic phases were washed with 5% brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until no liquid flowed out. Purification by column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:3) gave compound 440b. LC-MS: m / z = 496.38 (M+H) + .

[1244] Step 2:

[1245] Referring to the preparation method of step 7 in Example 439, 440b was used to replace 439g to prepare compound 440c. LC-MS: m / z=865.59 (M+H) + .

[1246] Step 3:

[1247] Referring to the preparation method of step 9 in Example 438, 440c was used to replace 438i to prepare compound 440. LC-MS: m / z=709.34 (M+H) + .

[1248] Embodiment 441

[1249]

[1250] Step 1:

[1251] Referring to the preparation method of step 2 in Example 439, 439b was replaced with 441a to prepare compound 441b. LC-MS: m / z=253.98 (M+H) + .

[1252] Step 2:

[1253] Disperse 441b (10.45 g) in dichloromethane (100 mL), slowly add trifluoroacetic anhydride (17.3 g) under ice bath, move to room temperature and stir to react for 15 min; add potassium nitrate (8.32 g) to the reaction system, stir and react overnight. Drop the reaction solution into saturated sodium bicarbonate solution (300 mL), stir and separate, extract the aqueous phase with ethyl acetate (100 mL*2), combine the organic phases, concentrate under reduced pressure until no liquid flows out, and purify compound 441c by column chromatography (ethyl acetate: petroleum ether = 1:100 to 1:10). LC-MS: m / z = 395.05 (M+H) + .

[1254] Step 3:

[1255] Disperse 441c (8.42 g) and saturated potassium carbonate aqueous solution (45 mL) in methanol (50 mL), heat to 65°C and stir for 24 h. Cool the reaction solution to room temperature and slowly drip into ice water (500 mL). Stir and crystallize for 15 min and filter. The filter cake is vacuum dried to constant weight to obtain compound 441d. LC-MS: m / z=298.80 (MH) - .

[1256] Step 4:

[1257] Referring to the preparation method of step 3 in Example 439, 439c was replaced with 441d to prepare compound 441e. LC-MS: m / z=408.07 (MH) - .

[1258] Step 5:

[1259] Referring to the preparation method of step 5 in Example 439, 439e was replaced with 441e to prepare compound 441f. LC-MS: m / z=379.90 (M+H) + .

[1260] Step 6:

[1261] Referring to the preparation method of step 1 in Example 439, 439a was replaced with 441f to prepare compound 441g. LC-MS: m / z=330.01 (M+H) + .

[1262] Step 7:

[1263] Referring to the preparation method of step 6 in Example 439, 441g was used to replace 439f to prepare compound 441h. LC-MS: m / z=378.27 (M+H) + .

[1264] Step 8:

[1265] Referring to the preparation method of step 7 in Example 439, 441h was used to replace 439g to prepare compound 441. LC-MS: m / z=747.26 (M+H) + .

[1266] Experimental Example 1 Nucleotide Exchange Experimental Method

[1267] 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)

[1268] 2. Prepare buffer :

[1269] 1) Assay buffer: HEPES pH 7.4, NaCl, MgCl2, DTT, BSA, Igepal;

[1270] 2) KRAS G12D working solution: Prepare KRAS G12D working solution containing 100 nM His-KRAS G12D and 2 nM Anti-6HIS-Cryptate using assay buffer;

[1271] 3) SOS1 cat Working solution: Prepare a 20 nM SOS1 buffer in the assay buffer. cat and 200 nM EDA-GTP-DY-647P1 for SOS1 cat Working fluid;

[1272] 4) Blank control working solution: Prepare a blank control solution containing 2 nM Anti-6HIS-Cryptate using assay buffer.

[1273] 3. Testing process:

[1274] 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 starting concentration of 100 μM to the experimental group, and the compound was diluted in 8 concentration gradients of 1:2 continuously, 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 min and the 665nm / 620nm signal value was detected using a PerkinElmer Envision HTS multi-label reader. The inhibition rate was calculated as follows: inhibition rate (%) = (average value of the negative control group - average value of the experimental group) / (average value of the negative control group - average value of the blank group) × 100%. The logarithm of the compound concentration was used as the horizontal axis and the inhibition rate as the vertical axis. The four-parameter logistic model was used to fit the curve and calculate the IC 50 value.

[1275] Test Example 2 AsPc-1 cell proliferation inhibitory activity assay

[1276] 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 / mL, inoculated on a 96-well plate (100μL / well), and used a nanoliter sampler to add compounds to a final concentration of 5000nM-0.31nM, 2 replicates, and set up controls. After continuing to culture in a cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10μL / well) was added. After incubation in a cell culture incubator for 3 hours, the absorbance was detected at 450nm using a PerkinElmer Envision microplate reader, and four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

[1277] Test Example 3: Assay for Capan-1 cell proliferation inhibitory activity

[1278] Take Capan-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 1.5×10 4 / mL, inoculated on a 96-well plate (100μL / well), and used a nanoliter sampler to add compounds to a final concentration of 20000nM-9.1nM, 2 replicates, and set up controls. After 5 days of continuous culture in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was detected at 450nm using a PerkinElmer Envision microplate reader, and four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

[1279] The above test results of some compounds disclosed in the present invention are shown in Table 1.

[1280] Table 1 Test results of some compounds

[1281]

[1282]

[1283]

[1284] Note: A stands for IC 50 ≤100nM;

[1285] B represents 100nM<IC 50 ≤500nM;

[1286] C represents 500nM<IC 50 ≤999nM;

[1287] ——Representative IC 50 Value not detected.

[1288] Test Example 4: In vitro liver microsome stability

[1289] Liver microsome incubation samples (species: human, monkey, rat and mouse) were prepared by mixing PBS buffer (pH7.4), liver microsome 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 (pH7.4), liver microsome solution (0.5 mg / mL), test compound. The sample was added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, and diluted for LC / MS / MS determination. The results are shown in Table 2.

[1290] Table 2. In vitro liver microsome metabolic stability results

[1291]

[1292] Experimental Example 5: Pharmacokinetic evaluation in mice

[1293] ICR mice, weighing 20-24 g, were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group, and the experimental compound was gavaged at a dose of 10 mg / kg.

[1294] The test animals (ICR mice) were fasted for 12 h before administration and given food 4 h after administration. They were allowed to drink water freely before, during and after the experiment.

[1295] After intragastric administration, blood samples were collected from each mouse at 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, and 10 h for 3 to 4 time points, with 3 mice at each time point. About 0.1 mL of blood was collected from the eye sockets, anticoagulated with EDTA-K2, and centrifuged at 4 ° C, 4000 rpm, and 10 min to separate plasma. After all plasma was collected, it was immediately stored at -20 ° C for testing.

[1296] 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 min, centrifuge at 13000 rpm for 10 min, 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.

[1297] The oral exposure of the compound of the present invention was evaluated by a pharmacokinetic experiment in mice. The experimental results are shown in Table 3.

[1298] Table 3

[1299]

[1300] aThe gavage parameters were fitted to 6 h.

[1301] Test Example 6: Pharmacokinetic evaluation in rats

[1302] SD rats, weighing 180-220 g, were randomly divided into 3 groups after acclimation for 3-5 days, with 3 rats in each group, and the compound was gavaged at a dose of 10 mg / kg.

[1303] The test animals (SD rats) were fasted for 12 h before administration and given food 4 h after administration. They were allowed to drink water freely before, during and after the experiment.

[1304] After intragastric administration, about 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, 4000 rpm, and centrifuged for 10 min to separate plasma within 30 min. After all plasma was collected, it was immediately stored at -20 ° C for testing.

[1305] 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.

[1306] Experimental Example 7: Pharmacodynamic evaluation of Aspc-1 human pancreatic cancer cell subcutaneous transplant tumor model in NOD-SCID mice

[1307] Aspc-1 human pancreatic cancer cells (1×107 cells / mouse) were subcutaneously inoculated into the right axilla of SPF female NOD-SCID mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.). When the average tumor volume reached about 200 mm3, the animals were divided into groups.

[1308] The day of grouping was day 0. From day 1, drugs were intraperitoneally injected once a day. Tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

[1309] The detection indicators and calculation formula are as follows:

[1310] 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.

[1311] Relative tumor volume, RTV=TVt / TV0; TV0 is the tumor volume on day 0, and TVt is the tumor volume at each measurement.

[1312] Relative tumor proliferation rate, T / C (%) = TRTV / CRTV × 100%; wherein TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.

[1313] 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.

[1314] 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 (III-c), a stereoisomer thereof, a tautomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in, 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 bonds, -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 AlkyleneNHC(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 AlkyleneNHSO2R 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 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 cycloalkyl 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 with the following 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 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkylthio, C 1-6 Haloalkylamino, or di-C 1-6 Haloalkylamino; R 3 is selected from H, deuterium, 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 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 AlkyleneNHC(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 AlkyleneNHSO2R 3d , or optionally one or more R 3b Substituted with the following 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 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 cycloalkyl 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 Haloalkyl; R 4 Selected from H, deuterium, halogen, -CN, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, 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 optionally substituted with one or more R 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, -P(O)(C 1-12 Alkyl)2, -P(O)HC 1-12 Alkyl, 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 2 , 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 , or R z Each is independently optionally substituted with one or more substituents.

2. The compound of formula (III-c) according to claim 1, 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 with 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 with one or more R 2a Substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 heteroalkyl, cyclopropane, cyclobutane, cyclopentane, Oxetane, azetidinyl, pyrrolidinyl, piperidinyl, pyrazolyl, Alternatively, the R 2 is selected from H, deuterium, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropane, cyclobutane, cyclopentane, 3. The compound of formula (III-c) according to claim 1 or 2, 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 with the following 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-.

4. The compound of formula (III-c) according to any one of claims 1 to 3, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, wherein: The R 3 is selected from H, deuterium, 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 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 is selected from H, deuterium, or optionally 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 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 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 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 is selected from H, deuterium, or optionally 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 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: C 1-4 Alkyl, 4-8 membered heterocyclic group, 3-8 membered cycloalkyl group 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 is selected from H, deuterium, or optionally 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 is selected from H, deuterium, or optionally one or more R 3a Substituted groups: 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, piperazine 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]heptylC 1-3 Alkylene, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or imidazolyl C 1-3 Alkylene; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted groups: methyl, piperidinyl, cyclopropyl 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, piperidinyl C 1-3 Alkylene, azetidinyl, cyclobutyl, cyclohexyl, cyclobutyl C 1-3 Alkylene, or piperazinyl; Alternatively, the R 3 is selected from H, deuterium, or optionally one or more R 3a Substituted with the following groups: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Alternatively, the R 3 Selected from H, deuterium, methyl, 5. The compound of formula (III-c) according to any one of claims 1 to 4, 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 Haloalkyl, 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 Haloalkyl, 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.

6. The compound of formula (III-c) according to any one of claims 1 to 5, 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 optionally one or more R 5 Substituted groups: 6-10 membered aryl, benzo 4-6 membered cycloalkenyl, benzo 4-6 membered heterocyclyl, or 5-10 membered heteroaryl; Alternatively, the ring A is selected from optionally one or more R 5 substituted 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; Alternatively, the ring A is selected from optionally one or more R 5 Substituted phenyl, naphthyl, benzocyclohexenyl, benzocyclopentenyl, pyridyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzothiophenyl, pyrazolyl, pyridopyrazolyl, or pyridopyrrolyl; Alternatively, the ring A is selected from optionally one or more R 5 Substituted phenyl, naphthyl, pyridyl, benzothiazolyl, benzothiophenyl, isoquinolyl, benzopyrazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolyl, indolyl, or benzimidazolyl; Alternatively, the ring A is selected from optionally one or more R 5 Substituted phenyl, naphthyl, pyridyl, isoquinolyl, benzopyrazolyl, benzothiazolyl, pyrazolyl, pyridopyrazolyl, pyridopyrrolyl, quinolyl, indolyl, or benzimidazolyl; Alternatively, the ring A is selected from 7. The compound of formula (III-c) according to any one of claims 1 to 6, 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, -P(O)(C 1-6 Alkyl)2, -P(O)HC 1-6 Alkyl, 3-12 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl; Alternatively, each R 5 independently selected from deuterium, -F, -Cl, -Br, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylamino, dimethylamino, methylthio, -P(O)(C 1-3 Alkyl)2, -P(O)HC 1-3 Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl; Alternatively, each R 5 independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, or optionally substituted by one or more R 5a Substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, methylamino, dimethylamino, methylthio, or cyclopropane; Alternatively, each 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 by -F, -Cl, -Br or methyl; Alternatively, each R 5 independently selected from deuterium, -F, -Cl, -CN, -OH, -NH2, methyl, ethyl, isopropyl, ethynyl, propynyl, trifluoromethyl, methoxy, trifluoromethoxy, methylamino, dimethylamino, methylthio, or a methyl-substituted cyclopropane.

8. The following compound, its stereoisomer, its tautomer, its deuterated compound, or its pharmaceutically acceptable salt, which is selected from: Or, it is selected from: Or, it is selected from:

9. A pharmaceutical composition comprising the compound of formula (III-c) according to any one of claims 1 to 8, its stereoisomers, its tautomers, its deuterated compounds, or pharmaceutically acceptable salts thereof; optionally, further comprising a pharmaceutically acceptable excipient.

10. Use of the compound of formula (III-c) according to any one of claims 1 to 8, its stereoisomers, its tautomers, its deuterated compounds, or their pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 9 in the preparation of drugs for treating diseases.

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