Benzo-fused nitrogen-containing heterocyclic derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a benzo-fused nitrogen-containing heterocyclic derivative, a preparation method therefor, and a use thereof. In particular, the present invention relates to a benzo-fused nitrogen-containing heterocyclic compound, a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a modulator in preparation of a medicament for treating metabolic diseases and related diseases.

Description

A benzo[a] nitrogen-containing heterocyclic derivative, its preparation method and application

[0001] Cross-reference to related applications

[0002] This application claims priority to international application PCT / CN2024 / 139904, filed on December 17, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention belongs to the field of pharmaceutical biology, specifically relating to a benzo[a] nitrogen-containing heterocyclic derivative, its preparation method, and its application. Background Technology

[0004] Diabetes mellitus is a common endocrine and metabolic disease caused by metabolic disorders resulting from various factors, leading to damage to multiple systems and organs. It has a high incidence rate, with approximately 425 million people living with diabetes worldwide. In China, the incidence rate is about 10%, with type 2 diabetes accounting for 90% of cases. Moreover, the prevalence is increasing, and the age of onset is becoming increasingly younger.

[0005] Currently, there are many types of drugs available for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and α-glucosidase inhibitors, among which GLP-1 receptor agonists have attracted the most attention.

[0006] GLP-1 is a peptide hormone secreted by L cells in the human intestine. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, neurons in the central nervous system, and peripheral nervous system. Activation of GLP-1 receptors promotes insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays gastric emptying. Clinical evidence shows that compared to other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effects and are less likely to cause side effects such as hypoglycemia. Furthermore, they offer additional cardiovascular benefits and can reduce food intake and delay gastric emptying, which is beneficial for weight control.

[0007] Currently available GLP-1 receptor agonists are all peptide drugs, most of which require subcutaneous administration, leading to poor patient compliance. Furthermore, the bioavailability of orally administered peptides is very low. Therefore, there is a significant clinical need to develop oral small-molecule GLP-1 receptor agonists.

[0008] Currently, no small molecule GLP-1 receptor agonists have been approved, indicating a significant clinical need. Lower-cost, better-compliant oral small molecule GLP-1 receptor agonists hold promise for treating a variety of metabolic diseases and have a broad market prospect. Summary of the Invention

[0009] The object of this invention is to provide compounds of general formula (XIX), their prodrugs, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0010] in,

[0011] R 13 -(CH2) n1 Cyclopropyl, optionally, the cyclopropyl group may be further substituted with halogen, hydroxyl or methyl;

[0012] L1, L2, or L3 are bonds;

[0013] Ring A is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0014] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1- 6-alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 1-6 One or more substituents in the deuterated haloalkoxy group are substituted;

[0015] Ring C is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1- 6-alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy or C 1-6 One or more substituents in the deuterated haloalkoxy group are substituted;

[0016] Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl groups;

[0017] Ring E is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0018] R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 14 R 15 Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0019] R c1 R c3 Or R c4 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 Rb1 Or -(CH2) m4 C(O)OR a2 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0020] R a1 R a2 R b1 Or R c2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0021] Or, R 9 Or R 16 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups;

[0022] Or, when n is not 1,

[0023] R 1 and R 1 R 4 and R 5 R 5 and R 6 R 7 and R 8 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0024] n, n1, m1, m2, m3 or m4 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0025] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0026] Ring A is selected from C 3-12 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or containing 1-3 5-12 heteroaryl groups selected from N, O or S atoms;

[0027] Preferably, ring A is selected from C. 6-12 Cycloalkyl, 6-12 membered heterocyclic groups containing 1-3 N, O or S atoms, or 6-12 membered heteroaryl groups containing 1-3 N, O or S atoms;

[0028] More preferably, ring A is selected from

[0029] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0030] Ring B is selected from C 3-8 Cycloalkyl groups, 3-8 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 further substituted with deuterium, halogen, amino, oxo, mercapto, thio, or C. 1-3 One or more substituents in the alkyl group are substituted;

[0031] Preferably, ring B is selected from C. 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, or 5-8 membered heteroaryl group containing 1-3 N, O or S atoms; optionally further coated with deuterium, halogen, amino, oxo, thio or C 1-3One or more substituents in the alkyl group are substituted;

[0032] More preferably, ring B is selected from Optional further additions include deuterium, halogen, amino, oxo, thio, or C. 1-3 It is replaced by one or more substituents in the alkyl group.

[0033] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0034] Ring C is selected from C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms; optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy or C 1-3 One or more substituents in the deuterated haloalkoxy group are substituted;

[0035] Preferably, ring C is selected from C 3-8 Cycloalkyl, containing 1-3 3-8 membered heterocyclic groups selected from N, O, or S, or containing 1-3 5-8 membered heteroaryl groups selected from N, O, or S; optionally further decorated with deuterium, hydroxyl, thiol, oxo, or C. 1-3 One or more substituents in the haloalkoxy group are substituted;

[0036] More preferably, ring C is selected from Optionally, it may be further substituted with one or more of the following substituents: deuterium, hydroxyl, thio, or oxo.

[0037] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0038] Ring D is selected from C 3-8 Cycloalkyl groups, 3-8 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;

[0039] Preferably, ring D is selected from C.3-6 Cycloalkyl, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, or 5-8 membered heteroaryl groups containing 1-3 N, O or S atoms;

[0040] More preferably, ring D is selected from

[0041] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0042] Ring E is selected from C 3-8 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 further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1- 3-hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0043] Preferably, ring E is selected from Optionally substituted with one or more of the following substituents: methyl, ethyl, methoxy, or ethoxy.

[0044] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0045] R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 14 R 15 Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0046] Preferably, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 14 R 15 Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 The amino group, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, -(CH2) m1 OR c1 Or (=C)R c3 R c4 Optional further additions include deuterium, amino, halogen, deuterated methyl, hydroxyl, methyl, cyclopropyl, oxo, thio, and C. 1-3 Alkyl or C 1-3 One or more substituents in the alkoxy group are substituted;

[0047] More preferably, R 1 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 14 R 15 Or R 16 Each group is independently selected from hydrogen, oxo, thio, cyano, methyl, fluorine, chlorine, cyclopropyl, ethynyl, and -(CH2). m1 ORc1 Or (=C)R c3 R c4 The cyclopropyl, ethynyl, and -(CH2) groups mentioned above. m1 OR c1 Or (=C)R c3 R c4 Optional further additions include deuterium, fluorine, chlorine, bromine, hydroxyl, -CD3, methyl, ethyl, cyclopropyl, oxo, thio, or... One or more substituents in it are replaced.

[0048] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0049] R c1 R c3 Or R c4 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0050] Preferably, R c1 R c3 Or R c4 Selected from fluorine, methyl, cyano, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl, oxetane, phenyl, -(CH2). m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino, methyl, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, cyclopropyl, oxetane, phenyl, -(CH2) group is mentioned. m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2)m4 C(O)OR a2 Optionally, it may be further substituted with one or more substituents selected from deuterium, halogen, methoxy, deuterated methyl, or hydroxyl.

[0051] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0052] R a1 R a2 R b1 Or R c2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0053] Preferably, R a1 R a2 R b1 Or R c2 Each of the following is independently selected from fluorine, methyl, ethyl, -CH2F, cyano, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl, oxetane, or phenyl, wherein the amino, methyl, ethyl, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, cyclopropyl, oxetane, or phenyl is optionally further substituted by one or more substituents selected from deuterium, halogen, methoxy, deuterated methyl, or hydroxyl.

[0054] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0055] R 9 Or R 16 The atoms connected to it link to form C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-8 membered heteroaryl groups selected from N, O or S atoms;

[0056] Preferably, R 9 Or R 16 The atoms connected to it link to form cyclopropyl groups.

[0057] In a further preferred embodiment of the invention, the compound of general formula (XIX):

[0058] R 1 and R 1 R 4 and R 5 R 5 and R 6 R 7 and R 8 The atoms connected to it link to form C 3-6Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0059] Preferably, R 1 and R 1 R 4 and R 5 R 5 and R 6 R 7 and R 8 The atoms connected to it respectively form cyclopropyl groups, Optionally, it may be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, oxo, thio, methyl, or ethyl.

[0060] The object of this invention is to provide a compound of general formula (XVIII), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0061] in,

[0062] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 14 R 15Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0063] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m2 OR c2-(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0064] R a1 R a2 R b1 Or R c2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0065] Or, R 9 Or R 16 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups;

[0066] or,

[0067] R 1 and R 10 R 2 and R 12 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 10 and R 12 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12Aryl or 5-12 heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0068] R 13 L1, L2, L3, ring A, ring B, ring C, and ring E are as described in general formula (XIX);

[0069] n1, m1, m2, m3 or m4 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0070] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0071] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 14 R 15 Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 membered heteroaryl, or -(CH2) m1 OR c1 The amino group, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0072] Preferably, R 1 R 2 R 3 R 4 R5 R 6 R 7 R 8 R 9 R 10 R 12 R 14 R 15 Or R 16 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 2-4 alkynyl group, C 3-6 cycloalkyl, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups or -(CH2) m1 OR c1 The amino group, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups or -(CH2) m1 OR c1 Optional further additions include deuterium, amino, halogen, deuterated methyl, hydroxyl, methyl, cyclopropyl, oxo, thio, and C. 1-3 Alkyl or C 1-3 One or more substituents in the alkoxy group are substituted;

[0073] More preferably, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 14 R 15 Or R 16 Each group is independently selected from hydrogen, oxo, thio, cyano, methyl, fluorine, chlorine, cyclopropyl, ethynyl, or -(CH2). m1 OR c1 The cyclopropyl, ethynyl, or -(CH2) group mentioned above. m1 OR c1 Optional further additions include deuterium, fluorine, chlorine, bromine, hydroxyl, -CD3, methyl, ethyl, cyclopropyl, oxo, thio, or... One or more substituents in it are replaced.

[0074] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0075] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-8 quinone heteroaryl, -(CH2) m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2Optional further additions include deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0076] Preferably, R c1 Selected from fluorine, methyl, cyano, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl, oxetane, phenyl, -(CH2). m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 The amino, methyl, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, cyclopropyl, oxetane, phenyl, -(CH2) group is mentioned. m2 OR c2 -(CH2) m3 C(O)NR a1 R b1 Or -(CH2) m4 C(O)OR a2 Optionally, it may be further substituted with one or more substituents selected from deuterium, halogen, methoxy, deuterated methyl, or hydroxyl.

[0077] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0078] R a1 R a2 R b1 Or R c2 Each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, and C. 1-3 Alkyl, C 1-3Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl, wherein the amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8-membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0079] Preferably, R a1 R a2 R b1 Or R c2 Each of the following is independently selected from fluorine, methyl, ethyl, -CH2F, cyano, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl, oxetane, or phenyl, wherein the methyl, ethyl, -CH2F, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl, oxetane, or phenyl is optionally further substituted by one or more substituents selected from deuterium, halogen, methoxy, deuterated methyl, or hydroxyl.

[0080] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0081] R 9 Or R 16 The atoms connected to it link to form C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-8 membered heteroaryl groups selected from N, O or S atoms;

[0082] Preferably, R 9 Or R 16 The atoms connected to it link to form cyclopropyl groups.

[0083] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0084] R 1 and R 10 R 2 and R 12 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 10 and R 12 The atoms connected to it link to form C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally further modified by deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-Deuterated hydroxyalkyl, C1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0085] Preferably, R 1 and R 10 R 2 and R 12 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 10 and R 12 The atoms connected to it respectively form cyclopropyl groups, Optionally, it may be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, oxo, thio, methyl, or ethyl.

[0086] In a further preferred embodiment of the invention, the compound of general formula (XVIII):

[0087] R 1 and R 10 R 2 and R 12 R 4 and R 5 R 5 and R 6 R 7 and R 8 R 10 and R 12 The atoms connected to it respectively form cyclopropyl groups, Optionally, it may be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, amino, nitro, hydroxyl, cyano, oxo, thio, methyl, or ethyl.

[0088] In a further preferred embodiment of the invention, the compound of general formula (XVIII) is further shown as general formula (XVIII-A):

[0089] Among them, rings A, B, C, E, and R 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 R 15 R 16 The definitions of L1, L2 and L3 are as described in general formula (XVIII).

[0090] In a further preferred embodiment of the invention, the compound of general formula (XVIII) is further shown as general formula (XVIII-B):

[0091] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 12 R 13 R 14 R 15 The definitions of L1 and L1 are as described in general formula (XVIII).

[0092] In a further preferred embodiment of the invention, the compound of general formula (XVIII) is further shown as general formula (XVIII-1):

[0093] In a further preferred embodiment of the invention, the compound of general formula (XVIII) is further shown as general formula (XVIII-A-1):

[0094] In a further preferred embodiment of the invention, the compound of general formula (XVIII) is further shown as general formula (XVIII-B-1):

[0095] The object of this invention is to provide a compound of general formula (V), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0096] in,

[0097] R 4R 5 Or R 6 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl, wherein the amino group, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0098] Or, R 5 and R 6 Linked with adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1- 6-thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0099] R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 -NR a5 S(O)NR a4 R b4 -(CH2) n2 R a5 R b5 or The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0100] R a1 R b1 R a2 R b2 R a3 R b3 R a4 R b4 R a5 R b5 R a6 Or R b6 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0101] Or, R a1 and R b1 R a2 and R b2 R a3 and R b3 R a4 and R b4 R a5 and R b5 R a6 and R b6 They link with adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0102] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0103] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aromatic or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0104] R 12 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic, 5-10 heteroaryl, -(CH2) n2 R a5 R b5 or Optional further additions include halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, oxo groups, and C groups. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0105] n1-n3 are integers from 0 to 5;

[0106] m1 is an integer from 0 to 5;

[0107] Where R 7 R 8 For hydrogen, R 9 R 10 R 12 It is methyl, R 3 R 5 When it is fluorine, R 4 and R 6 Not both methyl;

[0108] When R 7 and R 8 For hydrogen, R 9 R 10 R 12 It is methyl, R 3 For hydrogen, R 5 When it is halogen, R 4 and R 6 Not both methyl;

[0109] When R 7 R 8 R 9 R 10 R 12 It is methyl, R 5 When it is fluorine, R 4 When R is halogen, trifluoromethyl, or cyclopropyl, 6 They are not both hydrogen;

[0110] When R 7 R 8 R 9 R 10 It is methyl, R 12 It is a deuterated methyl group, R 3 It is fluorine, R 5 When it is halogen, R 4 When it is a deuterated methyl group, R 6 Not simultaneously deuterated methyl;

[0111] When R 4 R 6 R 7 R 8 R 9 R 10 It is methyl, R 3 R 5 When it is fluorine, R 12Not simultaneously deuterated methyl;

[0112] When R 7 R 8 R 9 R 10 R 12 It is methyl, R 3 It is fluorine, R 5 When it is halogen, R 4 When it is methyl, R 6 Not both methyl;

[0113] When R 7 R 8 R 9 R 10 It is methyl, R 12 It is a deuterated methyl group, R 3 It is fluorine, R 5 When it is halogen, R 4 When it is a deuterated methyl group, R 6 Not simultaneously deuterated methyl;

[0114] When R 4 R 6 R 7 R 8 R 9 R 10 It is methyl, R 3 R 5 When it is fluorine, R 12 It is not simultaneously a deuterated methyl group.

[0115] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0116] R 4 R 5 Or R 6 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, and C. 1-3 Alkyl, C 1-3 thioalkyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms; optionally further halogenated, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 One or more substituents in the alkoxy group are substituted;

[0117] Preferably, R 4 R 5 Or R 6 Each is independently selected from fluorine, methyl, cyano, ethynyl, methylthio, amino, cyclopropyl, and oxetane; optionally further substituted by halogen, methoxy, or deuterated methyl.

[0118] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0119] R 5 and R 6 Linked with adjacent atoms to form C 3-6 Cycloalkyl, 3-8 membered heterocyclic, C6-10 aryl, or 5-8 membered heteroaryl, optionally further modified by halogen, amino, C 1-3 The alkyl group or oxo group is substituted by one or more substituents.

[0120] Preferably, R 5 and R 6 Linked with adjacent atoms to form 5-7 membered heterocyclic groups containing 1-3 N, O, or S; optionally further bonded by halogens, amino groups, C... 1-3 The alkyl group or oxo group is substituted by one or more substituents.

[0121] More preferably, R 5 and R 6 Formed by linking with adjacent atoms Optional further additions of halogens, amino groups, and C 1-3 It is replaced by one or more substituents among alkyl and oxo groups.

[0122] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0123] R 7 R 8 Each is independently selected from deuterium or C. 1-6 Deuterated alkyl groups;

[0124] Preferably, R 7 R 8 Each is independently selected from deuterium or C. 1-3 Deuterated alkyl groups.

[0125] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0126] R 9 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aromatic or 5-10 heteroaryl groups, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0127] Preferably, R 9 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-8 Aromatic or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 The substituent is one or more of the following: cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl or 5-8 membered heteroaryl;

[0128] More preferably, R 9 Selected from cyano, cyclopropyl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6It is substituted by one or more substituents selected from cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl, or 5-8 membered heteroaryl.

[0129] In another embodiment of the invention, the compound of general formula (V) is:

[0130] R 9 The carbon atoms linked to it form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0131] Preferably, R 9 The carbon atoms linked to it form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0132] More preferably, R 9 The carbon atoms attached to it are further preferentially linked to form a cyclopropyl group.

[0133] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0134] R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl, 5-8 membered heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 -NR a5 S(O)NR a4 R b4 -(CH2) n2 R a5 R b5 or The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 The substituent is one or more of the following: cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl or 5-8 membered heteroaryl;

[0135] Preferably, R 3 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 -NR a5 S(O)NR a4 R b4 -(CH2) n2 R a5 R b5 or The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, optionally further halogenated, -NS(O)R a1 R b1 Or C 1- It is substituted by one or more substituents in the 3 alkyl group.

[0136] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0137] R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0138] Preferably, R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl, 5-8 membered heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocyclic, C6-10 aryl, or 5-8-membered heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 The substituent is one or more of the following: cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl or 5-8 membered heteroaryl;

[0139] More preferably, R 3 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, optionally further halogenated, -NS(O)R a1 R b1 Or C 1-3 It is replaced by one or more substituents in the alkyl group.

[0140] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0141] R 12 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n2 R a5 R b5 or Optional further additions include halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, oxo groups, and C groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0142] Preferably, R 12 Selected from methyl, cyclopropyl, and -(CH2) groups. n2 R a5 R b5 or Optional further additions include halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, oxo groups, and C groups. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 It is substituted by one or more substituents in aryl or 5-8 heteroaryl groups.

[0143] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0144] R 12Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl groups, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0145] Preferably, R 12 Selected from C 1-3 alkyl;

[0146] More preferably, R 12 Selected from methyl.

[0147] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0148] R a1 R b1 R a2 R b2 R a3 R b3 R a4 R b4 R a5 R b5 R a6 Or R b6 Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl;

[0149] Preferably, R a1 R b1 R a2 R b2 R a3 R b3 R a4 R b4 R a5 R b5 R a6 Or R b6 Each is independently selected from hydrogen, deuterium, halogen, or methyl.

[0150] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0151] R a1 and R b1 R a2 and R b2 R a3 and R b3 R a4 and R b4 R a5 and R b5 R a6 and R b6 They link with adjacent atoms to form C 3-8 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl;

[0152] Preferably, R a2 and R b2 R a3 and R b3 They link with adjacent atoms to form C 3-8 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 heteroatoms.

[0153] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0154] R a1 R b1 R a2 R b2 R a3 R b3 R a4 Or R b4 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0155] Preferably, R a1 R b1 R a2 R b2 R a3 R b3 R a4 Or R b4 Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0156] More preferably, R a1 R b1 R a2 R b2 R a3 R b3 R a4 Or R b4 Each is independently selected from hydrogen, deuterium, halogen, or methyl.

[0157] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0158] R a1 and R b1 R a2 and R b2 R a3 and R b3 R a4 and R b4 They link with adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0159] Preferably, R a1 and R b1 R a2 and R b2 R a3 and R b3 R a4 and R b4 They link with adjacent atoms to form C 3-8 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl;

[0160] More preferably, R a2 and R b2 R a3 and R b3 They link with adjacent atoms to form C 3-8 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 heteroatoms.

[0161] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0162] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl groups, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0163] Preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1- 3-Hydroalkyl;

[0164] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl groups.

[0165] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0166] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 3-alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aromatic or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0167] Preferably, R 7 R 8 R 9 Or R10 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0168] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl, fluorine, cyclopropyl, or ethynyl.

[0169] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0170] R 7 R 8 R 9 Or R 10 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups;

[0171] Preferably, R 7 R 8 R 9 Or R 10 The atoms connected to it link to form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6- 10 Aryl or 5-8 quinone heteroaryl;

[0172] More preferably, R 7 R 8 R 9 Or R 10 The atoms connected to it link to form cyclopropyl groups.

[0173] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0174] R 12 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C6-10 Aromatic or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 It is substituted by one or more substituents in aryl or 5-8 heteroaryl groups.

[0175] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0176] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0177] Preferably, R 7 R 8 R 9 Or R 10Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aromatic, 5-8 quinone heteroaryl or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0178] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups or -(CH2) m1 OR c1 ;

[0179] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl, fluorine, cyclopropyl, ethynyl, or -(CH2). m1 OR c1 .

[0180] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0181] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0182] Preferably, R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2- 4-Alynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aromatic or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0183] More preferably, R c1 It is selected from fluorine, methyl, cyano, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl or oxetane; optionally further substituted by halogen, methoxy or deuterated methyl.

[0184] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0185] R 10 The atoms bonded to it and adjacent atoms link together to form C. 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups;

[0186] Preferably, R 10 The atoms bonded to it and adjacent atoms link together to form C. 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 quinone heteroaryl;

[0187] More preferably, R 10 The atoms connected to it and the adjacent atoms link together to form

[0188] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0189] R 10 The atoms connected to it and the adjacent atoms link together to form

[0190] In a further preferred embodiment of the invention, the compound of general formula (V) is:

[0191] R 10 The atoms connected to it and the adjacent atoms link together to form

[0192] In a further preferred embodiment of the invention, the compound of general formula (V) is further shown as general formula (V-1):

[0193] On the other hand, the present invention provides a compound of general formula (VI), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0194] Ring F contains 1-2 elements selected from N, O, and S(O). m The 5-6 membered heterocyclic group of S(O)NH may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, methyl, cyclopropyl or oxo group;

[0195] m is 0, 1, or 2;

[0196] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Or R 12 As defined by general formula (V).

[0197] On the other hand, the present invention provides a compound of general formula (XVI-A), its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0198] in,

[0199] Further as As shown, optionally further reacted with halogens, methoxy groups, C 1- 3-cycloalkyl, C 3-6 It is substituted by one or more substituents in cycloalkyl or deuterated methyl groups;

[0200] L1 and L2 are bonds;

[0201] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl; optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, mercapto, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 One or more substituents in the haloalkoxy group are substituted;

[0202] Ring E is selected from C 3-8Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 heteroaryl containing 1-3 N, O or S atoms;

[0203] Ring M1, Ring M2, Ring M3, Ring M4, Ring M5, Ring M6, Ring M7, Ring M8, M9 or M 10 Each is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, optionally further bonded by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1- 6-Hydroalkoxy, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0204] R 4 R 5 Or R 6 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C2-6 alkynyl group, C 3- 8-cycloalkyl, 3-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0205] R 7 R 8 R 9 R 10 R 12 R 13 Or R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0206] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0207] Or, R 7 R 8 R 9 Or R 10 The atoms connected to it link to form C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6- 12 Aryl or 5-12 heteroaryl groups;

[0208] m1 is an integer from 0 to 5.

[0209] In a further preferred embodiment of the present invention, the compound of general formula (XVI-A):

[0210] Ring M1, Ring M2, Ring M3, Ring M4, Ring M5, Ring M6, Ring M7, Ring M8, M9 or M10 Each is independently selected from C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-8-membered heteroaryl containing 1-3 N, O or S atoms, optionally further bonded by halogen, methoxy, C 1-3 cycloalkyl, C 3-6 It is substituted by one or more substituents in cycloalkyl or deuterated methyl groups.

[0211] In a further preferred embodiment of the present invention, the compound of general formula (XVI-A):

[0212] In general formula (XVI-A) Further as As shown, optionally further reacted with halogens, methoxy groups, C 1-3 cycloalkyl, C 3-6 It is substituted by one or more substituents in cycloalkyl or deuterated methyl groups;

[0213] Rings M1, M2, M3, M4, M5, M6, M7, or M8 are each independently selected from C. 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, optionally further bonded by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6-Deuterated hydroxyalkyl, C 1-6 thioalkyl, C 1-6 Deuterated thioalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0214] In a further preferred embodiment of the present invention, the compound of general formula (XVI-A):

[0215] In general formula (XVI-A) Further as As shown, optionally further reacted with halogens, methoxy groups, C 1-3 cycloalkyl, C 3-6 It is substituted by one or more substituents in cycloalkyl or deuterated methyl groups;

[0216] Rings M1, M2, M3, M4, M5, M6, M7, or M8 are each independently selected from C. 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Deuterated hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Deuterated thioalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0217] Preferably, rings M1, M2, M3, M4, M5, M6, M7, or M8 are each independently selected from C. 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-8-membered heteroaryl containing 1-3 N, O or S atoms, optionally further bonded by halogen, methoxy, C 1-3 cycloalkyl, C 3-6 It is substituted by one or more substituents in cycloalkyl or deuterated methyl groups.

[0218] In a further preferred embodiment of the present invention

[0219] R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0220] Preferably, R 3 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10Aryl, 5-8 quinone heteroaryl, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-8 heteroaryl, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, -NS(O)R a1 R b1 C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 The substituent is one or more of the following: cycloalkyl, 3-6 membered heterocyclic, C6-10 aryl or 5-8 membered heteroaryl;

[0221] More preferably, R 3 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups, -NS(O)R a1 R b1 -(CH2) n1 S(O)NR a2 R b2 -P(O)R a3 R b3 or -NR a5 S(O)NR a4 R b4 The amino group, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3Haloalkyl, optionally further halogenated, -NS(O)R a1 R b1 Or C 1-3 It is replaced by one or more substituents in the alkyl group.

[0222] In a further preferred embodiment of the present invention

[0223] R 4 R 5 Or R 6 Each is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0224] Preferably, R 4 R 5 Or R 6 Each is independently selected from fluorine or methyl.

[0225] In a further preferred embodiment of the present invention

[0226] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0227] Preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl groups.

[0228] In a further preferred embodiment of the present invention:

[0229] R 4 R 5 Or R 6 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, and C. 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0230] Preferably, R 4 R 5 Or R 6 Each is independently selected from fluorine, cyano, cyclopropyl, or methyl.

[0231] In a further preferred embodiment of the present invention:

[0232] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0233] Preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl or cyclopropyl.

[0234] In a further preferred embodiment of the present invention:

[0235] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aromatic or 5-10 heteroaryl groups, optionally further modified by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 It is substituted by one or more substituents in aryl or 5-10 heteroaryl groups.

[0236] In a further preferred embodiment of the present invention:

[0237] R 7 R 8 R 9 Or R 10 The atoms connected to it link to form C3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups;

[0238] Preferably, R 7 R 8 R 9 Or R 10 The atoms connected to it link to form C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6- 10 Aryl or 5-8 quinone heteroaryl;

[0239] More preferably, R 7 R 8 R 9 Or R 10 The atoms connected to it link to form cyclopropyl groups.

[0240] In a further preferred embodiment of the present invention:

[0241] R c1 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 Hydroxyalkyl, C 1-3 thioalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aromatic or 5-8-membered heteroaryl, optionally further converted by halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0242] Preferably, R c1 It is selected from fluorine, methyl, cyano, difluoromethyl, trifluoromethyl, ethynyl, methylthio, amino, cyclopropyl or oxetane; optionally further substituted by halogen, methoxy or deuterated methyl.

[0243] In a further preferred embodiment of the present invention:

[0244] R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1- 6-alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6- 10 The aryl group or one or more substituents in the 5-10 heteroaryl group are substituted;

[0245] Preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aromatic, 5-8 quinone heteroaryl or -(CH2) m1 OR c1 Optional further additions of halogen, amino, nitro, hydroxyl, cyano, oxo, C1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group or one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0246] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 2-4 alkynyl group, C 3-6 cycloalkyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups or -(CH2) m1 OR c1 ;

[0247] More preferably, R 7 R 8 R 9 Or R 10 Each is independently selected from methyl, fluorine, cyclopropyl, ethynyl, or -(CH2). m1 OR c1 .

[0248] In a further preferred embodiment of the present invention:

[0249] Ring E is selected from

[0250] In a further preferred embodiment of the present invention:

[0251] Ring E is selected from

[0252] In a further preferred embodiment of the present invention:

[0253] Ring E is selected from

[0254] In a further preferred embodiment of the present invention:

[0255] Ring B is selected from C 3-6Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, or 5-8 membered heteroaryl group containing 1-3 N, O or S atoms; optionally further coated with halogen, amino, oxo, thio or C 1-3 One or more substituents in the alkyl group are substituted;

[0256] Preferably, ring B is selected from

[0257] In a further preferred embodiment of the invention, the compound of general formula (IV) is:

[0258] Ring B is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; optionally further coated with halogen, amino, oxo, thio or C 1-3 One or more substituents in the alkyl group are substituted;

[0259] Preferably, ring B is selected from

[0260] In a further preferred embodiment of the present invention:

[0261] Ring B is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, or 5-10 membered heteroaryl group containing 1-3 N, O or S atoms; optionally further coated with halogen, amino, oxo, thio or C 1-3 One or more substituents in the alkyl group are substituted;

[0262] Preferably, ring B is selected from

[0263] In a further preferred embodiment of the present invention:

[0264] Ring B is selected from

[0265] On the other hand, the present invention provides compounds as shown below:

[0266] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0267] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0268] 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.

[0269] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0270] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its prodrug, its stereoisomer or its pharmaceutically acceptable salt 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.

[0271] In some embodiments of the invention, the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof may be administered by any convenient method, such as by oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0272] In some embodiments of the invention, the compound, its prodrug, its stereoisomer, or its pharmaceutically acceptable salt may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0273] The present invention further relates to the use of any of the general formula compounds shown, their prodrugs, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of GLP-1 receptor agonist drugs.

[0274] The present invention further relates to the use of compounds of the general formula, their prodrugs, their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating metabolic-related diseases, wherein the diseases are selected from diabetes, obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.

[0275] The present invention further relates to a method of preparing a medicament for treating metabolic diseases and related diseases using compounds of the general formula, prodrugs thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0276] The present invention also relates to a method for treating, preventing, and / or treating metabolic-related diseases, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0277] 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 GLP-1 receptor modulators.

[0278] The present invention also relates to a method for treating metabolic disease-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.

[0279] Detailed description of the invention

[0280] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0281] 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 substituent can be substituted at any usable connection point. 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 groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0282] 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.

[0283] 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.

[0284] The term "alkenyl" refers to an alkenyl group in which one hydrogen atom is further substituted, for example, "vinylene" refers to -CH2=CH2-, and "propenylene" refers to -CH2-=CH2-CH2-, etc. The alkenyl 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, and heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even 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, cyclopentyl, cyclohexyl, and cycloheptyl.

[0285] 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 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0286] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0287] 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:

[0288] 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:

[0289] 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.

[0290] 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 portion 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 10 ring atoms; even more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, aziridine, oxacyclobutane, oxacyclohexane, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, etc.; preferably pyrrolidinyl, aziridine, oxacyclobutane, tetrahydrofuranyl, pyrazolyl, morpholinyl, etc. Piperazinyl and pyranyl; furthermore, pyrrolyl, azirrocyclobutyl, oxetaneyl, oxetanehexyl, piperidinyl, Piperazinyl and pyranyl. 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.

[0291] 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 ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It 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. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0292] 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:

[0293] 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:

[0294] 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:

[0295] 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.

[0296] 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 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0297] 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.

[0298] 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 10-membered, more preferably 5 to 8-membered, and most 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 or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, and pyrimidinyl. 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:

[0299] 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.

[0300] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. 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.

[0301] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0302] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0303] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0304] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms. The alkenyl group 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.

[0305] "Alkyne" refers to (CH≡C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms. The alkynyl group 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.

[0306] The term "ethynyl" refers to a group where one hydrogen atom of the alkynyl group is further substituted; for example, "ethynyl" refers to -C≡C- and "propenyl" refers to -C≡C-CH2-. The ethynyl group (containing three or more carbon atoms) 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.

[0307] "Fused ring group" refers to a polycyclic group formed by two or more carbon rings or heterocycles sharing a common ring edge. Fused ring groups include fused ring alkyl, fused ring heteroaryl, fused ring aryl, and fused ring heteroaryl. The fused ring alkyl refers to a polycyclic group formed by a cycloalkyl group and a heterocyclic group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring heterocyclic group refers to a polycyclic group formed by a heterocyclic group and a cycloalkyl group, aryl group, or heteroaryl group sharing a common ring edge; the fused ring aryl group refers to a polycyclic group formed by an aryl group and a cycloalkyl group, heterocyclic group, or heteroaryl group sharing a common ring edge; the fused ring heteroaryl group refers to a polycyclic group formed by a heteroaryl group and a cycloalkyl group, heterocyclic group, or heterol group sharing a common ring edge. For example:

[0308] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0309] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0310] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0311] "Hydroxy" refers to the -OH group.

[0312] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0313] "Amino" refers to -NH2.

[0314] “Cyano” refers to -CN.

[0315] "Nitro" refers to -NO2.

[0316] "Carboxyl group" refers to -C(O)OH.

[0317] "THF" refers to tetrahydrofuran.

[0318] “EtOAc” refers to ethyl acetate.

[0319] “MeOH” refers to methanol.

[0320] "DMF" refers to N,N-dimethylformamide.

[0321] "DIPEA" refers to diisopropylethylamine.

[0322] "TFA" refers to trifluoroacetic acid.

[0323] “MeCN” refers to Yi Qing.

[0324] “DMA” stands for N,N-dimethylacetamide.

[0325] “Et2O” refers to diethyl ether.

[0326] “DCE” refers to 1,2-dichloroethane.

[0327] "DIPEA" refers to N,N-diisopropylethylamine.

[0328] “NBS” refers to N-bromosuccinimide.

[0329] “NIS” refers to N-iodosuccinimide.

[0330] “Cbz-Cl” refers to benzyl chloroformate.

[0331] “Pd2(dba)3” refers to tris(dibenzylacetone)dipalladium.

[0332] “Dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene.

[0333] “HATU” refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0334] "KHMDS" refers to potassium hexamethyldisilamide.

[0335] "LiHMDS" refers to lithium bis(trimethylsilyl)amine.

[0336] “MeLi” refers to methyl lithium.

[0337] “n-BuLi” refers to n-butyllithium.

[0338] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0339] 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.

[0340] 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.

[0341] "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.

[0342] "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).

[0343] "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.

[0344] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0345] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0346] Example

[0347] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0348] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0349] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0350] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0351] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0352] Example 1

[0353] 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0354] Step 1: (4-bromo-2-fluorophenyl)(imino)(methyl)-1,6-thionone

[0355] Ammonium carbamate (2.82 g, 36.18 mmol) and [diacetoxy)iodo]benzene (8.74 g, 27.14 mmol) were added sequentially to a MeOH (100 mL) solution of (4-bromo-2-fluorophenyl)(methyl)thione (2 g, 9.05 mmol). The mixture was stirred at room temperature for 0.5 h, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oily substance (4-bromo-2-fluorophenyl)(imino)(methyl)-16-thionone (2 g, yield: 87.7%).

[0356] MS m / z (ESI): 251.9 253.9 [M+H].

[0357] Step 2: (4-Bromo-2-fluorophenyl)(methyl)(methylimino)-16-thionone

[0358] To a DMF (10 mL) solution of (4-bromo-2-fluorophenyl)(imino)(methyl)-16-thionone (600 mg, 2.38 mmol), NaH (190.38 mg, 4.76 mmol, 60%) was added, and the mixture was stirred at room temperature for 30 minutes. Then, iodomethane (675.62 mg, 4.76 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oily substance (4-bromo-2-fluorophenyl)(methyl)(methylimino)-16-thionone (600 mg, yield: 94.7%).

[0359] MS m / z(ESI): 266.0 268.0 [M+H].

[0360] Step 3: Tert-butyl(4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0361] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (100 mg, 226.50 μmol), (4-bromo-2-fluoro-phenyl)-methyl-methylimino-carbonyl-thione (120.56 mg, 453.00 μmol) were dissolved in NMP (5 mL), followed by the sequential addition of CuI (34.51 mg, 181.20 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (32.22 mg, 226.50 μmol), and potassium carbonate (93.77 mg, 453.77 μmol). (mg, 679.51 μmol), replaced with nitrogen, heated to 130℃ for 3 hours, cooled to room temperature, added water and saturated ammonium chloride solution, extracted with EtOAc, the organic phase was washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow solid tert-butyl(4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg, yield: 42.3%).

[0362] MS m / z (ESI): 627.2 [M+H].

[0363] Step 4: 1-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0364] TFA (1 mL) was added dropwise to a 2 mL solution of tert-butyl(4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (20 mg, 31.91 μmol) in DCM. The mixture was stirred at room temperature for 0.5 hours. LC-MS showed that the reaction was complete and the target product was present. MS, evaporate to dryness, adjust pH to 10 with saturated NaHCO3, extract three times with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness, and give a pale yellow oily substance 1-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (18 mg, crude product).

[0365] MS m / z (ESI): 527.2 [M+H].

[0366] Step 5: 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0367] To 5-(2,2-dimethyltetrahydropyran-4-yl)-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (21.10 mg, 51.27 μmol), 1-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylbenzene) A solution of 3 mL of pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (18 mg, 34.18 μmol) in DMF was added with HATU (19.34 mg, 51.27 μmol) and DIEA (8.84 mg, 68.36 μmol, 11.91 μL). The mixture was stirred at room temperature for 16 hours, then water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oil. The oil was separated by preparative chromatography (acidic) to obtain a white solid 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(N,S-dimethylsulfonamide)-3-fluorophenyl)-2-carbonyl-2,3-dihydro-1H- Imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (5 mg, yield: 15.9%)

[0368] MS m / z (ESI): 920.3 [M+H].

[0369] Example 2

[0370] 3-(1-(7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indene-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0371] Step 1: 6-Bromo-3,4-dihydroquinoline-2(1H)-thione

[0372] A mixture of 6-bromo-3,4-dihydroquinoline-2(1H)-one (1 g, 4.42 mmol), Lawson's reagent (1.79 g, 4.42 mmol), and toluene (20 mL) was stirred at 110 °C for 2 hours, cooled, concentrated directly with silica gel, and separated by column chromatography (petroleum ether / ethyl acetate = 4:1) to give a pale yellow solid 6-bromo-3,4-dihydroquinoline-2(1H)-thione (340 mg, yield: 31.7%).

[0373] MS m / z(ESI): 241.9 243.9 [M+H]

[0374] Step 2: 7-Bromo-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline

[0375] A mixture of 6-bromo-3,4-dihydroquinoline-2(1H)-thione (340 mg, 1.40 mmol), acetylhydrazine (124.83 mg, 1.69 mmol), and 1-butanol (10 mL) was stirred at 120 °C for 16 hours, cooled, concentrated directly with silica gel, and separated by column chromatography (DCM / MeOH = 10:1) to give 7-bromo-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (280 mg, yield: 75.5%).

[0376] MS m / z(ESI): 264.0 266.0 [M+H].

[0377] Step 3: Tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0378] The following substances were added: tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (80 mg, 181.20 μmol), 7-bromo-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (95.72 mg, 362.40 μmol), CuI (27.61 mg, 144.96 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (25.77 mg, 181.20 μmol), and potassium carbonate (75.02 mg, 543.60 μmol). The mixture of NMP (5 mL) and water was stirred at 130 °C for 5 hours under nitrogen protection, cooled, and extracted with DCM. The organic phases were combined and washed three times with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow solid tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (80 mg, yield: 70.7%).

[0379] MS m / z (ESI): 625.3 [M+H].

[0380] Step 4: (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one

[0381] Add 1 mL of TFA dropwise to a DCM solution (3 mL) of tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (80 mg, 76.84 μmol), stir at room temperature for 0.5 hours, evaporate to dryness, and add saturated N2. Adjust the pH to 10 with aHCO3, extract three times with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain a pale yellow oil (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, crude product).

[0382] MS m / z (ESI): 525.2 [M+H].

[0383] Step 5: 3-(1-(7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indene-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0384] To 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl) azido-2-carboxylic acid (36.36 mg, 91.50 μmol), (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyrazolium A solution of 30 mg (57.19 μmol) of pyridin-3-yl)-3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, 57.19 μmol) in DMF (3 mL) was added with HATU (43.15 mg, 114.37 μmol) and DIEA (22.17 mg, 171.56 μmol, 29.88 μL). The mixture was stirred at room temperature for 16 hours, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, yielding a pale yellow oil. Preparative chromatography (acidic) was used to separate the oil into a white solid 3-(1-(7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl- 3-(3-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indene-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (13.2 mg, yield 23.6%)

[0385] MS m / z (ESI): 904.4 [M+H].

[0386] Example 3

[0387] 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide

[0388] Step 1: 2-(4-bromo-2-nitrophenyl)-N,N-dimethylacetamide

[0389] HATU (2.90 g, 7.69 mmol) was added to a DCM solution of 2-(4-bromo-2-nitrophenyl)acetic acid (1 g, 3.85 mmol), triethylamine (1.17 g, 11.54 mmol, 1.61 mL), and dimethylamine hydrochloride (470.37 mg, 5.77 mmol) in 15.80 mL. The mixture was stirred at room temperature for 12 hours, and then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oily substance, 2-(4-bromo-2-nitrophenyl)-N,N-dimethylacetamide (800 mg, yield: 72.5%).

[0390] MS m / z(ESI): 287.0 289.0 [M+H].

[0391] Step 2: 2-(2-amino-4-bromophenyl)-N,N-dimethylacetamide

[0392] Sodium dithionite (1.94 g, 11.15 mmol) was added to a solution of 2-(4-bromo-2-nitrophenyl)-N,N-dimethylacetamide (400 mg, 1.39 mmol) in 20 mL of EtOH and 15 mL of water. The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with EtOH. The filtrate was extracted with water and 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. The filtrate was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give 2-(2-amino-4-bromophenyl)-N,N-dimethylacetamide (200 mg, yield: 55.8%).

[0393] MS m / z(ESI): 257.0 259.0 [M+H].

[0394] Step 3: 2-(4-bromo-2-(dimethylamino)phenyl)-N,N-dimethylacetamide

[0395] A mixture of iodomethane (165.61 mg, 1.17 mmol), 2-(2-amino-4-bromophenyl)-N,N-dimethylacetamide (100 mg, 388.91 μmol), potassium carbonate (161.01 mg, 1.17 mmol), and DMF (3 mL) was stirred in a microwave oven at 80 °C for 5 hours. Water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oily substance, 2-(4-bromo-2-(dimethylamino)phenyl)-N,N-dimethylacetamide (68 mg, yield: 61.3%).

[0396] MS m / z(ESI): 285.0 287.0 [M+H].

[0397] Step 4: tert-Butyl(S)-3-(3-(3-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)phenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0398] The following substances were added: tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (40 mg, 90.60 μmol), 2-(4-bromo-2-(dimethylamino)phenyl)-N,N-dimethylacetamide (38.76 mg, 135.90 μmol), CuI (13.80 mg, 72.48 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (12.89 mg, 90.60 μmol), and potassium carbonate (37.51 mg, 271.80 μmol). The mixture of l) and NMP (4 mL) was stirred at 130 °C for 4 hours under nitrogen protection, cooled, and water was added. The mixture was extracted with DCM, and the combined organic phases were washed three times with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oily substance, tert-butyl(S)-3-(3-(3-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)phenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (32 mg, yield: 54.7%).

[0399] MS m / z (ESI): 646.3 [M+H].

[0400] Step 5: (S)-2-(2-(dimethylamino)-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide

[0401] Add 1 mL of TFA dropwise to a DCM solution (32 mg, 49.55 μmol) of tert-butyl(S)-3-(3-(3-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)phenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (32 mg, 49.55 μmol), stir at room temperature for 0.5 hours, evaporate to dryness, and add saturated N2. Adjust the pH to 10 with aHCO3, extract three times with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain a pale yellow oily substance (S)-2-(2-(dimethylamino)-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide (24 mg, crude product).

[0402] MS m / z (ESI): 546.3 [M+H].

[0403] Step 6: 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide

[0404] To 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (27.15 mg, 65.98 μmol), (S)-2-(2-(dimethylamino)-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6 HATU (26.55 mg, 70.37 μmol) was added to a DMF (4 mL) solution of 7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide (24 mg, 43.98 μmol) and DIEA (11.37 mg, 87.97 μmol, 15.32 μL). The mixture was stirred at room temperature for 16 hours, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, yielding a pale yellow oil. Preparative chromatography (acidic) was used to separate the oil, yielding a white solid 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-( 5-Carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide (18 mg, yield: 43.6%)

[0405] MS m / z (ESI): 939.5 [M+H].

[0406] Example 4

[0407] 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5-fluorophenyl)-N,N-dimethylacetamide

[0408] Step 1: Diethyl-2-(4-bromo-5-fluoro-2-nitrophenyl)malonate

[0409] A mixture of diethyl malonate (3.70 g, 23.11 mmol) and 1-bromo-2,4-difluoro-5-nitrobenzene (5 g, 21.01 mmol) was added dropwise to a solution of sodium hydroxide (2.10 g, 52.52 mmol, 60%) in 50 mL of 1',4-Dioxane. The mixture was stirred at room temperature for 12 hours, then water was added, and the mixture was extracted three times with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give a pale yellow oil, diethyl 2-(4-bromo-5-fluoro-2-nitrophenyl)malonate (6 g, yield: 75.5%).

[0410] MS m / z(ESI): 378.0 380.0 [M+H].

[0411] Step 2: 2-(4-bromo-5-fluoro-2-nitrophenyl)acetic acid

[0412] A mixture of diethyl-2-(4-bromo-5-fluoro-2-nitrophenyl)malonate (6 g, 15.87 mmol) and hydrochloric acid (100 mL, 6 N) was stirred at 100 °C for 12 hours. Upon cooling, a solid precipitated out. After filtration, 2.5 g of white solid 2-(4-bromo-5-fluoro-2-nitrophenyl)acetic acid (yield: 56.7%) was obtained.

[0413] MS m / z(ESI): 278.0 280.0 [M+H].

[0414] Step 3: 2-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylacetamide

[0415] HATU (6.78 g, 17.98 mmol) was added to a DMF (30 mL) solution of 2-(4-bromo-5-fluoro-2-nitrophenyl)acetic acid (2.5 g, 8.99 mmol), triethylamine (2.73 g, 26.98 mmol, 3.76 mL), and dimethylamine hydrochloride (1.10 g, 13.49 mmol). The mixture was stirred at room temperature for 12 hours, then water was added, and the mixture was extracted with DCM. The combined organic phases were washed three times with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oily substance, 2-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylacetamide (1.5 g, yield: 54.7%).

[0416] MS m / z(ESI): 305.0 307.0 [M+H].

[0417] Step 4: 2-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylacetamide

[0418] To a DMF (20 mL) solution of 2-(4-bromo-5-fluoro-2-nitrophenyl)-N,N-dimethylacetamide (76.78 mg, 491.64 μmol), diboronic acid (1.76 g, 19.67 mmol) was added. The mixture was stirred at 0 °C for 10 minutes, cooled, and then water was added. The mixture was extracted with DCM. The combined organic phases were washed three times with water and then with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oily substance, 2-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylacetamide (900 mg, yield: 66.54%).

[0419] MS m / z(ESI): 275.0 277.0 [M+H].

[0420] Step 5: 2-(4-bromo-2-(dimethylamino)-5-fluorophenyl)-N,N-dimethylacetamide

[0421] A mixture of iodomethane (103.18 mg, 726.96 μmol), 2-(2-amino-4-bromo-5-fluorophenyl)-N,N-dimethylacetamide (100 mg, 363.48 μmol), potassium carbonate (150.48 mg, 1.09 mmol), and DMF (3 mL) was stirred in a microwave oven at 80 °C for 5 hours. Water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oily substance, 2-(4-bromo-2-(dimethylamino)-5-fluorophenyl)-N,N-dimethylacetamide (60 mg, yield: 54.5%).

[0422] MS m / z(ESI): 303.0 305.0 [M+H].

[0423] Step 6: Tert-butyl(S)-3-(3-(5-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0424] The following substances were added: 2-(4-bromo-2-(dimethylamino)-5-fluorophenyl)-N,N-dimethylacetamide (51.50 mg, 169.88 μmol), tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), CuI (17.25 mg, 90.60 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (16.11 mg, 113.25 μmol), and potassium carbonate (46.89 mg, 339.75 μmol). The mixture of ol) and NMP (3 mL) was stirred at 130 °C for 4 hours under nitrogen protection, cooled, and water was added. The mixture was extracted with DCM, and the organic phases were combined and washed three times with water. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oily substance, tert-butyl(S)-3-(3-(5-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (30 mg, yield: 39.9%).

[0425] MS m / z (ESI): 664.3 [M+H].

[0426] Step 7: (S)-2-(2-(dimethylamino)-5-fluoro-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide

[0427] Add 1 mL of TFA dropwise to a DCM solution (30 mg, 45.20 μmol) of tert-butyl(S)-3-(3-(5-(dimethylamino)-4-(2-(dimethylamino)-2-carbonylethyl)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (30 mg, 45.20 μmol), stir at room temperature for 0.5 hours, evaporate to dryness, and add saturated N2. The pH was adjusted to 10 with aHCO3, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow oily substance (S)-2-(2-(dimethylamino)-5-fluoro-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide (26 mg, crude product).

[0428] MS m / z (ESI): 564.3 [M+H].

[0429] Step 8: 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-5-fluorophenyl)-N,N-dimethylacetamide

[0430] To 5-(2,2-dimethyltetrahydropyran-4-yl)-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (28.47 mg, 69.19 μmol), (S)-2-(2-(dimethylamino)-5-fluoro-4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7 HATU (26.10 mg, 69.19 μmol) was added to a DMF (4 mL) solution of tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)-N,N-dimethylacetamide (26 mg, 46.13 μmol) and DIEA (11.92 mg, 92.26 μmol, 16.07 μL), and stirred at room temperature. Stir for 16 hours, add water, extract three times with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness, and obtain a pale yellow oily substance. Separate by preparative chromatography (acidic) to obtain a white solid 2-(2-(dimethylamino)-4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl) N,N-dimethylacetamide (13 mg, yield: 29.5%)

[0431] MS m / z (ESI): 957.5 [M+H].

[0432] Example 5

[0433] 3-((1S,2S)-1-(2-((4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0434] Step 1: (2,5-Difluorophenyl)(methyl-d3)thion

[0435] 2,5-Difluorophenylthiol (2.5 g, 17.10 mmol) was dissolved in THF (20 mL). NaH (1.03 g, 25.66 mmol, 60%) was added under ice-water bath conditions. After stirring at 0 °C for 0.5 hours, deuterated iodomethane (4.96 g, 34.21 mmol, 2.16 mL) was added dropwise. The reaction mixture was stirred at room temperature for another 2 hours. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give a colorless oily substance (2,5-difluorophenyl)(methyl-d3)thione (2.5 g, yield: 89.6%).

[0436] 1 H NMR (400MHz, CDCl3) δ6.98 (dt, J=8.9, 4.5Hz, 1H), 6.92 (ddd, J=8.8, 6.1, 3.2Hz, 1H), 6.84–6.77 (m, 1H).

[0437] Step 2: (4-bromo-2,5-difluorophenyl)(methyl-d3)thion

[0438] (2,5-Difluorophenyl)(methyl-d3)thion (2.5 g, 15.32 mmol) was dissolved in acetonitrile (25 mL), and liquid bromine (2.45 g, 15.32 mmol) was added at room temperature. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched by adding saturated sodium thiosulfate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to finally obtain a pale yellow solid (4-bromo-2,5-difluorophenyl)(methyl-d3)thion (2 g, yield: 53.9%).

[0439] MS m / z (ESI): 241.9 243.9 [M+H].

[0440] Step 3: (4-bromo-2,5-difluorophenyl)(imino)(methyl-d3)-16-thionone

[0441] To a solution of (4-bromo-2,5-difluorophenyl)(methyl-d3)thion (2 g, 8.26 mmol) in MeOH (15 mL), [dia(acetoxy)iodo]benzene (7.98 g, 24.78 mmol) and ammonium carbamate (2.58 g, 33.04 mmol) were added sequentially. The mixture was stirred at room temperature for 15 minutes, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oil ((4-bromo-2,5-difluorophenyl)(imino)(methyl-d3)-16-thionone (800 mg, yield: 35.5%)).

[0442] MS m / z(ESI): 273.0 275.0 [M+H].

[0443] 1 H NMR (400MHz, CDCl3) δ7.74 (dd, J=7.3, 5.9Hz, 1H), 7.50 (dd, J=8.4, 5.1Hz, 1H), 2.70 (s, 1H).

[0444] Step 4: (4-bromo-2,5-difluorophenyl)(methyl-d3)(methylimino)-1,6-thionone

[0445] Trimethyloxonium tetrafluoroborate (297.86 mg, 2.01 mmol) was added to a DCM solution of (4-bromo-2,5-difluorophenyl)(methyl-d3)-16-thionone (500 mg, 1.83 mmol) in 10 mL. The mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium carbonate (1.16 g, 10.98 mmol). The mixture was stirred at room temperature for 1 hour, and water was added. The mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a pale yellow oil (4-bromo-2,5-difluorophenyl)(methyl-d3)(methylimino)-16-thionone (260 mg, yield: 49.5%).

[0446] MS m / z(ESI): 287.0 289.0 [M+H].

[0447] 1 H NMR (400MHz, CDCl3) δ7.71 (dd, J=7.2, 5.8Hz, 1H), 7.49 (dd, J=8.3, 5.0Hz, 1H), 2.66 (s, 3H).

[0448] Step 5: (4-bromo-2-(cyclopropylamino)-5-fluorophenyl)(methyl)(methylimino)-1,6-thionone

[0449] A mixture of cyclopropylamine (79.54 mg, 1.39 mmol), (4-bromo-2,5-difluorophenyl)(methyl-d3)(methylimino)-16-thionone (200 mg, 696.50 μmol), potassium carbonate (288.8 mg, 2.08 mmol), and DMF (5 mL) was stirred at 120 °C for 12 hours. Water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oil (4-bromo-2-(cyclopropylamino)-5-fluorophenyl)(methyl)(methylimino)-16-thionone (60 mg, yield: 26.6%).

[0450] MS m / z(ESI): 321.0 323.0 [M+H].

[0451] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=8.0Hz,1H),7.36(d,J=5.5Hz,1H),6.80(s,1H),3 .01(s,3H),2.63(s,3H),2.45-2.41(m,1H),0.90-0.81(m,2H),0.61–0.46(m,2H).

[0452] Step 6: Tert-butyl(4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0453] The following substances were added: tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (45 mg, 101.93 μmol), (4-bromo-2-(cyclopropylamino)-5-fluorophenyl)(methyl)(methylimino)-16-thionone (49.57 mg, 152.89 μmol), CuI (15.53 mg, 81.54 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (14.50 mg, 101.93 μmol), and potassium carbonate (42.20 mg, 305.7 μmol). A mixture of 8 μmol NMP and 4 mL NMP was stirred at 130 °C for 3 hours under nitrogen protection, cooled, and extracted with DCM by adding water. The organic phases were combined and washed three times with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a pale yellow oily tert-butyl(4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (10 mg, yield: 14.3%).

[0454] MS m / z (ESI): 682.2 [M+H].

[0455] Step 7: 1-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0456] Add 1 mL of TFA dropwise to a 3 mL solution of tert-butyl(4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (10 mg, 14.67 μmol), stir at room temperature for 0.5 hours, evaporate to dryness, and add saturated... Adjust the pH to 10 with NaHCO3, extract three times with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain a pale yellow oily substance 1-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonyl)-2-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (5 mg, crude product).

[0457] MS m / z (ESI): 582.2 [M+H].

[0458] Step 8: 3-((1S,2S)-1-(2-((4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0459] To 5-(2,2-dimethyltetrahydropyran-4-yl)-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (7.07 mg, 17.19 μmol), 1-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-yl) ...N,S-dimethylsulfonamide)-3,5-yl)cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-3-(S)-2-(N,S-dimethylsulfonamide)-3,5-yl)cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-3-(S)-2-(N,S-dimethylsulfonamide HATU (6.49 mg, 17.19 μmol) and DIEA (3.33 mg, 25.79 μmol, 4.49 μL) were added to a DMF (2 mL) solution of (-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (5 mg, 8.60 μmol), and the mixture was stirred at room temperature for 1 minute. After 6 hours, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, yielding a pale yellow oil. Preparative chromatography (acidic) was used to separate the oil into a white solid 3-((1S,2S)-1-(2-((4S)-3-(3-(5-(cyclopropylamino)-4-(N,S-dimethylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1 H-Imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (5.3 mg, yield: 62.4%)

[0460] MS m / z (ESI): 975.4 [M+H].

[0461] Examples 6 and 7

[0462] Step 1: 3-(5-bromo-4-fluoro-2H-indazol-2-yl)-2,2-dimethylpropionitrile

[0463] 5-Bromo-4-fluoro-1H-indazole (0.2 g, 930.14 μmol) and 3-hydroxy-2,2-dimethylpropionitrile (184.41 mg, 1.86 mmol) were dissolved in 1',4-Dioxane (8 mL). Under nitrogen protection, cyanomethylenetri-n-butylphosphine (448.98 mg, 1.86 mmol) was added. The mixture was stirred at 110 °C for 12 hours. The reaction was quenched with saturated brine (50 mL), and the mixture was 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 (petroleum ether:ethyl acetate = 100:0 to 75:25 elution) to give the target product (80 mg, 270.14 μmol, 29.04% yield).

[0464] MS m / z(ESI): 296.0 [M+H].

[0465] Step 2: Tert-butyl(S)-3-(3-(2-(2-cyano-2-methylpropyl)-4-fluoro-2H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0466] tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), 3-(5-bromo-4-fluoro-2H-indazol-2-yl)-2,2-dimethylpropyl Nitrile (40.25 mg, 135.90 μmol) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (16.11 mg, 113.25 μmol) were dissolved in NMP (2 mL). Under nitrogen protection, cuprous iodide (10.78 mg, 56.63 μmol) and potassium carbonate (46.96 mg, 339.75 μmol) were added. The mixture was stirred at 130 °C for 5 hours. The reaction was quenched with saturated brine (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was 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 (petroleum ether:ethyl acetate = 100:0 to 30:70 elution) to give the target product (30 mg, 45.68 μmol, 40.34% yield).

[0467] MS m / z (ESI): 643.3 [M+H].

[0468] Step 3: (S)-3-(4-fluoro-5-(3-(2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2H-indazol-2-yl)-2,2-dimethylpropionitrile and (S)-3-(4-fluoro-5-(3-(2-(4-fluoro-3-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2H-indazol-2-yl)-2,2-dimethylpropionamide

[0469] tert-Butyl(S)-3-(3-(2-(2-cyano-2-methylpropyl)-4-fluoro-2H-indazole-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (30 mg, 45.68 μmol) was dissolved in dioxane hydrochloride (4 M, 2 mL). The mixture was stirred at 20 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product (25 mg, 44.91 μmol, 98.32% yield). The crude product was used directly in the next step.

[0470] MS m / z(ESI):543.2, 561.2[M+H].

[0471] Step 4: 3-(5-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-fluoro-2H-indazol-2-yl)-2,2-dimethylpropyl Nitriles and 3-(5-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-fluoro-2H-indazol-2-yl)-2,2-dimethylpropionamide

[0472] The mixture from step three (25 mg), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (22.18 mg, 53.90 μmol), and DIEA (34.83 mg, 269.49 μmol, 46.94 μL) were dissolved in DMF (2 mL), and HATU (25.62 mg, 67.37 μmol) was added under nitrogen protection. The mixture was stirred at 22 °C for 12 hours. The crude reaction solution was separated by preparative high performance liquid chromatography to obtain products P1 (4 mg, 4.13 μmol, 9.19% yield, 98% purity) and P2 (3 mg, 3.01 μmol, 6.69% yield, 97% purity), which were white solids.

[0473] Example 6, MS m / z (ESI): 950.4 [M+H].

[0474] Example 7, MS m / z (ESI): 968.4 [M+H].

[0475] Example 8

[0476] Step 1: tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(2-fluoro-4-(S-methylsulfonyl)phenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0477] tert-Butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), (4-bromo-3-fluorophenyl)(imino)(methyl)-16-thionone (57.10 mg, 226.50 μmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (16.11 mg, 113.25 μmol) were dissolved in NMP (2 mL). Under nitrogen protection, cuprous iodide (10.78 mg, 56.63 μmol) and potassium carbonate (46.96 mg, 339.75 μmol) were added. The mixture was stirred at 130°C for 5 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by adding saturated brine (20 mL), followed by stirring for another 0.5 hours. The mixture was separated; the aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed successively with saturated brine (30 mL × 3), 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 (60 mg, 97.93 μmol, 86.47% yield).

[0478] MS m / z (ESI): 613.2 [M+H].

[0479] Step 2: Tert-butyl(4S)-3-(3-(4-(N-cyano-S-methylsulfonyl)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0480] Dissolve 60 mg (97.93 μmol) and DMAP (13.16 mg, 107.72 μmol) in DCM (5 mL), and add cyanogen bromide (20.75 mg, 195.86 μmol) under nitrogen protection. The mixture is stirred at 23 °C for 12 hours. The reaction is quenched with saturated brine (50 mL), extracted with dichloromethane (20 mL), and the organic phases are combined and washed successively with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 10:90) to give the target product (62 mg, 97.22 μmol, 99.28% yield).

[0481] MS m / z (ESI): 638.2 [M+H].

[0482] Step 3: N-((3-fluoro-4-(3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)(methyl)(carbonyl)-16-thionyl)cyanoamide

[0483] tert-Butyl(4S)-3-(3-(4-(N-cyano-S-methylsulfonamide)-2-fluorophenyl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 78.41 μmol) was dissolved in DCM (3 mL), and dioxane hydrochloride (4 M, 3 mL) was added under nitrogen protection. The mixture was stirred at 23 °C for 1 hour. The reaction solution was evaporated to dryness to give crude product (42 mg, 73.17 μmol, 93.31% yield, CL), which was used directly in the next step.

[0484] MS m / z (ESI): 538.2 [M+H].

[0485] Step 4: N-((4-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-3-fluorophenyl)(methyl)(carbonyl)-16-thionyl)cyanoamide

[0486] N-((3-fluoro-4-(3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)(methyl)(carbonyl)-16-thionyl)cyanoamide (42 mg, 78.13 μmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4 1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (32.15 mg, 78.13 μmol) and DIEA (60.58 mg, 468.76 μmol, 81.65 μL) were dissolved in DMF (2 mL), and HATU (47.53 mg, 125.00 μmol) was added under nitrogen protection. The mixture was stirred at 23 °C for 12 hours. The crude product was separated by preparative high performance liquid chromatography to obtain the product (18 mg, 19.14 μmol, 24.50% yield, 99% purity), which was a white solid.

[0487] MS m / z (ESI): 931.3 [M+H].

[0488] Example 9

[0489] Step 1: tert-Butyl(S)-2-(trypan-6-yl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0490] The target compound was synthesized according to chemical formula 27 in CN109790161A.

[0491] MS m / z (ESI): 600.3 [M+H].

[0492] Step 2: (S)-1-(2-(trypanan-6-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0493] tert-Butyl(S)-2-(trypan-6-yl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (4 mg, 80.05 μmol) was dissolved in dioxane hydrochloride (4 M, 7 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was evaporated to dryness, and the crude product (42 mg, 78.36 μmol, 97.89% yield, CL) was used directly in the next step.

[0494] MS m / z (ESI): 500.3 [M+H].

[0495] Step 3: 3-((1S,2S)-1-(2-((S)-2-(trypan-6-yl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0496] (S)-1-(2-(trypan-6-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (42 mg, 78.36 μmol, CL), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S, 2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (38.69 mg, 94.03 μmol) and DIEA (50.64 mg, 391.79 μmol, 68.24 μL) were dissolved in DMF (2 mL), and HATU (47.67 mg, 125.37 μmol) was added under nitrogen protection. The mixture was stirred at 25 °C for 12 hours. The crude product was separated by preparative high performance liquid chromatography to obtain the product (14 mg, 15.36 μmol, 19.61% yield, 98% purity), which was a white solid.

[0497] MS m / z (ESI): 893.4 [M+H].

[0498] Example 10

[0499] 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(cyclopropylsulfonylimino)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0500] Step 1: (4S)-3-(3-(4-(cyclopropanesulfonylimino)-3-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0501] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 90.60 μmol), (4-bromo-2-fluorophenyl)-cyclopropyliminooxothioline (25.20 mg, 90.60 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (12.89 mg, 90.60 μmol), potassium carbonate (37.56 mg, 271.80 μmol), and cuprous iodide (17.25 mg, 90.60 μmol) were dissolved in N-methylpyrrolidone (5 mL). The reaction mixture was then protected with nitrogen and stirred at 130 °C for 2 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography using a dichloromethane and methanol eluent system to give the title product (4S)-3-[3-[4-(cyclopropylsulfonylimino)-3-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 62.62 μmol, 69.12% yield).

[0502] MS m / z (ESI): 639.2 [M+H]

[0503] Step 2: 1-(4-(cyclopropanesulfonylimino)-3-fluorophenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0504] In a 50 mL reaction flask, (4S)-3-[3-[4-(cyclopropylsulfonylimino)-3-fluoro-phenyl]-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 62.62 μmol) was dissolved in dichloromethane (2 mL), and a dioxane solution of hydrochloric acid (1 mL, 4 M) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 0.5 hours. The reaction was stopped, and the reaction solution was concentrated to give the title product 1-[4-(cyclopropylsulfonylimino)-3-fluorophenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (31 mg, 57.56 μmol, 91.91% yield).

[0505] MS m / z (ESI): 539.2 [M+H]

[0506] Step 3: 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(cyclopropylsulfonylimino)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0507] In a 50 mL reaction flask, 1-[4-(cyclopropylsulfonylimino)-3-fluorophenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (40 mg, 74.27 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1 ... [4-Oxadiazol-3-yl]cyclopropyl]indole-2-carboxylic acid (30.56 mg, 74.27 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28.02 mg, 74.27 μmol), and N,N-diisopropylethylamine (9.60 mg, 74.27 μmol, 12.94 μL) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the purified residue was prepared by prep-HPLC to give the title product 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(cyclopropylsulfonylimino)-3-fluorophenyl]-2-oxo [Imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (17 mg, 18.24 μmol, 24.56% yield)

[0508] MS m / z (ESI): 932.3 [M+H]

[0509] Example 11

[0510] 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(S-cyclopropyl-N-methylsulfonylimino)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0511] Step 1: (4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(3-fluoro-4-(N-methylcyclopropanesulfonylimino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0512] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 90.60 μmol), (4-bromo-2-fluorophenyl)-cyclopropylmethylaminooxothione (26.47 mg, 90.60 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (12.89 mg, 90.60 μmol), potassium carbonate (37.56 mg, 271.80 μmol), and cuprous iodide (17.25 mg, 90.60 μmol) were dissolved in N-methylpyrrolidone (5 mL). The reaction mixture was then protected with nitrogen and stirred at 130 °C for 2 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography using a dichloromethane and methanol eluent system to give the title product (4S)-3-[3-[4-(S-cyclopropyl-N-methylsulfonylimideyl)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 61.28 μmol, 67.64% yield).

[0513] MS m / z (ESI): 653.2 [M+H]

[0514] Step 2: 1-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(3-fluoro-4-(N-methylcyclopropanesulfonylimino)phenyl)-1,3-dihydro-2H-imidazol-2-one

[0515] In a 50 mL reaction flask, (4S)-3-[3-[4-(S-cyclopropyl-N-methylsulfonyliminoyl)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 61.28 μmol) was dissolved in dichloromethane (2 mL), and a dioxane solution of hydrochloric acid (1 mL, 4 M) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 0.5 hours. The reaction was stopped, and the reaction solution was concentrated to give the title product 1-[4-(S-cyclopropyl-N-methylsulfonylimino)-3-fluorophenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (31 mg, 56.09 μmol, 91.54% yield).

[0516] MS m / z (ESI): 553.2 [M+H]

[0517] Step 3: 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(S-cyclopropyl-N-methylsulfonylimino)-3-fluorophenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0518] In a 50 mL reaction flask, 1-[4-(S-cyclopropyl-N-methylsulfonylimino)-3-fluorophenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (40 mg, 72.38 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H- 1,2,4-Oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (29.78 mg, 72.38 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (27.31 mg, 72.38 μmol), and N,N-diisopropylethylamine (9.35 mg, 72.38 μmol, 12.61 μL) were dissolved in N,N-dimethylformamide (2 mL), and the reaction mixture was protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the purified residue was prepared by prep-HPLC to give the title product 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-(S-cyclopropyl-N-methylsulfonylimino)-3-fluorophenyl]-2 [-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (24.5 mg, 25.90 μmol, 35.78% yield)

[0519] MS m / z (ESI): 946.3 [M+H]

[0520] Example 12

[0521] 3-Cyclopropyl-6-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-7-fluoro-1,3-benzoxazol-2-one

[0522] Step 1: 3-Cyclopropyl-7-fluoro-1,3-benzoxazole-2-one

[0523] In a 50 mL reaction flask, 7-fluoro-3H-1,3-benzoxazol-2-one (200 mg, 1.31 mmol), potassium cyclopropyltrifluoroborate (579.88 mg, 3.92 mmol), copper acetate (130.40 mg, 653.12 μmol), potassium carbonate (361.06 mg, 2.61 mmol), and 1,10-phenanthroline (47.08 mg, 261.25 μmol) were dissolved in water (3 mL) and toluene (9 mL). The reaction solution was kept under oxygen protection and stirred at 70 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product 3-cyclopropyl-7-fluoro-1,3-benzoxazol-2-one (100 mg, 517.67 μmol, 39.63% yield).

[0524] MS m / z(ESI): 194.0 [M+H]

[0525] Step 2: 6-Bromo-3-cyclopropyl-7-fluoro-1,3-benzoxazol-2-one

[0526] In a 50 mL reaction flask, 3-cyclopropyl-7-fluoro-1,3-benzoxazole-2-one (100 mg, 517.67 μmol) and N-bromosuccinimide (101.35 mg, 569.43 μmol) were dissolved in acetic acid (5 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, the solvent was concentrated, and the reaction was quenched with an aqueous solution (10 mL). The mixture was 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 purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product 6-bromo-3-cyclopropyl-7-fluoro-1,3-benzoxazole-2-one (60 mg, 220.53 μmol, 42.60% yield).

[0527] MS m / z(ESI):271.9,273.9[M+H]

[0528] Step 3: (4S)-3-[3-(3-cyclopropyl-7-fluoro-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0529] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (50 mg, 113.25 μmol), 6-bromo-3-cyclopropyl-7-fluoro-1,3-benzoxazol-2-one (30.81 mg, 11...) were added... 3.25 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (16.11 mg, 113.25 μmol), potassium carbonate (46.96 mg, 339.75 μmol), and cuprous iodide (21.57 mg, 113.25 μmol) were dissolved in N-methylpyrrolidone (5 mL), and the reaction mixture was protected with nitrogen and stirred at 130 °C for 2 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed 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 purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product (4S)-3-[3-(3-cyclopropyl-7-fluoro-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, 94.84 μmol, 83.74% yield).

[0530] MS m / z (ESI): 633.2 [M+H]

[0531] Step 4: 3-Cyclopropyl-7-fluoro-6-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]-1,3-benzoxazol-2-one

[0532] In a 50 mL reaction flask, (4S)-3-[3-(3-cyclopropyl-7-fluoro-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, 94.84 μmol) was dissolved in dichloromethane (5 mL), and then a dioxane solution of hydrochloric acid (1 mL, 4 M) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. The reaction was stopped, and the reaction solution was concentrated to give the title product 3-cyclopropyl-7-fluoro-6-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]-1,3-benzoxazol-2-one (50 mg, 93.89 μmol, 99.00% yield).

[0533] MS m / z (ESI): 533.2 [M+H]

[0534] Step 5: 3-Cyclopropyl-6-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-

[0535] 4-Methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-7-fluoro-1,3-benzoxazol-2-one

[0536] In a 50 mL reaction flask, 3-cyclopropyl-7-fluoro-6-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-oxoimidazol-1-yl]-1,3-benzoxazol-2-one (40 mg, 75.11 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1)]-1,3-benzoxazol-2-one (40 mg, 75.11 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1)-1-yl ... [2,4-Oxadiazol-3-yl]cyclopropyl]indole-2-carboxylic acid (30.90 mg, 75.11 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28.34 mg, 75.11 μmol), and N,N-diisopropylethylamine (97.07 mg, 751.12 μmol, 130.83 μL) were dissolved in N,N-dimethylformamide (1.88 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the purified residue was prepared by prep-HPLC to give the title product 3-cyclopropyl-6-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2] [Methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-imidazol-1-yl]-7-fluoro-1,3-benzoxazol-2-one (45 mg, 48.60 μmol, 64.70% yield)

[0537] MS m / z (ESI): 926.3 [M+H]

[0538] Example 13

[0539] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-imino-1-oxo-1H-1l4-benzo[b]thiophene-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0540] Step 1: (4S)-3-[3-(benzothiophene-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0541] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (57.89 mg, 131.13 μmol), 5-bromobenzothiophene (55.89 mg, 262.26 μmol), (1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine (18.65 mg, 131.13 μmol), potassium carbonate (54.37 mg, 393.39 μmol), and cuprous iodide (24.97 mg, 131.13 μmol) were dissolved in N-methylpyrrolidone (5 mL). The reaction mixture was then protected with nitrogen and stirred at 130 °C for 1 hour. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography using a dichloromethane and methanol eluent system to obtain the title product (4S)-3-[3-(benzothiophene-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, 104.59 μmol, 79.76% yield).

[0542] MS m / z (ESI): 574.2 [M+H]

[0543] Step 2: (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-imino-1-oxo-benzothiophene-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0544] In a 100 mL reaction flask, (4S)-3-[3-(benzothiophene-5-yl)-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (60 mg, 104.59 μmol) was dissolved in methanol (2 mL), and then ammonium carbamate (40.83 mg, 522.94 μmol) and (diacetoxyiodine)benzene (67.38 mg, 209.18 μmol) were added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. LCMS showed a product peak. After concentration of the reaction solution, the residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to obtain the title product (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-imino-1-oxo-benzothiophene-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 66.15 μmol, 63.25% yield).

[0545] MS m / z (ESI): 605.2 [M+H]

[0546] Step 3: 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-imino-1-oxo-benzothiophene-5-yl)imidazol-2-one

[0547] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-imino-1-oxo-benzothiophene-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 66.15 μmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (75.42 mg, 661.49 μmol) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 min. The reaction was stopped, and the reaction solution was concentrated to give the title product 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-imino-1-oxo-benzothiophene-5-yl)imidazol-2-one (31 mg, 61.44 μmol, 92.88% yield).

[0548] MS m / z (ESI): 505.1 [M+H]

[0549] Step 4: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-imino-1-oxo-benzothiophene-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0550] In a 50 mL reaction flask, 35 mg (85.07 μmol) of 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid, 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(1-imino-1 2-(7-azobenzothiophene-5-yl)imidazol-2-one (42.92 mg, 85.07 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (32.09 mg, 85.07 μmol), and N,N-diisopropylethylamine (109.94 mg, 850.65 μmol, 148.16 μL) were dissolved in N,N-dimethylformamide (1.87 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and purified by prep-HPLC to obtain the title product 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-yl)-2 ... (-Fluoro-3,5-dimethylphenyl)-3-[3-(1-imino-1-oxo-benzothiophene-5-yl)-2-oxo-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (6 mg, 6.68 μmol, 7.85% yield)

[0551] MS m / z (ESI): 898.3 [M+H]

[0552] Example 14

[0553] Step 1: (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-4-oxo-2-thio-imidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0554] In a 50 mL reaction flask, 2-[[(4S)-5-tert-butoxycarbonyl-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]amino]acetic acid (41.74 mg, 96.51 μmol) was dissolved in water (2 mL) and ethanol (2 mL), followed by the addition of potassium hydroxide (10.83 mg, 193.02 μmol). After the starting materials were dissolved, an ethanol solution of 4-fluoro-5-isothiocyano-1-methylindazole (40 mg, 193.02 μmol) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. Then, 0.5 mL of 1 M HCl was added, and stirring continued at 25 °C for another 10 hours. The reaction solution was concentrated and then prepared by prep-hplc to yield the title product (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-4-oxo-2-thio-imidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (10 mg, 16.08 μmol, 16.67% yield).

[0555] MS m / z (ESI): 622.2 [M+H]

[0556] Step 2: 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl-indazol-5-yl)-2-thio-imidazolidine-4-one

[0557] In a 50 mL reaction flask, (4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-4-oxo-2-thio-imidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (10 mg, 16.08 μmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (18.34 mg, 160.85 μmol) was added. The reaction mixture was then protected with nitrogen and stirred at 25 °C for 1 hour. The reaction was stopped, and the reaction solution was concentrated to give the title product 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl-indazol-5-yl)-2-thio-imidazolidine-4-one (8 mg, 15.34 μmol, 95.36% yield).

[0558] MS m / z(ESI): 522.2 [M+H]

[0559] Step 3: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-4-oxo-2-thio-imidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0560] In a 50 mL reaction flask, 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (5 mg, 12.15 μmol), 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-(4-fluoro-1-methyl) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.58 mg, 12.15 μmol) and N,N-diisopropylethylamine (15.71 mg, 121.52 μmol, 21.17 μL) were dissolved in N,N-dimethylformamide (1.99 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. 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). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the purified residue was prepared by prep-HPLC to give the title product 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro- 3,5-Dimethyl-phenyl)-3-[3-(4-fluoro-1-methyl-indazol-5-yl)-4-oxo-2-thio-imidazolidine-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one (5.5 mg, 6.01 μmol, 49.46% yield)

[0561] MS m / z (ESI): 915.3 [M+H]

[0562] Example 15

[0563] 3-((1R, 2S)-1-(5-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0564] first step

[0565] 2-Bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester

[0566] Ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (9 g, 46.10 mmol) was dissolved in CHCl3 (100 mL), and NBS (8.20 g, 46.10 mmol) was added in three portions at 0 °C. The reaction mixture was stirred for 0.5 h. LCMS monitoring showed that the starting material disappeared and the product was formed, with a small amount of the two bromine byproducts. Extraction was performed with 500 mL of water and DCM (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was separated by column chromatography (PE:EtOAc = 96:4) to obtain ethyl 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (9 g, yellow solid), yield: 71.22%.

[0567] MS m / z(ESI): 273.9 [M+1].

[0568] Step 2

[0569] 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester

[0570] Ethyl 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (9 g, 32.83 mmol) and 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxorane (10.16 g, 42.68 mmol) were dissolved in H₂O (20 mL) and 1',4-Dioxane (100 mL). PddppfCl₂ (2.40 g, 3.28 mmol) and K₃PO₄ (13.94 g, 65.66 mmol) were added at room temperature. The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 8 hours. LCMS monitoring showed that the starting material disappeared and the product was formed. The reaction mixture was extracted with 500 mL of water and EtOAC (300 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was subjected to column chromatography (PE:EA = 90:10) to give ethyl 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (4.1 g, yellow solid), yield: 40.89%.

[0571] MS m / z(ESI): 306.1 [M+1].

[0572] Step 3

[0573] 2-[2,2-Dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester

[0574] Ethyl 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (4.1 g, 13.43 mmol) was dissolved in TFA (40 mL). Et3SiH (1.56 g, 13.43 mmol) was added at room temperature, and the reaction was stirred for 10 min. LCMS monitoring showed that the starting material disappeared and the product was formed, with approximately 25% byproducts. Ice was added to the reaction solution, and the pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. Extraction was performed with EtOAc (200 mL x 3). The solution was dried over anhydrous sodium sulfate, and the organic phase was concentrated under vacuum. The crude product was subjected to column chromatography to obtain ethyl 2-[2,2-dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylate (2.8 g, yellow solid), yield: 67.82%.

[0575] MS m / z(ESI): 308.1 [M+1].

[0576] Step 4

[0577] 2-[2,2-Dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylic acid

[0578] Ethyl 2-[2,2-dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylate (2.8 g, 9.11 mmol) was dissolved in MeOH (20 mL) and H₂O (10 mL). NaOH (801.49 mg, 20.04 mmol) was added at room temperature, and the reaction mixture was stirred at 70 °C for 3 hours. LCMS monitoring showed that the starting material disappeared and the product was formed. After the reaction solution was cooled to room temperature, 200 mL of EtOAc was added to extract the organic phase. The pH of the aqueous phase was adjusted to 5-6 with hydrochloric acid, and then EtOAc (200 mL x 3) was added to extract the organic phase again. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was subjected to column chromatography (DCM:MeOH = 96:4) to obtain the product 2-[2,2-dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (2.2 g, yellow solid), yield: 86.46%. MS m / z (ESI): 280.0 [M+1].

[0579] Step 5

[0580] 2-[2,2-Dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide

[0581] 2-[2,2-dimethyltetrahydropyran-4-yl]-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (2.2 g, 7.88 mmol) was dissolved in Tol. (20 mL) and purged with nitrogen three times. DMF (57.56 mg, 787.53 μmol, 60.98 μL) and oxalyl chloride (2.00 g, 15.75 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 2 hours. A sample was taken and methanol was added for monitoring. LCMS showed the formation of an intermediate and the disappearance of the starting material. The reaction mixture was directly concentrated under vacuum and dried. The mixture was dissolved in DCM (20 mL), and triethylamine (1.59 g, 15.75 mmol, 2.20 mL) and N-methylaniline (1.69 g, 15.75 mmol) were added sequentially. Nitrogen was purged three times, and the reaction was carried out at 30 °C for 8 hours. LCMS showed complete conversion of the intermediate and formation of the product. The reaction solution was concentrated under vacuum, and the crude product was subjected to column chromatography (PE:EA = 80:20) to give 2-[2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (1.9 g, yellow solid), yield: 65.47%.

[0582] MS m / z(ESI): 369.1 [M+1].

[0583] Step 6

[0584] 6-(cyanomethyl)-2-[2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenylthiopheno[2,3-b]pyrrole-5-carboxamide

[0585] 1.9 g (5.16 mmol) of 2-[2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide was dissolved in 15 mL of DMF, purged with nitrogen three times, and NaH (371.21 mg, 15.47 mmol) was slowly added at 0 °C. The mixture was stirred for 0.5 hours, followed by the addition of 1.86 g (15.47 mmol) of 2-bromoacetonitrile. The reaction was then stirred at 30 °C for 8 hours. LC-MS monitoring showed that a small amount of the starting material remained, and the product was formed. The reaction solution was extracted with 300 mL of H₂O and 3 x 200 mL of EtOAc. The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was subjected to column chromatography (PE:EtOAc = 74:26) to give 2 g of 6-(cyanomethyl)-2-[2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenylthiopheno[2,3-b]pyrrole-5-carboxamide (yellow solid), yield: 95.18%.

[0586] MS m / z(ESI): 408.1 [M+1].

[0587] Step 7

[0588] 6-(1-Cyano-2-methylcyclopropyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide

[0589] 6-(cyanomethyl)-2-[2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenylthiopheno[2,3-b]pyrrole-5-carboxamide and 4-methyl-1,3,2-dioxothiacyclohexane 2,2-dioxide (2.37 g, 17.18 mmol) were dissolved in DMPU (20 mL). After cooling to 0 °C in an ice bath, KHMDS (9.79 g, 49.08 mmol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 5 hours. LCMS monitoring showed that the starting material disappeared and the product was formed. Formic acid was added to adjust the pH to acidic, and the mixture was stirred for 5 min. Then, 300 mL of water and EtOAc (300 mL x 3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and the crude product was subjected to column chromatography (PE:EA = 55:45) to give 6-(1-cyano-2-methylcyclopropyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (450 mg, yellow solid), yield: 20.49%.

[0590] MS m / z(ESI): 448.2 [M+1].

[0591] Step 8

[0592] 2-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-6-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide

[0593] 6-(1-Cyano-2-methylcyclopropyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (450 mg, 1.01 mmol), K₂CO₃ (764.25 mg, 5.53 mmol), and hydroxylamine hydrochloride (349.32 mg, 5.03 mmol) were dissolved in THF (20 mL). The mixture was stirred at 90 °C for 2 hours. LCMS monitoring showed that an intermediate formed and the starting material disappeared. The reaction solution was concentrated to dryness, dissolved in anhydrous EtOH (20 mL), and the insoluble matter was filtered off. DBU (459.17 mg, 3.02 mmol, 450.17 μL) and CDI (318.40 mg, 2.21 mmol) were dissolved in 1 mL of THF (20 mL). The reaction solution was stirred for 3 hours. LCMS monitoring showed product formation and disappearance of the intermediate. The reaction solution was directly mixed with silica gel and evaporated to dryness. The crude product was subjected to column chromatography (DCM:MeOH = 98:2) to give 2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-6-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (390 mg, yellow solid), yield: 76.57%.

[0594] MS m / z(ESI): 507.2 [M+1].

[0595] Step 9

[0596] 2-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-6-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-6H-thieno[2,3-b]pyrrole-5-carboxylic acid

[0597] 2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-6-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (390 mg, 769.81 μmol) was dissolved in ethylene glycol dimethyl ether (10 mL), and KOH (345.53 mg, 6.16 mmol) was added at room temperature. Nitrogen gas was purged three times, and the reaction mixture was stirred at 100 °C for 8 hours. LCMS monitoring showed that the starting material disappeared and the product was formed. The reaction solution was extracted with H2O (200 mL) and EtOAc (100 mL x 3) to extract the organic phase. The aqueous phase was adjusted to pH 5 to 6 with hydrochloric acid, and then extracted with EA (100 mL x 3). The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was subjected to reverse-phase column chromatography (H2O:ACN = 55:45) to obtain 2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-(2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (168 mg, yellow solid), yield: 52.27%.

[0598] MS m / z(ESI): 418.1 [M+1].

[0599] Step 10

[0600] 3-(1-(5-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0601] In a 50 mL reaction flask, 25 mg (48.49 μmol) of 1-(1-cyclopropyl-4-fluoro-indazole-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one, 2-(2,2-dimethyltetrahydropyran-4-yl)-6-[(1S,2S)-2-methyl-1-(5-oxo-2H-1,2,4-oxadiazonium)]imidazolium ...1S,2S)-2-methyl-1-(5-oxo-2H-1,2,4-oxadiazonium)]imidazolium-2-one, 2-(1-cyclopropyl-4-fluoro-indazole-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazolium-2-one, 2-(2,2-dimethyltetrahydropyran-4-yl)-6-[(1S,2S)-2-methyl-1-(5-oxo-2H-1,2,4-oxadiazonium)]imidazolium-2-one, 2-(1-cyclopropyl-4-fluoro-indazole-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4 [Azol-3-yl]cyclopropyl]thieno[2,3-b]pyrrole-5-carboxylic acid (20.24 mg, 48.49 μmol), DIEA (31.34 mg, 242.46 μmol, 42.23 μL), Carter's condensing agent (19.80 mg, 96.98 μmol), and 4-dimethylaminopyridine (592.42 μg, 4.85 μmol) were dissolved in DMF (2.04 mL). The reaction mixture was then protected with nitrogen and stirred at 25 °C for 10 hours. The reaction was stopped, and the reaction was quenched by adding an aqueous solution (10 mL). Extraction was performed with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was prepared by prep-HPLC to give the title product 3-(1-(5-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl). 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrolo-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4 mg, 4.37 μmol, 9.02% yield)

[0602] MS m / z (ESI): 915.3 [M+1].

[0603] Step 11

[0604] 3-((1R, 2S)-1-(5-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0605] 3-(1-(5-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one was obtained by chiral resolution. The product is 3-((1R,2S)-1-(5-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one.

[0606] MS m / z (ESI): 915.3 [M+1].

[0607] Example 16

[0608] 3-((1S,2S)-1-(5-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0609] 3-(1-(5-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one was obtained by chiral resolution. The product is 3-((1S,2S)-1-(5-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6H-thieno[2,3-b]pyrrole-6-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one.

[0610] MS m / z (ESI): 915.3 [M+1].

[0611] Example 17

[0612] 3-((1S,2S)-1-(2-(4S)-3-(3-(3-chloro-4-(N,S-dimethylsulfonylimino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0613] The product was obtained by referring to the synthesis method of Example 5.

[0614] MS m / z(ESI): 936.3 [M+1].

[0615] Example 18

[0616] 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0617] Step 1: 4-(4-bromo-3-fluoro-phenyl)-2-methyl-but-3-yn-2-ol

[0618] 1-Bromo-2-fluoro-4-iodobenzene (1 g, 3.32 mmol) and 2-methylbut-3-yn-2-ol (335.46 mg, 3.99 mmol) were dissolved in THF (30 mL), and CuI (126.59 mg, 664.69 μmol), Pd(PPh3)2Cl2 (233.27 mg, 332.34 μmol), and DIPEA (1.29 g, 9.97 mmol, 1.74 mL) were added to it in sequence.

[0619] After the reaction system was purged with nitrogen several times, it was stirred at room temperature (20°C) for 16 hours. After the reaction was complete, water (20 mL) was added, followed by extraction with ethyl acetate (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. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 3:1, UV = 254 nm) to finally obtain a pale yellow solid, 4-(4-bromo-3-fluoro-phenyl)-2-methyl-but-3-yn-2-ol (700 mg, 2.72 mmol, 81.92% yield).

[0620] MS m / z(ESI): 257.0, 259.0 [M+1].

[0621] Step 2: Tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-1-butyl-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0622] Tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg, 135.90 μmol), 4-(4-bromo-3-fluoro-phenyl)-2-methyl-but-3-yn-2-ol (69.88 mg, 271.80 μmol) were dissolved in N-methylpyrrolidone (5 mL). CuI (25.88 mg, 135.90 μmol), K2CO3 (56.35 mg, 407.70 μmol), and ((1S,2S)-N N'-Dimethyl-1,2-cyclohexanediamine (38.66 mg, 271.80 μmol). After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 130 °C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (80 mg, crude).

[0623] The crude product is used directly in the next reaction step.

[0624] MS m / z(ESI): 618.2.[M+1].

[0625] Step 3: 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]imidazol-2-one

[0626] tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-1-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0627] (140 mg, 226.65 μmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (516.87 mg, 4.53 mmol) was added. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]imidazol-2-one (120 mg, crude).

[0628] The crude product is used directly in the next reaction step.

[0629] MS m / z(ESI): 518.2.[M+1].

[0630] Step 4: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0631] 1-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]imidazol-2-one (120 mg, 231.85 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S, [2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (114.48 mg, 278.22 μmol) was dissolved in DMF (10 mL), and HATU (174.94 mg, 463.71 μmol) and DIPEA (89.89 mg, 695.56 μmol, 121.15 μL) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 6 hours. After the reaction was complete, the solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to give a white solid 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-[2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)phenyl]-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one (15.8 mg, 17.34 μmol, 7.48% yield).

[0632] MS m / z(ESI): 911.4 [M+1]

[0633] Example 19

[0634] 1-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-3-fluoro-phenyl]-N,N-dimethyl-cyclopropylformamide

[0635] Step 1: 1-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-cyclopropylformamide

[0636] 1-(4-bromo-3-fluoro-phenyl)cyclopropionic acid (400 mg, 1.54 mmol) and N-methylmethylamine (139.22 mg, 3.09 mmol) were dissolved in DMF (10 mL), and HATU (1.16 g, 3.09 mmol) and DIPEA (598.63 mg, 4.63 mmol, 806.78 μL) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 6 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 3:1, UV = 254 nm) to give a pale yellow solid 1-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-cyclopropionic acid (300 mg, 1.05 mmol, 67.91% yield).

[0637] MS m / z(ESI): 286.0, 288.0 [M+1].

[0638] Step 2: Tert-butyl(4S)-3-[3-[4-[1-(dimethylcarbamoyl)cyclopropyl]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0639] tert-Butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), 1-(4-bromo-3-fluoro-phenyl)-N,N-dimethyl-cyclopropylformamide (64.81 mg, 226.50 μmol) were dissolved in N-methylpyrrolidone (5 mL), and CuI (21.57 mg, 113.25 μmol), K2CO3 (46.96 mg, 339.75 μmol) and (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (32.22 mg, 226.50 μmol) were added to the solution in sequence. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 130°C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid tert-butyl(4S)-3-[3-[4-[1-(dimethylcarbamoyl)cyclopropyl]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg, 92.78 μmol, 85.71% yield).

[0640] MS m / z(ESI): 647.3 [M+1].

[0641] Step 3: 1-[3-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]phenyl]-N,N-dimethyl-cyclopropylformamide

[0642] 60 mg (92.78 μmol) of tert-butyl(4S)-3-[3-[4-[1-(dimethylcarbamoyl)cyclopropyl]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (211.58 mg, 1.86 mmol) was added. The reaction mixture was stirred at room temperature (20 °C) for 4 hours. After the reaction was complete, a saturated sodium bicarbonate solution was added dropwise to extract the reaction mixture. The mixture was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-[3-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]phenyl]-N,N-dimethyl-cyclopropylformamide (50 mg). The crude product was used directly in the next reaction step.

[0643] MS m / z(ESI): 547.3 [M+1].

[0644] Step 4: 1-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-3-fluoro-phenyl]-N,N-dimethyl-cyclopropylformamide

[0645] 1-[3-fluoro-4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]phenyl]-N,N-dimethyl-cyclopropaneformamide (50 mg, 91.47 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[( [1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (45.16 mg, 109.77 μmol) was dissolved in DMF (6 mL), and HATU (69.02 mg, 182.95 μmol) and DIPEA (35.47 mg, 274.42 μmol, 47.80 μL) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 6 hours. After the reaction was complete, the solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to obtain a white solid 1-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-3-fluoro-phenyl]-N,N-dimethyl-cyclopropylformamide (46.6 mg, 49.57 μmol, 54.19% yield).

[0646] MS m / z(ESI): 940.4 [M+1]

[0647] Example 20

[0648] 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0649] Step 1: (4-Bromo-3-fluoro-phenyl)imino-diethyl-carbonyl-thione

[0650] 1-Bromo-2-fluoro-4-iodobenzene (500 mg, 1.66 mmol) and diethylimino-carbonyl-thione (241.68 mg, 1.99 mmol) were dissolved in 1,4-dioxane (20 mL). Tris-(dibenzylideneacetone)dipalladium(O) (152.17 mg, 166.17 μmol), Xantphos (192.30 mg, 332.34 μmol), and Cs₂CO₃ (1.62 g, 4.99 mmol) were added sequentially. The reaction mixture was purged with nitrogen several times and then stirred in an oil bath at 100 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 3:1, UV = 254 nm) to obtain a pale yellow solid (4-bromo-3-fluoro-phenyl)imino-diethyl-carbonyl-thione (300 mg, 1.02 mmol, 61.37% yield).

[0651] MS m / z(ESI): 294.0, 296.0 [M+1].

[0652] Step 2: Tert-butyl(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0653] Tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (40 mg, 90.60 μmol), (4-bromo-3-fluoro-phenyl)imino-diethyl-carbonyl-thione (53.31 mg, 181.20 μmol) were dissolved in N-methylpyrrolidone (5 mL), and CuI (17.25 mg, 90.60 μmol), K2CO3 (37.56 mg, 271.80 μmol) and (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (25.77 mg, 181.20 μmol) were added to the solution in sequence. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 130°C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude tert-butyl(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg). The crude product was used directly in the next reaction step.

[0654] MS m / z (ESI): 655.3 [M+1].

[0655] Step 3: 1-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one

[0656] 60 mg (91.64 μmol) of tert-butyl(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in dichloromethane (4 mL), and TFA (208.97 mg, 1.83 mmol) was added. The reaction mixture was stirred at room temperature (20 °C) for 4 hours. After the reaction was complete, the product was diluted with water, extracted with dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (50 mg, crude).

[0657] The crude product is used directly in the next reaction step.

[0658] MS m / z (ESI): 555.3 [M+1].

[0659] Step 4: 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0660] 1-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (50 mg, 90.15 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1 [S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (44.51 mg, 108.18 μmol) was dissolved in DMF (5 mL), and HATU (68.02 mg, 180.29 μmol) and DIPEA (34.95 mg, 270.44 μmol, 47.10 μL) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 6 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to obtain a white solid 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-[[diethyl(carbonyl)-thionyl]amino]-2-fluoro-phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one (27.5 mg, 29.01 μmol, 32.18% yield).

[0661] MS m / z(ESI): 948.4 [M+1].

[0662] Example 21

[0663] 7-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-8-fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one

[0664] Step 1: 3-Chloro-1-(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)propane-1-one

[0665] 6-Fluoro-3,4-dihydro-2H-1,4-benzoxazine (1 g, 6.53 mmol) was dissolved in acetone (20 mL), and 3-chloropropionyl chloride (1.24 g, 9.79 mmol) was added. The reaction mixture was stirred in an oil bath at 60 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 3-chloro-1-(6-fluoro-2,3-dihydro-1,4-benzoxazine-4-yl)propane-1-one (1.3 g, 5.34 mmol, 81.71% yield). The crude product was not further purified and was used directly in the next reaction.

[0666] MS m / z(ESI): 244.0 [M+1].

[0667] Step 2: 8-Fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]deca-5(13),6,8-trien-12-one

[0668] 3-Chloro-1-(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)propane-1-one (500 mg, 2.05 mmol) was mixed with anhydrous aluminum chloride (410.43 mg, 3.08 mmol) and stirred in an oil bath at 120 °C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (Petroleum ether: Ethyl acetate = 5:1, UV = 254 nm) to obtain a pale yellow solid 8-fluoro-4-oxa-1-azatricyclic [7.3.1.05,13]tridecane-5(13),6,8-trien-12-one (110 mg, 530.89 μmol, 25.87% yield).

[0669] MS m / z(ESI): 208.0 [M+1].

[0670] Step 3: 7-bromo-8-fluoro-4-oxa-1-azatricyclic [7.3.1.05,13]deca-5(13),6,8-trien-12-one

[0671] 8-Fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]tridecane-5(13),6,8-trien-12-one (110 mg, 530.89 μmol) was dissolved in DMF (10 mL), and NBS (141.73 mg, 796.33 μmol) was added. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was completed, saturated sodium thiosulfate was added dropwise to quench the reaction, followed by extraction with ethyl acetate, washing with saturated brine, drying with anhydrous sodium sulfate, filtration, and concentration to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate = 3:1, UV = 254nm) to obtain the target product 7-bromo-8-fluoro-4-oxa-1-azatricyclic [7.3.1.05,13]tetane-5(13),6,8-trien-12-one (80mg, 279.63μmol, 52.67% yield).

[0672] MS m / z(ESI):286.0, 288.0[M+1].

[0673] Step 4: tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-12-carbonyl-4-oxa-1-azatricyclo[7.3.1.05,13]tetane-5,7,9(13)-trien-7-yl)-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0674] tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (40 mg, 90.60 μmol), 7-bromo-8-fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5(13),6,8-triene- 12-ketool (51.84 mg, 181.20 μmol) was dissolved in N-methylpyrrolidone (6 mL), and CuI (17.25 mg, 90.60 μmol), K2CO3 (37.56 mg, 271.80 μmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (25.77 mg, 181.20 μmol) were added sequentially. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 130 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-12-carbonyl-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-7-yl)-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (59 mg, crude). The crude product was used directly in the next reaction.

[0675] MS m / z(ESI): 647.2 [M+1].

[0676] Step 5: 8-Fluoro-7-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one

[0677] 59 mg (91.23 μmol) of tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(8-fluoro-12-carbonyl-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-7-yl)-2-carbonyl-imidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in DCM (4 mL), and HCl-Dioxane (4 mL) was added dropwise. The reaction system was stirred at room temperature (20 °C) for 4 hours. After the reaction was complete, a saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 8-fluoro-7-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one (50 mg crude). The crude product was used directly in the next reaction step.

[0678] MS m / z(ESI): 547.2 [M+1].

[0679] Step 6: 7-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-8-fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one

[0680] 8-fluoro-7-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one (50 mg, 91.48 μmol), 5-[(4S)-2,2-dimethyl [Tetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (37.64 mg, 91.48 μmol) was dissolved in DMF (6 mL), and DIPEA (35.47 mg, 274.44 μmol, 47.80 μL) and HATU (69.03 mg, 182.96 μmol) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 16 hours. After the reaction was complete, the solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to finally obtain the target product 7-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-8-fluoro-4-oxa-1-azatricyclo[7.3.1.05,13]tetadeca-5,7,9(13)-trien-12-one (23.7 mg, 25.21 μmol, 27.56% yield).

[0681] MS m / z(ESI): 940.4 [M+1].

[0682] Example 22

[0683] 3-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide

[0684] Step 1: tert-butyl(4S)-3-[3-[4-(3-amino-3-carbonyl-propyl)-3-(methylamino)phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0685] 100 mg (226.50 μmol) of tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester and 3-[4-bromo-2-(methylamino)phenyl]propionamide (87.36 mg, 339.75 μmol) were dissolved in N-methylpyrrolidone (6 mL). CuI (43.14 mg, 226.50 μmol), K2CO3 (93.91 mg, 679.51 μmol) and (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (64.44 mg, 453.00 μmol) were added to the solution in sequence. After the reaction system was purged with nitrogen several times, it was stirred in an oil bath at 130°C for 3 hours. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-TLC (Dichloromethane:Methanol = 10:1, UV = 254nm) to finally obtain a pale yellow solid tert-butyl(4S)-3-[3-[4-(3-amino-3-carbonyl-propyl)-3-(methylamino)phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (100 mg, 161.89 μmol, 71.47% yield).

[0686] MS m / z (ESI): 618.3 [M+1].

[0687] Step 2: 3-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide

[0688] 90 mg (145.70 μmol) of tert-butyl(4S)-3-[3-[4-(3-amino-3-carbonyl-propyl)-3-(methylamino)phenyl]-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in dichloromethane (10 mL). In an ice-water bath, boron trifluoride diethyl ether (62.04 mg, 437.10 μmol) and 4A were added separately. o Molecular sieve (200 mg). The reaction system was stirred at room temperature (20 °C) for 2 hours. After the reaction was complete, saturated sodium bicarbonate was added dropwise to quench the reaction, followed by extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, filtration, and concentration to obtain crude 3-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide (75 mg).

[0689] The crude product is used directly in the next reaction step.

[0690] MS m / z(ESI): 518.3 [M+1].

[0691] Step 3: 3-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide

[0692] 3-[4-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide (75 mg, 144.90 μmol), 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S, [2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carboxylic acid (71.54 mg, 173.88 μmol) was dissolved in DMF (5 mL), and DIPEA (56.18 mg, 434.70 μmol, 75.72 μL) and HATU (109.33 mg, 289.80 μmol) were added sequentially. The reaction system was stirred at room temperature (20 °C) for 16 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by prep-HPLC to finally obtain the target product 3-[4-[3-[(4S)-5-[5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]indole-2-carbonyl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]-2-(methylamino)phenyl]propionamide (39.4 mg, 43.25 μmol, 29.85% yield).

[0693] MS m / z(ESI): 911.4 [M+1]

[0694] Example 23

[0695] 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-1-[(1R,5S)-6-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)-3-oxadicyclo[3.1.0]hexane-6-yl]-N-phenyl-indole-2-carboxamide

[0696] Step 1: (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxthiazole 2-oxidation

[0697] (3S,4R)-tetrahydrofuran-3,4-diol (250 g, 2.40 mol) was dissolved in dichloromethane (7.5 L), and triethylamine (729.01 g, 7.20 mol, 1.00 L) was added. Thionyl chloride (428.55 g, 3.60 mol, 261.63 mL) was slowly added dropwise at 0 °C. The reaction system was allowed to naturally warm to room temperature (20 °C) and stirred for 2 hours. After the reaction was complete, 4 L of water was added to quench the reaction, followed by extraction with dichloromethane (4 L x 3), washing with saturated sodium bicarbonate (2 L x 2), washing with saturated brine (2 L x 2), drying with anhydrous sodium sulfate, filtration, and concentration to obtain a brown solid crude product (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxthiazole 2-oxidation (360 g, crude).

[0698] The crude product requires no purification and can be used directly in the next reaction step.

[0699] Step 2 (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxathiazole 2,2-dioxane

[0700] (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxthiazole 2-oxidation (360 g, 2.40 mol) was dissolved in a mixed solvent of H₂O (3.5 L) and acetonitrile (3.5 L). NaIO₄ (769.23 g, 3.60 mol) and RuCl₃ (42.27 g, 203.79 mmol) were slowly added at 0 °C. The reaction mixture was allowed to warm to room temperature (20 °C) and stirred for 16 hours. After the reaction was complete, 4 L of water was added for dilution, and the mixture was extracted with ethyl acetate (4 L x 3).

[0701] The product was washed with saturated sodium thiosulfate (4L x 2) and saturated brine (4L x 2), dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude product (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxitazole 2,2-dioxide (400g, crude).

[0702] Step 3: 1-[(1R,5S)-6-cyano-3-oxabicyclo[3.1.0]hexane-6-yl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide

[0703] 1-(cyanomethyl)-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (2 g, 4.98 mmol) and (3aS,6aR)-3a,4,6,6a-tetrahydrofurano[3,4-d][1,3,2]dioxthiazole 2,2-dioxide (2.48 g, 14.94 mmol) were dissolved in a mixed solvent of THF (30 mL) and DMPU (30 mL). Under nitrogen protection at -40 °C, LDA (2 M, 14.94 mL) was slowly added dropwise. The reaction system was allowed to rise naturally to room temperature and stirred for 2 hours. After the reaction was complete, saturated ammonium chloride (30 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated to obtain crude 1-[(1R,5S)-6-cyano-3-oxabicyclo[3.1.0]hexane-6-yl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (2.4 g, crude).

[0704] MS m / z(ESI): 470.2 [M+1].

[0705] Step 4: 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1R,5S)-6-[(Z)-N'-hydroxyaminomethyleneiminoyl]-3-oxabicyclo[3.1.0]hexane-6-yl]-N-methyl-N-phenyl-indole-2-carboxamide

[0706] 1-[(1R,5S)-6-cyano-3-oxabicyclo[3.1.0]hexan-6-yl]-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-indole-2-carboxamide (30 g, 63.89 mmol) was dissolved in EtOH (600 mL), and TEA (19.39 g, 191.66 mmol, 26.73 mL) and hydroxylamine hydrochloride (8.88 g, 127.78 mmol) were added to the solution. The reaction mixture was stirred in an oil bath at 85 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the excess solvent was concentrated to obtain the residue. The residue was then diluted with water (200 mL), extracted with ethyl acetate (500 mL x 2), washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1R,5S)-6-[(Z)-N'-hydroxyaminomethyliminoyl]-3-oxabicyclo[3.1.0]hexane-6-yl]-N-methyl-N-phenyl-indole-2-carboxamide (32 g, crude). The crude product did not require purification and was used directly in the next reaction step.

[0707] MS m / z(ESI): 503.2 [M+1].

[0708] Step 5: 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-1-[(1R,5S)-6-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)-3-oxadicyclo[3.1.0]hexane-6-yl]-N-phenyl-indole-2-carboxamide

[0709] 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1R,5S)-6-[(Z)-N'-hydroxyaminomethyliminoyl]-3-oxabicyclo[3.1.0]hexane-6-yl]-N-methyl-N-phenyl-indole-2-carboxamide (32 g, 63.67 mmol) was dissolved in THF (200 mL), and 1,1'-carbonyldiimidazole (20.65 g, 127.34 mmol) and DBU (29.08 g, 191.01 mmol, 28.51 mL) were added sequentially. The reaction system was stirred in an oil bath at 50 °C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (500 mL x 2), washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude pale yellow solid 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-1-[(1R,5S)-6-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)-3-oxadicyclo[3.1.0]hexane-6-yl]-N-phenyl-indole-2-carboxamide (34 g, crude).

[0710] MS m / z(ESI): 529.2 [M+1]

[0711] Example 24

[0712] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1'-methyl-2'-carbonylspiro[cyclopropano-1,3'-dihydroindole]-5'-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0713] first step

[0714] 5'-Bromo-1'-methylspiro[cyclopropano-1,3'-dihydroindole]-2'-one

[0715] Under ice bath conditions, 5'-bromospiro[cyclopropano-1,3'-dihydroindole]-2'-one (0.20 g, 840.05 μmol) was dissolved in N,N-dimethylformamide (3 mL), and nitrogen gas was purged. Then, sodium hydroxide (50.40 mg, 1.26 mmol, 60% purity) was added, and the mixture was stirred at room temperature for 20 minutes. Then, iodomethane (238.57 mg, 1.68 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was stopped by LCMS. The reaction solution was quenched with saturated ammonium chloride solution (5 mL), diluted with ethyl acetate (20 mL), and washed with saturated brine (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product, which was used directly in the next step (0.20 g, yield: 94.4%).

[0716] MS m / z (ESI): 251.9, 253.9 [M+1].

[0717] Step 2

[0718] tert-Butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1'-methyl-2'-carbonylspiro[cyclopropano-1,3'-dihydroindole]-5'-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0719] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), 5'-bromo-1'-methyl-spiro[cyclopropano-1,3'-dihydroindole]-2'-one (57.10 mg, 226.50 μmol), cuprous iodide (10.20 mg, 53.58 μmol), potassium carbonate (46.96 mg, 339.75 μmol) and (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane (8.05 mg, 56.63 μmol) was dissolved in N-methylpyrrolidone (2 mL), nitrogen was purged, and the mixture was heated to 130 °C and reacted for 5 hours. After cooling to room temperature, the reaction was indicated to be complete by LCMS. The reaction solution was diluted with 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 purified by preparative thin-layer chromatography (PE:EA = 2:1) to obtain the target product as a yellow oil (0.05 g, yield: 72.1%).

[0720] MS m / z(ESI): 613.2 [M+1].

[0721] Step 3

[0722] (S)-5'-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-1'-methylspiro[cyclopropano-1,3'-dihydroindole]-2'-one

[0723] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-[3-(1'-methyl-2'-carbonyl-spiro[cyclopropano-1,3'-dihydroindole]-5'-yl)-2-carbonyl-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 81.61 μmol) was dissolved in dichloromethane (3 mL), and then hydrochloric acid / dioxane solution (4.0 M, 0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by LCMS. The solution was then evaporated to dryness to obtain the crude product, which was used directly in the next step (0.044 g, yield: 98.2%).

[0724] MS m / z(ESI): 513.2 [M+1].

[0725] Step 4

[0726] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1'-methyl-2'-carbonylspiro[cyclopropano-1,3'-dihydroindole]-5'-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0727] At room temperature, (S)-5'-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-1'-methylspiro[cyclopropano-1,3'-dihydroindole]-2'-one hydrochloride (44 mg, 80.14 μmol, hydrochloride) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (36.27 mg, 88.15 μmol) were prepared. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (42.33 mg, 112.20 μmol) and diisopropylethylamine (62.15 mg, 480.84 μmol) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred overnight at room temperature. The reaction was stopped by LCMS. The reaction solution was diluted with 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 residue was separated by thin-layer chromatography (dichloromethane:methanol = 25:1). The crude product was then separated by reversed-phase preparative chromatography (alkaline) and lyophilized to obtain the target product as a white solid (0.027 g, yield: 37.2%).

[0728] MS m / z(ESI): 906.4 [M+1].

[0729] Example 25

[0730] 3-((1S,2S)-1-(2-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0731] Step 1: A mixture of 1-((1S,2S)-2-((benzyloxy)methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (350 mg, 576.88 μmol), KOH (323.69 mg, 5.77 mmol), and polyethylene glycol (4 mL) was stirred at 165 °C for 3 hours. After cooling to room temperature, the reaction was considered complete according to LCMS. The reaction solution was neutralized with dilute hydrochloric acid (1N) and the pH was adjusted to 5-6. A solid precipitated out. The solid was filtered, washed successively with water and petroleum ether, dried, and used directly in the next step to obtain a brown solid (290 mg, crude product).

[0732] MS m / z(ESI): 518.2 [M+1]

[0733] Step 2: Add 1-(1-cyclopropyl-4-fluoro-indazole-5-yl)-3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]imidazol-2-one (79.69 mg, 154.57 μmol), 1-((1S,2S)-2-((benzyloxy)methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole HATU (145.78 mg, 386.42 μmol) and DIEA (74.91 mg, 579.63 μmol, 100.96 μL) were added to a DMF (5 mL) solution of 2-carboxylic acid (100 mg, 193.21 μmol). The mixture was stirred at room temperature for 12 hours, water was added, and the mixture was extracted three times with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow oil. The oil was separated by column chromatography (DCM / MeOH = 10:1) to obtain a white solid (120 mg, yield: 61.2%).

[0734] MS m / z (ESI): 1015.4 [M+1]

[0735] Step 3: Dissolve 120 mg (0.12 mmol) of 3-((1S,2S)-2-((benzyloxy)methyl)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazole-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (2 mL) in trifluoroacetic acid. Heat the reaction solution to 80 °C and stir for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed once with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily product (80 mg, crude product).

[0736] MS m / z(ESI): 925.4 [M+1]

[0737] Example 26

[0738] 3-((1S,2S)-2-((benzyloxy)methyl)-1-(2-(S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0739] The product was obtained by referring to the synthesis method of Example 25.

[0740] MS m / z (ESI): 1015.4 [M+1]

[0741] Example 27

[0742] 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1'-methyl-2'-oxospiro[cyclopentan-1,3'-indoline]-5'-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indo-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0743] The product was obtained by referring to the synthesis method of Example 24.

[0744] MS m / z(ESI): 934.4 [M+1]

[0745] Example 28

[0746] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(2,2-dihydroxy-1,3-dihydrobenzo[c]thiophene-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0747] first step

[0748] tert-Butyl(S)-3-(3-(2,2-dihydroxy-1,3-dihydrobenzo[c]thiophene-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0749] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), 5-bromo-1,3-dihydro-2-benzothiophene 2,2-dioxide (55.97 mg, 226.50 μmol), cuprous iodide (21.57 mg, 113.25 μmol), potassium carbonate (46.96 mg, 339.75 μmol), and (1S,2S) N,N'-Dimethyl-1,2-diaminocyclohexane (16.11 mg, 113.25 μmol) was dissolved in N-methylpyrrolidone (2 mL), nitrogen was purged, and the mixture was heated to 130 °C and reacted for 5 hours. After cooling to room temperature, the reaction was indicated to be complete by LCMS. The reaction solution was diluted with 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 residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 25:1) to obtain the target product as a yellow oil (0.06 g, yield: 87.2%).

[0750] MS m / z (ESI): 608.2 [M+1].

[0751] Step 2

[0752] (S)-1-(2,2-dihydroxy-1,3-dihydrobenzo[c]thiophene-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0753] At room temperature, tert-butyl(4S)-3-[3-(2,2-dicarbonyl-1,3-dihydro-2-benzothiophene-5-yl)-2-carbonyl-imidazol-1-yl]-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg, 98.73 μmol) was dissolved in dichloromethane (2 mL), and then hydrochloric acid / dioxane solution (4.0 M, 1 mL) was added. The mixture was stirred at room temperature for one hour. The reaction was stopped by LCMS. The solution was evaporated to dryness, and the crude product was used directly for the next step (0.053 g, yield: 98.7%).

[0754] MS m / z(ESI): 508.2 [M+1].

[0755] Step 3

[0756] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(2,2-dihydroxy-1,3-dihydrobenzo[c]thiophene-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0757] At room temperature, 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (38.80 mg, 94.30 μmol), (S)-1-(4-fluoro-2,2-dihydroxy-1,3-dihydrobenzo[c]thiophene-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (53 mg, 94.30 μmol, hydrochloride), diisopropyl 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (49.81 mg, 132.02 μmol) was dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred overnight at room temperature. The reaction was stopped by LCMS. The reaction solution was diluted with 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 (dichloromethane:methanol = 20:1). The crude product was then separated by reversed-phase preparative chromatography (alkaline) and lyophilized to obtain the target product as a white solid (0.038 g, yield: 44.7%).

[0758] MS m / z(ESI): 901.3 [M+1].

[0759] Example 29

[0760] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-2-((1-fluorocyclopropyl)methyl)-2H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0761] first step

[0762] 5-Bromo-4-fluoro-2-((1-fluorocyclopropyl)methyl)-2H-indazole

[0763] At room temperature, 5-bromo-4-fluoro-1H-indazole (0.20 g, 930.14 μmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of (1-fluorocyclopropyl)methanol (167.60 mg, 1.86 mmol) and 2-(tributylphosphine-1,4-acetonitrile) (448.98 mg, 1.86 mmol). Nitrogen was purged, and the mixture was heated to 110 °C for 14 hours. After cooling to room temperature, LC-MS indicated the formation of the target product. The reaction solution was diluted with ethyl acetate (20 mL) and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was separated by Flash column chromatography (PE:EA = 10:1-5:1-2:1) to obtain the target compound as a pale yellow oil (0.10 g, yield: 37.5%).

[0764] MS m / z (ESI): 286.9, 288.9 [M+1].

[0765] Step 2

[0766] tert-Butyl(S)-3-(3-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0767] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), 5-bromo-4-fluoro-2-((1-fluorocyclopropyl)methyl)-2H-indazole (39.02 mg, 135.90 μmol), cuprous iodide (21.57 mg, 113.25 μmol), potassium carbonate (46.96 mg, 339.75 μmol), and (1S,2S)-N,N'-dimethyl-1 2-Diaminocyclohexane (16.11 mg, 113.25 μmol) was dissolved in N-methylpyrrolidone (2 mL), nitrogen was purged, and the mixture was 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 diluted with ethyl acetate (20 mL), filtered, and the residue was washed with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the target product as a yellow oil (0.06 g, yield: 81.8%).

[0768] MS m / z(ESI): 648.2 [M+1].

[0769] Step 3

[0770] (S)-1-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0771] At room temperature, tert-butyl(S)-3-(3-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (60 mg, 92.64 μmol) was dissolved in dichloromethane (2 mL), and then hydrochloric acid / dioxane (4.0 M, 1 mL) was added. The mixture was stirred at room temperature for one hour. The reaction was stopped by LCMS. The solution was evaporated to dryness, and the crude product was used directly for the next step (0.054 g, yield: 99.8%).

[0772] MS m / z(ESI): 548.2 [M+1].

[0773] Step 4

[0774] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0775] At room temperature, (S)-1-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (54 mg, 92.46 μmol, hydrochloride), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl- 1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (38.04 mg, 92.46 μmol), diisopropylethylamine (71.70 mg, 554.76 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (48.84 mg, 129.44 μmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred overnight at room temperature, and the reaction was considered complete by LCMS. The reaction solution was diluted with ethyl acetate (20 mL), 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 reversed-phase preparative chromatography (acidic), lyophilized, and the target product was obtained as a white solid (0.028 g, yield: 31.9%). MS m / z(ESI): 941.4 [M+1].

[0776] Example 30

[0777] N-(6-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthyl)propionamide

[0778] first step

[0779] N-(6-bromo-1,2,3,4-tetrahydronaphth-1-yl)propionamide

[0780] Under ice bath conditions, 6-bromotetraoxine-1-amine (105 mg, 464.37 μmol) was dissolved in dichloromethane (3 mL), followed by the sequential addition of triethylamine (140.97 mg, 1.39 mmol, 194.31 μL) and propionyl chloride (55.86 mg, 603.68 μmol). The mixture was stirred at room temperature for 1 hour. The reaction was stopped by LCMS. The reaction solution was diluted with dichloromethane (20 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 used directly in the next step (0.13 g, yield: 99.2%).

[0781] MS m / z(ESI): 282.1, 284.1 [M+1].

[0782] Step 2

[0783] tert-Butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-3-(5-propionylamino-5,6,7,8-tetrahydronaphth-2-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0784] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-3-(2-carbonyl-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (50 mg, 113.25 μmol), N-(6-bromotetraoxynin-1-yl)propionamide (41.54 mg, 147.23 μmol), cuprous iodide (21.57 mg, 113.25 μmol), potassium carbonate (46.96 mg, 339.75 μmol), and (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane were added. Hexane (16.11 mg, 113.25 μmol) was dissolved in N-methylpyrrolidone (3 mL), nitrogen was purged, and the mixture was heated to 130 °C for 5.5 hours. After cooling to room temperature, the reaction was considered complete by LCMS. The reaction solution was diluted with ethyl acetate (25 mL), filtered, and the residue was washed with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (15 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 30:1) to obtain the target product as a yellow oil (0.065 g, yield: 89.3%).

[0785] MS m / z(ESI): 643.2 [M+1].

[0786] Step 3

[0787] N-(6-(3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthyl-1-yl)propionamide

[0788] At room temperature, tert-butyl(4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-carbonyl-3-(5-propionylamino-5,6,7,8-tetrahydronaphthyl-2-yl)-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (65 mg, 101.13 μmol) was dissolved in dichloromethane (2 mL), and then hydrochloric acid / dioxane (4.0 M, 1 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped by LCMS. The solution was evaporated to dryness, and the crude product was used directly for the next step (0.058 g, yield: 99.0%).

[0789] MS m / z(ESI): 543.2 [M+1].

[0790] Step 4

[0791] N-(6-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthyl)propionamide

[0792] At room temperature, N-[6-[3-[(4S)-2-(4-fluoro-3,5-dimethyl-phenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-2-carbonyl-imidazol-1-yl]tetraoxydin-1-yl]propionamide (58 mg, 100.15 μmol, hydrochloride), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-carbonyl-4,5-yl) Dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (45.33 mg, 110.17 μmol), diisopropylethylamine (338.63 mg, 2.62 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (52.90 mg, 140.22 μmol) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred overnight at room temperature, and the reaction was considered complete by LCMS. The reaction solution was diluted with ethyl acetate (20 mL), 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 reversed-phase preparative chromatography (acidic), lyophilized, and the target product was obtained as a white solid (0.038 g, yield: 40.5%).

[0793] MS m / z(ESI): 936.4 [M+1].

[0794] Example 31

[0795] first step

[0796] 5-Bromo-2-fluoro-1-methyl-3-(pent-4-en-1-oxy)benzene

[0797] 5-Bromo-2-fluoro-3-methylphenol (5.0 g, 24.39 mmol), 5-bromopent-1-ene (5.45 g, 36.58 mmol), and potassium carbonate (10.11 g, 73.16 mmol) were dispersed in N,N-dimethylformamide (100 mL) and reacted with the solution at room temperature for 18 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a colorless, oily crude product. This crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 10%, v / v) to give 6.5 g of the product.

[0798] MS m / z(ESI): 273.0 [M+1].

[0799] Step 2

[0800] Di-tert-butyl-1-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)hydrazine-1,2-dicarboxylic acid ester

[0801] 5-Bromo-2-fluoro-1-methyl-3-(pent-4-en-1-oxy)benzene (5.2 g, 19.04 mmol) was dissolved in tetrahydrofuran (100 mL), and the mixture was purged under nitrogen protection and cooled in a dry ice / ethanol bath for 5 minutes. Then, n-butyllithium (1.22 g, 19.04 mmol, 7.6 mL) was added to the reaction mixture, and the reaction was maintained at the dry ice bath temperature for 1 hour. Subsequently, di-tert-butyl azodicarbonate (4.38 g, 19.04 mmol) was added to the reaction mixture, and the mixture was stirred and reacted at the dry ice / ethanol bath temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. This crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 20%, v / v) to give 5.3 g of the product.

[0802] MS m / z(ESI): 425.2 [M+1].

[0803] Step 3

[0804] (4-Fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)hydrazine

[0805] Di-tert-butyl-1-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)hydrazine-1,2-dicarboxylic acid ester (5.0 g, 11.78 mmol) and methanesulfonic acid (2.26 g, 23.56 mmol) were dissolved in N-methylpyrrolidone (15 mL). The reaction solution was heated to 80 °C and stirred for 7 hours. The reaction solution was cooled to room temperature, and potassium carbonate (4.9 g) and water (10 mL) were added. The mixture was stirred for 10 minutes, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily crude product (902 mg). This crude product was used directly in the next reaction without purification.

[0806] MS m / z(ESI): 225.1 [M+1].

[0807] Step 4

[0808] tert-Butyl(S)-3-amino-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0809] (4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)hydrazine (902 mg, 4.02 mmol), tert-butyl(2S)-3-cyano-2-methyl-4-carbonyl-piperidine-1-carboxylic acid ester (958.34 mg, 4.02 mmol), and pyridine hydrochloride (46.48 mg, 402.19 μmol) were dissolved in toluene (20 mL). Under nitrogen protection, the reaction mixture was heated to 90 °C and stirred. After 4 hours, heating was stopped, and the reaction mixture was cooled to room temperature. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown oily crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 50%, v / v) to give 968 mg of the product.

[0810] MS m / z(ESI): 445.2 [M+1].

[0811] Step 5

[0812] tert-Butyl(S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0813] Tert-butyl(S)-3-amino-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (968 mg, 2.18 mmol), N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide (477.16 mg, 2.40 mmol), and potassium tert-butoxide (733.03 mg, 6.53 mmol) were dissolved in N,N-dimethylacetamide (10 mL) and the reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 50%, v / v) to give 1.18 g of the product.

[0814] MS m / z(ESI): 576.2 [M+1].

[0815] Step 6

[0816] tert-Butyl(S)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0817] 1.18 g (2.05 mmol) of tert-butyl(S)-3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid and 157.60 mg (1.64 mmol) were dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, the reaction mixture was heated to 60 °C and stirred. After 4 hours, the reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. This crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 50%, v / v) to give 905 mg of the product.

[0818] MS m / z(ESI): 512.2 [M+1].

[0819] Step 7

[0820] tert-Butyl(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester

[0821] tert-butyl(S)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-3-(2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (200 mg, 390.94 μmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (98.50 mg, 43 μmol) 0.03 μmol), cuprous iodide (74.45 mg, 390.94 μmol), potassium carbonate (162.09 mg, 1.17 mmol), and (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane (55.61 mg, 390.94 μmol) were dispersed in N-methylpyrrolidone (5 mL). Under nitrogen protection, the reaction mixture was heated to 130 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown, oily crude product. This crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 40%, v / v) to give 188 mg of the product.

[0822] MS m / z(ESI): 660.2 [M+1].

[0823] Step 8

[0824] (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0825] 188 mg (284.97 μmol) of tert-butyl(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester was dissolved in a mixed solvent of hydrochloric acid (4 M in dioxane) (1 mL) and dichloromethane (4 mL), and the reaction was stirred at room temperature. After 2 hours, the reaction solution was concentrated under reduced pressure to obtain a yellow solid crude product (128 mg). This crude product was used directly in the next reaction without purification.

[0826] MS m / z(ESI): 560.2 [M+1].

[0827] Step 9

[0828] tert-Butyl 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(methyl(phenyl)carbamoyl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-5-carbonyl-1,2,4-oxadiazole-4(5H)-carboxylic acid ester

[0829] 5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1-[(1S,2S)-2-(hydroxymethyl)-1-(5-carbonyl-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-N-methyl-N-phenyl-indole-2-carboxamide (283 mg, 547.83 μmol), ditert-butyl dicarbonate (239.12 mg, 1.10 mmol), triethylamine (166.30 mg, 1.64 mmol, 229.23 μL), and 4-dimethylaminopyridine (66.93 mg, 547.83 μmol) were dissolved in 1,2-dichloroethane (5 mL). After stirring at room temperature for 18 hours, the reaction solution was quenched with saturated ammonium chloride solution. The mixture was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 50%, v / v) to give 180 mg of product. MS m / z (ESI): 617.3 [M+1].

[0830] Step 10

[0831] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((hex-5-en-1-oxy)methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0832] 180 mg (291.87 μmol) of tert-butyl-3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(methyl(phenyl)carbamoyl)-1H-indol-1-yl)-2-(hydroxymethyl)cyclopropyl)-5-carbonyl-1,2,4-oxadiazol-4(5H)-carboxylic acid ester and sodium hydroxide (35 mg, 1.46 mmol) were dispersed in N,N-dimethylformamide (5 mL). The mixture was stirred for 15 minutes. 6-bromohex-1-ene (95.18 mg, 583.75 μmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 40%, v / v) to give 135 mg of product.

[0833] MS m / z(ESI): 599.2 [M+1].

[0834] Step 11

[0835] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((hex-5-en-1-oxy)methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0836] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((hex-5-en-1-oxy)methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (126 mg, 210.45 μmol) and potassium hydroxide (118.07 mg, 2.10 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 1 by adding hydrochloric acid (1 M). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product (102 mg). This crude product was used directly in the next reaction without purification.

[0837] MS m / z (ESI): 510.2 [M+1].

[0838] Step Twelve

[0839] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-((hex-5-en-1-oxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0840] (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (85 mg, 142.60 μmol, CL), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-((hex-5-en-1-oxy)) Methyl)-1-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (85.38 mg, 142.60 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80.70 mg, 213.90 μmol), and N,N-diisopropylethylamine (92.15 mg, 713.00 μmol, 124.19 μL) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was stirred at room temperature. After 18 hours, the reaction solution was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, the organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (developing solvent: methanol: dichloromethane = 10%, v / v) to obtain 129 mg of product.

[0841] MS m / z (ESI): 1051.4 [M+1].

[0842] Step Thirteen

[0843] (23Z,24S,51S,52S,12Z)-45-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-14-fluoro-23-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-15,24-dimethyl-51-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-24,25,26,27-tetrahydro-22H,41H-7,17-dioxa-2(2,5)-pyrazolo[4,3-c]pyridine-4(2,1)-indole-1(1,3)-benzene-5(1,2)-cyclopropanecycloheptadecane-12-en-3-one

[0844] 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-carbonyl-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-(pent-4-en-1-oxy)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazole [4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-((hex-5-en-1-oxy)methyl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 19.03 μmol) and HOVEYDA-GRUBBS catalyst (11.90 mg, 19.03 μmol) were dissolved in 1,2-dichloroethane (20 mL), and the reaction was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give 3.7 mg of product.

[0845] MS m / z(ESI): 1023.4 [M+1].

[0846] Biological testing evaluation

[0847] The present invention is further described and explained below with reference to test examples, but these examples are not intended to limit the scope of the invention. I. Determination of the ability of the compounds of the present invention to stimulate cAMP production in human GLP1 receptor-stabilized cell lines.

[0848] 1. Experimental Objective: The purpose of this test case is to evaluate the ability of the compound to activate the human GLP-1 receptor on the cell surface. Activation of this receptor stimulates the production of cAMP in ECs. 50 The activation ability of the compound on human GLP-1 receptor was characterized.

[0849] In this experiment, the compound and cells were co-incubated for 2 hours.

[0850] 2. Experimental reagents and instruments

[0851] 2.1 Experimental Apparatus:

[0852] ELISA reader, pipette

[0853] 2.2 Experimental Reagents

[0854] DMEM / F12 medium, casein, 384-well plates, IBMX, Cisbio cAMP-Gs Dynamic kit

[0855] 3. Experimental methods:

[0856] The frozen human GLP1 receptor stable cell line CHO-K1 / GLP-1R / CRE-luc was removed from the liquid nitrogen tank and rapidly thawed in a 37°C water bath. The cells were resuspended in DMEM / F12 medium, centrifuged, washed once, and resuspended in experimental buffer (DMEM / F12 medium containing 0.1% casein). After centrifugation, the cell density was adjusted with experimental buffer and seeded into 384-well plates at a density of 1500 cells / 5 μL / well. 2.5 μL of buffer-prepared IBMX working solution (final IBMX concentration 0.5 mM) and 2.5 μL of serially diluted compound samples (starting from 1000–333.33 nM, 3-fold dilution, 12 concentrations) were added to each well. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 37°C for 2 hours. The samples were then analyzed using the Cisbio cAMP-Gs Dynamic Kit, which analyzed cAMP-d2 and Anti-cAMP-Eu... 3+ Cryptate was diluted 18-fold and 20-fold with cAMP Lysis & Detection Buffer and mixed thoroughly. 5 μL of the diluted cAMP-d2 solution was added to each well, centrifuged at 1000 rpm for 1 minute, and vortexed for 30 seconds to mix. Then, 5 μL of the diluted Anti-cAMP-Eu3 solution was added. + -Cryptate solution, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature in the dark for 1 hour. HTRF signal was read using a Biotek Synergy H1 microplate reader with excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[0857] 4. Experimental data processing methods:

[0858] The signal-to-weight ratio (665nm / 620nm*10,000) was calculated, and the signal-to-weight ratio was nonlinearly fitted to the sample concentration using a four-parameter equation in GraphPad Prism 10 to obtain the EC. 50 value.

[0859] 5. Experimental Conclusion:

[0860] In some embodiments, the compounds of the present invention have shown good biological activity in experiments stimulating human GLP1 receptor stable cell lines to produce cAMP. The EC50 of the compounds of the present invention stimulating hGLP1R stable cell lines to produce cAMP is less than about 100 nM, preferably less than about 50 nM, more preferably less than about 10 nM, further preferably less than about 5 nM, even more preferably less than about 1 nM, and most preferably less than 0.1 nM.

[0861] II. Effects of a single dose of the compound of this invention on intraperitoneal glucose tolerance in GLP-1R humanized mice

[0862] 1. Experimental objective:

[0863] The effect of a single dose of the compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance (ipGTT) experiment in GLP-1R humanized C57BL / 6 mice was evaluated.

[0864] 2. Experimental materials:

[0865] C57BL / 6_hGLP-1R, male, 5-8 weeks; clean bench; electronic balance; active blood glucose meter; glucose.

[0866] 3. Experimental procedures and data processing:

[0867] 3.1 The day before the experiment, animals were randomly divided into groups of 5 based on their body weight. All animals were fasted overnight without food and remained fasted for at least 16 hours until the administration of the drug.

[0868] 3.2 Prepare a 0.2 g / mL glucose solution using pure water, filter it through a 0.22 μm filter membrane, and set it aside for later use;

[0869] 3.3 On the day of the test, before administering the medication, the blood glucose level of each animal was measured sequentially using the tail clipping method and recorded as the baseline value;

[0870] Blood glucose testing method: Place the mouse in a restraint, disinfect the tail tip with an alcohol swab, then cut off a small part of the tail tip with scissors, discard the first drop of blood, and drop the second drop of blood onto the prepared blood glucose test strip to test the blood glucose value.

[0871] 3.4. Administer medication according to the animal's body weight and record the administration time for each animal. One hour after administration, measure the blood glucose level of each animal sequentially and record it as the 0-minute blood glucose level.

[0872] 3.5. Subsequently, based on the patient's weight on that day, immediately administer an intraperitoneal injection of pure water or glucose solution at a volume of 10 mL / kg and a glucose dose of 2 g / kg.

[0873] 3.6. After injection of pure water or glucose solution for 15, 30, 60, 90 and 120 minutes, the blood glucose level of each mouse was measured and the time and data were recorded.

[0874] 3.7 After the test, all animals resumed eating.

[0875] 3.8 Data Processing:

[0876] Plot the blood glucose (BG)-time curve and calculate the area under the blood glucose-time curve using the following formula:

[0877] AUC (mmol / L.hr)=(BG0+BG15)×0.25 / 2+(BG15+BG30)×0.25 / 2+(BG30+BG60)×0.5 / 2+(BG60+BG90)×0.5 / 2+(BG90+BG120)×0.5 / 2.

[0878] Note: BG0, BG15, BG30, BG60, BG90 and BG120 represent blood glucose levels before glucose administration (0 min), and 15, 30, 60, 90 and 120 min after glucose administration, respectively.

[0879] The blood glucose reduction rate at each time point and AUC is calculated based on the average blood glucose value and blood glucose AUC. The calculation formula is: Blood glucose reduction rate = (Blood glucose in the model control group / AUC - Blood glucose in the treatment group / AUC) / Blood glucose in the model control group / AUC × 100%.

[0880] The compounds in the embodiments of the present invention can effectively reduce blood glucose in mice, with a blood glucose reduction rate of more than 20%, preferably more than 40%, and more preferably more than 60%.

[0881] III. Effects of long-term administration of the compounds of this invention on body weight and food intake in GLP-1R humanized mice fed a high-fat diet under CDAHFD conditions.

[0882] 1. Experimental objective:

[0883] The purpose of this test was to evaluate the effects of long-term administration of the compound on body weight and food intake in CDAHFD high-fat diet-fed GLP-1R humanized C57BL / 6 mice.

[0884] 2. Experimental reagents and instruments

[0885] C57BL / 6_hGLP-1R, male, 5-8 weeks old, purchased from Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[0886] Choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD, Research diet-A06071302) purchased from Shanghai Bopai Biotechnology Co., Ltd.

[0887] Clean bench (CJ-2F, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.)

[0888] Electronic balance (BSA2202S-CW, Sartorius)

[0889] 3. Experimental Methods

[0890] 3.1 On the day the high-fat diet was started, the C57BL / 6 mice were randomly divided into two groups according to their body weight. The first group was Blank, consisting of 7 mice, which were fed a normal control diet. The remaining animals were the model group, which were fed a high-fat diet. This continued until the end of the experiment.

[0891] 3.2 During the fourth week of CDAHFD feeding, the model group animals were randomly divided into groups of 7 animals each according to their body weight. The first group was the Vehicle group (Vehicle: 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 26mM NaOH, pH 9) buffer), which was given the solvent. The remaining groups were the drug administration groups. The administration regimen was: oral administration of the corresponding compound for 21 days, once a day, at doses of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg, with an administration volume of 10 mL / kg. The Blank group continued to be fed a normal diet and was given the solvent orally once a day.

[0892] 3.3 The day of administration is defined as Day 0.

[0893] 3.4 Each time an animal is given an administration, it is weighed and the data is recorded. The animal is then given an oral administration of 10 mL / kg based on its body weight.

[0894] 3.5 Starting from day 0 of the experiment, the food intake of mice in each group was measured every three days. Specifically, the feed was changed after each administration of medication and the amount added and the amount remaining were recorded.

[0895] 3.6 Day 21, the final day, all mice were euthanized in the order of grouping. Plasma and tissues (liver, kidney, ileum, pancreas, brain) were collected for PK testing, and serum was collected for blood biochemistry testing (ALT, AST, TG, TC, LDL-C).

[0896] 4. Experimental Data Processing and Statistical Analysis

[0897] The body weight and body weight change rate of mice after drug administration were summarized and statistically analyzed. The body weight change rate was calculated as: (BWt - BW0) / BW0 × 100%. BWt represents the body weight of the mouse on day t of the experiment, and BW0 represents the body weight of the mouse on day 0 of the experiment.

[0898] Food intake calculation: (addition amount (g) - remaining amount (g)) / number of animals per cage. The cumulative food intake is the total daily food intake of each animal during the drug administration period.

[0899] Experimental data were analyzed and plotted using GraphPad Prism software. Comparisons between two groups were performed using the t-test method. Comparisons between three or more groups were performed using the one-way ANOVA method. A p-value < 0.05 was defined as statistically significant.

[0900] The compounds in the embodiments of the present invention can effectively reduce the weight of mice, with a weight reduction rate of more than 5%, and more preferably more than 10%.

[0901] IV. Pharmacokinetic Evaluation Test in Mice

[0902] 1. Research Objective:

[0903] Using Balb / c mice as test animals, the pharmacokinetic behavior of the compound of the present invention in mice (plasma) was studied after oral administration at a dose of 5 mg / kg and intravenous administration at a dose of 1 mg / kg.

[0904] 2. Experimental Design:

[0905] 2.1 Experimental reagents:

[0906] The compounds used in this invention embodiment are self-made.

[0907] 2.2 Laboratory animals:

[0908] Each group of Balb / c mice contains 3 males.

[0909] 2.3 Formulation:

[0910] Oral administration drug preparation: 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64Mm NaOH, pH 10) buffer.

[0911] Measure 10 ml of PEG400, 10 ml of PG, and 80 ml of (100 mM glycine, 64 mM NaOH, pH = 9) into a 100 ml volumetric flask, vortex, mix, and sonicate to obtain a clear solution.

[0912] Single PK: Weigh the compound from the example and add it to a 4 mL glass bottle. Add the solution and sonicate for 10 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg / mL.

[0913] Cassette PK: Weigh out five compounds of similar weight from Example 5 and mix them in a 4 mL glass bottle. Add the solution and sonicate for 10 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg / mL.

[0914] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0915] Weigh out the compound from the examples, add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[0916] 2.4 Administration:

[0917] Three male Balb / c mice were administered oral medication (PO) after fasting overnight; the dose was 5 mg / kg, and the administration volume was 10 mL / kg.

[0918] Three male Balb / C mice were used. After fasting overnight, they were administered the drug intravenously at a dose of 1 mg / kg and a volume of 5 mL / kg.

[0919] 2.5 Sample Collection:

[0920] Blood collection: 0.04 mL of blood was collected from the orbital cavity of mice before and 0.083 (IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. The blood was placed in EDTA-K2 anticoagulant tubes and centrifuged at 6000 rpm for 6 min at 4 °C to separate the plasma. The plasma was stored at -80 °C. Mice were fed 4 h after administration.

[0921] 2.6 Sample preparation:

[0922] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5–20 minutes.

[0923] 2) Take the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the analyte. LC / MS / MS instrument: AB Sciex API 4000Qtrap.

[0924] 2.7 Liquid phase analysis:

[0925] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0926] ● Column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is acetonitrile

[0927] ● Flow rate: 0.4 mL / min

[0928] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0929] 3. Experimental conclusions:

[0930] The compounds in the embodiments of this invention exhibited favorable metabolic properties, with low exposure AUC and high peak plasma concentration C. max They all performed well.

[0931] V. Pharmacokinetic Determination in SD Rats

[0932] 1. Research Objective:

[0933] Using SD rats as test animals, the pharmacokinetic behavior of the following compounds in rat plasma after oral administration at a dose of 5 mg / kg was studied.

[0934] 2. Test Plan

[0935] 2.1 Test Drugs:

[0936] This invention is a self-made product.

[0937] 2.2 Experimental animals:

[0938] Three male SD rats were used in each group.

[0939] 2.3 Formulation:

[0940] Oral administration drug preparation: 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 64Mm NaOH, pH 10) buffer.

[0941] Measure 10 ml of PEG400, 10 ml of PG, and 80 ml of (100 mM glycine, 64 mM NaOH, pH = 9) into a 100 ml volumetric flask, vortex, mix, and sonicate to obtain a clear solution.

[0942] Weigh out the compound from the example and add it to a 4 mL glass bottle. Add the solution, first adjust the pH to clear with 1 M NaOH, then adjust it back to pH 9.0-9.5 with 1 M HCl, and sonicate for 10 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg / mL.

[0943] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0944] Weigh out the compound from the examples, add 5% DMSO according to the total volume ratio of the drug, vortex and sonicate for 2 min to completely dissolve it; then add 10% Solutol HS15, vortex and sonicate for 2 min to completely dissolve it; finally add 85% PBS, vortex and sonicate for 5 min, filter through a 0.22 μm filter membrane to obtain a colorless, transparent, and clear solution with a concentration of 0.2 mg / mL.

[0945] 2.4 Administration:

[0946] Three male rats were fasted overnight and then administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0947] Three male rats were administered the drug intravenously after fasting overnight. The dosage was 1 mg / kg, and the administration volume was 5 mL / kg.

[0948] 2.5 Sample Collection:

[0949] Before and after drug administration, 0.2 mL of blood was collected from the jugular vein of rats at 0.083 (IV), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4℃ to separate the plasma, and stored at -80℃. The rats were fed 4 hours after drug administration.

[0950] 2.6 Sample preparation:

[0951] 1) Add 40uL of plasma sample to 160uL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5-20 minutes.

[0952] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[0953] 2.6 Liquid Chromatography Analysis

[0954] ●Liquid phase conditions: Shimadzu LC-20AD pump

[0955] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0956] ● Column: phenomenex Gemiu 5um C18 50×4.6mm

[0957] ●Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is methanol.

[0958] ● Flow rate: 1.0 mL / min

[0959] ●Eluting time: 0-4.0 minutes, eluent as follows:

[0960] 3. Experimental Results and Analysis

[0961] The compounds in the embodiments of this invention exhibited favorable metabolic properties, with low exposure AUC and high peak plasma concentration C. max They all performed well.

[0962] VI. Effects of long-term administration of the compounds of this invention on body weight and food intake in GLP-1R humanized mice fed a high-fat diet under HFD conditions.

[0963] 1. Experimental objective:

[0964] The purpose of this test was to evaluate the effects of long-term administration of the compound on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0965] 2. Experimental reagents and instruments

[0966] C57BL / 6_hGLP-1R, male, 60% high-fat diet (HFD), clean bench, electronic balance.

[0967] 3. Experimental Methods

[0968] 3.1 On the day the high-fat diet was started, the C57BL / 6 mice were randomly divided into two groups according to their body weight. The first group was Blank, consisting of 7 mice, which were fed a normal control diet. The remaining animals were the model group, which were fed a high-fat diet. This continued until the end of the experiment.

[0969] 3.2 During week 8 of HFD feeding, the model group animals were randomly divided into groups of 7 animals each according to their body weight. The first group was the Vehicle group (Vehicle: 10% PEG400 / 10% PG / 80% glycine buffer (100mM glycine, 26mM NaOH, pH 9) buffer), which was given the solvent. The remaining groups were the drug administration groups. The administration regimen was: oral administration of the corresponding compound for 21 days, once a day, at a dose of 10 mg / kg and a volume of 10 mL / kg. The Blank group continued to be fed a normal diet and was given the solvent orally once a day.

[0970] 3.3 The day of administration is defined as Day 0.

[0971] 3.4 Each time an animal is given an administration, it is weighed and the data is recorded. The animal is then given an oral administration of 10 mL / kg based on its body weight.

[0972] 3.5 Starting from day 0 of the experiment, the food intake of mice in each group was measured every three days. Specifically, the feed was changed after each administration of medication and the amount added and the amount remaining were recorded.

[0973] 3.7 Day 21, the final day, all mice were euthanized in the order of grouping. Plasma and tissues (liver, kidney, ileum, pancreas, brain) were collected for PK testing, and serum was collected for blood biochemistry testing (ALT, AST, TG, TC, LDL-C).

[0974] 4. Experimental Data Processing and Statistical Analysis

[0975] The body weight and ...

Claims

1. The following compounds, their prodrugs, their stereoisomers, or their pharmaceutically acceptable salts:

2. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 1, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

3. The use of the compound, its prodrug, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 2, in the preparation of a GLP-1 receptor agonist drug.

4. The use of the compound of claim 1, its prodrug, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating metabolic-related diseases.

5. The application according to claim 4, characterized in that, The diseases mentioned are selected from those related to diabetes, obesity, or non-alcoholic steatohepatitis, or other related diseases caused by diabetes, obesity, or non-alcoholic steatohepatitis.

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