Benzophenol derivatives as inhibitors of the enzyme dihydroorotate dehydrogenase, process for their preparation and use

Abstract

The present invention relates to benzothiophene derivatives modulators, processes for their preparation and use. In particular, the present invention relates to compounds of general formula (I), processes for their preparation, pharmaceutical compositions containing them and their use as modulators in the preparation of medicaments for the treatment of menopausal symptoms, polycystic ovary syndrome, uterine fibroids, schizophrenia, irritable bowel syndrome, vasomotor symptoms, breast cancer and related conditions, wherein the substituents of general formula (I) are as defined in the description.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical biology, specifically relating to an inhibitor containing a benzene tricyclic derivative, its preparation method, and its application. Background Technology

[0002] Neurokinins (NK) comprise substance P (SP), neurokinin A, and neurokinin B, corresponding to three types of receptors: neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R), and neurokinin 3 receptor (NK3R). All three are G protein-coupled receptors. NK1R is the most widely distributed, found in both the central and peripheral nervous systems; NK2R is mainly distributed in the peripheral nervous system; and NK3R is mainly distributed in the central nervous system. Currently, NK receptor inhibitors are used to treat menopausal hot flashes, depression, schizophrenia, and other conditions. In particular, NK3R is closely related to menopausal symptoms such as hot flashes, and NK3R inhibitors have been shown to effectively alleviate menopausal hot flashes.

[0003] Menopausal hot flashes refer to the symptoms of hot flashes and sweating that often occur in women during menopause, and are a prominent manifestation of menopausal syndrome. Menopausal hot flashes are caused by vasomotor dysfunction due to a decline in estrogen levels. When estrogen levels drop, the brain mistakenly interprets this as excessively high body temperature. Therefore, the brain signals the heart to pump more blood and the sweat glands to release more sweat, accompanied by sweating, palpitations, and dizziness. More than three-quarters of women experience hot flashes during menopause, and 80% of patients experience these symptoms for more than a year, some even persisting for about five years after menopause. Currently, the main treatment for menopausal hot flashes is hormone replacement therapy, but this therapy carries a high risk of complications such as breast cancer, stroke, coronary heart disease, and dementia.

[0004] Therefore, there is an urgent need to develop highly active NK receptor inhibitors to improve menopausal hot flashes in order to meet the huge market demand. Summary of the Invention

[0005] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0006] in: Selected from single or double bonds; X1 or X2 is independently selected from CH, N, O or C(O); X3, X4, and X5 are each independently selected from C or N; X6 is selected from CH or N; Y1 is selected from CH, C(O), N, NH, O, S or does not exist; Y2, Y3, Y4, or Y5 are each independently selected from CH, C(O), N, NH, O, or S; Ring A is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroalkyl or heterocyclic group, wherein the aromatic heteroalkyl or heterocyclic group is optionally substituted with one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R1, R2, R3, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R3 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R3 groups form a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R1 groups form a cycloalkyl, heterocyclic, aryl, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Or, R1, R 11 It forms a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; R aa Or Rbb Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, or t are each independently 0, 1, 2, 3, or 4; z is 0, 1, or 2; m1 can be 0, 1, 2, or 3; n1 or n2 can be 0, 1, 2 or 3 independently; The conditions are: When X1, X2, X4, and X6 are N, X3 and X5 are C, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is -C(O)-, -CF2-, -CHCF3-, or -NHC(O)-, L2 is a bond, and R2 is selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, ... , , , , , , , , , , , , , , , , , , , , , , or When one of the substituents is substituted, y is 0 or 1, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring A is not [a specific value]. , , , , , , , , , , , , , , , , , , , , , , , , , , or ; When X1, X4, and X6 are N, X3 and X5 are C, X2, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... or ; When X2, X4, and X6 are N, X3 and X5 are C, X1, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, R2 is a methyl group, y is 1, z is 1, and R1, R2, R3, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... .

[0007] In some embodiments of the invention, a compound of general formula (I-1), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided:

[0008] in: X1 or X2 is independently selected from CH, N, O or C(O); X3, X4, and X5 are each independently selected from C or N; X6 is selected from CH or N; Y1 is selected from CH, C(O), N, NH, O, S or does not exist; Y2, Y3, Y4, or Y5 are each independently selected from CH, C(O), N, NH, O, or S; Ring A is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroalkyl or heterocyclic group, wherein the aromatic heteroalkyl or heterocyclic group is optionally substituted with one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R1, R2, R3, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 Rbb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R3 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R3 groups form a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R1 groups form a cycloalkyl, heterocyclic, aryl, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Or, R1, R 11 It forms a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; R aa Or R bbEach of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, or t are each independently 0, 1, 2, 3, or 4; z is 0, 1, or 2; m1 can be 0, 1, 2, or 3; n1 or n2 can be 0, 1, 2 or 3 independently; The conditions are: When X1, X2, X4, and X6 are N, X3 and X5 are C, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is -C(O)-, -CF2-, -CHCF3-, or -NHC(O)-, L2 is a bond, and R2 is selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, ... , , , , , , , , , , , , , , , , , , , , , , or When one of the substituents is substituted, y is 0 or 1, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring A is not [a specific value]. , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Alternatively, when X1, X4, and X6 are N, X3 and X5 are C, X2, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... or ; Alternatively, when X2, X4, and X6 are N, X3 and X5 are C, X1, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, R2 is a methyl group, y is 1, z is 1, and R1, R2, R3, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... .

[0009] In a preferred embodiment of the invention, general formula (I) or (I-1) is further a compound represented by general formula (IV), (IV-1), or (IV-2) or a pharmaceutically acceptable salt thereof:

[0010] in: Ring D is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C6-14 One or more substituents of aryl, 3-14 heteroaryl or carboxyl groups are used for substitution; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 3-14 heteroaryl or carboxyl, wherein the amino, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl or 3-14 heteroaryl groups, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Haloalkenyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 One or more substituents of aryl, 3-14 heteroaryl or carboxyl groups are used for substitution; Alternatively, R6 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R6 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R6 groups form a cycloalkyl, heterocyclic, aryl, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally converted by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; R9 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C6-14 aryl, 3-14 heteroaryl or carboxyl, wherein the amino, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 3-14 heteroaryl or carboxyl, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Haloalkenyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 One or more substituents of aryl, 3-14 heteroaryl or carboxyl groups are used for substitution; s is 0, 1, or 2; w can be 0, 1, 2, 3, or 4.

[0011] In a preferred embodiment of the present invention Selected from , , , , , , , , , , , , , or .

[0012] In a preferred embodiment of the present invention Selected from , , , , , , , , , , , , , , , , or .

[0013] In a preferred embodiment of the present invention Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0014] In a preferred embodiment of the present invention Selected from , , , , , , , , , , , , , , , , , , , , , , or .

[0015] In a preferred embodiment of the present invention Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0016] In some embodiments of the present invention, a compound of general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided, the structure of which is as follows:

[0017] in: Y1, Y2, Y3, Y4, or Y5 are each independently selected from CH or N; Cycle A or Cycle B is each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; Alternatively, ring A does not exist; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroyl or heterocyclic group, wherein the aromatic heteroyl or heterocyclic group is optionally substituted by one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R1, R2, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bbThe amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Or, R1, R 11 The cycloalkyl, heterocyclic or heteroaryl group is formed with the attached atom, and the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted with one or more substituents from the group consisting of hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano. R aa Or R bb Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, or t are each independently 0, 1, 2, or 3; m1 can be 0, 1, 2, or 3; n1 or n2 can be 0, 1, 2 or 3 independently; The conditions are: When ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, -CF2-, -CHCF3-, or -NHC(O)-, L2 is a bond, and R 21 Selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, , , , , , , , , , , , , , , , , , , , , , , or When one of the substituents is substituted, y is 0 or 1. When R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring A is not [a specific value]. , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Or, when ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, L2 is a bond, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are connected to. In this case, ring A is not a cycloalkyl or heterocyclic group. or ; Or, when ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, L2 is a bond, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are connected to. In this case, ring A is not a cycloalkyl or heterocyclic group. .

[0018] In a preferred embodiment of the invention, general formula (II) is further a compound of general formula (V) or a pharmaceutically acceptable salt thereof:

[0019] in: R6 is selected from halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 3-14 heteroaryl or carboxyl, wherein the amino, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl or 3-14 heteroaryl groups, optionally covered by halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C1-8 Haloalkenyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 One or more substituents of aryl, 3-14 heteroaryl or carboxyl groups are used for substitution; Alternatively, R6 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally replaced by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl or C 1-8 One or more substituents in a cyano-substituted alkyl group are substituted; Alternatively, R6 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally replaced by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl or C 1-8 One or more substituents in a cyano-substituted alkyl group are substituted; Or, R6, R 11 It forms a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl or C 1-8 One or more substituents in a cyano-substituted alkyl group are substituted; s can be 0, 1, or 2.

[0020] In some embodiments of the present invention, a compound of general formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof is provided, the structure of which is as follows:

[0021] in: Y2, Y3, Y4, Y5, or Y7 are each independently selected from CH or N; Y1 or Y6 are each independently selected from C or N; Cycle A or Cycle B is each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroalkyl or heterocyclic group, wherein the aromatic heteroalkyl or heterocyclic group is optionally substituted with one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R1, R2, R4, or R5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R1 and R5 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R2 and R5 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R4 and R5 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Or, R1, R 11 The cycloalkyl, heterocyclic or heteroaryl group is formed with the attached atom, and the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted with one or more substituents from the group consisting of hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano. R aa Or R bb Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, t, or q are each independently 0, 1, 2, or 3; n1 or n2 are each independently 0, 1 or 2; m1 can be 0, 1, 2 or 3.

[0022] The conditions are: When Y2, Y3, Y4, and Y5 are CH, Y1 and Y6 are C, Y7 is N, n1 is 0 or 1, n2 is 2, q is 0, L1 is -C(O)-, L2 is a bond, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring B is not a cycloalkyl group. ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2.

[0023] In some embodiments of the present invention, ring A is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, carboxyl, dicarboxyl 1-6 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample.

[0024] In a preferred embodiment of the present invention, ring A is selected from C. 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 aryl, 5-12 membered heteroaryl containing 1-3 N, O or S atoms, carboxyl, dicarbonyl 1-3 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample.

[0025] In a preferred embodiment of the present invention, ring A is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-5 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 Aryl, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, carboxyl, dicarbonyl1-3 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample.

[0026] In a further preferred embodiment of the present invention, ring A is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused-heteroaryl containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 Aryl, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, carboxyl, dicarbonyl 1-3 Alkylamino or -(CH2) n1 OR aa One or more substituents are substituted in the sample.

[0027] In a further preferred embodiment of the present invention, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Optionally, it can be replaced by hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, dimethylamino, -CD3, , , , , , , , , , , , , or One or more substituents are substituted in the sample.

[0028] In a further preferred embodiment of the present invention, ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Optionally, it can be replaced by hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, dimethylamino, -CD3, , , , , , , , , , , , , or One or more substituents are substituted in which This indicates that ring A is connected to L2.

[0029] In some embodiments of the present invention, ring A is absent.

[0030] In some embodiments of the present invention, ring B is selected from C. 3-14Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution.

[0031] In a preferred embodiment of the present invention, ring B is selected from C. 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 Aryl or 5-14 membered heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 A aryl group or a 5-14 membered heteroaryl group containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0032] In a preferred embodiment of the present invention, ring B is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-14 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-14 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C group. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0033] In a preferred embodiment of the present invention, ring B is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-13 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, a 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or an 8-13 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0034] In a further preferred embodiment of the present invention, cycloB is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... , , , , , , , , , , , , , , , or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or carboxyl.

[0035] In a further preferred embodiment of the invention, ring B is selected from... , , , , , , , , , , , , , , , , or Optionally substituted with one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or carboxyl, wherein This indicates that ring B is connected to L1. This indicates that ring B is connected to L2.

[0036] In some embodiments of the present invention, ring D is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution.

[0037] In a preferred embodiment of the present invention, ring D is selected from C. 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 Aryl or 5-14 membered heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 A aryl group or a 5-14 membered heteroaryl group containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0038] In a preferred embodiment of the present invention, ring D is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-14 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-14 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C group. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0039] In a preferred embodiment of the present invention, ring D is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-13 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, a 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or an 8-13 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted.

[0040] In a further preferred embodiment of the present invention, ring D is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, , , , , , , , , , , , , , , , , , or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl.

[0041] In a further preferred embodiment of the invention, ring D is selected from... , , , , , , , , , , , , , , , , , , , , , or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl.

[0042] In some embodiments of the present invention, L1 or L2 is independently selected from bond, -C(O)-, -(CR)-, etc. 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroyl or heterocyclic group, wherein the aromatic heteroyl or heterocyclic group is optionally surrounded by an oxo group or a C-shaped group. 1-6 Alkyl, C2 1-6 alkenyl, C 2-6 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; R 11 R 12 R 13 Or R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 It is substituted by one or more substituents of aryl, 5-12 heteroaryl or carboxyl.

[0043] In a preferred embodiment of the present invention, L1 or L2 is independently selected from bond, -C(O)-, -(CR)-, etc. 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - A 5-8 membered aromatic heteromethyl group containing 1-3 N, O, or S atoms, or a 3-8 membered heterocyclic heterocyclic group containing 1-3 N, O, or S atoms, wherein the aromatic heteromethyl group or heterocyclic group is optionally surrounded by an oxo group or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3One or more substituents in the alkyl or carboxyl group are substituted; R 11 R 12 R 13 Or R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl groups, including amino, hydroxyl, cyano, nitro, and C groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl groups, optionally replaced by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C4 groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 It is substituted by one or more substituents, including aryl, 5-8 member mono-heteroaryl containing 1-3 N, O or S atoms, or 8-14 member fused heteroaryl containing 1-4 N, O or S atoms.

[0044] In a preferred embodiment of the present invention, L1 or L2 is independently selected from bond, -C(O)-, -(CR)-, etc. 11 R 12 ) m1- -O-, -S-, -C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14- A 5-6 membered aromatic heteromethyl group containing 1-3 N, O, or S atoms, or a 3-6 membered heterocyclic heteromethyl group containing 1-3 N, O, or S atoms, wherein the aromatic heteromethyl group or heterocyclic heteromethyl group is optionally surrounded by an oxo group or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, phenyl, benzyl, or naphthyl, wherein the amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, phenyl, benzyl, or naphthyl groups are optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, or trifluoroethyl groups.

[0045] In a further preferred embodiment of the present invention, L1 or L2 is independently selected from bond, -C(O)-, and -CH. 2- , -CH(CH3)-, -O-, -S-, -C(O)NH-, -NHC(O)-, -C(S)NH-, -NHC(S)-, , or The or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or carboxyl.

[0046] In certain embodiments of the present invention, R1, R2, R3, R4, R5, R6, or R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 1-6 Alkyl acyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl, carboxyl, -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, thiol, and C groups mentioned above 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution.

[0047] In some embodiments of the present invention, R1, R2 and the adjacent atoms form C 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0048] In some embodiments of the present invention, R1, R4 and the adjacent atoms form C 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; In some embodiments of the present invention, R2, R4 and the adjacent atoms form C 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C1-6 One or more substituents in an alkyl group are substituted.

[0049] In some embodiments of the present invention, R1, R 11 Forming C with the attached atoms 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0050] In some embodiments of the invention, two R1 atoms form C with the adjacent atoms. 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 The aryl group or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 Aryl or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0051] In some embodiments of the present invention, R3, R4 and the adjacent atoms form C 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0052] In some embodiments of the invention, two R3 atoms form C with the adjacent atoms. 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0053] In some embodiments of the present invention, R6, R2 and the adjacent atoms form C 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0054] In some embodiments of the present invention, R6, R4 and the adjacent atoms form C 3-12Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0055] In some embodiments of the present invention, R6, R 11 Forming C with the attached atoms 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0056] In some embodiments of the invention, two R6 atoms form C with the adjacent atoms. 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 The aryl group or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 Aryl or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in an alkyl group are substituted.

[0057] In some embodiments of the present invention, R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12 heteroaryl, carboxyl, and the aforementioned amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution.

[0058] In certain preferred embodiments of the present invention, R1, R2, R3, R4, R5, R6, or R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 1-3 Alkyl acyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 N, O, or S atoms, carboxyl, carboxyl, -OR aa -NR aa R bb -NR aa C(O)R bb -C(O)NR aa R bb Or -N=S(O)R aa R bb The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 hydroxyalkyl, cyano-substituted C 1-3Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0059] In some preferred embodiments of the invention, R1, R2 and the adjacent atoms form C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in an alkyl group are substituted.

[0060] In some preferred embodiments of the invention, R1, R4 and the adjacent atoms form C 3-10 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in an alkyl group are substituted.

[0061] In some preferred embodiments of the invention, the two R1 atoms form C with the adjacent atoms. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 The aryl group or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 Alkyl, Halogenated C 1-3 Alkoxy, C 1-3 Deuterated alkyl or C 1-3 One or more substituents in the deuterated alkoxy group are substituted.

[0062] In some preferred embodiments of the invention, R2, R4 and the adjacent atoms form C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo group or C 1-3 One or more substituents in an alkyl group are substituted.

[0063] In some preferred embodiments of the invention, R3, R4 and the adjacent atoms form C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo group or C 1-3 One or more substituents in an alkyl group are substituted.

[0064] In some preferred embodiments of the invention, the two R3 atoms form C with the adjacent atoms. 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in an alkyl group are substituted.

[0065] In certain preferred embodiments of the present invention, R1, R 11 Forming C with the attached atoms 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in an alkyl group are substituted.

[0066] In some preferred embodiments of the invention, R6, R2 and the adjacent atoms form C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in an alkyl group are substituted.

[0067] In some preferred embodiments of the invention, R6, R4 and the adjacent atoms form C 3-5 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-15 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3One or more substituents in an alkyl group are substituted.

[0068] In certain preferred embodiments of the present invention, R6, R 11 Forming C with the attached atoms 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in an alkyl group are substituted.

[0069] In some preferred embodiments of the invention, the two R6 atoms form C with the adjacent atoms. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 The aryl group or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 Alkyl, Halogenated C 1-3 Alkoxy, C 1-3 Deuterated alkyl or C 1-3 One or more substituents in the deuterated alkoxy group are substituted.

[0070] In certain preferred embodiments of the present invention, R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, and a carboxyl group, wherein the amino, hydroxyl, and C groups are present. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group is substituted with one or more substituents, including 1-3 5-10 heteroaryl or carboxyl groups selected from N, O or S atoms.

[0071] In a further preferred embodiment of the invention, R aa Or R bb Each is independently selected from hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, , or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl.

[0072] In a further preferred embodiment of the present invention, R1, R2, R3, R4, R5, R6, or R9 are each independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, acetyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -CD3, -OCD3, -SCH3, -OCF3. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The groups mentioned include amino, methylamino, dimethylamino, hydroxy, mercapto, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, acetyl, -NHCH3, -NHCH2CH3, -N(CH3)2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or It may be optionally substituted by one or more substituents of hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl.

[0073] In a further preferred embodiment of the invention, R1, R2 and the adjacent atoms form or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0074] In a further preferred embodiment of the invention, R1, R4 and the adjacent atoms form It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0075] In a further preferred embodiment of the invention, R2, R4 and the adjacent atoms form or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0076] In a further preferred embodiment of the invention, R3, R4 and the adjacent atoms form or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0077] In a further preferred embodiment of the invention, the two R3s form with the adjacent atoms or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0078] In a further preferred embodiment of the present invention, R1, R 11 Formed with adjacent atoms It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0079] In a further preferred embodiment of the invention, the two R1s form with the adjacent atoms , , , , , , , , , , , , , , , , , , , , , It may optionally be substituted by one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, carboxyl, -CD3, or -OCF3.

[0080] In a further preferred embodiment of the invention, R6, R2 and the adjacent atoms form or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0081] In a further preferred embodiment of the invention, R6, R4 and the adjacent atoms form It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0082] In a further preferred embodiment of the present invention, R6, R 11 Formed with adjacent atoms It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

[0083] In a further preferred embodiment of the invention, the two R6 atoms form a bonded structure with the adjacent atoms. , , , , , , , , , , , , , , , , , , , , , or It may optionally be substituted by one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, carboxyl, -CD3, or -OCF3.

[0084] The present invention further provides a method for preparing compounds of the aforementioned general formula or pharmaceutically acceptable salts thereof, comprising the following steps:

[0085] Deprotection of general formula (M-1) yields a compound of general formula (M-2) or a pharmaceutically acceptable salt thereof; then, general formula (M-2) undergoes a condensation reaction with general formula (M-3) to yield a compound of general formula (IV) or a pharmaceutically acceptable salt thereof; in, Pg is selected from amino protecting groups; R is selected from halogen, hydroxyl group, or -C(O)OR A ; R A Selected from C 1-6 alkyl; The definitions of X1, X2, X3, X4, X5, R2, R3, R6, y, z, and s are as described in general formula (IV).

[0086] In some preferred embodiments of the present invention, Pg is selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenemethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-toluoxy.

[0087] In some preferred embodiments of the present invention, Pg is selected from 2,4-dimethoxybenzyl or tert-butoxycarbonyl.

[0088] In some preferred embodiments of the present invention, R is selected from fluorine, chlorine, bromine, iodine or hydroxyl.

[0089] In some preferred embodiments of the present invention, R is selected from chlorine or hydroxyl.

[0090] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0091] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0092] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0093] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0094] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0095] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0096] In some embodiments of the invention, the compound, its stereoisomers, or pharmaceutically acceptable salts thereof may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0097] The present invention further relates to the use of any of the general formula compounds shown, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of NK inhibitor-related drugs, particularly in the preparation of NK3 inhibitor-related drugs.

[0098] The present invention further relates to the use of compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the treatment and / or prevention of psychotic disorders, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, sex hormone-dependent diseases or gynecological diseases.

[0099] The present invention further relates to the use of compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of remedies for the treatment and / or prevention of menopausal syndrome, polycystic ovary syndrome, uterine fibroids, schizophrenia, irritable bowel syndrome, vasomotor disorders or breast cancer-related diseases, wherein the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness and obesity.

[0100] The present invention further relates to compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in methods for preparing medicaments for treating NK3-related and related diseases.

[0101] The present invention also relates to a method for treating, preventing, and / or treating diseases related to NK3, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0102] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to NK3.

[0103] The present invention also relates to a method for treating NK3-related diseases in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0104] Detailed description of the invention Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0105] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0106] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0107] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0108] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include: wait; It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include: and wait.

[0109] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include: and wait.

[0110] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0111] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0112] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; even more preferably, it contains a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0113] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0114] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The heteroatom is a carbon atom (where m is an integer from 0 to 2). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 fused, more preferably 7 to 10 fused. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, they are 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0115] wait.

[0116] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include: and wait.

[0117] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: and wait.

[0118] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: and wait.

[0119] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0120] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0121] The ring connected to the parent structure is an aryl ring, and non-limiting examples include: and wait.

[0122] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0123] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: and wait.

[0124] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0125] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0126] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0127] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0128] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0129] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, which is a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located anywhere within the alkenyl group. Alkenyl groups have a carbon density of 2 to 20 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkenyl groups include: , , , , or The alkenyl group described therein may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0130] "Alynyl" refers to (CH≡C-) that contains at least one carbon-carbon triple bond, which can be located anywhere within the alkynyl group, and at least one carbon-carbon double bond, which can be located anywhere within the alkenyl group. The alkynyl group has 2 to 20 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkynyl groups include: , , or The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0131] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0132] "Hydroxy" refers to the -OH group.

[0133] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0134] "Amino" refers to -NH2.

[0135] “Cyano” refers to -CN.

[0136] "Nitro" refers to -NO2.

[0137] "Carbonyl" refers to -C(O)-.

[0138] "Carboxyl group" refers to -C(O)OH.

[0139] "THF" refers to tetrahydrofuran.

[0140] “EtOAc” refers to ethyl acetate.

[0141] “MeOH” refers to methanol.

[0142] "DMF" refers to N,N-dimethylformamide.

[0143] "DIPEA" refers to diisopropylethylamine.

[0144] "TFA" refers to trifluoroacetic acid.

[0145] “MeCN” refers to Yi Qing.

[0146] “DMA” stands for N,N-dimethylacetamide.

[0147] “Et2O” refers to diethyl ether.

[0148] “DCE” refers to 1,2-dichloroethane.

[0149] "DIPEA" refers to N,N-diisopropylethylamine.

[0150] “NBS” refers to N-bromosuccinimide.

[0151] “NIS” refers to N-iodosuccinimide.

[0152] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0153] The compounds of this invention include all pharmaceutically acceptable isotopically labeled compounds, wherein one or more atoms of the compounds disclosed herein are replaced by atoms having the same atomic number but a different atomic mass or mass number than those commonly found. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, and examples of isotopes include tritium, etc.

[0154] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0155] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0156] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0157] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0158] "Pharmaceutical acceptable salt" or "medicinal salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0159] The compounds of this invention, such as those of formulas (I) to (III) or specific compounds, are intended to include one or more of the following: a free base of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, or a mixture of two or more stereoisomers. A stereoisomer is a compound that differs only in its spatial arrangement. Stereoisomers include all diastereomers and enantiomers of the compound. An enantiomer is a stereoisomer that is a mirror image of another. A diastereomer is a stereoisomer having two or more distinct chiral centers that are not mirror images of each other. Detailed Implementation

[0160] Example The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shift ( ) with 10 -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0161] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0162] HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6mm column).

[0163] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0164] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.15 mm to 0.2 mm, and the size used for thin-layer chromatography separation and purification of products is 0.4 mm to 0.5 mm.

[0165] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0166] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0167] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0168] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0169] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0170] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0171] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0172] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0173] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0174] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0175] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0176] The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0177] Example 1 (R)-(1,7-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluorophenyl)methyl ketone

[0178] Step 1: tert-butyl-3-hydroxy-1,7-dimethyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester 1-(tert-butyl)-4-methyl-2-methyl-3-carbonylpiperidine-1,4-dicarboxylic acid ester (2 g, 7.37 mmol) and methylhydrazine (339.62 mg, 7.37 mmol) were dissolved in ethanol (50 mL) under nitrogen protection, and the mixture was incubated at 80 °C. o The reaction mixture was stirred at C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography to obtain tert-butyl-3-hydroxy-1,7-dimethyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester (0.8 g, yield: 40.60%) and tert-butyl 3-hydroxy-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester (0.75 g, yield: 38.06%).

[0179] MS m / z (ESI): 268.3 [M+H]. Step 2: Tert-butyl-1,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxo)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester Tert-butyl-3-hydroxy-1,7-dimethyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester (0.6 g, 2.24 mmol) and N,N-diisopropylethylamine (290.08 mg, 2.24 mmol, 370.95 μL) were dissolved in dichloromethane (20 mL), and N-phenylbis(trifluoromethanesulfonyl)imide (801.84 mg, 2.24 mmol) was added under nitrogen protection. The mixture was then heated at 25 °C. o The reaction mixture was stirred at C for 12 hours. The reaction was quenched by adding saturated brine (50 mL), the organic phase was separated, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product (0.62 g, yield: 69.16%).

[0180] MS m / z (ESI): 400.1 [M+H]. Step 3: Tert-butyl-1,7-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester tert-Butyl-1,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxo)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester (0.5 g, 1.25 mmol) and (3-methyl-1,2,4-thiadiazol-5-yl)boronic acid (198.25 mg, 1.38 mmol) were dissolved in dioxane (15 mL) and water (4 mL). Under nitrogen protection, tetrakis(triphenylphosphine)palladium (72.33 mg, 62.60 μmol) and sodium carbonate (398.07 mg, 3.76 mmol) were added. The mixture was heated at 90 °C. o The mixture was stirred at C for 5 hours. After cooling, the reaction was quenched with saturated brine (50 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 60:40) to give the target product (0.38 g, yield: 86.86%).

[0181] MS m / z (ESI): 350.2 [M+H]. Step 4: 5-(1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methyl-1,2,4-thiadiazole 0.38 g (1.09 mmol) of tert-butyl-1,7-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid ester was dissolved in dichloromethane (1 mL). Dioxane hydrochloride (4 M, 10 mL) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated to 0... o The reaction mixture was stirred at C for 1 hour. The reaction solution was evaporated to dryness, and the crude hydrochloride (0.31 g) was used directly in the next step.

[0182] MS m / z (ESI): 250.2 [M+H]. Step 5: (1,7-Dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluorophenyl) methyl ketone 5-(1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-methyl-1,2,4-thiadiazole hydrochloride (0.31 g, 1.08 mmol) and triethylamine (329.28 mg, 3.25 mmol, 453.55 μL) were dissolved in dichloromethane (8 mL). Under ice-water bath cooling and nitrogen protection, p-fluorobenzoyl chloride (34.40 mg, 216.94 μmol) was added. The mixture was then heated at 0°C. o The reaction mixture was stirred at C for 1 hour. The reaction solution was quenched with saturated brine (5 mL), the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography to obtain the product (0.15 g, yield: 40.27%).

[0183] MS m / z (ESI): 372.1 [M+H]. Step 6: (R)-(1,7-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluorophenyl) methyl ketone The target product was obtained through chiral separation.

[0184] MS m / z (ESI): 372.1 [M+H]. The following examples are prepared with reference to Example 1.

[0185] Example 7 (R)-(4-Fluorophenyl)(5-Methyl-10-(3-methyl-1,2,4-thiadiazol-5-yl)-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazin-6(5H)-yl)methyl ketone

[0186] Step 1: 1-(6H-pyrrolo[3,4-b]pyridin-5-yl)ethane-1-one Acetic anhydride (10.37 g, 101.58 mmol) and boron trifluoride diethyl ether (10.81 g, 76.18 mmol) were dissolved in 1,2-dichloroethane (100 mL). Under ice-water bath cooling and nitrogen protection, 6H-pyrrolo[3,4-b]pyridine (6 g, 50.79 mmol) was added. The mixture was then heated at 25 °C. o The mixture was stirred at C for 12 hours. The reaction was quenched by adding saturated brine (150 mL), the organic phase was separated, washed with saturated sodium bicarbonate aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 100:0 to 60:40) to give the target product (3.1 g, yield: 38.11%).

[0187] MS m / z (ESI): 161.10 [M+H]. Step 2: Tert-butyl (2-(5-acetyl-6H-pyrrolo[3,4-b]pyridin-6-yl)ethyl)carbamate 1-(6H-pyrrolo[3,4-b]pyridin-5-yl)ethane-1-one (3.1 g, 19.35 mmol) and N-(2-bromoethyl)carbamate tert-butyl ester (5.20 g, 23.22 mmol) were dissolved in N,N-dimethylformamide (35 mL), and potassium carbonate (8.02 g, 58.06 mmol) was added under nitrogen protection. The mixture was heated at 80 °C. o The mixture was stirred at C for 5 hours. The reaction was quenched with saturated brine (150 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed successively with saturated brine (100 mL × 5). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product (5.1 g, yield: 86.86%).

[0188] MS m / z (ESI): 304.2 [M+H]. Step 3: 5-Methyl-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazine 5.1 g (16.81 mmol) of tert-butyl (2-(5-acetyl-6H-pyrrolo[3,4-b]pyridin-6-yl)ethyl)carbamate was dissolved in dichloromethane (10 mL). Dioxane hydrochloride (4 M, 50 mL) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated to 0°C. o The reaction mixture was stirred at C for 3 hours. The crude hydrochloride (3.7 g) was evaporated to dryness and proceeded directly to the next step.

[0189] MS m / z (ESI): 186.1 [M+H]. Step 4: 5-Methyl-5,6,7,8-tetrahydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazine 5-Methyl-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazine hydrochloride (3.7 g, 16.69 mmol) was dissolved in methanol (100 mL), and sodium borohydride (1.26 g, 33.38 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated to 0... o The reaction mixture was stirred at C for 1 hour. Most of the solvent was removed from the reaction solution under reduced pressure, and the reaction was quenched with saturated brine (100 mL). Stirring continued for 0.5 hours. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate aqueous solution (50 mL × 2) and saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with dichloromethane:methanol = 100:0 to 95:5) to give the target product (0.91 g, yield: 29.12%).

[0190] MS m / z (ESI): 188.1 [M+H]. Step 5: 10-Bromo-5-methyl-5,6,7,8-tetrahydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazine 5-Methyl-5,6,7,8-tetrahydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazine (0.9 g, 4.81 mmol) was dissolved in dichloromethane (20 mL), and NBS (941.06 mg, 5.29 mmol) was added under nitrogen protection. The mixture was then heated at 25 °C. oThe reaction mixture was stirred at C for 2 hours. The reaction solution was washed with saturated sodium bicarbonate aqueous solution (50 mL × 2), and the organic phase was dried and evaporated to dryness to obtain crude product (1.2 g), which was directly used in the next step.

[0191] MS m / z (ESI): 266.2, 268.0[M+H]. Step 6: (10-bromo-5-methyl-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazin-6(5H)-yl)(4-fluorophenyl) methyl ketone The target product was obtained by referring to step 5 of Example 1.

[0192] MS m / z (ESI): 388.0, 390.0[M+H]. Step 7: (4-Fluorophenyl)(5-methyl-10-(3-methyl-1,2,4-thiadiazol-5-yl)-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazin-6(5H)-yl) methyl ketone The target product was obtained by referring to step 3 of Example 1.

[0193] MS m / z (ESI): 408.1 [M+H]. Step 8: (R)-(4-fluorophenyl)(5-methyl-10-(3-methyl-1,2,4-thiadiazol-5-yl)-7,8-dihydropyrido[3',2':3,4]pyrrolo[1,2-a]pyrazin-6(5H)-yl) methyl ketone The target product was obtained by chiral separation.

[0194] MS m / z (ESI): 408.1 [M+H]. Example 8

[0195] Step 1: 4-Methyl-2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine 4-(methylamino)-1H-pyrrole-3-phenol (2 g, 17.84 mmol) and 1,2-dibromoethane (3.35 g, 17.84 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (4.93 g, 35.67 mmol) was added under nitrogen protection. The mixture was then heated at 25 °C. o The reaction mixture was stirred at C for 12 hours. The reaction solution was filtered, and the organic phase was separated by preparative high performance liquid chromatography to obtain the product (0.31 g, yield: 12.58%).

[0196] MS m / z (ESI): 139.1 [M+H]. Step 2: (R)-(4,10-dimethyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4,7,8-tetrahydro-2H-pyrano[1',2':1,2]pyrrolo[3,4-b][1,4]oxazin-9(10H)-yl)(4-fluorophenyl)methyl ketone The target product was obtained with reference to Example 7.

[0197] MS m / z (ESI): 428.2 [M+H]. Example 9 (R)-(4-Fluorophenyl)(1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl ketone

[0198] Step 1: (R)-(4-fluorophenyl)(1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl) methyl ketone The target product was obtained with reference to Example 7.

[0199] MS m / z (ESI): 357.1 [M+H]. Example 10 (R)-(4-Fluorophenyl)(1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-7-(pyrrolid-1-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl ketone

[0200] Step 1: (R)-(4-fluorophenyl)(1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-7-(pyrrolidine-1-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl) methyl ketone The target product was obtained using 1-(4,5-dibromo-1H-pyrrole-2-yl)ethane-1-one as a starting material, referring to Example 7.

[0201] MS m / z (ESI): 426.2 [M+H]. Example 11 (R)-(4-Fluorophenyl)(1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl ketone

[0202] Step 1: (R)-(4-fluorophenyl)(1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl) methyl ketone The target product was obtained using 1-(3,5-dibromo-1H-pyrrole-2-yl)ethane-1-one as a starting material, referring to Example 7.

[0203] MS m / z (ESI): 434.1 [M+H]. Example 13 7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

[0204] Step 1: 1-(1-(4-fluorophenyl)ethyl)piperazine-2,3-dione Piperazine-2,3-dione (1.0 g, 8.76 mmol) was dissolved in N,N-dimethylformamide (20 mL) under ice bath conditions, and nitrogen was purged. Sodium hydroxide (420.63 mg, 10.52 mmol, 60% purity) was added in portions, and the mixture was stirred under ice bath conditions for 20 minutes. Then, 1-(1-bromoethyl)-4-fluorobenzene (2.14 g, 10.52 mmol) was added, and the mixture was heated to 60°C and reacted for 2 hours. The reaction was stopped by LCMS. The mixture was cooled to room temperature, and the reaction solution was quenched with saturated ammonium chloride solution (20 mL). The solution was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target compound (0.60 g, yield: 29%).

[0205] MS m / z (ESI): 237.1 [M+1]. Step 2: 3-Ethoxy-1-(1-(4-fluorophenyl)ethyl)-5,6-dihydropyrazine-2(1H)-one Under ice bath conditions, 1-(1-(4-fluorophenyl)ethyl)piperazin-2,3-dione (0.60 g, 2.54 mmol) was dissolved in dichloromethane (20 mL), and nitrogen gas was purged. Then, triethyloxytetrafluoroborate (1.21 g, 6.35 mmol) was added in portions. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. When the LCMS indicated the end of the reaction, the reaction solution was added dropwise to an aqueous sodium hydroxide solution (2N, 10 mL) under ice bath conditions, and stirred for 10 minutes under ice bath conditions. The mixture was separated, and the organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness at low temperature to give 3-ethoxy-1-(1-(4-fluorophenyl)ethyl)-5,6-dihydropyrazin-2(1H)-one (0.67 g, yield: 99.8%).

[0206] MS m / z (ESI): 265.1 [M+1]. Step 3: 7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one At room temperature, 3-methyl-1,2,4-thiadiazole-5-carboxylhydrazine (100 mg, 632.19 μmol) was dissolved in methanol (5 mL), and then a methanol (5 mL) solution of 3-ethoxy-1-(1-(4-fluorophenyl)ethyl)-5,6-dihydropyrazine-2(1H)-one (0.20 g, 756.73 μmol) was added dropwise. The mixture was heated to 65°C and reacted for 14 hours. The reaction was completed by LCMS. The mixture was cooled to room temperature, evaporated to dryness, and the crude product was separated by Flash column chromatography to obtain the target compound (0.18 g, yield: 79.6%).

[0207] MS m / z (ESI): 359.1 [M+1]. Step 4: (R)-7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one; (S)-7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one Chiral resolution of 7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one yielded compound (R)-7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one and compound (S)-7-(1-(4-fluorophenyl)ethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one.

[0208] MS m / z (ESI): 359.1 [M+1]. Example 14 (R)-6-fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one

[0209] Step 1: Ethyl 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)propionate Using 6-fluoro-3,4-dihydroisoquinoline-1(2H)-one and ethyl 2-bromopropionate as raw materials, the target compound was obtained by referring to the first step of Example 13.

[0210] MS m / z (ESI): 266.1 [M+1]. Step 2: 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)propionic acid At room temperature, ethyl 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)propionate (0.5 g, 1.88 mmol) was dissolved in methanol (20 mL), and then a solution of lithium hydroxide (135.41 mg, 5.65 mmol) in water (2 mL) was added. The mixture was stirred overnight at room temperature. The reaction was completed by LCMS. The reaction solution was neutralized with aqueous formic acid, and a solid precipitated. The solid was filtered, evaporated to dryness, and the target compound (0.30 g, yield: 67.1%) was obtained.

[0211] MS m / z (ESI): 238.1 [M+1]. Step 3: 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylpropionamide At room temperature, 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)propionic acid (0.30 g, 1.26 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of methylamine hydrochloride (102.46 mg, 1.52 mmol, CL), diisopropylethylamine (817.21 mg, 6.32 mmol, 1.10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (715.65 mg, 1.90 mmol). The mixture was stirred overnight at room temperature. LC-MS indicated the end of the reaction. The reaction solution was diluted with ethyl acetate (60 mL) and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target compound (0.20 g). g, yield: 63.2%.

[0212] MS m / z (ESI): 251.1 [M+1]. Step 4: 6-Fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one Using 2-(6-fluoro-1-carbonyl-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylpropionamide as a starting material, and referring to steps two and three of Example Thirteen, 6-fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one was obtained.

[0213] MS m / z (ESI): 373.1 [M+1]. Step 5: (R)-6-fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one Chiral resolution of 6-fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one yielded (R)-6-fluoro-2-(1-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydroisoquinoline-1(2H)-one.

[0214] MS m / z (ESI): 373.1 [M+1]. Example 15 (R)-(2,9-dimethyl-6,7,11,12-tetrahydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepepta[3,2-d]pyrimidin-10(9H)-yl)(4-fluorophenyl)methyl ketone

[0215] Step 1: 2,9-Dimethyl-6,7-dihydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepepto[3,2-d]pyrimidine Under ice bath conditions, 1.0 g (3.51 mmol) of 4-[2-(2-hydroxyethyl)-8-methyl-imidazo[1,2-a]pyrazin-3-yl]-2-methyl-pyrimidin-5-phenol (obtained by the synthetic method of compound 13 in patent WO2017 / 216292) was dissolved in tetrahydrofuran (20 mL), and nitrogen gas was purged. Then, potassium tert-butoxide (393.31 mg, 3.51 mmol) was added, and the mixture was stirred under ice bath conditions for 20 minutes. Then, p-toluenesulfonyl chloride (668.23 mg, 3.51 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, potassium tert-butoxide (393.31 mg, 3.51 mmol) was added again, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by LCMS, and the reaction solution was quenched with saturated ammonium chloride solution (20 mL). The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target compound (0.40 g, yield: 42.7%).

[0216] MS m / z (ESI): 268.1 [M+1]. Step 2: 2,9-Dimethyl-6,7,9,10,11,12-hexahydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepepto[3,2-d]pyrimidine At room temperature, 2,9-dimethyl-6,7-dihydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepepta[3,2-d]pyrimidine (0.40 g, 1.50 mmol) was dissolved in ethanol (10 mL), and then platinum dioxide (0.05 g) was added to replace hydrogen gas. The mixture was stirred at room temperature for 14 hours. The reaction was stopped by LCMS. The mixture was filtered, and the residue was washed with ethanol and evaporated to dryness to give the target compound (0.40 g, yield: 98.5%).

[0217] MS m / z (ESI): 272.1 [M+1]. Step 3: (2,9-Dimethyl-6,7,11,12-tetrahydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepyno[3,2-d]pyrimidin-10(9H)-yl)(4-fluorophenyl)methyl ketone Under ice bath conditions, 2,9-dimethyl-6,7,9,10,11,12-hexahydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepepta[3,2-d]pyrimidine (0.40 g, 1.47 mmol) was dissolved in dichloromethane (20 mL), followed by the sequential addition of triethylamine (447.55 mg, 4.42 mmol, 616.89 μL) and 4-fluorobenzoyl chloride (280.51 mg, 1.77 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was considered complete by LC-MS. The reaction solution was diluted with dichloromethane (20 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target compound (0.40 g, yield: 69.0%). ) .

[0218] MS m / z (ESI): 394.1 [M+1]. Step 4: (R)-(2,9-dimethyl-6,7,11,12-tetrahydropyranazono[2'',1'':2',3']imidazo[4',5':4,5]oxepyno[3,2-d]pyrimidin-10(9H)-yl)(4-fluorophenyl)methyl ketone Chiral resolution of (2,9-dimethyl-6,7,11,12-tetrahydropyrano[2'',1'':2',3']imidazo[4',5':4,5]oxepyn[3,2-d]pyrimidin-10(9H)-yl)(4-fluorophenyl) ketone yielded (R)-(2,9-dimethyl-6,7,11,12-tetrahydropyrano[2'',1'':2',3']imidazo[4',5':4,5]oxepyn[3,2-d]pyrimidin-10(9H)-yl)(4-fluorophenyl) ketone.

[0219] MS m / z (ESI): 394.1 [M+1]. Example 16 (4-Fluorophenyl)((3R)-3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azine-4(3H)-yl) methyl ketone

[0220] Step 1: Methyl 3-chloro-2-methylisonicotinic acid ester At room temperature, 4-bromo-3-chloro-2-methylpyridine (0.82 g, 3.99 mmol), triethylamine (4.03 g, 39.85 mmol, 5.56 mL), and diphenylphosphine-ferrocene-palladium dichloride (327 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (10 mL) and methanol (10 mL), and the mixture was heated to 100°C for 14 hours, replacing the carbon monoxide gas. After cooling to room temperature, methanol and triethylamine were removed by rotary evaporation. The residue was diluted with ethyl acetate (40 mL) and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography to give the target compound (0.30 g, yield: 40.5%).

[0221] MS m / z (ESI): 186.1 [M+1]. Step 2: 3-Chloro-2-methylisonicotinylhydrazine At room temperature, methyl 3-chloro-2-methylisonicotinic acid ester (0.30 g, 1.62 mmol) and water and hydrazine (285.2 mg, 4.86 mmol) were dissolved in methanol (10 mL) and stirred overnight at room temperature. The reaction was stopped by LCMS. A solid precipitated out; the solid was filtered, washed with petroleum ether, and then evaporated to dryness to give the target product (0.15 g, yield: 50.0%).

[0222] MS m / z (ESI): 186.1 [M+1]. Step 3: 6-(hydroxymethyl)-3-methylpiperazin-2-one Under ice bath conditions, 2,3-diaminopropane-1-ol (2 g, 22.19 mmol) was dissolved in dichloromethane (20 mL), followed by the sequential addition of triethylamine (6.74 g, 66.58 mmol, 9.29 mL) and 2-chloropropionyl chloride (3.38 g, 26.63 mmol). The mixture was stirred overnight at room temperature, and the reaction was allowed to proceed to completion by LC-MS. The reaction solution was diluted with dichloromethane (30 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the target compound (0.90 g, yield: 28.13%).

[0223] MS m / z (ESI): 145.1 [M+1]. Step 4: 4-(4-fluorobenzoyl)-6-(hydroxymethyl)-3-methylpiperazin-2-one Using 6-(hydroxymethyl)-3-methylpiperazin-2-one as a starting material, 4-(4-fluorobenzoyl)-6-(hydroxymethyl)-3-methylpiperazin-2-one was obtained by referring to step 3 of Example 15.

[0224] MS m / z (ESI): 267.1 [M+1]. Step 5: (4-(4-fluorobenzoyl)-5-methyl-6-carbonylpiperazin-2-yl)methylmethanesulfonate 4-(4-fluorobenzoyl)-6-(hydroxymethyl)-3-methylpiperazin-2-one (0.5 g, 1.88 mmol) was dissolved in dichloromethane (10 mL) under ice bath conditions. Triethylamine (570.05 mg, 5.63 mmol, 785.73 μL) and methanesulfonyl chloride (279.64 mg, 2.44 mmol) were then added sequentially. The mixture was stirred overnight at room temperature, and the reaction was considered complete by LCMS. The reaction solution was diluted with dichloromethane (30 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the target compound (0.60 g, yield: 92.8%).

[0225] MS m / z (ESI): 345.1 [M+1]. Step 6: 4-(4-fluorobenzoyl)-3-methyl-6-((methylamino)methyl)piperazin-2-one (4-(4-fluorobenzoyl)-5-methyl-6-carbonylpiperazin-2-yl)methylmethanesulfonate (0.60 g, 1.74 mmol) was dissolved in acetonitrile (10 mL) at room temperature, followed by the sequential addition of potassium carbonate (722.42 mg, 5.23 mmol) and methylamine hydrochloride (81.17 mg, 1.20 mmol, CL). The mixture was heated to 80°C and reacted for 14 hours, with LCMS indicating completion. After cooling to room temperature, the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (30 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to give the target compound (0.30 g, yield: 61.6%).

[0226] MS m / z (ESI): 280.1 [M+1]. Step 7: (3-(3-chloro-2-methylpyridin-4-yl)-8-methyl-5-((methylamino)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone Using 4-(4-fluorobenzoyl)-3-methyl-6-((methylamino)methyl)piperazin-2-one as a starting material, referring to the second step of Example 13, (5-ethoxy-6-methyl-3-((methylamino)methyl)-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) methyl ketone was obtained. Then, using (5-ethoxy-6-methyl-3-((methylamino)methyl)-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) methyl ketone and 3-chloro-2-methylisonicotinyl hydrazine as starting materials, referring to the third step of Example 13, (3-(3-chloro-2-methylpyridin-4-yl)-8-methyl-5-((methylamino)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0227] MS m / z (ESI): 429.2 [M+1]. Step 8: (4-Fluorophenyl)(3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azine-4(3H)-yl) methyl ketone At room temperature, (3-(3-chloro-2-methylpyridin-4-yl)-8-methyl-5-((methylamino)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) ketone (0.09 g, 211.26 μmol), (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane (30.05 mg, 211.26 μmol), potassium carbonate (87.59 mg, 633.79 μmol), and cuprous iodide (40.24 mg, 211.26 μmol) were dissolved in N-methylpyrrolidone (5 mL), purged with nitrogen, heated to 130°C, and reacted for 5 hours. After cooling to room temperature, the reaction was considered complete by LCMS. The reaction solution was filtered, and the residue was washed with ethyl acetate (20 μL). The organic phases were combined (20 mL × 2), washed with saturated brine (20 mL × 4), dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain (4-fluorophenyl)(3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azine-4(3H)-yl) methyl ketone (0.05 g, yield: 60.3%).

[0228] MS m / z (ESI): 393.2 [M+1]. Step 9: (4-Fluorophenyl)((3R)-3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azine-4(3H)-yl) methyl ketone Chiral resolution of (4-fluorophenyl)(3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azu-4(3H)-yl) ketone yielded (4-fluorophenyl)((3R)-3,7,8-trimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7,9-hexaazadibenzo[cd,h]azu-4(3H)-yl) ketone.

[0229] MS m / z (ESI): 393.2 [M+1]. Example 17 (R)-(4-Fluorophenyl)(8-Methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0230] Step 1: Pyrrolo[1,2-a]pyrimidine-2-carbamoylhydrazine Using methylpyrrolo[1,2-a]pyrimidine-2-carboxylic acid ester as a raw material, pyrrolo[1,2-a]pyrimidine-2-carboxylic acid hydrazide was obtained by referring to step 2 of Example 16.

[0231] MS m / z (ESI): 177.1 [M+1]. Step 2: (R)-(5-ethoxy-6-methyl-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl)methyl ketone Using (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one as a starting material, (R)-(5-ethoxy-6-methyl-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) methyl ketone was obtained by referring to the second step of Example 13.

[0232] MS m / z (ESI): 265.1 [M+1]. Step 3: (R)-(4-fluorophenyl)(8-methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone Using (R)-(5-ethoxy-6-methyl-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) methyl ketone and pyrrolo[1,2-a]pyrimidin-2-carboxylhydrazine as raw materials, (R)-(4-fluorophenyl)(8-methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone was obtained by referring to step 3 of Example 13.

[0233] MS m / z (ESI): 376.1 [M+1]. The following examples are prepared with reference to Example 17.

[0234] Example 20 5-(7-(4-fluorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-methyl-1,2,4-thiadiazole

[0235] Step 1: 4-(4-fluorophenoxy)pyridine-2-phenol 4-Fluorophenol (991.26 mg, 8.84 mmol) was dissolved in N,N-dimethylformamide (5 mL) under ice bath conditions, purging with nitrogen. Sodium hydroxide (389.03 mg, 9.73 mmol, 60%) was then added in portions, and the mixture was stirred under ice bath conditions for 30 minutes. 4-Fluoropyridine-2-phenol (0.5 g, 4.42 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The reaction was considered complete by LC-MS. The reaction solution was quenched with saturated ammonium chloride solution (15 mL), diluted with ethyl acetate (50 mL), and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (0.5 g, yield: 55.1%).

[0236] MS m / z (ESI): 206.1 [M+1]. Step 2: 5-(7-(4-fluorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-methyl-1,2,4-thiadiazole Using 4-(4-fluorophenoxy)pyridine-2-phenol and 3-methyl-1,2,4-thiadiazole-5-carboxylhydrazine as raw materials, and referring to the second and third steps of Example 13, 5-(7-(4-fluorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-methyl-1,2,4-thiadiazole was obtained.

[0237] MS m / z (ESI): 328.1 [M+1]. Example 21 (R)-(4-Fluorophenyl)(8-Methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl)methyl ketone

[0238] Step 1: (4,8-Dimethyl-5,8-dihydro-1,7-diazanaphth-7(6H)-yl)(4-fluorophenyl)methyl ketone Using 4,8-dimethyl-5,6,7,8-tetrahydro-1,7-diazanaphthalene as a raw material, (4,8-dimethyl-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl)(4-fluorophenyl) methyl ketone was obtained by referring to step 3 of Example 15.

[0239] MS m / z (ESI): 285.1 [M+1]. Step 2: (4-(bromomethyl)-8-methyl-5,8-dihydro-1,7-diazanaphth-7(6H)-yl)(4-fluorophenyl)methyl ketone At room temperature, (4,8-dimethyl-5,8-dihydro-1,7-diazanaphth-7(6H)-yl)(4-fluorophenyl) methyl ketone (0.5 g, 1.76 mmol) was dissolved in carbon tetrachloride (20 mL), and then N-bromosuccinimide (375.59 mg, 2.11 mmol) and azobisisobutyronitrile (14.44 mg, 0.088 mmol) were added sequentially. The mixture was heated to 100°C and reacted for 14 hours. The reaction was completed according to LCMS. The mixture was cooled to room temperature, evaporated to dryness, and the crude product was separated by Flash column chromatography to obtain the target product (0.3 g, yield: 47.0%).

[0240] MS m / z (ESI): 363.1,365.1[M+1]. Step 3: (R)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl)methyl ketone At -78°C, 3-methyl-1,2,4-thiadiazole (124.07 mg, 1.24 mmol) was dissolved in tetrahydrofuran (5 mL), nitrogen was purged, and then a solution of diisopropylaminolithium (2.0 M, 1.48 mmol, 0.74 mL) was added dropwise. The mixture was stirred at -78°C for half an hour, and then a solution of [4-(bromomethyl)-8-methyl-6,8-dihydro-5H-1,7-diazanaphthyl-7-yl]-(4-fluorophenyl)methyl ketone (0.30 g, 825.94 μmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at -78°C for 1 hour and allowed to cool to room temperature. LCMS indicated the formation of the target product. The reaction solution was quenched with saturated ammonium chloride solution (10 mL), separated, the organic phase was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and the crude product was separated by Flash column chromatography to obtain the target product (0.1 g, yield: 31.7%).

[0241] MS m / z (ESI): 383.2 [M+1]. Step 4: (R)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl) methyl ketone; (S)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl) methyl ketone Chiral resolution of (R)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) ketone yielded compounds (R)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) ketone and (S)-(4-fluorophenyl)(8-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) ketone.

[0242] MS m / z (ESI): 383.2 [M+1]. Example 22 (R)-(4-Fluorophenyl)(8-Methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl)methyl ketone

[0243] Step 1: (R)-(4-fluorophenyl)(8-methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl) methyl ketone; (S)-(4-fluorophenyl)(8-methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthyl-7(6H)-yl) methyl ketone Referring to Example 21, compound (4-fluorophenyl)(8-methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) methyl ketone was obtained, and then chiral resolution was performed to obtain compound (R)-(4-fluorophenyl)(8-methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) methyl ketone and compound (S)-(4-fluorophenyl)(8-methyl-3-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5,8-dihydro-1,7-diazanaphthalene-7(6H)-yl) methyl ketone.

[0244] MS m / z (ESI): 383.2 [M+1]. Example 24 2-(4-Fluorophenyl)-4-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)oxazole

[0245] Step 1: 2-(4-fluorophenyl)-N-methyloxazol-4-carboxamide Using 2-(4-fluorophenyl)oxazole-4-carboxylic acid as a raw material, 2-(4-fluorophenyl)-N-methyloxazole-4-carboxamide was obtained by referring to step 3 of Example 14.

[0246] MS m / z (ESI): 221.1 [M+1]. Step 2: 2-(4-fluorophenyl)-4-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)oxazole Using 2-(4-fluorophenyl)-N-methyloxazol-4-carboxamide as a raw material, and referring to the second and third steps of Example 13, 2-(4-fluorophenyl)-4-(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)oxazol was obtained.

[0247] MS m / z (ESI): 343.1 [M+1]. Example 25 5-(2,4-Dimethyl-4H-imidazo[4,5-d]thiazolyl-5-yl)-3-(4-fluorophenyl)-1-methylpyridin-2(1H)-one

[0248] Step 1: 5-(4-fluorophenyl)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid Using 4-fluorophenylboronic acid and 5-bromo-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid as starting materials, the target product was obtained in step 3 of Example 1. MS m / z (ESI): 248.1 [M+H] Step 2: 5-(4-fluorophenyl)-1-methyl-N-(2-methylthioazol-4-yl)-6-carbonyl-1,6-dihydropyridine-3-carboxamide Using 5-(4-fluorophenyl)-1-methyl-6-carbonyl-1,6-dihydropyridine-3-carboxylic acid and 2-methylthioazole-4-amine as starting materials, the target product was obtained in step 3 of Example 14. MS m / z (ESI): 344.1 [M+H] Step 3: 5-(4-fluorophenyl)-N,1-dimethyl-N-(2-methylthioazol-4-yl)-6-carbonyl-1,6-dihydropyridine-3-carboxamide Using 5-(4-fluorophenyl)-1-methyl-N-(2-methylthioazol-4-yl)-6-carbonyl-1,6-dihydropyridine-3-carboxamide as a starting material, the target product was obtained according to the second step of Example 7. MS m / z (ESI): 358.1 [M+H] Step 4: N-(5-bromo-2-methylthioazol-4-yl)-5-(4-fluorophenyl)-N,1-dimethyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide Using 5-(4-fluorophenyl)-N,1-dimethyl-N-(2-methylthioazol-4-yl)-6-carbonyl-1,6-dihydropyridine-3-carboxamide as a starting material, the target product was obtained according to step 5 of Example 7. MS m / z (ESI):436.0 438.0 [M+H] Step 5: N-(5-amino-2-methyl-thiazolyl-4-yl)-5-(4-fluorophenyl)-N,1-dimethyl-6-carbonyl-pyridine-3-carboxamide A mixed solution of N-(5-bromo-2-methyl-thiazolyl-4-yl)-5-(4-fluorophenyl)-N,1-dimethyl-6-carbonyl-pyridine-3-carboxamide (700 mg, 1.60 mmol), tert-butylcarbamate (281.93 mg, 2.41 mmol), tris(dibenzylidene indeneacetone)palladium (146.80 mg, 160.44 μmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (139.10 mg, 240.66 μmol), cesium carbonate (1.56 g, 4.81 mmol), and 1,4-dioxane (10 mL) was purged three times with nitrogen and then subjected to nitrogen protection at 100 °C. o The mixture was stirred at C for 12 hours, cooled, and quenched with dilute hydrochloric acid (3 M). The mixture was stirred at room temperature for 1 hour, evaporated to dryness, filtered, and purified by preparative chromatography to obtain the target product N-(5-amino-2-methylthioazol-4-yl)-5-(4-fluorophenyl)-N,1-dimethyl-6-carbonyl-1,6-dihydropyridine-3-carboxamide (230 mg, yield: 38.5%). MS m / z (ESI): 373.1 [M+H] Step 6: 5-(2,4-dimethylimidazo[4,5-d]thiazolyl-5-yl)-3-(4-fluorophenyl)-1-methylpyridin-2-one A mixture of N-(5-amino-2-methyl-thiazolyl-4-yl)-5-(4-fluorophenyl)-N,1-dimethyl-6-carbonyl-pyridin-3-carboxamide (200 mg, 537.03 μmol) and AcOH (5 mL) was stirred at 100 °C for 12 hours, cooled, quenched with water and saturated ammonium chloride, extracted three times with EtOAc, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Preparative chromatography was performed to obtain the target product 5-(2,4-dimethylimidazo[4,5-d]thiazolyl-5-yl)-3-(4-fluorophenyl)-1-methylpyridin-2-one (23 mg, yield: 12.1%). MS m / z (ESI): 355.1 [M+H] Example 26 2-(4-fluorophenyl)-2-methyl-4-(6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)morpholin-3-one

[0249] Step 1: 4-Benzyl-2-(4-fluorophenyl)-2-methylmorpholin-3-one Sodium hydroxide (560.74 mg, 60%) was added to a 20 mL THF solution of 4-benzyl-2-(4-fluorophenyl)morpholin-3-one (2 g, 7.01 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 h, followed by dropwise addition of a 5 mL THF solution of iodomethane (1.19 g, 8.41 mmol). The mixture was stirred at room temperature for 1 h, quenched with water, and extracted with EtOAc (20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The product was then separated by column chromatography to obtain the target product, 4-benzyl-2-(4-fluorophenyl)-2-methylmorpholin-3-one (500 mg, yield: 23.8%). MS m / z (ESI): 300.1 [M+H] Step 2: 2-(4-fluorophenyl)-2-methylmorpholin-3-one A Pd-C catalyst (50 mg, 5% Pd) was added to a MeOH (15 mL) solution of 4-phenylmethyl-2-(4-fluorophenyl)-2-methylmorpholin-3-one (500 mg, 1.67 mmol). After three hydrogen purgings, the mixture was stirred at room temperature for 1 hour under hydrogen protection. The mixture was then filtered, and the filtrate was concentrated to dryness under reduced pressure. Preparative chromatography was then performed to obtain the target product 2-(4-fluorophenyl)-2-methylmorpholin-3-one (300 mg, yield: 85.9%). MS m / z (ESI): 210.1 [M+H] Step 3: 4-(6-bromo-2-pyridyl)-2-(4-fluorophenyl)-2-methylmorpholin-3-one A mixture of 2-bromo-6-fluoropyridine (277.59 mg, 1.58 mmol), 2-(4-fluorophenyl)-2-methylmorpholin-3-one (300 mg, 1.43 mmol), cesium carbonate (932.05 mg, 2.87 mmol), and DMF (8 mL) was stirred at 100 °C for 12 hours under nitrogen protection. After cooling, the reaction was quenched with water, extracted with dichloromethane (50 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was then separated by column chromatography (DCM / MeOH = 10:1) to give the target product 4-(6-bromo-2-pyridyl)-2-(4-fluorophenyl)-2-methylmorpholin-3-one (220 mg, yield: 42%). MS m / z (ESI):365.0 367.0 [M+H] Step 4: 2-(4-fluorophenyl)-2-methyl-4-(6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)morpholin-3-one Using 4-(6-bromo-2-pyridyl)-2-(4-fluorophenyl)-2-methylmorpholin-3-one as a starting material, the target product was obtained according to the third step of Example 1. MS m / z (ESI): 385.1 [M+H] Example 27 2-(4-fluorophenyl)-2-methyl-4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)morpholin-3-one

[0250] Step 1: 5-Bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine Using trimethylcycloboroxane and 5-bromo-2-iodo-[1,2,4]triazolo[1,5-a]pyridine as starting materials, the target product was obtained in step 3 of Example 1. MS m / z (ESI):211.9 213.9 [M+H] Step 2: 2-(4-fluorophenyl)-2-methyl-4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)morpholin-3-one was obtained by referring to step 5 of Example 25 to obtain the target product. MS m / z (ESI): 341.1 [M+H] Example 28 (4-Fluorophenyl)(4-(3-methyl-1,2,4-thiadiazol-5-yl)-2H-indazol-2-yl)methyl ketone

[0251] Step 1: (4-bromo-2H-indazol-2-yl)(4-fluorophenyl)methyl ketone Using 4-bromo-2H-indazole as a starting material, the target product (4-bromo-2H-indazole-2-yl)(4-fluorophenyl) methyl ketone was obtained in step 5 of Example 1. MS m / z (ESI):319.0 321.0 [M+H] Step 2: (4-Fluorophenyl)(4-(3-methyl-1,2,4-thiadiazol-5-yl)-2H-indazol-2-yl)methyl ketone The target product (4-fluorophenyl)(4-(3-methyl-1,2,4-thiadiazol-5-yl)-2H-indazol-2-yl) methyl ketone was obtained by referring to step four of Example 1. MS m / z (ESI): 339.1 [M+H] The following compounds were prepared according to Example 28.

[0252] Example 31 (R)-(4-Fluorophenyl)(8-Methyl-3-(2-methylpyrimidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0253] Step 1: Methyl 2-methylpyrimidine-4-carboxylic acid ester 2-Methylpyrimidine-4-carboxylic acid (2 g, 14.48 mmol) was dissolved in MeOH (30 mL), and concentrated sulfuric acid (1 mL) was added. The reaction system was refluxed in an oil bath at 80 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, excess solvent was concentrated, and excess acid was quenched by adding saturated sodium bicarbonate solution (20 mL x 2). The mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 2:1) to finally obtain methyl 2-methylpyrimidine-4-carboxylic acid (1.8 g, yield: 81.7%).

[0254] MS m / z (ESI): 153.1 [M+H]. Step 2: 2-Methylpyrimidin-4-formylhydrazide 1.8 g (11.83 mmol) of methyl 2-methylpyrimidin-4-carboxylic acid ester was dissolved in 30 mL of EtOH, and hydrazine hydrate (2.27 g, 70.98 mmol) was added. The reaction mixture was stirred in an oil bath at 80 °C for 2 hours. TLC (PE / EtOAc = 3:1) showed that the starting material had almost disappeared and new spots had formed. After the reaction solution cooled to room temperature, the excess solvent was directly concentrated to obtain crude 2-methylpyrimidin-4-carboxyhydrazide (1.8 g, crude product).

[0255] MS m / z (ESI): 153.1 [M+H]. Step 3: [(5R)-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazin-4-yl]-(4-fluorophenyl)methyl ketone (3R)-4-(4-fluorobenzoyl)-3-methyl-piperazin-2-one (1 g, 4.23 mmol) was dissolved in dichloromethane (20 mL), and sodium carbonate (1.01 g, 9.52 mmol, 1.39 mL) and triethyloxonium tetrafluoroborate (965.05 mg, 5.08 mmol) were added sequentially. The reaction mixture was stirred at room temperature (20 °C) for 2 hours. After the reaction was complete, 20 mL of saturated sodium bicarbonate solution was added to quench the reaction, followed by extraction with dichloromethane (20 mL x 3), washing with saturated brine (20 mL x 2), drying with anhydrous sodium sulfate, filtration and concentration to obtain the crude product, which was then purified by column chromatography (DCM: MeOH = 20:1) to obtain the target product [(5R)-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazin-4-yl]-(4-fluorophenyl)methyl ketone (750 mg, yield: 67%).

[0256] MS m / z (ESI): 265.1 [M+H]. Step 4: (R)-(4-fluorophenyl)(8-methyl-3-(2-methylpyrimidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone [(5R)-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazin-4-yl]-(4-fluorophenyl) methyl ketone (100 mg, 378.37 μmol) and 2-methylpyrimidin-4-carboxylhydrazine (57.57 mg, 378.37 μmol) were dissolved in MeOH (10 mL) and stirred in an oil bath at 80 °C for 16 hours. After cooling to room temperature, the excess solvent was concentrated to obtain the crude product. The crude product was purified by preparative chromatography to obtain the target product (R)-(4-fluorophenyl)(8-methyl-3-(2-methylpyrimidin-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (18 mg, yield: 13.5%).

[0257] MS m / z (ESI): 353.1 [M+H]. Example 32 (R)-(2-(3-(difluoromethylene)pyrrolidin-1-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0258] The target product was obtained by using (R)-(2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone and 3-(difluoromethylene)pyrrolidine as starting materials, following the synthetic method in step 5 of Example 25.

[0259] MS m / z (ESI): 475.1 [M+H] Example 33 (R)-(1-(3-(difluoromethylene)pyrrolidin-1-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0260] Using (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone as a starting material, the target product was obtained by referring to the synthesis method in steps four and five of Example 25.

[0261] MS m / z (ESI): 475.1 [M+H] Example 34 (R)-(3-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0262] The target product was synthesized and resolved using methyl 5-chloro[1,3]thiazo[5,4-d]pyrimidine-2-carboxylate as the starting material, following the synthesis method described in Example 13.

[0263] MS m / z (ESI): 430.1 [M+H] Example 35 (R)-(4-Fluorophenyl)(8-Methyl-3-(5-methylthioazolo[5,4-d]pyrimidin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0264] Using trimethylcycloboroxane and (R)-(3-(5-chlorothiazo[5,4-d]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone as starting materials, the target product was synthesized and resolved according to the third step of Example 1.

[0265] MS m / z (ESI): 410.1 [M+H] Example 36 (R)-(4-Fluorophenyl)(8-Methyl-3-(5-methylthioazolo[5,4-d]thiazo-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0266] Step 1: (R)-Ethyl-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazo[5,4-d]thiazolyl-2-carboxylic acid ester The target product was obtained by referring to the synthesis method of Example 13 using diethylthiazo[5,4-d]thiazolyl-2,5-dicarboxylic acid ester as the starting material.

[0267] MS m / z (ESI): 473.1 [M+H] Step 2: (R)-(4-fluorophenyl)(8-methyl-3-(5-methylthioazolo[5,4-d]thiazo-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone References [Russian Journal of Organic Chemistry, 2007, vol. 43, # 5, p. 753 - 757] The synthesis method yields the target product through synthesis and resolution.

[0268] MS m / z (ESI): 415.1 [M+H] Example 37 (R)-(3-(6-Fluorimidazolo[1,2-b][1,2,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0269] Step 1: 1-Benzyl-3-(5-fluoro-1H-imidazol-2-yl)thiourea In a 100 mL reaction flask, 5-fluoro-1H-imidazol-2-amine (1 g, 9.89 mmol) and triethylamine (2 g, 19.79 mmol) were dissolved in dichloromethane (20 mL). Isothiocyanomethylbenzene (1.48 g, 9.89 mmol) was then slowly added at 25°C under nitrogen protection and stirred at 25°C for 3 hours. The reaction was stopped, quenched with ammonium chloride aqueous solution (10 mL), and extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to give the title product 1-benzyl-3-(5-fluoro-1H-imidazol-2-yl)thiourea (2.1 g, yield: 84.81%).

[0270] MS m / z (ESI): 251.0 [M+H]. Step 2: N-benzyl-6-fluoroimidozono[1,2-b][1,2,4]thiadiazole-2-amine In a 100 mL reaction flask, 2.1 g (8.39 mmol) of 1-benzyl-3-(5-fluoro-1H-imidazol-2-yl)thiourea was dissolved in an aqueous sodium hydroxide solution (2 M, 20 mL). Then, 4 mL of hydrogen peroxide was slowly added at 0°C. The reaction mixture was kept under nitrogen protection and stirred at 0°C for 3 hours. The reaction was stopped, and concentrated hydrochloric acid was added to neutralize the reaction. A white solid precipitated out. The solid was filtered off, dried, and the title product N-benzyl-6-fluoroimidazo[1,2-b][1,2,4]thiadiazole-2-amine (1.5 g, yield: 72.01%) was obtained.

[0271] MS m / z (ESI): 249.0 [M+H]. Step 3: 6-Fluorimidozono[1,2-b][1,2,4]thiadiazole-2-amine N-Benzyl-6-fluoroimidazolo[1,2-b][1,2,4]thiadiazole-2-amine (1.5 g, 6.04 mmol) was dissolved in 30 mL of methanol, and palladium / carbon (150 mg, 10%) was added. The mixture was purged with hydrogen three times and stirred for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title product 6-fluoroimidazolo[1,2-b][1,2,4]thiadiazole-2-amine (600 mg, yield: 62.79%).

[0272] MS m / z (ESI): 159.0 [M+1] Step 4: 2-Bromo-6-fluoroimidazole [1,2-b][1,2,4]thiadiazole 6-Fluorimidazolo[1,2-b][1,2,4]thiadiazole-2-amine (600 mg, 3.79 mmol) was slowly added to 10 mL of hydrobromic acid (40%), and the mixture was cooled to 0°C after the addition was complete. While stirring, a 30% sodium nitrite solution (314.10 mg, 4.55 mmol) was slowly added dropwise to the reaction system over 15 minutes, with the reaction temperature maintained below 5°C. Stirring continued for 20 minutes after the addition. Cuprous bromide (653.06 mg, 4.55 mmol) and 3 mL of hydrobromic acid (40%) were added to a 100 mL three-necked flask, and the mixture was stirred vigorously at room temperature. The diazonium salt solution was then slowly added to the three-necked flask. Stirring continued for 20 minutes. The reaction solution was adjusted to neutral with sodium hydroxide aqueous solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, and washed successively with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated brine solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with dichloromethane and methanol as the eluent system to give the title product 2-bromo-6-fluoroimidazole[1,2-b][1,2,4]thiadiazole (400 mg, yield: 47.49%).

[0273] MS m / z (ESI):221.9, 223.9 [M+1] Step 5: 6-Fluorimidozono[1,2-b][1,2,4]thiadiazole-2-carboxylic acid methyl ester A mixture of 2-bromo-6-fluoroimidazole[1,2-b][1,2,4]thiadiazole (400 mg, 1.8 mmol), triethylamine (911.5 mg, 9.01 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (131.67 mg, 180.0 μmol), and methanol (10 mL) was substituted three times with carbon monoxide and stirred at 100 °C for 4 hours under carbon monoxide protection. The reaction was stopped, quenched with water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using a dichloromethane and methanol eluent system to obtain the title product, methyl 6-fluoroimidazole[1,2-b][1,2,4]thiadiazole-2-carboxylate (200 mg, yield: 55.18%).

[0274] MS m / z (ESI): 202.0 [M+1] Step 6: (R)-(3-(6-fluoroimidazolo[1,2-b][1,2,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to the synthesis in Example 13, the title product (R)-(3-(6-fluoroimidazolo[1,2-b][1,2,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0275] MS m / z (ESI): 402.0 [M+1] The following examples are prepared with reference to Example 37.

[0276] Example 42 (R) –(3-(3-fluoro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0277] Step 1: 4-Amino-5-fluoro-4H-1,2,4-triazol-3-thiol In a 100 mL reaction flask, 5-fluoro-1,3,4-oxadiazol-2-thiol (1 g, 8.33 mmol) was dissolved in ethanol (20 mL), and then hydrazine hydrate (625.23 mg, 12.49 mmol) was slowly added at 25°C. The reaction mixture was kept under nitrogen protection and stirred at 80°C for 8 hours. The reaction was stopped, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluents to give the title product 4-amino-5-fluoro-4H-1,2,4-triazol-3-thiol (900 mg, yield: 80.59%).

[0278] MS m / z (ESI): 135.0 [M+H]. Step 2: Methyl 3-fluoro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6-carboxylate In a 100 mL reaction flask, 4-amino-5-fluoro-4H-1,2,4-triazol-3-thiol (900 mg, 6.71 mmol) was dissolved in pyridine (10 mL), and then methyl 2-chloro-2-oxoacetate (904.17 mg, 7.38 mmol) was slowly added. The reaction mixture was kept under nitrogen protection and stirred at 80°C for 8 hours. The reaction was stopped, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluents to give the title product methyl 3-fluoro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6-carboxylic acid (600 mg, yield: 44.23%).

[0279] MS m / z (ESI): 203.0 [M+H]. Step 3: (R) –(3-(3-fluoro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to the synthesis in Example 13, the title product (R) –(3-(3-fluoro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-8-methyl-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0280] MS m / z (ESI): 403.0 [M+1] Example 43 (R)-(3-(3-chloro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0281] Referring to the synthesis in Example 42, the title product (R)-(3-(3-chloro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-8-methyl-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0282] MS m / z (ESI): 419.0 [M+1] Example 44 (R) –(3-(6-chloroimidozolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0283] Step 1: 2-(2-imino-5-(methoxycarbonyl)-1,3,4-thiadiazole-3(2H)-yl)acetic acid Methyl 5-amino-1,3,4-thiadiazole-2-carboxylic acid (1 g, 6.28 mmol) was dissolved in ethanol (20 mL) in a 100 mL reaction flask. Then, 2-bromoacetic acid (872.99 mg, 6.28 mmol) was slowly added at 25°C. The reaction was carried out under nitrogen protection and stirred at 80°C for 8 hours. The reaction was stopped, cooled to room temperature, and a solid precipitated. The solid was filtered to give the title product 2-(2-imino-5-(methoxycarbonyl)-1,3,4-thiadiazole-3(2H)-yl)acetic acid (800 mg, yield: 58.62%).

[0284] MS m / z (ESI): 218.0 [M+H]. Step 2: Methyl 6-cloimidazole[2,1-b][1,3,4]thiadiazole-2-carboxylate In a 100 mL reaction flask, 2-(2-imino-5-(methoxycarbonyl)-1,3,4-thiadiazole-3(2H)-yl)acetic acid (800 mg, 3.68 mmol) was dissolved in phosphorus oxychloride (10 mL). The reaction solution was protected with nitrogen and stirred at 90°C for 2 hours. The reaction was stopped, cooled to room temperature, concentrated, and the reaction solution was adjusted to neutral with sodium bicarbonate aqueous solution. It was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to obtain the title product. The residue was filtered to obtain the title product 6-chloroimidazolo[2,1-b][1,3,4]thiadiazole-2-carboxylic acid methyl ester (600 mg, yield: 74.85%).

[0285] MS m / z (ESI): 218.0 [M+H]. Step 3: R) –(3-(6-chloroimidozolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to the synthesis in Example 13, the title product (R) – (3-(6-chloroimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0286] MS m / z (ESI): 418.0 [M+1] Example 45 (R) –(3-(6-Fluorimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0287] Step 1: Methyl 6-bromoimidazole[2,1-b][1,3,4]thiadiazole-2-carboxylate Referring to the second step of Example 44 and replacing phosphorus oxychloride with phosphorus tribromooxychloride, the title product 6-bromoimidazole[2,1-b][1,3,4]thiadiazole-2-carboxylic acid methyl ester was obtained.

[0288] MS m / z (ESI): 261.9, 263.9 [M+H]. Step 2: Methyl 6-hydroxyimidazo[2,1-b][1,3,4]thiadiazole-2-carboxylate In a 100 mL reaction flask, methyl 6-bromoimidazolo[2,1-b][1,3,4]thiadiazole-2-carboxylic acid (600 mg, 2.29 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (90.93 mg, 114.47 μmol) were dissolved in dioxane (10 mL). Potassium hydroxide (256.89 mg, 4.58 mmol) was then added at 25°C. The reaction mixture was kept under nitrogen protection and stirred at 100°C for 3 hours. The reaction was stopped, quenched with an aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using a dichloromethane and methanol eluent system to give the title product methyl 6-hydroxyimidazo[2,1-b][1,3,4]thiadiazole-2-carboxylate (220 mg, yield: 48.25%).

[0289] MS m / z (ESI): 200.0 [M+H]. Step 3: Methyl 6-fluoroimidozono[2,1-b][1,3,4]thiadiazole-2-carboxylate 220 mg (1.1 mmol) of 6-hydroxyimidazo[2,1-b][1,3,4]thiadiazole-2-carboxylic acid methyl ester was dissolved in acetonitrile (5 mL), and DAST (178.03 mg, 1.1 mmol) was slowly added at 25 °C. The reaction mixture was kept under nitrogen protection and stirred at 90 °C for 3 hours. The reaction was stopped, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product 6-fluoroimidazo[2,1-b][1,3,4]thiadiazole-2-carboxylic acid methyl ester (150 mg, yield: 67.51%).

[0290] MS m / z (ESI): 202.0 [M+1] Step 4: (R) –(3-(6-Fluorimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to the synthesis in Example 13, the title product (R) – (3-(6-fluoroimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0291] MS m / z (ESI): 402.0 [M+1] Example 46 (R) –(3-(5-chloroimidozolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0292] Step 1: 2-Bromo-5-chloroimidazole[2,1-b][1,3,4]thiadiazole 2-Bromoimidazolo[2,1-b][1,3,4]thiadiazole (1 g, 4.90 mmol) was dissolved in DMF (20 mL) in a 100 mL reaction flask. Then, NCS (654.42 mg, 4.90 mmol) was slowly added at 25°C. The reaction mixture was kept under nitrogen protection and stirred at 20°C for 8 hours. The reaction was stopped, quenched with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (10 mL × 2), saturated ammonium chloride solution (10 mL × 2), and saturated brine (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product 2-bromo-5-chloroimidazolo[2,1-b][1,3,4]thiadiazole (650 mg, yield: 55.61%).

[0293] MS m / z (ESI): 237.8, 239.8 [M+H]. Step 2: (R) –(3-(5-chloroimidozolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to the synthesis of Example 37, the title product (R) – (3-(5-chloroimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0294] MS m / z (ESI): 418.0 [M+1] Example 47 (R) –(3-(5-Fluorimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0295] Referring to the synthesis of Examples 45 and 46, the title product R) –(3-(5-fluoroimidazolo[2,1-b][1,3,4]thiadiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0296] MS m / z (ESI): 402.0 [M+1] Example 48 (R)-(3-(5-chloroimidozolo[2,1-b]thiazo-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0297] Using methyl 5-chloroimidozolo[2,1-b]thiazol-2-carboxylate as a raw material, the title product ((R)-(3-(5-chloroimidozolo[2,1-b]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained with reference to Example 13.

[0298] MS m / z (ESI): 417.0 [M+1] Example 49 (R)-(3-(6-chloroimidozolo[2,1-b]thiazo-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0299] Step 1: Methyl-6-chloroimidozono[2,1-b]thiazole-2-carboxylic acid ester Using methylimidazo[2,1-b]thiazole-2-carboxylate as a raw material, and referring to the literature [Organic Letters, 2022, vol. 24, # 21, p. 3834 - 3838], the target product methyl-6-chloroimidazo[2,1-b]thiazole-2-carboxylate was obtained.

[0300] MS m / z (ESI): 216.9 [M+H]. Step 2: 6-Clonimidozono[2,1-b]thiazol-2-carbamoylhydrazine Using the methyl 6-chloroimidazolo[2,1-b]thiazole-2-carboxylic acid ester obtained in the previous step as a starting material, refer to the literature. [European Journal of Medicinal Chemistry, 2021, vol. 209, art. no. 112944] The target product 6-chloroimidazole[2,1-b]thiazole-2-formylhydrazide was obtained.

[0301] MS m / z (ESI): 216.9 [M+H]. Step 3: (R)-(3-(6-chloroimidozolo[2,1-b]thiazo-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Using 6-chloroimidazolo[2,1-b]thiazol-2-carboxylhydrazine and (R)-(5-ethoxy-6-methyl-3,6-dihydropyrazin-1(2H)-yl)(4-fluorophenyl) methyl ketone as raw materials, and referring to Example 31, the target product (R)-(3-(6-chloroimidazolo[2,1-b]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was finally obtained.

[0302] MS m / z (ESI): 417.1 [M+H]. Example 50 (R)-(3-(6-Fluorimidazolo[2,1-b]thiazo-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0303] Step 1: Methyl 6-fluoroimidozono[2,1-b]thiazole-2-carboxylate Using imidazo[2,1-b]thiazole-2-carboxylic acid methyl ester as a raw material, and referring to PROVINCIAL HEALTH SERVICESAUTHORITY - WO2021 / 50059, 2021, A1, the target product 6-fluoroimidazo[2,1-b]thiazole-2-carboxylic acid methyl ester was obtained.

[0304] MS m / z (ESI): 201.0 [M+H]. Step 2: (R)-(3-(6-fluoroimidozolo[2,1-b]thiazo-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Using methyl 6-fluoroimidozolo[2,1-b]thiazol-2-carboxylate as a raw material, and referring to Example 31, the target product (R)-(3-(6-fluoroimidozolo[2,1-b]thiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was finally obtained.

[0305] MS m / z (ESI): 401.1 [M+H]. Example 51 (R)-(3-(3-chloroimidazolo[1,2-a]pyrimidin-7-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0306] Using imidazo[1,2-a]pyrimidin-7-carboxylic acid methyl ester as a raw material, and referring to Example 49, the target product (R)-(3-(3-chloroimidazo[1,2-a]pyrimidin-7-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was finally obtained.

[0307] MS m / z (ESI): 412.1 [M+H]. Example 52 (R)-(3-(2-chloroimidozolo[1,2-a]pyrimidin-7-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0308] Using methyl 2-amino-4-pyrimidinecarboxylate as the starting material, refer to [Organic Letters, 2010, vol. 12, # 3, p. 412 - 415] And in Example 37, the target product (R)-(3-(2-chloroimidazolo[1,2-a]pyrimidin-7-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was finally obtained. MS m / z (ESI): 412.1 [M+H] The following examples are prepared with reference to other examples.

[0309] Example 61 (R)-(4-Fluorophenyl)(3-(3-Fluoropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0310] Step 1: Methyl-3-flupyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester Under a nitrogen atmosphere, 2.40 g (6.77 mmol) of 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo2,2,2-octanebis(tetrafluoroborate) salt was added to a mixture of methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (1 g, 5.64 mmol) in acetonitrile (20 mL) and water (20 mL). The mixture was stirred at 25 °C for 4 hours. The reaction solution was diluted with saturated brine (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain methyl-3-fluoropyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (350 mg, 1.79 mmol, yield: 31.77%). MS m / z (ESI): 196.0 [M+H]. Step 2: (R)-(4-fluorophenyl)(3-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(4-fluorophenyl)(3-(3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone was obtained.

[0311] MS m / z (ESI): 396.1 [M+H]. Example 62 (R)-(3-(3-chloropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0312] Step 1: Methyl-3-chloropyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester Under a nitrogen atmosphere, N-chlorosuccinimide (753.74 mg, 5.64 mmol) was added to a solution of methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (1 g, 5.64 mmol) in dichloromethane (20 mL), and the mixture was stirred at 25 °C for 4 hours. The reaction solution was diluted with saturated brine (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain methyl-3-chloropyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (600 mg, 2.84 mmol, yield: 50.23%). MS m / z (ESI): 212.0 [M+H]. Step 2: (R)-(3-(3-chloropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(3-(3-chloropyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0313] MS m / z (ESI): 412.1 [M+H]. Example 63 (R)-(4-fluorophenyl)(8-methyl-3-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone

[0314] Step 1: (R)-(4-fluorophenyl)(8-methyl-3-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone was obtained with reference to Example 64.

[0315] MS m / z (ESI): 393.2 [M+H]. Example 64 (R)-(4-Fluorophenyl)(8-Methyl-3-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone

[0316] Step 1: (R)-(4-fluorophenyl)(8-methyl-3-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (27.99 mg, 24.22 μmol) was added to a mixed solution of [(8R)-3-(2-chloro-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-fluorophenyl)methyl ketone (100 mg, 242.24 μmol), trimethylepoxyborane (91.23 mg, 726.73 μmol), and potassium carbonate (100.44 mg, 726.73 μmol) in dioxane (5 mL). After purging with nitrogen, the reaction mixture was heated to 100 °C and stirred for 8 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% formic acid)-acetonitrile) to give (R)-(4-fluorophenyl)(8-methyl-3-(2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone (25 mg, 63.71 μmol, yield: 26.30%).

[0317] MS m / z (ESI): 393.2 [M+H]. Example 66 (R)-(3-(6-Fluorimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0318] Step 1: Methyl-6-fluoroimidazole[1,5-a]pyrimidine-2-carboxylic acid ester The methyl 6-fluoroimidazole [1,5-a]pyrimidine-2-carboxylic acid ester was obtained according to Example 58.

[0319] MS m / z (ESI): 196.0 [M+H]. Step 2: Methyl-6-fluoroimidozono[1,5-a]pyrimidine-2-carboxylic acid ester Referring to steps 2 and 4 of Example 31, (R)-(3-(6-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0320] MS m / z (ESI): 396.1 [M+H]. Example 67 (R)-(3-(6-Fluorimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0321] Step 1: Methyl-6-clomizo[1,5-a]pyrimidine-2-carboxylic acid ester The methyl 6-chloroimidazole [1,5-a]pyrimidine-2-carboxylic acid ester was obtained with reference to Example 52.

[0322] MS m / z (ESI): 212.0 [M+H]. Step 2: (R)-(3-(6-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(3-(6-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0323] MS m / z (ESI): 412.1 [M+H]. Example 68 (R)-(3-(8-fluoroimidazo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0324] Step 1: Methyl 8-fluoroimidazole [1,5-a]pyrimidine-2-carboxylic acid ester Referring to Example 61, the first step yielded methyl 8-fluoroimidazole [1,5-a]pyrimidine-2-carboxylic acid ester.

[0325] MS m / z (ESI): 196.0 [M+H]. Step 2: (R)-(3-(8-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(3-(8-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0326] MS m / z (ESI): 396.1 [M+H]. Example 69 (R)-(3-(8-chloroimidozolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0327] Step 1: Methyl-8-clomizo[1,5-a]pyrimidine-2-carboxylic acid ester Referring to Example 62, the first step yielded methyl 8-chloroimidazole [1,5-a]pyrimidine-2-carboxylic acid ester.

[0328] MS m / z (ESI): 212.0 [M+H]. Step 2: (R)-(3-(8-fluoroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(3-(8-chloroimidazolo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0329] MS m / z (ESI): 412.1 [M+H]. Example 70 (R)-(3-(6,8-difluoroimidazo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0330] Step 1: (R)-(3-(6,8-difluoroimidazo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone Referring to Example 61, the first step yielded (R)-(3-(6,8-difluoroimidazo[1,5-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone.

[0331] MS m / z (ESI): 414.1 [M+H]. Example 71 ((8R)-3-(1-(1H-pyrazol-1-yl)ethyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0332] Step 1: ((8R)-3-(1-(1H-pyrazol-1-yl)ethyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone Referring to steps two and four of Example 31, ((8R)-3-(1-(1H-pyrazol-1-yl)ethyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained. Chiral resolution yielded ((R)-3-((S)-1-(1H-pyrazol-1-yl)ethyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone and ((R)-3-((R)-1-(1H-pyrazol-1-yl)ethyl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone.

[0333] MS m / z (ESI): 355.2 [M+H]. Example 72 (6-Fluoro-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)methyl ketone

[0334] Step 1: (5-bromo-4-methyl-1,2,4-triazol-3-yl)-(6-fluoro-1-methyl-3,4-dihydro-1H-isoquinoline-2-yl) methyl ketone Under a nitrogen atmosphere, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (915.71 mg, 2.43 mmol) was added to a mixed solution of 5-bromo-4-methyl-1,2,4-triazol-3-carboxylic acid (500 mg, 2.43 mmol), 6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (400.99 mg, 2.43 mmol), and N,N-diisopropylethylamine (313.70 mg, 2.43 mmol, 422.78 μL) in N,N-dimethylformamide (10 mL). After purging with nitrogen, the reaction mixture was heated to 40 °C and stirred for 5 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% formic acid)-acetonitrile) to give (5-bromo-4-methyl-1,2,4-triazol-3-yl)-(6-fluoro-1-methyl-3,4-dihydro-1H-isoquinoline-2-yl) methyl ketone (450 mg, 1.27 mmol, yield: 52.49%).

[0335] MS m / z (ESI): 353.0 [M+H]. Step 2: (6-fluoro-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl) methyl ketone Under a nitrogen atmosphere, tetraphenylphosphine palladium (102.22 mg, 88.46 μmol) was added to a mixed solution of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1,2,4-thiadiazole (200 mg, 884.55 μmol), (5-bromo-4-methyl-1,2,4-triazol-3-yl)-(6-fluoro-1-methyl-3,4-dihydro-1H-isoquinoline-2-yl) methyl ketone (312.41 mg, 884.55 μmol), and potassium carbonate (366.75 mg, 2.65 mmol) in water (12 mL) and dioxane (12 mL). After purging with nitrogen, the reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% formic acid)-acetonitrile) to give (6-fluoro-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl) methyl ketone, which was chirally resolved to give (R)-(6-fluoro-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl) methyl ketone. Isoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl) methyl ketone and (S)-(6-fluoro-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)(4-methyl-5-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl) methyl ketone.

[0336] MS m / z (ESI): 373.1 [M+H]. Example 73 (R)-(4-Fluorophenyl)(3-(6-Fluoropyrrolo[1,2-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0337] Step 1: Methyl 6-fluoropyrrolo[1,2-a]pyrimidine-2-carboxylate 5-Fluoro-1H-pyrrole-2-amine (1 g, 9.99 mmol) was dissolved in acetic acid (30 mL) under nitrogen protection and cooled in an ice-water bath. Methyl 3-(1,3-dioxolane-2-yl)-2-oxopropionate (1.74 g, 9.99 mmol) was then added. The mixture was heated at 110 °C. o The mixture was stirred at C for 12 hours. The mixture was evaporated to dryness to remove the solvent. The reaction was quenched with saturated sodium bicarbonate aqueous solution (150 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product (1.4 g, yield: 72.17%).

[0338] MS m / z (ESI): 195.1 [M+H]. Step 2: (R)-(4-fluorophenyl)(3-(6-fluoropyrrolo[1,2-a]pyrimidin-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone The target product was obtained with reference to Example 31.

[0339] MS m / z (ESI): 395.1 [M+H]. The following examples are prepared with reference to other examples.

[0340] Example 89 (R)-(4-Fluorophenyl)(8-Methyl-3-(3-methylimidazo[1,2-b]pyridazin-6-yl)-5,6-dihydro-[1,2,4]triazo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0341] Step 1: methyl 3-methylimidazo[1,2-b]pyridazine-6-carboxylic acid ester The title product, methyl 3-methylimidazo[1,2-b]pyridazine-6-carboxylic acid ester, was obtained by synthesizing according to step 4 of Example 37.

[0342] MS m / z (ESI): 192.0 [M+1] Step 2: (R)-(4-fluorophenyl)(8-methyl-3-(3-methylimidazo[1,2-b]pyridazin-6-yl)-5,6-dihydro-[1,2,4]triazo[4,3-a]pyrazin-7(8H)-yl) methyl ketone Referring to Example 13, the title product (R)-(4-fluorophenyl)(8-methyl-3-(3-methylimidazo[1,2-b]pyridazin-6-yl)-5,6-dihydro-[1,2,4]triazo[4,3-a]pyrazin-7(8H)-yl) methyl ketone was obtained.

[0343] MS m / z (ESI): 392.1 [M+1] Example 93 (R)-(3-([1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0344] Step 1: (R)-(3-([1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone Referring to steps 2 and 4 of Example 31, (R)-(3-([1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone was obtained.

[0345] MS m / z (ESI): 379.2 [M+H]. Example 94 (16R)-11-fluoro-16-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-14H,16H-5,15-methylbenzo[b][1,2,4]triazol[3,4g][1]oxa[5,8]diazacyclododecane-14-one

[0346] Step 1: 4-(4-fluoro-2-hydroxybenzoyl)-6-(3-hydroxypropyl)-3-methylpiperazin-2-one The target product was synthesized according to steps three and four of Example 16.

[0347] MS m / z (ESI): 311.1 [M+H]. Step 2: 13-Fluoro-8-methyl-3,4,5,6-tetrahydro-2H,10H-5,9-methylbenzo[b][1]oxa[5,8]diazacyclododecane-7,10(8H)-dione The target product was synthesized in the first step of Example 15.

[0348] MS m / z (ESI): 293.1 [M+H]. Step 3: (16R)-11-fluoro-16-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-14H,16H-5,15-methylbenzo[b][1,2,4]triazol[3,4g][1]oxa[5,8]diazacyclododecane-14-one The target product was synthesized according to steps two through four of Example 13.

[0349] MS m / z (ESI): 415.1 [M+H]. Example 95 ((3R)-3,9-dimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7a,8,10-heptaazabenzo[cd]cyclopenta[h]aza-4(3H)-yl)(4-fluorophenyl)methyl ketone

[0350] Step 1: 4-(4-fluorobenzoyl)-6-(2-hydroxyethyl)-3-methylpiperazin-2-one The target product was synthesized in the first step of Example 94.

[0351] MS m / z (ESI): 281.1 [M+H]. Step 2: (4-Fluorophenyl)(5-(2-hydroxyethyl)-8-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone The target product was synthesized in step three of Example 94.

[0352] MS m / z (ESI): 386.2 [M+H]. Step 3: (3,9-Dimethyl-5,5a,6,7-Tetrahydro-1,2,2a1,4,7a,8,10-Heptaazabenzo[cd]cyclopenta[h]aza-4(3H)-yl)(4-fluorophenyl)methyl ketone The target product was synthesized in the second step of Example 94.

[0353] MS m / z (ESI): 368.2 [M+H]. Step 4: ((3R)-3,9-dimethyl-5,5a,6,7-tetrahydro-1,2,2a1,4,7a,8,10-heptaazabenzo[cd]cyclopenta[h]aza-4(3H)-yl)(4-fluorophenyl)methyl ketone The target product was obtained through chiral separation.

[0354] MS m / z (ESI): 368.2 [M+H]. Example 96 (28R)-44-fluoro-13,28-dimethyl-25,26,27,28-tetrahydro-11H-5-oxa-2(3,7)-[1,2,4]triazolo[4,3-a]pyrazine-1(5,1)-triazol-4(1,2)-benzocyclononane-3-one

[0355] Step 1: (R)-4-(4-fluoro-2-hydroxybenzoyl)-3-methylpiperazin-2-one The target product was synthesized in step four of Example 16.

[0356] MS m / z (ESI): 253.1 [M+H]. Step 2: (R)-(4-fluoro-2-hydroxyphenyl)(8-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methyl ketone The target product was synthesized in the second step of Example 95.

[0357] MS m / z (ESI): 358.1 [M+H]. Step 3: (28R)-44-fluoro-13,28-dimethyl-25,26,27,28-tetrahydro-11H-5-oxa-2(3,7)-[1,2,4]triazolo[4,3-a]pyrazine-1(5,1)-triazol-4(1,2)-benzocyclononane-3-one The target product was synthesized according to the third and fourth steps of Example 95.

[0358] MS m / z (ESI): 412.2 [M+H]. Example 98 (R)-(4-Fluorophenyl)(7-Methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)methyl ketone

[0359] The target product was obtained using (R)-3-hydroxy-7-methyl-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylic acid tert-butyl ester as a starting material, referring to Example 1.

[0360] MS m / z (ESI): 359.1 [M+H]. Example 99 1-(6-fluoro-1-methyl-1H-indazol-3-yl)-4-(3-methyl-1,2,4-thiadiazole-5-carbonyl)pyridine-2(1H)-one

[0361] Step 1: 1-(6-fluoro-1-methyl-1H-indazol-3-yl)pyridin-2(1H)-one The target product was obtained by referring to the third step of Example 26, using 3-bromo-6-fluoro-1-methyl-1H-indazole and pyridine-2(1H)-one as raw materials.

[0362] MS m / z (ESI): 244.1 [M+H]. Step 2: 1-(6-fluoro-1-methyl-1H-indazol-3-yl)-4-(3-methyl-1,2,4-thiadiazole-5-carbonyl)pyridine-2(1H)-one 1-(6-fluoro-1-methyl-1H-indazol-3-yl)pyridin-2(1H)-one (0.15 g, 616.69 μmol) and 3-methyl-1,2,4-thiadiazole-5-carbonyl chloride (100.27 mg, 616.69 μmol) were dissolved in DCE (6 mL), and aluminum trichloride (246.69 mg, 1.85 mmol) was added under nitrogen protection. The mixture was then heated at 80 °C. o The reaction mixture was stirred at C for 2 hours. The reaction solution was quenched with saturated saline (5 mL), the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography to obtain the product (93 mg, yield: 40.83%).

[0363] MS m / z (ESI): 370.1 [M+H]. Example 100 (4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperazin-1-yl)(3-methyl-1,2,4-thiadiazol-5-yl)methyl ketone

[0364] Step 1: (3-Methyl-1,2,4-thiadiazol-5-yl)(piperazin-1-yl)methyl ketone The target product was obtained by referring to step 5 of Example 1.

[0365] MS m / z (ESI): 213.1 [M+H]. Step 2: (4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperazin-1-yl)(3-methyl-1,2,4-thiadiazol-5-yl)methyl ketone The target product was obtained by referring to the third step of Example 26.

[0366] MS m / z (ESI): 361.1 [M+H]. Example 101 (6-(6-fluoro-1-methyl-1H-indazol-3-yl)pyridin-3-yl)(3-methyl-1,2,4-thiadiazol-5-yl)methyl ketone

[0367] Step 1: 3-(5-chloropyridin-2-yl)-6-fluoro-1-methyl-1H-indazole At room temperature, 3-bromo-6-fluoro-1-methyl-indazole (0.20 g, 0.87 mmol), (5-chloro-2-pyridyl)boronic acid (137.41 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium (100.94 mg, 0.087 mmol), and sodium carbonate (277.64 mg, 2.62 mmol) were dissolved in water (1 mL) and ethanol (4 mL), purged with nitrogen, heated to 80°C, and reacted for 14 hours. The mixture was then cooled to room temperature, and the reaction was considered complete by LC-MS. The solution was evaporated to dryness, and the residue was directly separated by Flash column chromatography to give 3-(5-chloropyridin-2-yl)-6-fluoro-1-methyl-1H-indazole (0.10 g, yield: 43.8%).

[0368] MS m / z (ESI): 262.1 [M+1]. Step 2: (6-(6-fluoro-1-methyl-1H-indazol-3-yl)pyridin-3-yl)(3-methyl-1,2,4-thiadiazol-5-yl)methyl ketone At -78 °C, 3-(5-chloro-2-pyridyl)-6-fluoro-1-methyl-indazole (0.10 g, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL), and nitrogen was purged. Then, diisopropylaminolithium (1.0 M / tetrahydrofuran, 0.46 mL, 0.46 mmol) was added dropwise, and the mixture was stirred at -78 °C for 30 minutes. Then, a tetrahydrofuran solution (5 mL) of N-methoxy-N,3-dimethyl-1,2,4-thiadiazole-5-carboxamide (85.85 mg, 0.46 mmol) was added dropwise, and the mixture was stirred at -78 °C and allowed to cool to room temperature. LCMS indicated the formation of the target product. The reaction solution was quenched with saturated ammonium chloride solution (5 mL), separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain (6-(6-fluoro-1-methyl-1H-indazol-3-yl)pyridin-3-yl)(3-methyl-1,2,4-thiadiazol-5-yl) methyl ketone (0.05 g, yield: 37%).

[0369] MS m / z (ESI): 354.1 [M+1]. Example 102 (R)-(4-Fluorophenyl)(2-Methyl-4-((3-Methyl-1,2,4-thiadiazol-5-yl)methyl)piperazin-1-yl)methyl ketone

[0370] Step 1: tert-butyl(R)-4-(4-fluorobenzoyl)-3-methylpiperazine-1-carboxylic acid ester At 0°C, tert-butyl(3R)-3-methylpiperazine-1-carboxylic acid ester (0.20 g, 1 mmol) was dissolved in dichloromethane (5 mL), followed by the dropwise addition of 4-fluorobenzoyl chloride (174.17 mg, 1.10 mmol) and triethylamine (0.30 g, 3.00 mmol). The mixture was stirred in an ice bath for 2 hours, and the reaction was considered complete by LCMS. The reaction solution was diluted with dichloromethane (15 mL), washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give tert-butyl(R)-4-(4-fluorobenzoyl)-3-methylpiperazine-1-carboxylic acid ester (0.25 g, yield: 77.7%).

[0371] MS m / z (ESI): 323.2 [M+1]. Step 2: (R)-(4-fluorophenyl)(2-methylpiperazin-1-yl)methyl ketone Under ice bath conditions, tert-butyl(R)-4-(4-fluorobenzoyl)-3-methylpiperazine-1-carboxylic acid ester (0.25 g, 0.78 mmol) was dissolved in dichloromethane (5 mL), and then dioxane hydrochloride (4.0 M, 2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by LCMS. The solution was evaporated to dryness, and the residue was dissolved in ethyl acetate (15 mL). The solution was then washed with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine solution (15 mL × 2) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give tert-butyl(R)-4-(4-fluorobenzoyl)-3-methylpiperazine-1-carboxylic acid ester (0.15 g, yield: 87%).

[0372] MS m / z (ESI): 223.1 [M+1]. Step 3: (R)-(4-fluorophenyl)(2-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)piperazin-1-yl)methyl ketone At 0°C, (R)-(4-fluorophenyl)(2-methylpiperazin-1-yl) methyl ketone (0.05 g, 0.22 mmol) and 3-methyl-1,2,4-thiadiazole-5-carboxaldehyde (31.71 mg, 0.25 mmol) were dissolved in dichloromethane (3 mL), and then acetic acid (0.2 mL) was added dropwise. The mixture was stirred at room temperature for 20 minutes, and then sodium cyanoborohydride (21.21 mg, 0.34 mmol) was added. The mixture was stirred overnight at room temperature, and the reaction was indicated to be complete by LCMS. The reaction solution was diluted with dichloromethane (15 mL), then washed successively with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by thin-layer chromatography to obtain (R)-(4-fluorophenyl)(2-methyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)piperazin-1-yl)methyl ketone (0.03 g, yield: 39.9%).

[0373] MS m / z (ESI): 335.1 [M+1]. Example 103 (R)-(4-Fluorophenyl)(2-Methyl-4-((2-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)piperazin-1-yl)methyl ketone

[0374] Using (R)-(4-fluorophenyl)(2-methylpiperazin-1-yl) ketone and 2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-carboxaldehyde as raw materials, (R)-(4-fluorophenyl)(2-methyl-4-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)piperazin-1-yl) was obtained in step 3 of Example 102.

[0375] MS m / z (ESI): 368.2 [M+1]. Example 104 (4-Fluorophenyl)((2R)-2-methyl-4-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)piperidin-1-yl)methyl ketone

[0376] Step 1: (R)-1-(4-fluorobenzoyl)-2-methylpiperidin-4-one The target product was obtained by referring to step 5 of Example 1.

[0377] MS m / z (ESI): 236.1 [M+H]. Step 2: (R,E)-(4-fluorophenyl)(2-methyl-4-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methylene)piperidin-1-yl)methyl ketone The target product was obtained by referring to the synthesis method of patent US2014 / 5103, using 2-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxaldehyde and (R)-1-(4-fluorobenzoyl)-2-methylpiperidin-4-one as raw materials.

[0378] MS m / z (ESI): 365.2 [M+H]. Step 3: (4-Fluorophenyl)((2R)-2-methyl-4-((2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methyl)piperidin-1-yl)methyl ketone The target product was obtained by referring to the second step of Example 26.

[0379] MS m / z (ESI): 367.2 [M+H]. Example 105 (R)-(4-fluorophenyl)(2-methyl-4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperazin-1-yl)methyl ketone

[0380] The mixture of (R)-(4-fluorophenyl)(2-methylpiperazin-1-yl) methyl ketone (100 mg, 449.92 μmol), 5-bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (95.40 mg, 449.92 μmol), cesium carbonate (293.18 mg, 899.83 μmol), Pd2dba3 (41.20 mg, 44.99 μmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (52.07 mg, 89.98 μmol), and 1'4-Dioxane (5 mL) was purged with nitrogen three times and then stirred at 100°C for 3 hours under nitrogen protection. The reaction was stopped, and the reaction was quenched by adding ammonium chloride aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with dichloromethane and methanol as the eluent system to give the title product (R)-(4-fluorophenyl)(2-methyl-4-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)piperazin-1-yl) methyl ketone (35 mg, yield: 22.01%).

[0381] MS m / z (ESI): 354.1 [M+H]. Example 109 (R)-(4-fluorophenyl)(2-methyl-4-(2-methylpyridino[3,4-d]pyrimidin-8-yl)piperazin-1-yl)methyl ketone

[0382] Step 1: (R)-(4-(2-chloropyridino[3,4-d]pyrimidin-8-yl)-2-methylpiperazin-1-yl)(4-fluorophenyl)methyl ketone The title product (R)-(4-(2-chloropyridino[3,4-d]pyrimidin-8-yl)-2-methylpiperazin-1-yl)(4-fluorophenyl) methyl ketone was obtained by the synthesis of the product according to Example 105.

[0383] MS m / z (ESI): 386.1 [M+H]. Step 2: (R)-(4-fluorophenyl)(2-methyl-4-(2-methylpyridino[3,4-d]pyrimidin-8-yl)piperazin-1-yl)methyl ketone The mixture of (R)-(4-(2-chloropyrido[3,4-d]pyrimidin-8-yl)-2-methylpiperazin-1-yl)(4-fluorophenyl) methyl ketone (100 mg, 259.18 μmol), trimethylcycloboroxane (65.07 mg, 518.37 μmol), cesium carbonate (168.89 mg, 518.37 μmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (21.17 mg, 25.92 μmol), 1',4-Dioxane (5 mL), and water (2 mL) was purged with nitrogen three times and then stirred at 80 °C for 10 hours under nitrogen protection. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol as the eluent system to give the title product (R)-(4-fluorophenyl)(2-methyl-4-(2-methylpyridino[3,4-d]pyrimidin-8-yl)piperazin-1-yl) methyl ketone (20 mg, yield: 21.12%).

[0384] MS m / z (ESI): 366.1 [M+H]. Example 110 4-Fluoro-N-(5-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl)benzamide

[0385] The target product was obtained by following the synthesis method in Example 1, using 5-bromo-2-pyridylamine as the starting material.

[0386] MS m / z (ESI): 315.1 [M+H]. Example 111 4-Fluoro-N-(4-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)cyclohexyl)benzamide

[0387] The target product was obtained by referring to the synthesis method of Example 104.

[0388] MS m / z (ESI): 334.1 [M+H]. Example 112 4-Fluoro-N-((8S)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzamide

[0389] Using (3S)-4-amino-3-methylpiperidin-2-one as the starting material, and referring to Example 37, the target product 4-fluoro-N-((8S)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzamide was finally obtained.

[0390] MS m / z (ESI): 373.1 [M+H] Example 113 (4-Fluorophenyl)(4-((2-methylpyrimidin-4-yl)methyl)-3-phenylpiperidin-1-yl)methyl ketone

[0391] Starting with tert-butyl-5-bromo-4-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid ester, and referring to Example 37 and BASILEA PHARMACEUTICA INTERNATIONAL - WO2019 / 113542, 2019, A1, the target product (4-fluorophenyl)(4-((2-methylpyrimidin-4-yl)methyl)-3-phenylpiperidin-1-yl) methyl ketone was finally obtained.

[0392] MS m / z (ESI): 390.2 [M+H] Example 114 (4-(benzyl(2-methylpyrimidin-4-yl)amino)piperidin-1-yl)(4-fluorophenyl)methyl ketone

[0393] Using tert-butylpiperidin-4-ylcarbamate as the starting material, and referring to Example 37, the target product (4-(benzyl(2-methylpyrimidin-4-yl)amino)piperidin-1-yl)(4-fluorophenyl)methyl ketone was finally obtained.

[0394] MS m / z (ESI): 405.2 [M+H] Example 115 (R)-(4-fluorophenyl)(2-methyl-4-(3-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)piperazin-1-yl)methyl ketone

[0395] Step 1: 2-Chloro-3-(1-Methylimidazol-4-yl)pyridine Under a nitrogen atmosphere, sodium carbonate (398.39 mg, 3.76 mmol) was added to a mixture of 1,4-dioxane (10 mL) and water (2.5 mL) of 2-chloro-3-iodopyridine (300 mg, 1.25 mmol), (1-methylimidazol-4-yl)boronic acid (157.77 mg, 1.25 mmol), and tetraphenylphosphine palladium (144.78 mg, 125.29 μmol). After purging with nitrogen, the reaction mixture was heated to 60 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography with an eluent system (petroleum ether: ethyl acetate = 1:1) to give 2-chloro-3-(1-methylimidazol-4-yl)pyridine (180 mg, yield: 74.19%).

[0396] MS m / z (ESI): 194.0 [M+H]. Step 2: (R)-(4-fluorophenyl)(2-methyl-4-(3-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)piperazin-1-yl)methyl ketone Under a nitrogen atmosphere, palladium acetate (34.78 mg, 51.64 μmol) was added to a solution of 2-chloro-3-(1-methylimidazol-4-yl)pyridine (100 mg, 516.44 μmol), (4-fluorophenyl)-[(2R)-2-methylpiperazin-1-yl] ketone (114.78 mg, 516.44 μmol), 2-(dicyclohexylphosphino)biphenyl (131.74 mg, 375.88 μmol), and sodium tert-butoxide (148.90 mg, 1.55 mmol) in 1',4-dioxane (5 mL). After purging with nitrogen, the reaction mixture was heated to 100°C and stirred for 5 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% formic acid)-acetonitrile) to give (R)-(4-fluorophenyl)(2-methyl-4-(3-(1-methyl-1H-imidazol-4-yl)pyridin-2-yl)piperazin-1-yl)methyl ketone (35 mg, yield: 17.86%).

[0397] MS m / z (ESI): 380.2 [M+H]. The following examples are prepared with reference to other examples.

[0398] Example 126 (R)-(4-fluorophenyl)(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl) methyl ketone

[0399] Step 1: (R,E)-3-((dimethylamino)methylene)-2-methyl-4-oxoperidin-1-carboxylic acid tert-butyl ester DMF-DMA (5.59 g, 46.89 mmol) was added to a DMF (30 mL) solution of (R)-2-methyl-4-oxopiridine-1-carboxylate (5 g, 23.44 mmol). The mixture was stirred at 90°C for 16 hours. TLC showed that the starting material had been consumed. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the title product (R,E)-3-((dimethylamino)methylene)-2-methyl-4-oxopiridine-1-carboxylate (6 g), yield: 95.37%.

[0400] MS m / z (ESI): 269.0 [M+1] Step 2: (R)-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester Hydrazine hydrate (1.68 g, 33.54 mmol) was added to an ethanol (30 mL) solution of compound (R, E)-3-((dimethylamino)methylene)-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (6 g, 22.36 mmol). The mixture was stirred at 50°C for 2 hours. TLC showed that the starting material had been consumed. The reaction was treated with saturated aqueous solution of Na₂S₂O₃ (10 mL) and NaHCO₃ (30 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to give the residue, which was purified preparatively to give the title product (R)-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.2 g), yield: 22.62%.

[0401] MS m / z (ESI): 238.2 [M+1] Step 3: (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester NaH (168.55 mg, 4.21 mmol, 60% purity) was added to a THF (20 mL) solution of (R)-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (500 mg, 2.11 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. Then, 5-chloro-3-methyl-1,2,4-thiadiazole (425.35 mg, 3.16 mmol) was added at 0 °C, and the resulting mixture was stirred at 20 °C for 2 h. The reaction solution was quenched with a saturated aqueous solution of NH4Cl (60 mL) and extracted with EtOAc (80 mL × 2). The organic matter was washed with water (100 ml) and brine (100 ml), dried with Na2SO4 and concentrated to obtain a crude residue, which was purified by silica gel column chromatography (PE:EA=10:1-4:1) to give the title product (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (500 mg), yield: 70.75%.

[0402] MS m / z (ESI): 336.1 [M+1] Step 4: (R)-3-methyl-5-(4-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,2,4-thiadiazole TFA (2 mL) was added to a DCM (4 mL) solution of (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-carboxylic acid tert-butyl ester (300 mg, 894.39 μmol) at 0 °C under nitrogen atmosphere. The resulting mixture was then stirred at 20 °C for 2 hours. The reaction solution was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM (10 mL × 2). The organic matter was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated to give the title product (R)-3-methyl-5-(4-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,2,4-thiadiazole (210 mg), yield: 99.78%.

[0403] MS m / z (ESI): 236.0 [M+1] Step 5: (R)-(4-fluorophenyl)(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl) methyl ketone HATU (156.41 mg, 414.58 μmol) and DIPEA (133.95 mg, 1.04 mmol) were added to a mixture of 4-fluorobenzoic acid (58.09 mg, 414.58 μmol) and (R)-3-methyl-5-(4-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,2,4-thiadiazole (97.55 mg, 414.58 μmol) in DMF (2 mL) at 0°C, and the resulting mixture was stirred at 20°C for 3 hours. The solution was quenched with water, extracted with EtOAc, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain the title product (R)-(4-fluorophenyl)(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl) methyl ketone (56 mg), yield: 37.80%.

[0404] MS m / z (ESI): 358.1 [M+1] Example 127 (R)-1-(5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-2-one

[0405] Step 1: (R)-3-iodo-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester Under nitrogen atmosphere, NIS (1.71 g, 7.59 mmol) was added to a DCE (20 mL) solution of (R)-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.2 g, 5.06 mmol). The resulting mixture was stirred at 80°C for 4 hours. The reaction solution was quenched with a saturated aqueous solution of Na₂SO₃ (60 mL) and extracted with DCM (60 mL × 2). The organic matter was washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated to give a crude residue, which was purified by silica gel column chromatography (PE:EA = 6:1-1:2) to give the title product (R)-3-iodo-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.25 g), yield: 68.06%.

[0406] MS m / z (ESI): 364.0 [M+1] Step 2: (R)-3-iodo-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester NaH (165.19 mg, 4.13 mmol, 60% purity) was added to a THF (20 mL) solution of (R)-3-iodo-4-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1 g, 2.75 mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. Then, 5-chloro-3-methyl-1,2,4-thiadiazole (444.68 mg, 3.30 mmol) was added at 0 °C, and the resulting mixture was stirred at 20 °C for 2 h. The reaction solution was quenched with a saturated aqueous solution of NH4Cl (60 mL) and extracted with EtOAc (80 mL × 2). The organic matter was washed with water (100 ml) and brine (100 ml), dried with Na2SO4 and concentrated to obtain a crude residue, which was purified by silica gel column chromatography (PE:EA=10:1-4:1) to give the title product (R)-3-iodo-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1 g), yield: 78.73%.

[0407] MS m / z (ESI): 462.0 [M+1] Step 3: (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(2-oxopyrrolidone-1-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester Under nitrogen atmosphere, (R)-3-iodo-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.44 g, 953.79 μmol), pyrrolidone-2-one (121.76 mg, 1.43 mmol), CuI (90.82 mg, 476.89 μol), potassium carbonate (395.46 mg, 2.86 mmol), and N,N'-dimethylethylenediamine (84.08 mg, 953.77 μmol) were dissolved in dioxane (10 mL), and the resulting mixture was stirred at 100°C for 5 hours. The solution was filtered through diatomaceous earth and washed with EtOAc (50 mL). The organic matter was washed with water (100 ml) and brine (100 ml), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=20:1-1:1) to give the title product (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(2-oxopyrrolidone-1-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (127 mg), yield: 31.82%.

[0408] MS m / z (ESI): 419.1 [M+1] Step 4: (R)-1-(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-2-one At 0°C and under nitrogen atmosphere, TFA (2 mL) was added to a DCM (4 mL) solution of (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(2-oxopyrrolidone-1-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (127 mg, 303 μmol), and the resulting mixture was stirred at 20°C for 2 hours. The reaction solution was quenched with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL × 2). The organic matter was washed with water (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated to give the title product (R)-1-(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-2-one (110 mg), crude product.

[0409] MS m / z (ESI): 319.1 [M+1] Step 5: (R)-1-(5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-2-one HATU (156.41 mg, 414.58 μmol) and DIPEA (133.95 mg, 1.04 mmol) were added to a mixture of 4-fluorobenzoic acid (58.09 mg, 414.58 μmol) and (R)-1-(4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidone-2-one (0.11 G, crude) in DMF (2 mL) at 0°C, and the resulting mixture was then stirred at 20°C for 3 hours. The solution was quenched with water, extracted with EtOAc, dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain the title product (R)-1-(5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidine-2-one (68 mg), yield: 44.68%.

[0410] MS m / z (ESI): 441.1 [M+1] 1 H NMR (400 MHz CDCl3): 7.51-7.47 (m, 2H),7.17-7.13 (t, J= 8.6 Hz,2H), 6.23-5.78 (m, 1H), 4.99 (m, 1H), 4.16-4.10 (dd, J = 18.2, 8.1 Hz, 1H), 3.94-3.17(m, 4H), 2.61(s, 3H), 2.53 (m, 2H), 2.26-2.22 (m, 2H), 1.32 (m, 3H). Example 129 (R)-5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2(1H)-one

[0411] Using methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate as a raw material, and referring to Example 7, the target product methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate was finally obtained.

[0412] MS m / z (ESI): 374.1 [M+H] Example 130 (R)-5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(2-carbonylpyrrolidine-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2(1H)-one

[0413] Using methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylic acid as a raw material, and referring to Example 7, the target product (R)-5-(4-fluorobenzoyl)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(2-carbonylpyrrolidine-1-yl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-2(1H)-one was finally obtained.

[0414] MS m / z (ESI): 457.1 [M+H] Example 131 (R)-1-(2-(dimethylamino)pyrimidin-4-yl)-5-(4-fluorobenzoyl)-4-methyl-3-(2-carbonylpyrrolidone-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2(1H)-one

[0415] Using methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylic acid as a raw material, and referring to Example 7, the target product (R)-1-(2-(dimethylamino)pyrimidin-4-yl)-5-(4-fluorobenzoyl)-4-methyl-3-(2-carbonylpyrrolidone-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2(1H)-one was finally obtained.

[0416] MS m / z (ESI): 480.2 [M+H] Example 132 (R)-1-(2-(4-fluorobenzoyl)-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one

[0417] Step 1: Methyl 5-acetyl-1H-pyrrole-2-carboxylate Acetic anhydride (81.59 g, 799.20 mmol, 75.06 mL) and boron trifluoride diethyl ether (85.07 g, 599.40 mmol) were dissolved in 1,2-dichloroethane (600 mL). Methyl 1H-pyrrole-2-carboxylate (50 g, 399.60 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated at 25°C. o The reaction mixture was stirred at C for 12 hours. The reaction was quenched by adding saturated brine (500 mL), and the organic phase was separated by washing successively with saturated sodium bicarbonate aqueous solution (500 mL × 2) and saturated brine (500 mL × 2), drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 100:0 to 70:30) to give the target product (25 g, yield: 37.43%).

[0418] MS m / z (ESI): 168.1 [M+H]. Step 2: Methyl 5-acetyl-4-nitro-1H-pyrrole-2-carboxylate Methyl 5-acetyl-1H-pyrrole-2-carboxylate (25 g, 149.56 mmol) was dissolved in acetic anhydride (400 mL), and nitric acid (18.85 g, 299.11 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated at 10 °C. oThe mixture was stirred at C for 3 hours. Most of the solvent was removed from the mixture under reduced pressure, followed by extraction with dichloromethane (150 mL × 2). The organic phases were combined and washed successively with saturated sodium bicarbonate solution (150 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 50:50) to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography to obtain methyl 5-acetyl-4-nitro-1H-pyrrole-2-carboxylate (4 g, yield: 12.61%) and methyl 5-acetyl-3-nitro-1H-pyrrole-2-carboxylate (13 g, yield: 40.97%).

[0419] MS m / z (ESI): 213.0 [M+H]. Step 3: Methyl 5-acetyl-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-nitro-1H-pyrrole-2-carboxylate Methyl 5-acetyl-4-nitro-1H-pyrrole-2-carboxylate (3 g, 14.14 mmol) and tert-butyl (2-bromoethyl)carbamate (6.34 g, 28.28 mmol) were dissolved in acetone (100 mL), and potassium carbonate (9.77 g, 70.70 mmol) was added under nitrogen protection. The mixture was then heated at 80 °C. o The mixture was stirred at C for 12 hours. The mixture was filtered, the liquid phase was evaporated to dryness, the reaction was quenched with saturated brine (150 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 75:25) to give the target product (3.2 g, yield: 63.69%).

[0420] MS m / z (ESI): 356.1 [M+H]. Step 4: Methyl 1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-6-carboxylic acid ester Methyl 5-acetyl-1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-nitro-1H-pyrrole-2-carboxylate (3.2 g, 9.01 mmol) was dissolved in 4N hydrochloric acid / dioxane (70 mL) under nitrogen protection. o The reaction mixture was stirred at C for 1 hour. The reaction solution was evaporated to dryness, and the crude product (2.1 g) was used directly in the next step.

[0421] MS m / z (ESI): 238.1 [M+H]. Step 5: Methyl 1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid ester Methyl 1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-6-carboxylic acid ester (2.1 g, 8.85 mmol) was dissolved in methanol (70 mL), and sodium borohydride (502.39 mg, 13.28 mmol) was added under ice-water bath cooling and nitrogen protection. The mixture was then heated to 22°C. o The reaction mixture was stirred at C for 0.5 hours. The reaction solution was evaporated to dryness, and the crude product (2.1 g) was used directly in the next step.

[0422] MS m / z (ESI): 240.1 [M+H]. Step 6: 2-(tert-butyl)-6-methyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2,6(1H)-dicarboxylate Methyl 1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylate (2.1 g, 8.78 mmol) and triethylamine (2.66 g, 26.33 mmol, 3.67 mL) were dissolved in dichloromethane (50 mL), and di-tert-butyl dicarbonate (2.87 g, 13.17 mmol) was added under nitrogen protection. The mixture was then heated to 22°C. o The reaction was stirred at C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with petroleum ether: ethyl acetate = 100:0 to 70:30) to give the target product (2.6 g, yield: 87.28%).

[0423] MS m / z (ESI): 340.1 [M+H]. Step 7: 2-(tert-Butoxycarbonyl)-1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid 2-(tert-butyl)-6-methyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2,6(1H)-dicarboxylate (2.6 g, 7.66 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Under nitrogen protection, lithium hydroxide monohydrate (321.52 mg, 7.66 mmol) and sodium hydroxide (306.45 mg, 7.66 mmol) were added. The mixture was then heated at 20 °C. oThe reaction mixture was stirred at C for 12 hours. Most of the solvent was removed from the reaction solution under reduced pressure, the pH was adjusted to 6 with 1N hydrochloric acid, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was dried and evaporated to dryness, and the residue (2.48 g) was used directly in the next step.

[0424] MS m / z (ESI): 326.1 [M+H]. Step 8: 6-Carbamoyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 2-(tert-Butoxycarbonyl)-1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid (2.48 g, 7.62 mmol), ammonium chloride (611.67 mg, 11.44 mmol), and N,N-diisopropylethylamine (2.96 g, 22.87 mmol, 3.78 mL) were dissolved in N,N-dimethylformamide (15 mL). Under nitrogen protection, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.64 g, 12.20 mmol) was added. The mixture was then heated at 20°C. o The reaction mixture was stirred at C for 12 hours. The reaction was quenched by adding saturated brine (150 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed successively with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with petroleum ether:ethyl acetate = 100:0 to 0:100) to give the target product (2.4 g, yield: 97.07%).

[0425] MS m / z (ESI): 325.1 [M+H]. Step 9: 6-Carbamoyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 6-Carbamoyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (2.4 g, 7.40 mmol) was dissolved in toluene (70 mL), and Lawson's reagent (2.99 g, 7.40 mmol) was added under nitrogen protection. The mixture was then dissolved in 100 mL of water. o The mixture was stirred at C for 2 hours. The mixture was evaporated to dryness, and the residue was purified by rapid silica gel chromatography (eluting with petroleum ether: ethyl acetate = 100:0 to 0:100) to give the target product (0.8 g, yield: 31.76%).

[0426] MS m / z (ESI): 341.1 [M+H]. Step 10: 6-((1-(dimethylamino)ethylene)carbamoyl)-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 0.9 g (2.64 mmol) of 6-carbamoyl-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester was dissolved in dichloromethane (5 mL), and 1,1-dimethoxy-N,N-dimethylethyl-1-amine (5 mL) was added under nitrogen protection. The mixture was then heated to 22 °C. o The reaction mixture was stirred at C for 1 hour. The reaction solution was evaporated to dryness, and the crude product (1 g) was used directly in the next step.

[0427] MS m / z (ESI): 410.2 [M+H]. Step 11: 1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 6-((1-(dimethylamino)ethylidene)carbamoyl)-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (0.96 g, 2.34 mmol) and pyridine (370.87 mg, 4.69 mmol, 377.71 μL) were dissolved in ethanol (5 mL), and a methanol (5 mL) solution of ammonium bisulfate (265.13 mg, 2.34 mmol) was added under nitrogen protection. The mixture was then heated to 22°C. o The reaction mixture was stirred at C for 12 hours. The reaction was quenched with saturated brine (100 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 40:60) to give 0.35 g of the target product (yield: 39.35%).

[0428] MS m / z (ESI): 380.1 [M+H]. Step 12: 8-Amino-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (0.35 g, 922.43 μmol) and 4,4'-bipyridine (14.41 mg, 92.24 μmol) were dissolved in N,N-dimethylformamide (4 mL), and tetrahydroxydiboron (330.79 mg, 3.69 mmol) was added under nitrogen protection. The mixture was then heated to 22°C. o The reaction mixture was stirred at C for 0.3 hours. The reaction solution was quenched with saturated brine (30 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 6), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.29 g). The crude product was used directly in the next step.

[0429] MS m / z (ESI): 350.2 [M+H]. Step 13: 8-(4-chlorobutamido)-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 8-Amino-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (0.29 g, 829.88 μmol) and triethylamine (419.87 mg, 4.15 mmol, 578.74 μL) were dissolved in dichloromethane (4.54 mL), and 4-chlorobutyryl chloride (140.41 mg, 995.85 μmol) was added under nitrogen protection. The mixture was then heated at 22°C. o The reaction mixture was stirred at C for 0.5 hours. The reaction solution was quenched with saturated brine (30 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (0.37 g). The crude product was used directly in the next step.

[0430] MS m / z (ESI): 454.2 [M+H]. Step 14: 1-Methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-(2-oxopyrrolidine-1-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester 8-(4-chlorobutamido)-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (0.36 g, 792.98 μmol) was dissolved in tetrahydrofuran (4 mL), and 60% w / w sodium hydrogen (47.57 mg, 1.19 mmol) was added under nitrogen protection. The mixture was then heated at 22°C. o The mixture was stirred at C for 1 hour. The reaction was quenched with saturated brine (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed successively with saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 10:90) to give the target product (0.23 g, yield: 69.47%).

[0431] MS m / z (ESI): 418.2 [M+H]. Step 15: 1-(1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one 0.23 g (550.87 μmol) of 1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-8-(2-oxopyrrolidine-1-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester was dissolved in dichloromethane (3 mL), and 4N HCl / dioxane (6 mL) was added under nitrogen protection. The mixture was then dissolved at 20 °C. o The reaction mixture was stirred at C for 0.5 hours. The reaction solution was evaporated to dryness, and the crude product (0.17 g) was used directly in the next step.

[0432] MS m / z (ESI): 318.1 [M+H]. Step 16: 1-(2-(4-fluorobenzoyl)-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one 1-(1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one (0.17 g, 535.59 μmol) and triethylamine (162.59 mg, 1.61 mmol, 223.95 μL) were dissolved in dichloromethane (4 mL), and 4-fluorobenzoyl chloride (127.38 mg, 803.38 μmol) was added under nitrogen protection. The mixture was then heated at 22°C. o The reaction was stirred at C for 0.5 hours. The reaction solution was quenched with saturated saline (5 mL), the mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography to obtain the product (60 mg, yield: 25.49%).

[0433] MS m / z (ESI): 440.2 [M+H]. Step 17: (R)-1-(2-(4-fluorobenzoyl)-1-methyl-6-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one The target product was obtained through chiral separation.

[0434] MS m / z (ESI): 440.2 [M+H]. Example 134 (R)-1-(6-(2-(dimethylamino)pyrimidin-4-yl)-7-fluoro-2-(4-fluorobenzoyl)-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one

[0435] Step 1: 2-(tert-butyl)-6-methyl-7-fluoro-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2,6(1H)-dicarboxylic acid ester The target product was synthesized in the first step of Example 61.

[0436] MS m / z (ESI): 358.1 [M+H]. Step 2: 2-(tert-butoxycarbonyl)-7-fluoro-1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid The target product was synthesized in step 7 of Example 132.

[0437] MS m / z (ESI): 344.1 [M+H]. Step 3: Tert-butyl-6-(2-(dimethylamino)pyrimidin-4-yl)-7-fluoro-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid ester Under a nitrogen atmosphere, palladium acetate (261.58 mg, 1.17 mmol) was added to a mixed solution of 2-(tert-butoxycarbonyl)-7-fluoro-1-methyl-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid (2 g, 5.83 mmol), 4-bromo-N,N-dimethylpyrimidine-2-amine (1.18 g, 5.83 mmol), cuprous iodide (221.90 mg, 1.17 mmol), 3A molecular sieve (1 g), and N-methylpyrrolidone (30 mL). After purging with nitrogen, the reaction solution was heated to 160 °C and stirred for 4 hours. The reaction solution was cooled to room temperature and quenched slowly with saturated brine (20 mL). The reaction solution was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (mobile phase: pure water (0.1% formic acid)-acetonitrile) to give tert-butyl-6-(2-(dimethylamino)pyrimidin-4-yl)-7-fluoro-1-methyl-8-nitro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid ester (0.5 g, 1.19 mmol, 20.41% yield). MS m / z (ESI): 421.1 [M+H]. Step 4: (R)-1-(6-(2-(dimethylamino)pyrimidin-4-yl)-7-fluoro-2-(4-fluorobenzoyl)-1-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-8-yl)pyrrolidine-2-one The target product was synthesized according to steps 12 to 17 of Example 132.

[0438] MS m / z (ESI): 481.2 [M+H]. Example 140 (R)-1-(3-(2-(dimethylamino)pyrimidin-4-yl)-7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidine-2-one

[0439] Step 1: 8-Methyl-3-(tributyltinyl)imidazo[1,2-a]pyrazine The target product was obtained by the synthetic method described in the reference [Journal of Medicinal Chemistry, 2024, vol. 67, 21, 19121-19142].

[0440] MS m / z (ESI): 424.2 [M+H]. Step 2: N,N-Dimethyl-4-(8-methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-amine The target product was obtained by the synthetic method described in the reference [Organic Process Research and Development, 2003, vol. 7, 5, 676-683].

[0441] MS m / z (ESI): 255.1 [M+H]. Step 3: N,N-Dimethyl-4-(8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-amine N,N-dimethyl-4-(8-methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-amine (500 mg, 1.96 mmol) was added to ethanol (5 mL), followed by acetic acid (5 mL) and sodium cyanoborohydride (370 mg, 5.88 mmol). The reaction mixture was reacted overnight at 50 °C under nitrogen protection. The solution was concentrated under reduced pressure, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted multiple times with DCM and concentrated to dryness under reduced pressure to obtain the target product N,N-dimethyl-4-(8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-amine (410 mg, crude product). MS m / z (ESI): 259.2 [M+H]. Step 4: (3-(2-(dimethylamino)pyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone The target product was obtained by referring to step 5 of Example 1. MS m / z (ESI): 381.2 [M+H]. Step 5: (2-bromo-3-(2-(dimethylamino)pyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone The target product was obtained by referring to step 5 of Example 7.

[0442] MS m / z (ESI):459.1, 461.1 [M+H]. Step 6: (R)-1-(3-(2-(dimethylamino)pyrimidin-4-yl)-7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidine-2-one Following the synthesis method in step 8 of Example 16, the target product was obtained through preparative chromatographic separation and chiral resolution. MS m / z (ESI): 464.2 [M+H]. Example 143 (R)-(3-(3-(dimethylamino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0443] Step 1: Methyl 3-bromopyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester At room temperature, methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (0.5 g, 2.82 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of N-bromosuccinimide (0.55 g, 3.10 mmol). The mixture was stirred at room temperature for 1 hour, and the reaction was stopped by LCMS. The solution was evaporated to dryness, and the crude product was separated by Flash column chromatography (dichloromethane: ethyl acetate = 90:10) to give the target compound (0.70 g, yield: 96.9%).

[0444] MS m / z (ESI): 256.0,258.0 [M+1]. Step 2: 3-Brompyrazole[1,5-a]pyrimidine-5-carbamoylhydrazine At room temperature, methyl 3-bromopyrazolo[1,5-a]pyrimidine-5-carboxylic acid ester (1.4 g, 5.47 mmol) was dissolved in methanol (20 mL), followed by the addition of hydrazine hydrate (643.24 mg, 10.94 mmol, 85% purity). The mixture was stirred overnight at room temperature, and the reaction was stopped by LCMS. The solid was filtered, washed with petroleum ether, dried, and used directly in the next step (1.22 g, yield: 87.1%).

[0445] MS m / z (ESI): 256.0,258.0 [M+1]. Step 3: (R)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-7-(3,5-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Under ice bath conditions, (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazin-2-one (2.50 g, 9.46 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of triethyloxonium tetrafluoroboric acid (5.39 g, 28.37 mmol) in portions. After the addition was complete, the mixture was stirred at room temperature for 3 hours, and the reaction was considered complete by TLC. Under ice bath conditions, the reaction mixture was slowly added dropwise to an aqueous sodium hydroxide solution (2N, 15 mL), stirred for 10 minutes, separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (30 mL), and then 3-bromopyrazolo[1,5-a]pyrimidine-5-carboxylhydrazine (0.60 g, 2.34 mmol) was added. The mixture was heated to 75°C and reacted for 14 hours. After cooling to room temperature, the reaction was considered complete by LCMS. The crude product was evaporated to dryness and separated by Flash column chromatography (dichloromethane: methanol = 96:4) to obtain the target product (0.56 g, yield: 49.3%).

[0446] MS m / z (ESI): 484.1,486.1 [M+1]. Step 4: (R)-5-(7-(3,5-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-amine At room temperature, (8R)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-7-[(3,5-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine (0.23 g, 0.48 mmol), dimethylamine hydrochloride (0.06 g, 0.72 mmol), sodium trimethylsilanolate (0.16 g, 1.44 mmol), and GPhosPdG6 (45.24 mg, 0.05 mmol) were dissolved in tetrahydrofuran (4 mL), purged with nitrogen, heated to 80°C, and reacted for 14 hours. After cooling to room temperature, LCMS indicated the formation of the target product. The crude product was evaporated to dryness, dissolved in ethyl acetate (20 mL), and then washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by thin-layer chromatography (DCM:MeOH = 20:1) to obtain the target product (65 mg, yield: 30.3%).

[0447] MS m / z (ESI): 449.2 [M+1]. Step 5: (R)-N,N-dimethyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazolo[1,5-a]pyrimidine-3-amine At room temperature, (R)-5-(7-(3,5-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-amine (25 mg, 55.74 μmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (0.3 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was indicated to be complete by LCMS. The reaction solution was quenched with water (2 mL), and stirred at room temperature for ten minutes. A solid precipitated out. The solid was filtered and washed with water (5 mL × 3). The pH of the reaction solution was adjusted to 10-12 with sodium hydroxide aqueous solution (2N), and then extracted with dichloromethane (15 mL × 3). The organic phases were combined and dried with anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the crude product was used directly in the next step (16 mg, yield: 96.2%).

[0448] MS m / z (ESI): 299.2 [M+1]. Step 6: (R)-(3-(3-(dimethylamino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone At room temperature, (R)-N,N-dimethyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazolo[1,5-a]pyrimidine-3-amine (16 mg, 53.63 μmol) was dissolved in dichloromethane (3 mL), followed by the sequential addition of triethylamine (21.71 mg, 214.52 μmol, 29.92 μL) and 4-fluorobenzoyl chloride (11.05 mg, 69.72 μmol). The mixture was stirred at room temperature for 2 hours, and the reaction was considered complete by LCMS. The reaction solution was diluted with dichloromethane (20 mL), then washed sequentially with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was then separated by reversed-phase preparative chromatography and lyophilized to obtain the target product (6.7 mg, yield: 29.7%).

[0449] MS m / z (ESI): 421.2 [M+1]. 1 ¹H NMR (400 M, CDCl₃) δ 8.57 (br , 1H), 7.62-7.99 (m, 2H), 7.48-7.52 (m, 2H), 7.18 (t, J = 8.4 Hz 2H), 5.51-5.87 ( br , 1H), 4.95-5.20 ( br , 1H), 4.52-4.79 ( br , 1H), 4.39-4.46 (m, 1H), 3.50-3.55 (m, 1H), 3.08 (S, 6H),1.76 (d, J = 6.8 Hz, 3H). Example 144 (R)-(4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyranazono[1',2':1,2]imidazo[4,5-b]pyrimidino[4,5-d]acoxane-10-yl) methyl ketone

[0450] Step 1: 3-Iodo-8-methylimidazo[1,2-a]pyrazine At room temperature, 8-methylimidazo[1,2-a]pyrazine (2 g, 15.02 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N-iodosuccinimide (3.72 g, 16.52 mmol). The mixture was stirred at room temperature for 14 hours. The reaction was stopped by LCMS. The reaction solution was diluted with ethyl acetate (40 mL) and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (1.50 g, yield: 38.6%).

[0451] MS m / z (ESI): 260.0 [M+1]. Step 2: 8-Methyl-3-(tributyltinyl)imidazo[1,2-a]pyrazine At -78°C, 3-iodo-8-methylimidazo[1,2-a]pyrazine (1.50 g, 5.79 mmol) was dissolved in tetrahydrofuran (20 mL), and nitrogen was purged. Then, a complex solution of isopropyl magnesium chloride and lithium chloride (1.30 M, 8.9 mL, 11.6 mmol) was added dropwise, and the mixture was stirred at -78°C for one hour. Tributyltin chloride (3.77 g, 11.6 mmol) was then added, and the mixture was stirred at -78°C for four hours. The reaction was considered complete by LC-MS. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL), then extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (1.50 g, yield: 61.4%).

[0452] MS m / z (ESI): 424.2.0 [M+1]. Step 3: N-methyl-2-(2-methyl-4-(8-methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-5-yl)ethane-1-amine At room temperature, 8-methyl-3-(tributyltinyl)imidazo[1,2-a]pyrazine (1.50 g, 3.55 mmol) and 2-(4-bromo-2-methylpyrimidin-5-yl)-N-methylethylamine (899.28 mg, 3.91 mmol) were dissolved in 1,4-dioxane (20 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (0.41 g, 0.355 mmol). The mixture was purged with nitrogen, heated to 100°C, and reacted for 14 hours. After cooling to room temperature, the reaction was considered complete by LCMS, and the solution was evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (0.75 g, yield: 74.8%).

[0453] MS m / z (ESI): 283.2 [M+1]. Step 4: 2-(4-(2-bromo-8-methylimidazo[1,2-a]pyrazin-3-yl)-2-methylpyrimidin-5-yl)-N-methylethane-1-amine Using N-methyl-2-(2-methyl-4-(8-methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-5-yl)ethane-1-amine as a starting material, the target compound was obtained by referring to the first step of Example 143.

[0454] MS m / z (ESI): 361.1,363.1 [M+1]. Step 5: 2,7,9-Trimethyl-6,7-dihydro-5H-pyranazono[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]azapyrrolidone Using 2-(4-(2-bromo-8-methylimidazo[1,2-a]pyrazin-3-yl)-2-methylpyrimidin-5-yl)-N-methylethane-1-amine as a starting material, the target compound was obtained by referring to step 5 of Example 25.

[0455] MS m / z (ESI): 280.2 [M+1]. Step 6: 2,7,9-Trimethyl-6,7,9,10,11,12-hexahydro-5H-pyranazono[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]azapyrrolidone At room temperature, 2,7,9-trimethyl-6,7-dihydro-5H-pyranazino[1',2':1,5]pyrrolo[3,2-b]pyrimidino[4,5-d]azapyrrolidone (0.50 g, 1.78 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of acetic acid (3 mL) and sodium cyanoborohydride (0.22 g, 3.56 mmol). The mixture was heated to 50°C and reacted for 5 hours. The reaction was completed by LCMS. The mixture was cooled to room temperature and evaporated to dryness. The crude product was dissolved in ethyl acetate (25 mL) and washed successively with saturated sodium bicarbonate solution (15 mL × 3) and saturated brine (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (0.12 g, yield: 23.7%).

[0456] MS m / z (ESI): 284.2 [M+1]. Step 7: (4-Fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyranadiazono[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone Using 2,7,9-trimethyl-6,7,9,10,11,12-hexahydro-5H-pyranadiazono[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]azapyrrolidone as a starting material, the target compound was obtained by referring to step 6 of Example 143.

[0457] MS m / z (ESI): 406.2 [M+1]. Step 8: (S)-(4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyrano-[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone; (R)-(4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyrano-[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone Chiral resolution of (4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyranazono[1',2':1,5]pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone yielded (S)-(4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H- Pyrano-bis(1',2':1,5)pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone and (R)-(4-fluorophenyl)(2,7,9-trimethyl-5,6,7,9,11,12-hexahydro-10H-pyrano-bis(1',2':1,5)pyrrolo[3,2-b]pyrimido[4,5-d]acoxane-10-yl) methyl ketone.

[0458] MS m / z (ESI): 406.2 [M+1]. Example 145 (R)-5-(4-fluorobenzoyl)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one

[0459] Step 1: tert-Butyl(R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-carbonyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester At room temperature, 1-(tert-butyl)-3-methyl(2R)-2-methyl-4-carbonylpiperidin-1,3-dicarboxylic acid ester (as synthesized in Journal of Medicinal Chemistry, 2024, 67, 23, 21009-21029) (1.0 g, 3.69 mmol) and (3-methyl-1,2,4-thiadiazol-5-yl)hydrazine (527.77 mg, 4.05 mmol) were dissolved in methanol (20 mL), heated to 70°C, and reacted for 14 hours. After cooling to room temperature, the reaction was considered complete by LCMS. The product was evaporated to dryness, and the crude product was separated by Flash column chromatography to obtain the target product (0.80 g, yield: 61.8%).

[0460] MS m / z (ESI): 352.1 [M+1]. Step 2: Tert-butyl(R)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-carbonyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester Under ice bath conditions, tert-butyl(R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-carbonyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (0.8 g, 2.28 mmol) was dissolved in N,N-dimethylformamide (10 mL), and nitrogen was purged. Then, sodium hydrogen (128.54 mg, 4.55 mmol, 85% purity) was added in portions, and the mixture was stirred under ice bath conditions for 30 minutes. Then, iodomethane (646.51 mg, 4.55 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was considered complete under LC-MS conditions. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), then diluted with ethyl acetate (50 mL), separated, and the organic phase was washed with saturated brine (15 mL × 4). The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was separated by Flash column chromatography to obtain the target product (0.4 g, yield: 48.1%).

[0461] MS m / z (ESI): 366.1 [M+1]. Step 3: (R)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one At room temperature, tert-butyl(R)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-carbonyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (0.4 g, 1.09 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours, and the reaction was considered complete by LCMS. The solution was evaporated to dryness, and the residue was dissolved in ethyl acetate (20 mL). The solution was then washed successively with saturated sodium bicarbonate solution (15 mL × 3) and saturated brine (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was used directly in the next step (0.25 g, yield: 86.1%).

[0462] MS m / z (ESI): 266.1 [M+1]. Step 4: (R)-5-(4-fluorobenzoyl)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one The target compound was obtained from (R)-2,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one, referring to step 6 of Example 143.

[0463] MS m / z (ESI): 388.1 [M+1]. Example 146 (R)-1-(3-(2-chloropyrimidin-4-yl)-7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidine-2-one

[0464] Step 1: 8-Methylimidazo[1,2-a]pyrazine Chloroacetaldehyde (12.95 g, 164.94 mmol) and 3-methylpyrazine-2-amine (12.00 g, 109.96 mmol) were dissolved in 50 mL of acetonitrile, and NaHCO3 (18.48 g, 219.95 mmol) was added. The mixture was stirred at 80°C for 12 hours. Water was added to the reaction solution, and the mixture was extracted with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (PE / EtOAc = 4:1) to give 8-methylimidazo[1,2-a]pyrazine (12.5 g, yield: 85.37%).

[0465] MS m / z (ESI): 134.1 [M+H]. Step 2: (R)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine PtO2 (1.07 g, 4.69 mmol) was added to a MeOH (100 mL) solution of 12.5 g (93.88 mmol) of 8-methylimidazo[1,2-a]pyrazine. The mixture was stirred at 40 °C in H2 for 16 hours. The reaction mixture was filtered and concentrated to give (R)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (12 g, crude product). MS m / z (ESI): 138.1 [M+H]. Step 3: (R)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester TEA (17.70 g, 174.95 mmol, 24.40 mL) was added to a DCM (100 mL) solution of (R)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (12 g, 87.48 mmol) and Boc₂O (28.64 g, 131.21 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was treated with water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE / EtOAc = 1:1) gave (R)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (15 g, 63.21 mmol, 72.26% yield).

[0466] MS m / z (ESI): 238.2 [M+H]. Step 4: (R)-3-iodo-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester NIS (11.38 g, 50.57 mmol) was added to a MeCN (100 mL) solution of (R)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (10 g, 42.14 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction was treated with saturated aqueous Na₂SO₃ (100 mL), NaHCO₃ (100 mL), and ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by column chromatography (PE / EtOAc = 1:1) yielded (R)-3-iodo-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (10 g, 27.53 mmol, 65.34% yield).

[0467] MS m / z (ESI): 364.0 [M+H]. Step 5: (R)-8-methyl-3-(tributyltin)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester Under nitrogen atmosphere at -10 °C, iPrMgCl (1 M, 3.30 mL) was added to a THF (10 mL) solution of (R)-3-iodo-8-methyl-5,6-dihydroimidazolo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (1 g, 2.75 mmol), and the mixture was stirred at -10 °C for 0.5 h. Tributyltin chloride (896.23 mg, 2.75 mmol) was added to the mixture, and the mixture was stirred at -10 °C for 0.5 h. The reaction was treated with saturated aqueous NH4Cl solution (3 mL) and ethyl acetate (3 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated. The product was purified by column chromatography (PE / EtOAc = 1:1) to give (R)-8-methyl-3-(tributyltinyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (620 mg, 1.18 mmol, 42.78% yield).

[0468] MS m / z (ESI): 528.2 [M+H]. Step 6: (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester Under nitrogen atmosphere, Pd(PPh3)4 (136.12 mg, 117.79 μmol) was added to a solution of (R)-8-methyl-3-(tributyltinyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (620 mg, 1.18 mmol), 4-bromo-2-chloropyrimidine (250.63 mg, 1.30 mmol), and K2CO3 (325.58 mg, 2.36 mmol) in 1'4-dioxane (1 mL). The mixture was stirred at 100 °C for 4 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purified by column chromatography (PE / EtOAc = 1:1), (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (400 mg, 1.14 mmol, 97.07% yield) was obtained.

[0469] MS m / z (ESI): 350.1 [M+H]. Step 7: (R)-2-bromo-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester NBS (771.78 mg, 3.43 mmol) was added to a DMF (1 mL) solution of (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (800 mg, 2.29 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction was quenched with a saturated aqueous solution of Na₂SO₃ (10 mL), and extracted with ethyl acetate (30 mL). The organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. The product was purified by column chromatography (PE / EtOAc = 1:1) to give (R)-2-bromo-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (300 mg, 699.77 μmol, 30.60% yield).

[0470] MS m / z (ESI): 428.0 [M+H]. Step 8: (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-2-(2-oxopyrrolidone-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester To a solution of (R)-2-bromo-3-(2-chloropyrimidin-4-yl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (300 mg, 699.77 μmol) and CuI (66.64 mg, 349.89 μmol) in 1'4-dioxane (5 mL), pyrrolidone (59.55 mg, 699.7 μmol) and K2CO3 (193.42 mg, 1.40 mmol) were added, and the mixture was stirred at 100 °C for 2 hours. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated. Purified by column chromatography (PE / EtOAc = 1:2), (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-2-(2-oxopyrrolidone-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (280 mg, 646.80 μmol, 92.43% yield) was obtained.

[0471] MS m / z (ESI): 433.1 [M+H]. Step 9: (R)-1-(3-(2-chloropyrimidin-4-yl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidine-2-one TFA (73.75 mg, 646.8 μmol) was added to a DCM (5 mL) solution of (R)-3-(2-chloropyrimidin-4-yl)-8-methyl-2-(2-oxopyrrolidone-1-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylic acid tert-butyl ester (280 mg, 646.80 μmol), and the mixture was stirred at 24 °C for 2 h. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated to give (R)-1-(3-(2-chloropyrimidin-4-yl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidone (210 mg, crude).

[0472] MS m / z (ESI): 333.1 [M+H]. Step 10: (R)-1-(3-(2-chloropyrimidin-4-yl)-7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidine-2-one DIEA (116.51 mg, 901.48 μmol, 157.02 μL) was added to a DMF (3 mL) solution of (R)-1-(3-(2-chloropyrimidin-4-yl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidone-2-one (200 mg, 600.98 μmol), 4-fluorobenzoic acid (101.05 mg, 721.18 μmol), and HATU (226.73 mg, 600.99 μmol). The mixture was stirred at 24 °C for 12 h. The reaction was quenched with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated. The product was separated and purified by column chromatography (PE / EtOAc = 1:2) and preparative chromatography (acidic) to obtain (R)-1-(3-(2-chloropyrimidin-4-yl)-7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrrolidone (150 mg, 329.75 μmol, 54.87% yield).

[0473] MS m / z (ESI): 455.1 [M+H]. Example 149

[0474] Step 1: 5-(tert-butyl)-3-methyl(R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate The target compound was synthesized according to step 5 of Example 37.

[0475] MS m / z (ESI): 394.2 [M+1] Step 2: (R)-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-3-(methylcarbamoyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester The target compound was synthesized using methylamine hydrochloride as a raw material, following steps seven and eight of Example 132.

[0476] MS m / z (ESI): 393.2 [M+1] Step 3: (R)-5-(4-fluorobenzoyl)-N,4-dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide The target product was synthesized in steps five and six of Example 143.

[0477] MS m / z (ESI): 415.1 [M+1] Example 150 (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one

[0478] Step 1: (R)-3-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-oxopropionic acid ethyl ester The title product (R)-3-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-oxopropionate ethyl ester was obtained by the synthesis of the product according to Example 32.

[0479] MS m / z (ESI): 375.1 [M+H]. Step 2: (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-7-hydroxy-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one Ethyl (R)-3-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-oxopropionate (1 g, 2.67 mmol) and 5-amino-2-methyl-1,2-dihydro-3H-pyrazole-3-one (302.16 mg, 2.67 mmol) were dissolved in acetic acid (10 mL). The reaction mixture was stirred at 110 °C under nitrogen protection for 10 hours. The reaction was then stopped, cooled to room temperature, and concentrated. Purification of the residue by silica gel column chromatography with dichloromethane and methanol as eluent yielded the title product (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-7-hydroxy-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (600 mg), yield: 53.05%.

[0480] MS m / z (ESI): 424.1 [M+H]. Step 3: (R)-7-chloro-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-7-hydroxy-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (600 mg, 1.42 mmol) was placed in a 50 mL flask, and POCl3 (1.09 g, 7.09 mmol) and TEA (143.40 mg, 1.42 mmol) were added at room temperature. The reaction mixture was kept under nitrogen protection and reacted at 25°C for 10 h. The reaction was then stopped and concentrated. Purification of the residue by silica gel column chromatography with dichloromethane and methanol as eluent yielded the title product (R)-7-chloro-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (500 mg), yield: 79.85%.

[0481] MS m / z (ESI): 442.1 [M+H]. Step 4: (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (R)-7-chloro-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (100 mg, 226.32 μmol), 5% palladium on carbon (55% water) (50 mg) were dissolved in methanol (5 mL). The reaction system was stirred under hydrogen atmosphere for 1 hour. The reaction was stopped, filtered, and the filtrate was concentrated. Purification of the residue by prep-HPLC yielded the title product (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1-methylpyrazolo[1,5-a]pyrimidin-2(1H)-one (20 mg), yield: 21.69%.

[0482] MS m / z (ESI): 408.1 [M+H]. Example 152 (R)-(4-Fluorophenyl)(8-Methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl ketone

[0483] Step 1: Methyl-8-methylimidazo[1,2-a]pyrazine-6-carboxylic acid ester 6-Bromo-8-methyl-imidazo[1,2-a]pyrazine (1.5 g, 7.07 mmol) was dissolved in a mixed solvent of DMSO (40 mL) and methanol (20 mL). Palladium acetate (635.26 mg, 2.83 mmol), 1,3-bis(diphenylphosphine)propane (1.46 g, 3.54 mmol), and triethylamine (2.15 g, 21.22 mmol, 2.96 mL) were added sequentially. After the reaction system was purged with CO, it was placed in a CO atmosphere and stirred in an oil bath at 80 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Dichloromethane : Methanol = 20 / 1, UV = 254 nm) to finally obtain methyl 8-methylimidazo[1,2-a]pyrazine-6-carboxylate (1.1 g, 81.4% yield). MS m / z (ESI): 192.1 [M+H]. Step 2: 8-Methylimidazo[1,2-a]pyrazine-6-carbamoylhydrazine 200 mg (1.05 mmol) of methyl 8-methylimidazo[1,2-a]pyrazine-6-carboxylic acid ester was dissolved in methanol (5 mL), and hydrazine hydrate (61.61 mg, 1.05 mmol, 85% purity) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was directly filtered to obtain a pale yellow solid, 8-methylimidazo[1,2-a]pyrazine-6-carboxyhydrazide (200 mg, crude).

[0484] MS m / z (ESI): 192.1 [M+H]. Step 3: (8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (458.77 mg, 1.57 mmol) and 8-methylimidazo[1,2-a]pyrazine-6-carboxylhydrazine (200 mg, 1.05 mmol) were dissolved in methanol (10 mL) and stirred in an oil bath at 80 °C for 16 hours. After the reaction solution cooled to room temperature, the excess solvent was concentrated to obtain crude (8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-3-(8-methylimidazo[1,2-a]pyrazine-6-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine (440 mg, crude).

[0485] The crude product is used directly in the next reaction step.

[0486] MS m / z (ESI): 420.2 [M+H]. Step 4: (8R)-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin (8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine (440 mg, 1.05 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added to the solution. The reaction system was stirred at room temperature (20°C) for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (10 ml) was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (8R)-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (280 mg, crude). The crude product was used directly in the next reaction step.

[0487] MS m / z (ESI): 270.1 [M+H]. Step 5: (4-Fluorophenyl)-[(8R)-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl] methyl ketone 4-Fluorobenzoyl chloride (197.83 mg, 1.25 mmol, 147.41 μL) and (8R)-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (280 mg, 1.04 mmol) were dissolved in dichloromethane (20 mL), and triethylamine (315.63 mg, 3.12 mmol, 435.05 μL) was added. The reaction mixture was stirred at room temperature (20 °C) for 4 hours. After the reaction solution cooled to room temperature, it was diluted with water (20 mL), extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC to obtain (4-fluorophenyl)-[(8R)-8-methyl-3-(8-methylimidazo[1,2-a]pyrazin-6-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl] methyl ketone (22.8 mg).

[0488] MS m / z (ESI): 392.2 [M+H]. 1 H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.56 – 7.45 (m, 2H), 7.17 (t, 2H), 5.74 (s, 1H), 4.96 (dd, 1H), 4.59 (s, 1H), 4.35 (t, 1 H), 3.55 (t, 1H), 2.95 (s, 3H), 1.76 (d, 3H). The following examples are prepared with reference to other examples.

[0489] Biological testing evaluation The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0490] I. Cell Function Experiments Test Example 1: Determination of the effect of the compound of the present invention on calcium ion mobility in cells stably expressing the NK3 receptor. Experimental objective: The purpose of this test case is to measure the inhibitory effect of the compound on the NK3 receptor.

[0491] Experimental methods: 1. Buffer preparation: 1 x HBSS, 20 mM HEPES, 2.5 mM probenecid (probenecid is 250 mM stock in HBSS), 0.1% BSA; Probenecid and BSA are added fresh on the day of the experiment; experimental buffers include dye buffer and compound dilution buffer, etc.

[0492] 2. After digestion with trypsin, the cells were then... 4 Seed at a density of 1 cell / well in 384-well plates and incubated for 16–24 hours (at least overnight).

[0493] 3. On the day of the calcium flow experiment, add 20 µL of dye to each well of the cell plate; incubate at 37°C in the dark for 120 min.

[0494] 4. Prepare the antagonist before the experiment; add 10 μL / well of the 5x antagonist compound to the 384-well plate using a FLIPR and read the calcium signal values ​​(excitation light 470–495 nM, emission light 515–575 nM), and incubate at room temperature in the dark for 20 min; after the compound incubation, add 5 μL of the 11x EC80 agonist Neurokinin B to each well using a FLIPR; read the values ​​using a FLIPR and save the data; the total test volume is 55 μL, including 20 μL / well of culture medium, 20 μL / well of dye buffer, 10 μL / well of the 5x experimental compound, and 5 μL / well of the 11x agonist compound.

[0495] Experimental data processing methods: Calcium signal values ​​were read using FLIPR. Data at each sampling time point in the experiment are presented as the ratio of the reading at that time point to the baseline reading before agonist administration. The maximum value minus the minimum value represents the agonist-induced fold change in signal strength. The IC50 of the compound was calculated using a four-parameter nonlinear logic formula fitted with the percentage inhibition rate and twelve-point concentration data using GraphPad Prism. 50 value.

[0496] Experimental conclusion: The compounds in this invention showed good inhibitory activity in the functional calcium flow assay of stably expressed NK3 cells, IC50. 50 The value is less than 500 nM, preferably less than 100 nM, and more preferably less than 50 nM.

[0497] Test Example 2: Determination of the effect of the compound of the present invention on calcium ion mobility in cells stably expressing NK1 / NK2 receptors. Experimental objective: The purpose of this test case is to measure the inhibitory effect of the compound on NK1 / NK2 receptors.

[0498] Experimental methods: 1. Buffer preparation: 1 x HBSS, 20 mM HEPES, 2.5 mM probenecid (probenecid is 250 mM stock in HBSS), 0.1% BSA; Probenecid and BSA are added fresh on the day of the experiment; experimental buffers include dye buffer and compound dilution buffer, etc.

[0499] 2. After digestion with trypsin, the cells were then... 4 Seed at a density of 1 cell / well in 384-well plates and incubated for 16–24 hours (at least overnight).

[0500] 3. On the day of the calcium flow experiment, add 20 µL of dye to each well of the cell plate; incubate at 37°C in the dark for 120 min.

[0501] 4. Prepare the antagonist before the experiment; add 10 μL / well of the 5x antagonist compound to a 384-well plate using a FLIPR and read the calcium signal values ​​(excitation light 470–495 nM, emission light 515–575 nM), and incubate at room temperature in the dark for 20 min; after compound incubation, add 5 μL of the 11x EC80 agonist (Substance P for NK1 receptor cells, Neurokinin A for NK2 receptor cells) to each well using a FLIPR; read the values ​​using a FLIPR and save the data; the total assay volume is 55 μL, including 20 μL / well of culture medium, 20 μL / well of dye buffer, 10 μL / well of the 5x experimental compound, and 5 μL / well of the 11x agonist compound.

[0502] Experimental data processing methods: Calcium signal values ​​were read using FLIPR. Data at each sampling time point in the experiment are presented as the ratio of the reading at that time point to the baseline reading before agonist administration. The maximum value minus the minimum value represents the agonist-induced fold change in signal strength. The IC50 of the compound was calculated using a four-parameter nonlinear logic formula fitted with the percentage inhibition rate and twelve-point concentration data using GraphPad Prism. 50 value.

[0503] Experimental conclusion: The compounds in this invention exhibit NK1RIC-like calcium ion mobility in cells stably expressing NK1 / NK2 receptors. 50 (nM) value and NK2R IC 50 (nM) values ​​are all >10,000. The compounds of the present invention showed good selectivity in the functional calcium flow assay of cells stably expressing NK3 and NK1 / NK2 receptors.

[0504] Test Example 3: Determination of the effect of the compound of the present invention on IP1 in cells stably expressing CHO-NK3. 1. Experimental objective: The purpose of this test case is to measure the antagonistic activity of the compound on cells that stably express the human NK3 receptor.

[0505] 2. Experimental instruments and reagents: 2.1 Experimental Instruments and Consumables: Cell counter (Invitrogen: Countess II) 384-well test cell plate (Corning: 3824); Compound dilution in 96-well plates (Corning: 3894); Compound separatory plate (Dispendix: M_220718_100S_B); Dispendix iDOT nano-dispensing system; EnVision plate reader (PerkinElmer: 2105-0020) Cell incubator (ThermoFisher: 311GP) 2.2 Experimental reagents: Ham's F-12K (Kaighn's) (Gibco: 21127022); Fetal Bovine Serum, Premium Plus (Gibco: A5669701); Penicillin-Streptomycin (P / S) (Gibco: 15140122); HTRF IP-One Gq Detection Kit (Revvity: 62IPAPEB); 0.25% Trypsin-EDTA (Gibco: 25200-056) Complete culture medium: Ham's F-12K + 10% FBS + 1X P / S; Agonist Neurokinin B TFA (MCE: HYP0242A); Stable cell line: CHO-K1 / NK3 Stable Cell Line (GenScript, M00201) 3. Experimental Methods: Day 1: CHO-NK3 cells were digested and collected, resuspended, counted, and seeded into 384-well cell culture plates at a density of 2.0 × 10⁶ cells / well. 4 Cells / 40 μL / well. The cell plate was then incubated overnight at 37°C in a 5% CO2 cell culture incubator.

[0506] 2. Day 2: Prepare the stimulation buffer according to the IP-1 kit instructions. Invert the cell plate and centrifuge at 300 rpm for 30 seconds to remove the supernatant.

[0507] 3. Add 24 μL of stimulation buffer to each well and incubate in a 5% CO2 incubator in the dark to equilibrate; 4. Prepare a concentration gradient of the compound to be tested, and use a nanoliter liquid separator to add 200 nL of the compound to the cells and incubate for half an hour; 5. Manually add 4 µL of agonist (final concentration of EC80 of agonist) to the cell plate, incubate at 37 ℃ for 45 min, then add 6 µL of IP-1 d2 and 6 µL of IP-1 Tb Cryptate Antibody in sequence, centrifuge at 1000 rpm for 60 seconds at room temperature, and incubate at room temperature for 2 h.

[0508] 6. Use the EnVision board reader HTRF program to read the board and collect data simultaneously.

[0509] Experimental data processing methods: The EnVision plate reader reads the ratio of collected fluorescence signals. Based on the readings of the Low control (DMSO control) and High control (positive compound Fezolinetant) experimental groups, the percentage antagonism data is calculated as {% antagonism rate = (Ratio sample - Ratio low control) / (Ratio high control - Ratio low control) × 100}. The concentrations of the test compound, after being diluted 3-fold in the reaction system, range from 30 μM to 0.17 nM. The IC50 of the compound is calculated using a non-linear logic formula fitted to the percentage antagonism rate and the 12 concentration data using Graphpad. 50 value.

[0510] 4. Experimental Conclusion: The compounds in this invention demonstrated good antagonistic activity in the IP1 functional assay of stably expressed NK3 cells, IC50 50 The value is less than 500 nM, preferably less than 100 nM, and more preferably less than 50 nM.

[0511] Test Example 4: Determination of the effect of the compound of the present invention on IP1 in transiently transgenic CHO-NK3 cells. 1. Experimental objective: The purpose of this test case is to measure the antagonistic activity of the compound on cells that transiently express human NK3 receptor.

[0512] 2. Experimental instruments and reagents: 2.1 Experimental Instruments and Consumables: 100mm cell culture dish (NEST: 704001); Cell counter (Invitrogen: Countess II) 384-well test cell plate (Corning: 3824); Compound dilution in 96-well plates (Corning: 3894); Compound separatory plate (Dispendix: M_220718_100S_B); Dispendix iDOT nano-dispensing system; EnVision plate reader (PerkinElmer: 2105-0020); Cell culture incubator (ThermoFisher: 311GP).

[0513] 2.2 Experimental reagents: FuGENE® HD transfection reagent (Promega: E2312) Opti-MEM medium (Gibco: 51985034) Ham's F-12K (Kaighn's) (Gibco: 21127022); Fetal Bovine Serum, Premium Plus (Gibco: A5669701); Penicillin-Streptomycin (P / S) (Gibco: 15140122); HTRF IP-One Gq Detection Kit (Revvity: 62IPAPEB); 0.25% Trypsin-EDTA (Gibco: 25200-056); Complete culture medium: Ham's F-12K + 10% FBS + 1X P / S; Agonist Neurokinin B TFA (MCE: HYP0242A); Cells: CHO-K1 (ATCC); Plasmid: humanNK3 receptor overexpression plasmid (NM_001059.3, Azenta Life Science).

[0514] 3. Experimental Methods: 1. Day 1: Digest and collect CHO-K1 cells, resuspend and count them, then adjust the seeding to 100 mm culture dishes, with a seeding density of 1.5 × 10⁶ cells per dish. 6 Cells. Place the cell plate in a 37 ℃, 5% CO2 incubator overnight.

[0515] 2. Day 2: Transfect CHO-K1. The transfection system for plasmid in a 100 mm culture dish is: 18 μg plasmid + 54 μL transfection reagent + 450 μL Opti-MEM.

[0516] 3. Day 3: Digest and count the cells after transient transfection, and seed them into 384-well test cell plates at 2.0 × 10⁶ cells / well. 4 Cells / 40 μL / well. Incubate the cell plate overnight at 37°C in a 5% CO2 cell culture incubator.

[0517] 4. Day 4: Prepare the stimulation buffer according to the IP-1 kit instructions. Invert the cell plate and centrifuge at 300 rpm for 30 seconds to remove the supernatant.

[0518] 5. Add 24 μL of stimulation buffer to each well and incubate in a 5% CO2 incubator in the dark for equilibration; 6. Prepare a concentration gradient of the compound to be tested, and use a nanoliter liquid-liquid separator to add 200 nL of the compound to the cells and incubate for half an hour; 7. Manually add 4 µL of agonist (final concentration of EC80 of agonist) to the cell plate, incubate at 37 ℃ for 45 min, then add 6 µL of IP-1 d2 and 6 µL of IP-1 Tb Cryptate Antibody in sequence, centrifuge at 1000 rpm for 60 seconds at room temperature, and incubate at room temperature for 2 h.

[0519] 8. Read the microplate with the EnVision microplate reader using the HTRF program, and collect data simultaneously.

[0520] Experimental data processing method: The EnVision microplate reader reads and collects the fluorescence signal value ratio (Ratio). According to the readings of the Low control (DMSO control) and High control (positive compound Fezolinetant) experimental groups, calculate the percentage antagonism data {% Antagonism rate = (Ratio sample - Ratio low control) / (Ratio high control - Ratio low control) × 100}. The concentrations of the test compounds are 12 concentrations from 30 uM to 0.17 nM after being diluted 3 times in the reaction system. Use Graphpad to fit the percentage antagonism rate and the 12-point concentration data to the parametric non-linear logistic formula to calculate the IC 50 value.

[0521] 4. Experimental conclusion: The compounds in the embodiments of the present invention showed good antagonistic activity in the transient expression NK3 cell function IP1 experiment, and the IC 50 value is less than 500 nM, preferably the compound is less than 100 nM, and more preferably the compound is less than 50 nM.

[0522] Test Example 5. Pharmacokinetic determination in SD rats 1. Research purpose: Using SD rats as the test animals, study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma and brain tissue) after oral administration at a dose of 5 mg / kg.

[0523] 2. Experimental protocol: 2.1 Experimental drugs: The compounds in the embodiments of the present invention, self-made.

[0524] 2.2 Experimental animals: 21 male SD rats in each group, from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

[0525] 2.3 Formulation prescription: 0.5% CMC-Na (1% Tween80), dissolved by ultrasound to prepare a clear solution or a homogeneous suspension.

[0526] 2.4 Administration: Each group consisted of 21 male SD rats. After fasting overnight, the rats were administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0527] 2.5 Sample Collection: Before and af...

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: Selected from single or double bonds; X1 or X2 is independently selected from CH, N, O or C(O); X3, X4, and X5 are each independently selected from C or N; X6 is selected from CH or N; Y1 is selected from CH, C(O), N, NH, O, S or does not exist; Y2, Y3, Y4, or Y5 are each independently selected from CH, C(O), N, NH, O, or S; Ring A is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroalkyl or heterocyclic group, wherein the aromatic heteroalkyl or heterocyclic group is optionally substituted with one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R1, R2, R3, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R3 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R3 groups form a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R1 groups form a cycloalkyl, heterocyclic, aryl, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Or, R1, R 11 It forms a cycloalkyl, heterocyclic, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, or heteroaryl group is optionally substituted with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, or -(CH2). n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; R aa Or R bb Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, or t are each independently 0, 1, 2, 3, or 4; z is 0, 1, or 2; m1 can be 0, 1, 2, or 3; n1 or n2 can be 0, 1, 2 or 3 independently; The conditions are: When X1, X2, X4, and X6 are N, X3 and X5 are C, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is -C(O)-, -CF2-, -CHCF3-, or -NHC(O)-, L2 is a bond, and R2 is selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, ... , , , , , , , , , , , , , , , , , , , , , , or When one of the substituents is substituted, y is 0 or 1, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring A is not [a specific value]. , , , , , , , , , , , , , , , , , , , , , , , , , , or ; When X1, X4, and X6 are N, X3 and X5 are C, X2, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, z is 0, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... or ; When X2, X4, and X6 are N, X3 and X5 are C, X1, Y1, Y2, Y3, Y4, and Y5 are CH, L1 is C(O), L2 is a bond, R2 is a methyl group, y is 1, z is 1, and R1, R2, R3, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, then ring A is not... .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The general formula (I-1) is further shown as general formula (IV): in: Selected from , , , , , , , , , , , , , or ; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, and C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 3-14 heteroaryl or carboxyl, wherein the amino, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl or 3-14 heteroaryl groups, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Haloalkenyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 One or more substituents of aryl, 3-14 heteroaryl or carboxyl groups are used for substitution; Alternatively, R6 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally replaced by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, R6 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; Alternatively, the two R6 groups form a cycloalkyl, heterocyclic, aryl, or heteroaryl group with the attached atom, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally converted by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-8 Alkyl, C 1-8 Deuterated alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Hydroxyalkyl, C 1-8 Cyano-substituted alkyl groups or -(CH2) n1 C(O)(CH2) n2 R aa One or more substituents are substituted in the sample; s can be 0, 1, or 2.

3. A compound of general formula (II) or a pharmaceutically acceptable salt thereof: in: Y1, Y2, Y3, Y4, or Y5 are each independently selected from CH or N; Cycle A or Cycle B is each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, alkynylcarboxyl, or dialkylamino groups; Alternatively, ring A does not exist; L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroyl or heterocyclic group, wherein the aromatic heteroyl or heterocyclic group is optionally substituted by one or more substituents selected from oxo, alkyl, alkenyl, alkynyl, halogen, amino, hydroxyl, cyano, nitro, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl. R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R1, R2, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, and -(CH2). n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, mercapto, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, R1 and R2 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R1 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Alternatively, R2 and R4 form a cycloalkyl or heterocyclic group with the attached atom, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano alkyl groups. Or, R1, R 11 The cycloalkyl, heterocyclic or heteroaryl group is formed with the attached atom, and the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted with one or more substituents from the group consisting of hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl or cyano. R aa Or R bb Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups, wherein the amino, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, deuterated alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, alkylacyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups; x, y, or t are each independently 0, 1, 2, or 3; m1 can be 0, 1, 2, or 3; n1 or n2 can be 0, 1, 2 or 3 independently; The conditions are: When ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, -CF2-, -CHCF3-, or -NHC(O)-, L2 is a bond, and R 21 Selected from hydrogen, methyl, ethyl, propyl, hydroxyethyl, , , , , , , , , , , , , , , , , , , , , , , or When one of the substituents is substituted, y is 0 or 1. When R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are attached to, ring A is not [a specific value]. , , , , , , , , , , , , , , , , , , , , , , , , , , or ; When ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, L2 is a bond, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are connected to. In this case, ring A is not a cycloalkyl or heterocyclic group. or ; When ring B is ,in This indicates that ring B is connected to L1. This indicates that ring B is connected to L2, and L1 is -C(O)-, L2 is a bond, and R1, R2, and R4 do not form cycloalkyl or heterocyclic groups with the atoms they are connected to. In this case, ring A is not a cycloalkyl or heterocyclic group. .

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, Ring A is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, carboxyl, dicarboxyl 1-6 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample; Preferably, ring A is selected from C. 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 aryl, 5-12 membered heteroaryl containing 1-3 N, O or S atoms, carboxyl, dicarbonyl 1-3 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample; More preferably, ring A is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-5 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 Aryl, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, carboxyl, dicarbonyl 1-3 Alkylamino or -(CH2) n1 O(CH2) n2 R aa One or more substituents are substituted in the sample; More preferably, ring A is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused-heteroaryl containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 6-12 Aryl, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, carboxyl, dicarbonyl 1-3 Alkylamino or -(CH2) n1 OR aa One or more substituents are substituted in the sample; More preferably, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Optionally, it can be replaced by hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, dimethylamino, -CD3, , , , , , , , , , , , , or One or more substituents are substituted in the sample; More preferably, ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Optionally, it can be replaced by hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, dimethylamino, -CD3, , , , , , , , , , , , , or One or more substituents are substituted in which This indicates that ring A is connected to L2; Alternatively, ring A does not exist.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, Ring B is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; Preferably, ring B is selected from C. 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 Aryl or 5-14 membered heteroaryl containing 1-5 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 N, O or S atoms, C 6-12 A aryl group or a 5-14 membered heteroaryl group containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; More preferably, ring B is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-14 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-14 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C group. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; More preferably, ring B is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-13 member fused heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-13 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, a 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or an 8-13 membered fused heteroaryl containing 1-4 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, oxo group, halogen, amino group, hydroxyl group, cyano group, nitro group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; More preferably, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... , , , , , , , , , , , , , , , or It may be optionally substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or carboxyl. More preferably, ring B is selected from... , , , , , , , , , , , , , , , , or Optionally substituted with one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or carboxyl, wherein This indicates that ring B is connected to L1. This indicates that ring B is connected to L2.

6. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, characterized in that, L1 or L2 are each independently selected from the bond, -C(O)-, -(CR-). 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - An aromatic heteroyl or heterocyclic group, wherein the aromatic heteroyl or heterocyclic group is optionally surrounded by an oxo group or a C-shaped group. 1-6 Alkyl, C2 1-6 alkenyl, C 2-6 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; R 11 R 12 R 13 Or R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally surrounded by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 The aryl group, a 5-12 membered heteroaryl group, or a carboxyl group is substituted by one or more substituents. Preferably, L1 or L2 is independently selected from bond, -C(O)-, -(CR)-, etc. 11 R 12 ) m1 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - A 5-8 membered aromatic heteromethyl group containing 1-3 N, O, or S atoms, or a 3-8 membered heterocyclic heterocyclic group containing 1-3 N, O, or S atoms, wherein the aromatic heteromethyl group or heterocyclic group is optionally surrounded by an oxo group or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; R 11 R 12 R 13 Or R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl groups, including amino, hydroxyl, cyano, nitro, and C groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl groups, optionally replaced by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, or C4 groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 It is substituted by one or more substituents, including aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-14 member fused heteroaryl containing 1-4 N, O or S atoms; More preferably, L1 or L2 is independently selected from the bond, -C(O)-, and -CR. 11 R 12 -、-O-、-S-、-C(O)NR 13 -、-NR 13 C(O)-、-C(S)NR 13 -、-NR 13 C(S)-、-NR 14 - A 5-6 membered aromatic heteromethyl group containing 1-3 N, O, or S atoms, or a 3-6 membered heterocyclic heteromethyl group containing 1-3 N, O, or S atoms, wherein the aromatic heteromethyl group or heterocyclic heteromethyl group is optionally surrounded by an oxo group or a C group. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl or carboxyl group are substituted; R 11 R 12 R 13 Or R 14 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, phenyl, benzyl, or naphthyl, wherein the amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, phenyl, benzyl, or naphthyl groups are optionally substituted by one or more substituents selected from hydroxyl, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, or trifluoroethyl groups; More preferably, L1 or L2 is independently selected from bonds, -C(O)-, -CH2-, -CH(CH3)-, -O-, -S-, -C(O)NH-, -NHC(O)-, -C(S)NH-, -NHC(S)-, , or The or It may optionally be substituted by one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or carboxyl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, R1, R2, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl, carboxyl, -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, thiol, and C groups mentioned above 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; Alternatively, R1 and R2 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, R1 and R4 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, R2 and R4 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Or, R1, R 11 Forming C with the attached atoms 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, two R1 atoms form C with the adjacent atoms. 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 The aryl group or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 Aryl or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12 heteroaryl, carboxyl, and the aforementioned amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; Preferably, R1, R2, or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 N, O or S atoms, carboxyl, -OR aa -NR aa R bb -NR aa C(O)R bb -C(O)NR aa R bb Or -N=S(O)R aa R bb The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. Alternatively, R1 and R2 form C with the adjacent atoms. 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in the alkyl group are substituted; Alternatively, R1 and R4 form C with the adjacent atoms. 3-10 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-15 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in the alkyl group are substituted; Alternatively, R2 and R4 form C with the adjacent atoms. 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in the alkyl group are substituted; Or, R1, R 11 Forming C with the attached atoms 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in the alkyl group are substituted; Alternatively, two R1 atoms form C with the adjacent atoms. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 The aryl group or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 Alkyl, Halogenated C 1-3 Alkoxy, C 1-3 Deuterated alkyl or C 1-3 One or more substituents in the deuterated alkoxy group are substituted; R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, and a carboxyl group, wherein the amino, hydroxyl, and C groups are present. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group is substituted with one or more substituents selected from 1-3 5-10 heteroaryl or carboxyl groups chosen from N, O or S atoms; More preferably, R aa Or R bb Each is independently selected from hydrogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, , or It may be optionally substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl. More preferably, R1, R2, or R4 are each independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, acetyl, -NHCH3, -NHCH2CH3, -CD3, -OCD3, -SCH3, -OCF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or The amino, methylamino, dimethylamino, hydroxy, mercapto, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, -NHCH3, -NHCH2CH3, etc. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or It may be optionally substituted by one or more substituents of hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl. Alternatively, R1 and R2 form with the adjacent atoms or It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, R1 and R4 form with the adjacent atoms It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, R2 and R4 form with the adjacent atoms or It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Or, R1, R 11 Formed with adjacent atoms It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, two R1 atoms form with the adjacent atoms. , , , , , , , , , , , , , , , , , , , , , or It may optionally be substituted by one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, carboxyl, -CD3, or -OCF3.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl, carboxyl, -(CH2) n1 O(CH2) n2 R aa -(CH2) n1 NR aa (CH2) n2 R bb -(CH2) n1 NR aa C(O)R bb -(CH2) n1 C(O)NR aa R bb Or -(CH2) n1 N=S(O)R aa R bb The amino, hydroxyl, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Alternatively, R3 and R4 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, two R3 atoms form C with the adjacent atoms. 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12 heteroaryl, carboxyl, and the aforementioned amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl, 5-12 heteroaryl or carboxyl groups are used for substitution; Preferably, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 N, O or S atoms, carboxyl, -OR aa -NR aa R bb -NR aa C(O)R bb -C(O)NR aa R bb Or -N=S(O)R aa R bb The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. Alternatively, R3 and R4 form C with the adjacent atoms. 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or 5-10 membered heterocyclic group, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo group or C 1-3 One or more substituents in the alkyl group are substituted; Alternatively, two R3 atoms form C with the adjacent atoms. 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in the alkyl group are substituted; R aa Or R bb Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, and a carboxyl group, wherein the amino, hydroxyl, and C groups are present. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group is substituted with one or more substituents selected from 1-3 5-10 heteroaryl or carboxyl groups chosen from N, O or S atoms; More preferably, R aa Or R bb Each is independently selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, , or It may be optionally substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl. More preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, -NHCH3, -N(CH3)2, , , , , , , , , , or The amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, -NHCH3, -N(CH3)2, etc. , , , , , , , , , or It may be optionally substituted by one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl. Alternatively, R3 and R4 form with the adjacent atoms or It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, two R3 atoms form with the adjacent atoms. or It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

9. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12 heteroaryl, carboxyl, and the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 2-6 alkenyl, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Alternatively, R6 and R2 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, R6 and R4 form C with the adjacent atoms. 3-12 Cycloalkyl or containing 1-6 3-16 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-12 Cycloalkyl or 3-16 membered heterocyclic groups containing 1-6 N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Alternatively, two R6 atoms form C with the adjacent atoms. 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 The aryl group or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, or S atoms, C 6-12 Aryl or containing 1-5 5-12 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Or, R6, R 11 Forming C with the attached atoms 3-12 Cycloalkyl, 3-16 membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14 membered heteroaryl groups containing 1-5 N, O, or S atoms, wherein the C 3-12 Cycloalkyl, 3-16-membered heterocyclic groups containing 1-6 N, O, or S atoms, or 5-14-membered heteroaryl groups containing 1-5 N, O, or S atoms, optionally prefixed with hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl or cyano-substituted C 1-6 One or more substituents in the alkyl group are substituted; Preferably, R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 aryl, containing 1-3 5-10 heteroaryl or carboxyl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydrogen, deuterium, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. Alternatively, R6 and R2 form C with the adjacent atoms. 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl or containing 1-4 5-10 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in the alkyl group are substituted; Alternatively, R6 and R4 form C with the adjacent atoms. 3-5 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, wherein the C 3-15 Cycloalkyl or containing 1-4 5-15 membered heterocyclic groups selected from N, O or S atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, oxo or C. 1-3 One or more substituents in the alkyl group are substituted; Alternatively, two R6 atoms form C with the adjacent atoms. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 The aryl group or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 Alkyl, Halogenated C 1-3 Alkoxy, C 1-3 Deuterated alkyl or C 1-3 One or more substituents in the deuterated alkoxy group are substituted; Or, R6, R 11 Forming C with the attached atoms 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered monoheteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, or 5-6 membered mono-heteroaryl groups containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, or C. 1-3 One or more substituents in the alkyl group are substituted; More preferably, R6 is selected from fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, etc. , , , or The amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, , , , or It may be optionally substituted by one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, or carboxyl. Alternatively, R6 and R2 form with the adjacent atoms or It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, R6 and R4 form with the adjacent atoms It may be optionally substituted with one or more substituents selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl or isopropyl. Alternatively, two R6 atoms form with the adjacent atoms. , , , , , , , , , , , , , , , , , , , , , or It may be optionally substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, acetyl, carboxyl, -CD3, or -OCF3. More preferably, R6, R 11 Formed with adjacent atoms It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, oxo, methyl, ethyl, or isopropyl.

10. The following compounds or their pharmaceutically acceptable salts are shown below, with the specific structures of the compounds as follows: 。 11. A method for preparing the compound of claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, It includes the following steps: Deprotection of general formula (M-1) yields a compound of general formula (M-2) or a pharmaceutically acceptable salt thereof; then, general formula (M-2) undergoes a condensation reaction with general formula (M-3) to yield a compound of general formula (IV) or a pharmaceutically acceptable salt thereof; in, Pg is selected from amino protecting groups, preferably allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, benzyl or p-toluoxy; more preferably 2,4-dimethoxybenzyl or tert-butyloxycarbonyl. R is selected from halogen, hydroxyl group, or -C(O)OR A The preferred elements are fluorine, chlorine, bromine, iodine, or hydroxyl; more preferably, chlorine or hydroxyl. R A Selected from C 1-6 alkyl; The definitions of X1, X2, X3, X4, X5, R2, R3, R6, y, z, and s are as described in claim 2.

12. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claims 1-10 and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. The use of the compound, stereoisomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, in the preparation of NK inhibitor-related drugs, preferably in the preparation of NK3 inhibitor-related drugs.

14. The use of the compound of any one of claims 1-10, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 12 in the preparation of a medicament for the treatment and / or prevention of psychotic disorders, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, sex hormone-dependent diseases or gynecological diseases.

15. The use of any compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, in the preparation of a medicament for the treatment and / or prevention of menopausal syndrome, polycystic ovary syndrome, uterine fibroids, schizophrenia, irritable bowel syndrome, vasomotor syndrome, or breast cancer-related diseases, wherein the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, or obesity.

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