Amide compounds and their use as integrin alpha 4 beta 7 antagonists

Abstract

This invention proposes a new class of compounds that effectively antagonize integrin α4β7, which are compounds represented by formula (II) below, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of compounds represented by formula (II) below:

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically, it relates to amide compounds, and more specifically, it relates to amide compounds and their use as integrin α4β7 antagonists. Background Technology

[0002] Integrins are dimers formed by two subunits: α (120–185 kDa) and β (90–110 kDa). Mammalian species have 18 α subunits and 8 β subunits. Different combinations can form more than 20 different integrins. α4β7 is a member of the integrin family, and intestinal inflammatory diseases associated with α4β7 include Crohn's disease and ulcerative colitis. The main ligand for α4β7 is the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM-1 is a transmembrane glycoprotein molecule selectively expressed in the hyperendothelial veins of mucosal lymphoid organs and the veins of the lamina propria of the intestine. Under inflammatory conditions, various cytokines can promote the high expression of MAdCAM-1 on endothelial cells, and MAdCAM-1 then mediates the migration of α4β7-expressing leukocytes to the site of inflammation. Targeting either integrin α4β7 or MAdCAM-1 can alleviate the severity of intestinal inflammation.

[0003] Integrins have long been recognized as drug targets for the treatment of various indications, including inflammatory bowel disease, multiple sclerosis, psoriasis, and acute coronary syndrome. However, oral bioavailable integrin inhibitors have rarely been successful in treating these conditions.

[0004] Of the more than 20 known integrin dimers, at least half are associated with inflammation, fibrosis, oncology, and vascular diseases. Therefore, new integrin inhibitors are needed. Summary of the Invention

[0005] The present invention aims to provide an amide compound used as an integrin α4β7 antagonist, its preparation method and uses.

[0006] In a first aspect, the present invention provides a compound of formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of formula (II):

[0007]

[0008] in:

[0009] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0010] R4 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0011] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0012] Ring E is selected from

[0013] R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3;

[0014] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0015] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0016] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0017] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0018] R 10 Selected from hydrogen or C 1-6 alkyl;

[0019] R 11 Selected from hydrogen, halogen, cyano, hydroxyl, C 1-6Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups.

[0020] According to certain embodiments of the present invention, the compound is not

[0021] According to certain embodiments of the present invention, ring E is selected from... At least one R3 is a halogen.

[0022] This invention provides a compound of formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of formula (II):

[0023]

[0024] in:

[0025] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0026] R4 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0027] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0028] Ring E is selected from

[0029] R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -NR 8a R 8b n is an integer selected from 0, 1, 2, and 3;

[0030] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0031] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0032] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0033] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0034] R 10 Selected from hydrogen or C 1-6 alkyl;

[0035] R 11 Selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups.

[0036] According to certain embodiments of the present invention, R1 and R2 are each independently selected from halogens and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0037] According to certain embodiments of the present invention, R1 and R2 are each independently selected from halogens and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0038] According to certain embodiments of the present invention, R1 and R2 are each independently selected from halogen, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one or more substituents selected from halogen; undefined groups are as described in any embodiment of the present invention.

[0039] According to certain embodiments of the present invention, R1 and R2 are each independently selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more substituents selected from F and Cl; undefined groups are as described in any embodiment of the present invention.

[0040] According to certain embodiments of the present invention, R1 is selected from F, Cl, -CH3, -CHF2, -CF3, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0041] According to certain embodiments of the present invention, R2 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0042] According to certain embodiments of the present invention, R4 is selected from H, halogens, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; undefined groups as described in any embodiment of the invention.

[0043] According to certain embodiments of the present invention, R4 is selected from H, halogens, and methyl groups; undefined groups are as described in any embodiment of the present invention.

[0044] According to certain embodiments of the present invention, R4 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0045] According to certain embodiments of the present invention, R4 is selected from H or F; undefined groups are as described in any embodiment of the present invention.

[0046] According to certain embodiments of the present invention, R4 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0047] According to certain embodiments of the present invention, R 11 Selected from H, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; undefined groups as described in any embodiment of the invention.

[0048] According to certain embodiments of the present invention, R 11Selected from H, halogens, and methyl groups; undefined groups are as described in any of the embodiments of this invention.

[0049] According to certain embodiments of the present invention, R 11 Selected from H and F; undefined groups are as described in any of the embodiments of this invention.

[0050] According to certain embodiments of the present invention, R 11 Selected from H or F; undefined groups are as described in any of the embodiments of this invention.

[0051] According to certain embodiments of the present invention, R 11 Selected from H; undefined groups are as described in any embodiment of this invention.

[0052] According to certain embodiments of the present invention, Selected from Undefined groups are as described in any embodiment of this invention.

[0053] According to certain embodiments of the present invention, R3 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0054] According to certain embodiments of the present invention, R3 is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0055] According to certain embodiments of the present invention, R3 is independently selected from halogen, cyano, methyl, methoxy, cyclopropyl, wherein the methyl, methoxy, or cyclopropyl group is optionally substituted by one or more substituents selected from halogen; undefined groups are as described in any embodiment of the present invention.

[0056] According to certain embodiments of the present invention, R3 is independently selected from F, methyl, and methoxy; undefined groups are as described in any embodiment of the present invention.

[0057] According to certain embodiments of the present invention, Selected from Undefined groups are as described in any embodiment of this invention.

[0058] According to certain embodiments of the present invention, Selected from Undefined groups are as described in any embodiment of this invention.

[0059] According to certain embodiments of the present invention, Selected from Undefined groups are as described in any embodiment of this invention.

[0060] According to certain embodiments of the present invention, Selected from Undefined groups are as described in any embodiment of this invention.

[0061] According to certain embodiments of the present invention, R5 is selected from C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0062] According to certain embodiments of the present invention, R5 is selected from C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0063] According to certain embodiments of the present invention, R5 is selected from C. 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-4 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0064] According to certain embodiments of the present invention, R5 is selected from C. 1-6 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 Cycloalkyl; undefined groups as described in any embodiment of the invention.

[0065] According to certain embodiments of the present invention, R5 is selected from C. 1-4 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 Cycloalkyl; undefined groups as described in any embodiment of the invention.

[0066] According to certain embodiments of the present invention, R5 is selected from... Undefined groups are as described in any embodiment of this invention.

[0067] According to certain embodiments of the present invention, R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5; R9 is independently selected from halogen, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3The alkoxy group is optionally substituted by one or more substituents selected from halogen, cyano, or hydroxyl; the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, or S; undefined groups are as described in any embodiment of the invention.

[0068] According to certain embodiments of the present invention, R 8a R 8b Each is independently selected from hydrogen or C. 1-3 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, and 3; R9 is independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy group; the heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O or S; undefined groups are as described in any embodiment of the present invention.

[0069] According to certain embodiments of the present invention, R 8a R 8b Selected from methyl; or R 8a and R 8b Together with the N atom to which it is attached, it forms a 4- to 5-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0 and 1; R9 is independently selected from F, methyl, and methoxy; the heterocyclic alkyl group contains 1 N atom; undefined groups are as described in any embodiment of the present invention.

[0070] According to certain embodiments of the present invention, R 8c R 8d Each is independently selected from H, halogen, C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0071] According to certain embodiments of the present invention, R 6a R 7a Each is independently selected from -(CH2) n -NR 8a R 8b -CF2-CH2-NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0072] According to certain embodiments of the present invention, R 6a R 7a Each is independently selected from -(CH2) n -N(R 8a )R 8b-CF2-CH2-N(R) 8a )R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0073] According to certain embodiments of the present invention, R 6a R 7a Each is independently selected from -(CH2) n -NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0074] According to certain embodiments of the present invention, R 6a R 7a Each is independently selected from -(CH2) n -N(R 8a )R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0075] According to certain embodiments of the present invention, R 6a R 7a Each independently selected Undefined groups are as described in any embodiment of this invention.

[0076] According to certain embodiments of the present invention, R 8c R 8d Each group is independently selected from H and F; undefined groups are as described in any embodiment of this invention.

[0077] According to certain embodiments of the present invention, R 7a Independently selected from H, -(CR 8c R 8d ) n -N(R 8a )R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0078] According to certain embodiments of the present invention, R 7a Independently selected from H, -(CR 8c R 8d ) n -NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0079] According to certain embodiments of the present invention, R 7aIndependently selected from H,

[0080] Undefined groups are as described in any embodiment of this invention.

[0081] According to certain embodiments of the present invention, R 7a Independently selected from H; undefined groups are as described in any embodiment of the invention.

[0082] According to certain embodiments of the present invention, R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; undefined groups as described in any of the embodiments of the present invention.

[0083] According to certain embodiments of the present invention, R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; undefined groups as described in any of the embodiments of the present invention.

[0084] According to certain embodiments of the present invention, R 6b Selected from C 1-3 Alkoxy, C3-6 cycloalkyl, R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; undefined groups as described in any of the embodiments of the present invention.

[0085] According to certain embodiments of the present invention, R 6c Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6b R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; undefined groups as described in any of the embodiments of the present invention.

[0086] According to certain embodiments of the present invention, R 6b Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6c R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0087] According to certain embodiments of the present invention, R 6c Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6b R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0088] According to certain embodiments of the present invention, R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0089] According to certain embodiments of the present invention, R 7b Each is independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0090] According to certain embodiments of the present invention, R 7b Each group is independently selected from hydrogen, F, cyano, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more F groups; undefined groups are as described in any embodiment of the present invention.

[0091] According to certain embodiments of the present invention, R 7b Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0092] According to certain embodiments of the present invention, ring E is selected from...

[0093] Undefined groups are as described in any embodiment of this invention.

[0094] According to certain embodiments of the present invention, the compound is a compound of formula (IA):

[0095]

[0096] The definitions of R1, R2, R3, R4, R5, ring E, and p are as described in any embodiment of this invention.

[0097] According to certain embodiments of the present invention, the compound is a compound of formula (II-A):

[0098]

[0099] R1, R2, R3, R4, R5, R 10 R 11 The definitions of ring E and p are as described in any embodiment of this invention.

[0100] According to certain embodiments of the present invention, the compound is a compound of formula (II-B):

[0101]

[0102] Where p' is an integer selected from 3 or 4;

[0103] Ring E' is selected from

[0104] R' 6a 、R' 7a Each is independently selected from H and -(CH2). n -N(R' 8a )R' 8b The -(CH2) mentioned above n -N(R' 8a )R' 8b Optionally selected by one or more halogens, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; n is an integer selected from 0, 1, 2, 3;

[0105] R' 8a 、R' 8b Each is independently selected from hydrogen or C. 1-3 Alkyl; or R' 8a 、R' 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group, wherein the 3- to 6-membered heterocyclic alkyl group is optionally bonded by one or more atoms selected from halogens, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0106] R' 6b Selected from H, C 3-6 cycloalkyl, C 1-6 Alkoxy, the C 3-6 cycloalkyl, C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, C 1-6 Substituents of haloalkyl groups;

[0107] R' 6c Selected from H, C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens;

[0108] R' 6b and R' 6c At least one of them is selected from C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0109] R1, R3, R4, R 10 R11 The definition is as described in any embodiment of this invention.

[0110] According to certain embodiments of the present invention, R1 is selected from F, Cl, -CH3, -CHF2, -CF3, cyclopropyl; R4 is selected from H and F; R3 is independently selected from F, methyl, methoxy; p' is an integer selected from 3 or 4; R 11 Selected from H and F; R 10 Selected from H or ethyl; undefined groups are as described in any of the embodiments of the present invention.

[0111] According to certain embodiments of the present invention, R1 is selected from F, Cl, -CH3, -CHF2, -CF3, cyclopropyl; R4 is selected from H and F; R3 is independently selected from F, methyl, methoxy; p' is an integer selected from 3 or 4; R 11 Selected from H and F; R 10 Selected from H; undefined groups are as described in any embodiment of this invention.

[0112] According to certain embodiments of the present invention, R' 8a 、R' 8b Each is independently selected from methyl; or R' 8a and R' 8b Together with the N atom to which it is attached, it forms a 4- to 5-membered heterocyclic alkyl group, which is optionally substituted by one or more substituents selected from F, methyl, and methoxy; undefined groups are as described in any embodiment of the present invention.

[0113] According to certain embodiments of the present invention, R' 6a 、R' 7a Each is independently selected from -(CH2)2-N(R' 8a )R' 8b -CF2-CH2-N(R' 8a )R' 8b Undefined groups are as described in any embodiment of this invention.

[0114] According to certain embodiments of the present invention, R' 6a 、R' 7a Each is independently selected from H, Undefined groups are as described in any embodiment of this invention.

[0115] According to certain embodiments of the present invention, R' 6b Selected from cyclopropyl, -OCHF2, R' 6c Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0116] According to certain embodiments of the present invention, R'6c Selected from -OCF3, -OCHF2, R' 6b Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0117] According to certain embodiments of the present invention, ring E' is selected from...

[0118] Undefined groups are as described in any embodiment of this invention.

[0119] According to certain embodiments of the present invention, the compound is a compound of formula (II-C):

[0120]

[0121] R1, R3, R4, R 10 R 11 The definitions of ring E' and p' are as described in any embodiment of this invention.

[0122] According to certain embodiments of the present invention, the compound is a compound of formula (II-D):

[0123]

[0124] Wherein, X is selected from F, methyl, and methoxy;

[0125] R'4 is selected from H or F;

[0126] Ring E1 is selected from

[0127] R” 6a 、R” 7a Each is independently selected from -(CH2) n -N(R” 8a )R” 8b n is an integer selected from 1, 2, and 3;

[0128] R” 8a 、R” 8b Each was independently selected from C 1-3 Alkyl; or R” 8a and R” 8b Together with the N atom to which it is attached, it forms a 4-membered heterocyclic alkyl group, which is optionally substituted by one or more substituents selected from halogens;

[0129] R” 6c Selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens.

[0130] According to certain embodiments of the present invention, R” 6a 、R” 7a Each independently selected Undefined groups are as described in any embodiment of this invention.

[0131] According to certain embodiments of the present invention, R” 6c Selected from -OCF3, -OCHF2; undefined groups are as described in any of the embodiments of this invention.

[0132] According to certain embodiments of the present invention, ring E1 is selected from... Undefined groups are as described in any embodiment of this invention.

[0133] According to certain embodiments of the present invention, the compound is a compound of formula (II-E):

[0134]

[0135]

[0136] The definitions of X, R'4, and ring E1 are as described in any embodiment of this invention.

[0137] According to certain embodiments of the present invention, the compound is a compound of formula (III):

[0138]

[0139] The definitions of X, R'4, and ring E1 are as described in any embodiment of this invention.

[0140] According to certain embodiments of the present invention, the compound is a compound of formula (III-A):

[0141]

[0142] The definitions of X, R'4, and ring E1 are as described in any embodiment of this invention.

[0143] According to certain embodiments of the present invention, the compound is a compound of formula (IV-A1):

[0144]

[0145] Ring E2 is selected from

[0146]

[0147] R1, R2, R3, R4, R5, R 7a R 7b R10 R 11 The definitions of p and q are as described in any embodiment of this invention.

[0148] According to certain embodiments of the present invention, R2 is selected from F; R5 is selected from Undefined groups are as described in any embodiment of this invention.

[0149] According to certain embodiments of the present invention, the compound is a compound of formula (IV-A2):

[0150]

[0151] Rings E2, R1, R2, R3, R4, R5, R 10 R 11 The definitions of and p are as described in any embodiment of this invention.

[0152] According to certain embodiments of the present invention, the compound is a compound of formula (IV-B1):

[0153]

[0154] Where p1 is selected from 2 or 3;

[0155] Rings E, R1, R2, R3, R4, R5, R 10 R 11 The definition is as described in any embodiment of this invention.

[0156] According to certain embodiments of the present invention, in the compound represented by formula (IV-B1), Selected from Undefined groups are as described in any embodiment of this invention.

[0157] According to certain embodiments of the present invention, the compound is a compound of formula (IV-B2):

[0158]

[0159] Rings E, R1, R2, R3, R4, R5, R 10 R 11 The definitions of p1 are as described in any embodiment of this invention.

[0160] According to certain embodiments of the present invention, the compound is a compound of formula (IV-C1):

[0161]

[0162] Among them, ring E2 is selected from p1 is selected from 2 or 3;

[0163] R1, R2, R3, R4, R5, R 7a R 7b R 10 R 11 The definitions of q are as described in any embodiment of this invention.

[0164] According to certain embodiments of the present invention, in the compound represented by formula (IV-C1), R2 is selected from F; R5 is selected from... Selected from Undefined groups are as described in any embodiment of the invention. According to certain embodiments of the invention, the compound is a compound of formula (IV-C2):

[0165]

[0166] Rings E2, R1, R2, R3, R4, R 10 R 11 The definitions of p1 are as described in any embodiment of this invention.

[0167] According to certain embodiments of the present invention, the compound is a compound of formula (IV-D1):

[0168]

[0169] R1, R2, R3, R4, R5, R 6a R 6b R 6c R 6d R 10 R 11 The definitions of and p are as described in any embodiment of this invention.

[0170] According to certain embodiments of the present invention, the compound is a compound of formula (IV-D2):

[0171]

[0172]

[0173] R1, R2, R3, R4, R5, R 6a R 6b R 6c R 6d R 10 R 11 The definitions of and p are as described in any embodiment of this invention.

[0174] According to certain embodiments of the present invention, the compound is a compound of formula (IV-E1):

[0175]

[0176] Where p1 is selected from 2 or 3;

[0177] R1, R2, R3, R4, R5, R 6a R 6b R 6c R 6d R 10 R 11 The definition is as described in any embodiment of this invention.

[0178] According to certain embodiments of the present invention, the compound is a compound of formula (IV-E2):

[0179]

[0180] R1, R2, R3, R4, R5, R 6a R 6b R 6c R 6d R 10 R 11 The definitions of p1 are as described in any embodiment of this invention.

[0181] According to certain embodiments of the present invention, the present invention provides a compound as shown in formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I):

[0182]

[0183]

[0184] in:

[0185] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0186] R4 is selected from hydrogen or halogen;

[0187] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0188] Ring E is selected from

[0189] R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3; t is an integer selected from 1 and 2.

[0190] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0191] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0192] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0193] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0194] R 10 Selected from hydrogen or C 1-6 alkyl.

[0195] According to certain embodiments of the present invention, the present invention provides a compound as shown in formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I):

[0196]

[0197] in:

[0198] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0199] R4 is selected from hydrogen or halogen;

[0200] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0201] Ring E is selected from

[0202] R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -NR 8a R 8b n is an integer selected from 0, 1, 2, and 3;

[0203] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0204] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0205] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0206] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0207] R 10 Selected from hydrogen or C 1-6 alkyl.

[0208] According to certain embodiments of the present invention, the present invention provides a compound as shown in formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I):

[0209]

[0210]

[0211] in:

[0212] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0213] R4 is selected from hydrogen or halogen;

[0214] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0215] Ring E is selected from

[0216] R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -NR 8a R 8b n is an integer selected from 0, 1, 2, and 3;

[0217] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0218] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0219] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0220] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0221] R 10 Selected from hydrogen or C 1-6 alkyl.

[0222] According to certain embodiments of the present invention, the present invention provides a compound as shown in formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I):

[0223]

[0224]

[0225] in:

[0226] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0227] R4 is selected from hydrogen or halogen;

[0228] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0229] Ring E is selected from

[0230] R 6a R 7a Each independently selected from -(CR 8c R 8d ) n -NR 8a R 8b n is an integer selected from 0, 1, 2, and 3;

[0231] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8bTogether with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0232] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0233] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0234] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl substituents; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0235] R 10 Selected from hydrogen or C 1-6 alkyl.

[0236] According to certain embodiments of the present invention, the present invention provides a compound as shown in formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I):

[0237]

[0238] in:

[0239] R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5;

[0240] R4 is selected from hydrogen or halogen;

[0241] R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0242] Ring E is selected from

[0243] R 6a R 7a Each independently selected from -(CR 8c R 8d ) n -NR 8a R 8bn is an integer selected from 0, 1, 2, and 3;

[0244] R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5.

[0245] R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups;

[0246] R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups;

[0247] R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; q is an integer selected from 0, 1, 2, 3, 4, and 5;

[0248] R 10Selected from hydrogen or C 1-6 alkyl.

[0249] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0250] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are each independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0251] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are each independently selected from halogen, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one or more substituents selected from halogen; undefined groups are as described in any embodiment of the present invention.

[0252] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are each independently selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more substituents selected from F and Cl; undefined groups are as described in any embodiment of the present invention.

[0253] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 is selected from F, -CH3, -CF3, cyclopropyl, and R2 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0254] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 is selected from F, Cl, -CH3, -CHF2, -CF3, cyclopropyl, and R2 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0255] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 is selected from F, Cl, -CH3, -CHF2, -CF3, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0256] According to certain embodiments of the present invention, in the compound shown in formula (I), R2 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0257] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from H or F; undefined groups are as described in any embodiment of the present invention.

[0258] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0259] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0260] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0261] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from

[0262] Undefined groups are as described in any embodiment of this invention.

[0263] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0264] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, C 1-6 Alkyl, C 1-6Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0265] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0266] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is independently selected from halogen, cyano, methyl, methoxy, cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one or more substituents selected from halogens; undefined groups are as described in any embodiment of the present invention.

[0267] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is independently selected from F, methyl, and methoxy; undefined groups are as described in any embodiment of the present invention.

[0268] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is independently selected from F and methyl; undefined groups are as described in any embodiment of the present invention.

[0269] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0270] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0271] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0272] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0273] According to certain embodiments of the present invention, in the compound shown in formula (I), Selected from Undefined groups are as described in any embodiment of this invention.

[0274] According to certain embodiments of the present invention, in the compound shown in formula (I), R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0275] According to certain embodiments of the present invention, in the compound shown in formula (I), R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0276] According to certain embodiments of the present invention, in the compound shown in formula (I), R5 is selected from C 1-6 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 Cycloalkyl; undefined groups as described in any embodiment of the invention.

[0277] According to certain embodiments of the present invention, in the compound shown in formula (I), R5 is selected from... Undefined groups are as described in any embodiment of this invention.

[0278] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6a R 7a Each is independently selected from -(CH2) n -NR 8a R 8b -CF2-CH2-NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0279] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6a R 7a Each is independently selected from -(CH2) n -NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0280] According to certain embodiments of the present invention, in the compound shown in formula (I), R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5; R9 is independently selected from halogen, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from halogen, cyano, or hydroxyl; the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, or S; undefined groups are as described in any embodiment of the invention.

[0281] According to certain embodiments of the present invention, in the compound shown in formula (I), R 8a R 8b Each is independently selected from hydrogen or C. 1-3 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, and 3; R9 is independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy group; the heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O or S; undefined groups are as described in any embodiment of the present invention.

[0282] According to certain embodiments of the present invention, in the compound shown in formula (I), R 8a R 8b Selected from methyl; or R 8a and R 8b Together with the N atom to which it is attached, it forms a 4- to 5-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0 and 1; R9 is independently selected from F, methyl, and methoxy; the heterocyclic alkyl group contains 1 N atom; undefined groups are as described in any embodiment of the present invention.

[0283] According to certain embodiments of the present invention, in the compound shown in formula (I), R 8c R 8d Each is independently selected from H, halogen, C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0284] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6a R 7a Each independently selected

[0285] Undefined groups are as described in any embodiment of this invention.

[0286] According to certain embodiments of the present invention, in the compound shown in formula (I), R 8c R 8d Each group is independently selected from H and F; undefined groups are as described in any embodiment of this invention.

[0287] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6a R 7a Each independently selected Undefined groups are as described in any embodiment of this invention.

[0288] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7a Independently selected from H, -(CR 8c R 8d ) n -NR 8a R 8b ; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0289] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7a Independently selected from H, Undefined groups are as described in any embodiment of this invention.

[0290] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7a Independently selected from H; undefined groups are as described in any embodiment of the invention.

[0291] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0292] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0293] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0294] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6c Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6b R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0295] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6c R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0296] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6c Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6b R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0297] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl substituents; undefined groups as described in any of the embodiments of the present invention.

[0298] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogens and halogenated C. 1-3 Alkyl substituents; undefined groups as described in any of the embodiments of the present invention.

[0299] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens and halogenated C. 1-3 Alkyl substituents; undefined groups as described in any of the embodiments of the present invention.

[0300] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6c Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6b R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens and halogenated C. 1-3Alkyl substituents; undefined groups as described in any of the embodiments of the present invention.

[0301] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6b Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6c R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0302] According to certain embodiments of the present invention, in the compound shown in formula (I), R 6c Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6b R 6d Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0303] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy substituents; undefined groups as described in any of the embodiments of the present invention.

[0304] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7b Each is independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups and 3- to 6-membered heterocyclic alkyl groups are optionally substituted with one or more substituents selected from halogens; undefined groups are as described in any embodiment of the invention.

[0305] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7bEach group is independently selected from hydrogen, F, cyano, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more F groups; undefined groups are as described in any embodiment of the present invention.

[0306] According to certain embodiments of the present invention, in the compound shown in formula (I), R 7b Selected from hydrogen; undefined groups are as described in any embodiment of this invention.

[0307] According to certain embodiments of the present invention, in the compound shown in formula (I), ring E is selected from...

[0308]

[0309] Undefined groups are as described in any embodiment of this invention.

[0310] According to certain embodiments of the present invention, in the compound shown in formula (I), ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0311] According to certain embodiments of the present invention, in the compound shown in formula (I), ring E is selected from...

[0312]

[0313] Undefined groups are as described in any embodiment of this invention.

[0314] According to certain embodiments of the present invention, in the compound shown in formula (I), ring E is selected from...

[0315] Undefined groups are as described in any embodiment of this invention.

[0316] According to certain embodiments of the present invention, the compound shown in formula (I) is the same as the compound shown in formula (IA):

[0317]

[0318] The definitions of R1, R2, R3, R4, R5, ring E, and p are as described in any embodiment of this invention.

[0319] According to certain embodiments of the present invention, the compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound, may be any of the following compounds or any of the following compounds: tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug.

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] According to certain embodiments of the present invention, the compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound, may be any of the following compounds or any of the following compounds: tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug.

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] In a second aspect, the present invention also provides a pharmaceutical composition comprising: the compound described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound described in the first aspect of the present invention; and optionally a pharmaceutically acceptable carrier.

[0337] According to certain embodiments of the present invention, in the pharmaceutical composition, the compound described in the first aspect of the present invention, or a pharmaceutical composition of a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound described in the first aspect of the present invention, may be a therapeutically effective dose.

[0338] The present invention also provides a pharmaceutical composition comprising: a compound of formula (I) above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound of formula (I); and a pharmaceutically acceptable carrier.

[0339] According to certain embodiments of the present invention, in the pharmaceutical composition, the pharmaceutical composition of the compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), may be a therapeutically effective dose.

[0340] In a third aspect, the present invention also provides the use of the compound described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect of the present invention, or the pharmaceutical composition described in the second aspect of the present invention, in the preparation of a medicament for treating or preventing diseases related to integrin α4β7.

[0341] The present invention also provides the use of the compound of formula (I) above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or the pharmaceutical composition of the second aspect in the preparation of a medicament for treating or preventing diseases related to integrin α4β7.

[0342] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from autoimmune diseases.

[0343] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from inflammatory bowel diseases.

[0344] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from ulcerative colitis and Crohn's disease.

[0345] In a fourth aspect of the invention, a method for treating or preventing integrin α4β7-related diseases is provided, comprising the steps of: administering to a desired subject an effective amount of the compound of the first aspect of the invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of the first aspect of the invention, or a pharmaceutical composition as described in the second aspect.

[0346] The present invention also provides a method for treating or preventing integrin α4β7-related diseases, comprising the steps of: administering to a desired subject an effective amount of a compound of formula (I) of the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect.

[0347] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from autoimmune diseases.

[0348] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from inflammatory bowel diseases.

[0349] According to certain embodiments of the present invention, the integrin α4β7-related diseases are selected from ulcerative colitis and Crohn's disease.

[0350] In a fifth aspect of the invention, a compound described in the first aspect of the invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of a compound described in the first aspect of the invention, or a pharmaceutical composition as described in the second aspect, is provided for the treatment or prevention of diseases related to integrin α4β7.

[0351] The compound described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases related to integrin α4β7, wherein the integrin α4β7-related diseases are selected from autoimmune diseases.

[0352] The compound described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases associated with integrin α4β7, wherein the integrin α4β7-related diseases are selected from inflammatory bowel diseases.

[0353] The compound described in the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect of the present invention, or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases associated with integrin α4β7, said integrin α4β7-related diseases being selected from ulcerative colitis and Crohn's disease.

[0354] The compound of formula (I) of the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases related to integrin α4β7.

[0355] The compound of formula (I) of the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases related to integrin α4β7, said integrin α4β7-related diseases being selected from autoimmune diseases.

[0356] The compound of formula (I) of the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases associated with integrin α4β7, wherein the integrin α4β7-related diseases are selected from inflammatory bowel diseases.

[0357] The compound of formula (I) of the first aspect of the present invention, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect, is used to treat or prevent diseases associated with integrin α4β7, said integrin α4β7-related diseases being selected from ulcerative colitis and Crohn's disease.

[0358] Terminology Definitions and Explanations

[0359] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0360] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent applications, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0361] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the descriptions of this application. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0362] The numerical ranges described in this application specification and claims, when interpreted as "integers," should be understood to include both endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 1, 2, 3, 4, 5, and 6. When the numerical range is interpreted as "numbers," it should be understood to include both endpoints of the range, every integer within that range, and every decimal within that range. For example, "numbers from 1 to 10" should be understood to include not only every integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0363] In this application, when specifying the number of substituents, the term "one or more" means from one substitution to the maximum possible number of substitutions, i.e., from substituting one hydrogen to substituting all hydrogens. When specifying the number of substituents, for example, the term "1-4" means 1, 2, 3, or 4 substitutions, i.e., 1, 2, 3, or 4 hydrogens are substituted by substituents.

[0364] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0365] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0366] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0367] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers. The stereochemical definitions and conventions used in this invention are generally in accordance with those defined by S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994.

[0368] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0369] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0370] When the bonds to chiral carbons in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge-shaped solid lines represent bonds. and wedge-shaped dashed key The absolute configuration representing the center of a solid.

[0371] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0372] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0373] For pharmaceuticals or pharmacologically active agents, the terms "effective dose," "effective amount," or "therapeutic effective amount" refer to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0374] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “activator” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0375] The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0376] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0377] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0378] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0379] The term "alkyl" refers to a straight-chain or branched saturated monovalent or divalent hydrocarbon group. For example, "C 1-6 "Alkyl" should be understood as representing a straight-chain or branched saturated monovalent or divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, methylene, ethylidene, propylene, 1-methylpropylene, butylidene, etc.

[0380] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens. For example, "C 1-6 "Halogenated alkyl" should be understood as referring to a C that has been substituted by one or more halogens. 1-6Alkyl groups. The alkyl halogenated groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,2-dibromoethyl, heptafluoropropyl, heptachloropropyl, 3-bromo-2-fluoropropyl, etc.

[0381] The term "alkoxy group" refers to an alkyl group bonded to an oxygen atom via a single bond, with the alkoxy group attached to the molecule through an oxygen atom. Alkoxy groups can be described as alkyl-O-. For example, "C 1-6 "Alkoxy" should be understood as representing "C". 1-6 Alkyl-O-". The alkoxy group includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0382] Term "C" 3-6 "Cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic, or bridged ring hydrocarbon ring having 3, 4, 5, or 6 carbon atoms, including fused or bridged polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, and bicyclo[3.1.0]hexane.

[0383] The term "3-6 membered heterocyclic alkyl" should be understood to mean a saturated monocyclic or bicyclic ring having 3, 4, 5, or 6 ring atoms, wherein 1, 2, or 3 ring atoms are selected from N, O, and S. Unless otherwise stated, "3-6 membered heterocyclic alkyl" may be attached to the rest of the molecule by a carbon atom or a heteroatom. It should be understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. Examples of heterocyclic alkyl groups include, but are not limited to: oxobutyl, dioxopentyl, imidazoalkyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, morpholinyl, piperidinyl, piperazine, pyrrolyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiaranyl.

[0384] When a substituent is attached to a bicyclic ring, the substituent can substitute on any ring of the bicyclic ring and bond to any atom on the bicyclic ring. For example,

[0385] Indicates substituent R 7b Substitution can occur at any position on pyridine or cyclopentene.

[0386] Beneficial effects

[0387] According to a specific example of the present invention, the compound represented by formula (I) of the present invention has good antagonistic effects on integrin α4β7 and good pharmacokinetic properties in its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and has good drug-like properties and low risk of drug-drug interactions.

[0388] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Detailed Implementation

[0389] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0390] The embodiments of the present invention provide the compound of formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, cocrystals or prodrugs thereof, methods and intermediates for preparing the compound of formula (I) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, cocrystals or prodrugs thereof, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the present invention in the preparation of pharmaceuticals.

[0391] The reaction solvents used in each reaction step of this invention are not particularly limited; any solvent that can dissolve the starting materials to a certain extent without inhibiting the reaction is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are all considered to be within the scope of this invention.

[0392] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0393] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters Acquity H-class Uplc-QDA mass spectrometer, monitored with an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm). Gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1 at a flow rate of 1.0 mL / min, followed by incubation of 95% B1 and 5% A1 for 0.5 min. Percentages represent the volume percentage of a specific solvent in the total solvent volume. Solvent A1: 0.1% aqueous solution of formic acid; Solvent B1: 0.1% acetonitrile solution of formic acid. Percentages represent the volume percentage of the solute in the solution.

[0394] Example 1: Preparation of target compounds 1-P1 and 1-P2

[0395] (3S)-3-((2R)-2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0396] (3S)-3-((2S)-2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0397]

[0398] Compound 1-P1 is one of the structures of the two compounds mentioned above, while compound 1-P2 is the other structure.

[0399] The synthetic routes for the target compounds 1-P1 and 1-P2 are as follows:

[0400]

[0401] Step 1: Synthesis of 5-bromo-3-(difluoromethoxy)pyridine-2(1H)-one (1B)

[0402]

[0403] 3-(difluoromethoxy)pyridine-2(1H)-one (1A) (1.5 g, 9.3 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (1.73 g, 9.8 mmol) was added at 0 °C. After the addition was complete, the mixture was heated to 25 °C and stirred for 2 h. After the reaction was complete, water (30 mL) was added to quench the reaction, and the mixture was extracted three times with dichloromethane (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether PE / ethyl acetate EA (v / v) = 1 / 1) to give 5-bromo-3-(difluoromethoxy)pyridine-2(1H)-one (1B).

[0404] LC-MS, M / Z (ESI): 240.2 (M+H) +

[0405] Step 2: Synthesis of ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1D)

[0406]

[0407] 5-Bromo-3-(difluoromethoxy)pyridin-2(1H)-one (1B) (1.35 g, 5.6 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1C) (1.62 g, 6.8 mmol), and potassium carbonate (1.55 g, 11.2 mmol) were dissolved in acetonitrile (150 mL), and the mixture was slowly heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 10 / 1) to give ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1D).

[0408] LC-MS, M / Z (ESI): 382.2 (M+H) +

[0409] Step 3: Synthesis of ethyl 2-(3-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1E)

[0410]

[0411] Ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1D) (1.65 g, 4.33 mmol), pinacol 1-ethoxyvinyl-2-boronate (1.71 g, 8.66 mmol), potassium carbonate (1.79 g, 12.99 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (314 mg, 0.43 mmol) were dissolved in dioxane (20 mL) and water (2 mL), and reacted at 80 °C for 15 h. After the reaction was complete, the reaction was quenched with water (30 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=2 / 1) to obtain ethyl 2-(3-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1E).

[0412] LC-MS, M / Z (ESI): 374.2 (M+H) +

[0413] Step 4: Synthesis of ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1F)

[0414]

[0415] Ethyl 2-(3-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1E) (1.21 g, 3.24 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) and reacted at 40 °C for 2 h. After the reaction was complete, the solution was concentrated to dryness, and the reaction was quenched by adding saturated sodium bicarbonate solution (20 mL). The solution was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1F).

[0416] LC-MS, M / Z (ESI): 346.1 (M+H) +

[0417] Step 5: Synthesis of ethyl 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1G)

[0418]

[0419] Ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1F) (726 mg, 2.10 mmol) and a THF solution of dimethylamine (1.58 mL, 3.15 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (263 mg, 4.20 mmol) was added, and the reaction was continued for 16 h. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain ethyl 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1G).

[0420] LC-MS, M / Z (ESI): 375.2 (M+H) +

[0421] Step 6: Synthesis of 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (1H)

[0422]

[0423] Ethyl 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1g) (310mg, 0.83mmol) and lithium hydroxide (40mg, 1.66mmol) were dissolved in tetrahydrofuran (5mL) and water (1mL) and reacted at 25°C for 2h. After the reaction was complete, water (10mL) was added, and the pH of the solution was adjusted to about 4 with 1N hydrochloric acid. The solution was extracted three times with ethyl acetate (20mL), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (1H).

[0424] LC-MS, M / Z (ESI): 347.1 (M+H) +

[0425] Step 7: Synthesis of (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1K)

[0426]

[0427] 2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (1H) (200 mg, 0.58 mmol), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1J) (243 mg, 0.70 mmol), N-methylimidazolium (95 mg, 1.16 mmol), and tetramethylchlorourea hexafluorophosphate (245 mg, 0.87 mmol) were dissolved in acetonitrile (5 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH(v / v)=10 / 1) to give ethyl (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1K).

[0428] LC-MS, M / Z (ESI): 676.2 (M+H) +

[0429] Step 8: Synthesis of target compounds 1-P1 and 1-P2

[0430]

[0431] Ethyl (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1K) (281 mg, 0.41 mmol) and lithium hydroxide (50 mg, 2.05 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 5 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187 μm 30 mm × 40 cm, mobile phase A: 10 mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient B%: 60-100) to obtain the target compounds 1-P1 and 1-P2.

[0432] Target compound 1-P1:

[0433] Retention time: 9.04 min

[0434] LC-MS, M / Z (ESI): 648.3 (M+H) +

[0435] 1 H NMR(600MHz,CD3OD)δ7.55(s,1H),7.40(s,1H),7.05–6.73(m,5H),5.55(dd,J=10.2,5.3Hz,1 H),5.37(t,J=5.5Hz,1H),3.29–3.27(m,1H),3.19–3.12(m,1H),2.92–2.84(m,1H),2.81(dd,J =13.1,7.5Hz,1H),2.69(s,6H),2.62(dd,J=14.5,5.3Hz,1H),2.52(dd,J=14.5,6.0Hz,1H),2. 27(s,3H),2.04–1.90(m,8H),1.47–1.37(m,1H),0.93(d,J=6.6Hz,3H),0.88(d,J=6.5Hz,3H).

[0436] Target compound 1-P2:

[0437] Retention time: 10.38 min

[0438] LC-MS, M / Z (ESI): 648.3 (M+H) +

[0439] 1 H NMR (600MHz, CD3OD) δ7.53(s,1H),7.38(s,1H),7.02–6.74(m,5H),5.61–5.57(m,1H),5.54(dd,J= 9.6,3.9Hz,1H),3.43–3.35(m,1H),3.26–3.20(m,1H),2.93(ddd,J=14.8,9.9,4.5Hz,1H),2.82(t, J=4.9Hz,1H),2.79(s,6H),2.56(dd,J=14.9,4.0Hz,1H),2.41(dd,J=14.9,9.7Hz,1H),2.29(s,3H) ,2.03–1.95(m,7H),1.84–1.77(m,1H),1.39(dt,J=13.6,6.9Hz,1H),0.89(dd,J=11.9,6.6Hz,6H).

[0440] Example 2: Preparation of target compounds 6-P1 and 6-P2

[0441] (3S)-3-((2R)-2-(3-(difluoromethoxy)-5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0442] (3S)-3-((2S)-2-(3-(difluoromethoxy)-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0443]

[0444] Compound 6-P1 is one of the structures of the two compounds mentioned above, while compound 6-P2 is the other structure.

[0445] The synthetic routes for the target compounds 6-P1 and 6-P2 are as follows:

[0446]

[0447] Step 1: Synthesis of ethyl 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (6A)

[0448]

[0449] 3-Fluorobutylidine hydrochloride (254 mg, 1.74 mmol) and triethylamine (351 mg, 3.48 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at 25 °C for 10 min. Then, a solution of ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1F) (400 mg, 1.16 mmol) in 1,2-dichloroethane (2 mL) was added to the reaction solution, and the reaction was carried out at 25 °C for 30 min. Sodium cyanoborohydride (146 mg, 2.32 mmol) was added to the reaction solution, and the reaction was continued for 18 h. After the reaction was completed, the solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH(V / V)=1 / 0-10 / 1) to give ethyl 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (6A).

[0450] LC-MS, M / Z (ESI): 405.2 (M+H)+

[0451] Step 2: Synthesis of 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (6B)

[0452]

[0453] Lithium hydroxide monohydrate (83 mg, 2.0 mmol) was added to a solution of ethyl 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (6A) (160 mg, 0.4 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL), and the mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL × 3). The organic phase was washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reversed-phase preparative chromatography (column: Phenomenex Synergi C18100×25mm×4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to obtain 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (6B).

[0454] LC-MS, M / Z (ESI): 378.3 (M+H) +

[0455] Step 3: Synthesis of (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (6C)

[0456]

[0457] To a solution of 2-(3-(difluoromethoxy)-5-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (6B) (130 mg, 0.35 mmol) in acetonitrile (2.6 mL), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1J) (144 mg, 0.41 mmol), N-methylimidazolium (57 mg, 0.69 mmol), and tetramethylchlorourea hexafluorophosphate (145 mg, 0.52 mmol) were added, and the mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (V / V) = 1 / 0-10 / 1) to give ethyl (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (6C).

[0458] LC-MS, M / Z (ESI): 706.2 (M+H) +

[0459] Compound 6C can be separated into 6C-P1 and 6C-P2 by SFC. Specific SFC separation method: Instrument: Waters 150Q; Column: DAICL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[0460] The structures of compounds 6C-P1 and 6C-P2 are as follows:

[0461]

[0462] Compound 6C-P1 is one of the structures of the two compounds mentioned above, while compound 6C-P2 is the other structure.

[0463] Step 4: Synthesis of target compounds 6-P1 and 6-P2

[0464]

[0465] Lithium hydroxide monohydrate (30 mg, 0.70 mmol) was added to a solution of (3S)-3-(2-(3-(difluoromethoxy)-5-(2-(3-fluoroazacyclobutan-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (6C) (100 mg, 0.14 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL), and then stirred at room temperature for 5 h. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 55-75) to obtain the target compounds 6-P1 and 6-P2.

[0466] Target compound 6-P1:

[0467] Retention time: 8.05 min

[0468] LC-MS, M / Z (ESI): 678.2 (M+H) +

[0469] 1 H NMR (600MHz, DMSO-d6) δ8.99(d,J=6.3Hz,1H),7.43(s,2H),7.28(d,J=1.6Hz,1H),7.17-6.96(m,1H),6. 96–6.87(m,4H),5.58–5.51(m,1H),5.44–5.38(m,1H),5.15–5.00(m,1H),3.56–3.48(m,1H),3.11–3.00( m,2H),2.65(d,J=7.1Hz,2H),2.59–2.52(m,2H),2.40–2.28(m,3H),2.23(s,3H),1.94(s,3H),1.92–1.86 (m,1H),1.80(s,3H),1.78–1.67(m,1H),1.33–1.26(m,1H),0.87(d,J=6.6Hz,3H),0.82(d,J=6.6Hz,3H).

[0470] Target compound 6-P2:

[0471] Retention time: 9.61 min

[0472] LC-MS, M / Z (ESI): 678.2 (M+H) +

[0473] 1 H NMR(600MHz,DMSO-d6)δ9.07(d,J=7.5Hz,1H),7.46(s,1H),7.31(d,J=1.5Hz,1H),7.12(t, J=75.2Hz,1H),6.99–6.92(m,4H),5.60–5.56(m,1H),5.48–5.43(m,1H),5.17–5.04(m,1H), 3.58–3.55(m,2H),3.14–3.04(m,2H),2.67–2.55(m,4H),2.45–2.30(m,3H),2.25(s,3H),1 .96(s,6H),1.73–1.67(m,1H),1.61–1.55(m,1H),1.19–1.11(m,1H),0.74(d,J=5.6Hz,6H).

[0474] Example 3: Preparation of target compounds 13-P1 and 13-P2

[0475] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0476] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoyl)propionic acid

[0477]

[0478] Compound 13-P1 is one of the structures of the two compounds mentioned above, while compound 13-P2 is the other structure.

[0479] The synthetic routes for the target compounds 13-P1 and 13-P2 are as follows:

[0480]

[0481] Step 1: Synthesis of 3-(trifluoromethoxy)pyridine-2-ol (13B)

[0482]

[0483] 2-Chloro-3-(trifluoromethoxy)pyridine (13A) (1.0 g, 5.0 mmol), potassium carbonate (5.0 g, 35.0 mmol), and acetyloxyoxime acid (1.5 g, 20.0 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the mixture was purged with argon three times. The reaction mixture was then reacted at 100 °C for 18 h. Water (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-1 / 1) to obtain 3-(trifluoromethoxy)pyridine-2-ol (13B).

[0484] LC-MS, M / Z (ESI): 180.2 (M+H) + .

[0485] Step 2: Synthesis of 5-bromo-3-(trifluoromethoxy)pyridine-2-ol (13C)

[0486]

[0487] 3-(trifluoromethoxy)pyridine-2-ol (13B) (500 mg, 2.8 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, and N-bromosuccinimide (500 mg, 2.8 mmol) was slowly added to the reaction system. The reaction was stirred for 30 min. After the reaction was complete, the crude product was concentrated. The crude product was subjected to column chromatography (PE / EA(v / v) = 1 / 5) to give 5-bromo-3-(trifluoromethoxy)pyridine-2-ol (13C).

[0488] LC-MS, M / Z (ESI): 257.9 (M+H) +

[0489] Step 3: Synthesis of ethyl 2-(5-bromo-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13E)

[0490]

[0491] 5-Bromo-3-(trifluoromethoxy)pyridin-2-ol (13C) (550 mg, 2.1 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (760 mg, 3.2 mmol), and potassium carbonate (580 mg, 4.2 mmol) were dissolved in acetonitrile (20 mL), and the mixture was slowly heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 5 / 1) to give ethyl 2-(5-bromo-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13E).

[0492] LC-MS, M / Z (ESI): 400.0 (M+H) +

[0493] Step 4: Synthesis of ethyl 2-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13F)

[0494]

[0495] Ethyl 2-(5-bromo-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13E) (500 mg, 1.25 mmol), pinacol 1-ethoxyvinyl-2-boronate (495 mg, 2.50 mmol), potassium carbonate (520 mg, 3.75 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (240 mg, 0.32 mmol) were dissolved in dioxane (20 mL) and water (2 mL), and reacted at 80 °C for 15 h. After the reaction was complete, water (30 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=3 / 1) to obtain ethyl 2-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13F).

[0496] LC-MS, M / Z (ESI): 392.2 (M+H) +

[0497] Step 5: Synthesis of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-3-(trifluoromethoxy)pyridin-1(2H)-yl)valerate (13G)

[0498]

[0499] Ethyl 2-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13F) (480 mg, 1.23 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 40 °C for 2 h. After the reaction was completed, the mixture was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The mixture was extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-3-(trifluoromethoxy)pyridin-1(2H)-yl)pentanoate (13G).

[0500] LC-MS, M / Z (ESI): 364.1 (M+H) +

[0501] Step 6: Synthesis of ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13H)

[0502]

[0503] Ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-3-(trifluoromethoxy)pyridin-1(2H)-yl)valerate (13G) (460 mg, 1.27 mmol) and a THF solution of dimethylamine (1.50 mL, 3.3 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (276 mg, 4.40 mmol) was added, and the reaction was continued for 16 h. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to give ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylvalerate (13H).

[0504] LC-MS, M / Z (ESI): 393.2 (M+H) +

[0505] Step 7: Synthesis of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoic acid (13J)

[0506]

[0507] Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoate (13H) (500 mg, 1.27 mmol) and lithium hydroxide monohydrate (101 mg, 2.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoic acid (13J).

[0508] LC-MS, M / Z (ESI): 365.1 (M+H) +

[0509] Step 8: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentamido)propionate (13K)

[0510]

[0511] 2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentanoic acid (13J) (400 mg, 1.10 mmol), (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate ethyl ester (1J) (460 mg, 1.32 mmol), N-methylimidazole (180 mg, 2.20 mmol), and tetramethylchlorourea hexafluorophosphate (463 mg, 1.65 mmol) were dissolved in acetonitrile (6 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentamido)propionate (13K).

[0512] LC-MS, M / Z (ESI): 694.3 (M+H) +

[0513] Compound 13K can be resolved into 13K-P1 and 13K-P2 by SFC. Specific SFC resolution method: Instrument: Waters 150Q; Column: DAICEL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[0514] The structures of compounds 13K-P1 and 13K-P2 are as follows:

[0515]

[0516] Compound 13K-P1 is one of the structures of the two compounds mentioned above, while compound 13K-P2 is the other structure.

[0517] Step 9: Synthesis of target compounds 13-P1 and 13-P2

[0518]

[0519] Crude (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl)-4-methylpentamido)propionate (13K) and lithium hydroxide monohydrate (114 mg, 2.70 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187 μm 30 mm × 40 cm, mobile phase A: 10 mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient B%: 58-70) to obtain the target compounds 13-P1 and 13-P2.

[0520] Target compound 13-P1:

[0521] Retention time: 10.27 min

[0522] LC-MS, M / Z (ESI): 666.3 (M+H) +

[0523] 1H NMR(400MHz,CD3OD)δ7.67(s,1H),7.63(s,1H),6.83–6.76(m,4H),5.62-5.59( m,1H),5.40(t,1H),3.18–3.15(m,1H),3.05–3.03(m,1H),2.90–2.85(m,2H),2 .72(s,6H),2.64(dd,1H),2.55(dd,1H),2.26(s,3H),2.04–1.98(m,1H),1.97( s,3H),1.93(dd,1H),1.90(s,3H),1.43–1.36(m,1H),0.92(d,3H),0.88(d,3H).

[0524] Target compound 13-P2:

[0525] Retention time: 11.82 min

[0526] LC-MS, M / Z (ESI): 666.3 (M+H) +

[0527] 1H NMR(400MHz,CD3OD)δ7.67(s,1H),7.64(s,1H),6.87-6.85(m,2H),6.80(d ,2H),5.60-5.56(m,2H),3.36–3.30(m,1H),3.24-3.20(m,1H),2.95-2.90 (m,1H),2.84–2.80(m,1H),2.78(s,6H),2.56(dd,1H),2.43(dd,1H),2.29 (s,3H),1.98(s,7H),1.80–1.78(m,1H),1.40–1.36(m,1H),0.88(dd,6H).

[0528] Example 4: Preparation of target compounds 16-P1 and 16-P2

[0529] (3S)-3-((2R)-2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0530] (3S)-3-((2S)-2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0531]

[0532] Compound 16-P1 is one of the structures of the two compounds mentioned above, while compound 16-P2 is the other structure.

[0533] The synthetic routes for the target compounds 16-P1 and 16-P2 are as follows:

[0534]

[0535] Step 1: Synthesis of 5-bromo-4-(difluoromethoxy)-2-methoxypyridine (16B)

[0536]

[0537] 2-Methoxy-4-hydroxy-5-bromopyridine (16A) (5 g, 24.5 mmol), potassium carbonate (4.06 g, 29.4 mmol), and sodium difluorochloroacetate (7.57 g, 49.0 mmol) were dissolved in DMF (100 mL) and water (13 mL), and the mixture was heated to 100 °C and stirred for 2 h. After the reaction was complete, water (100 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 8 / 1) to give 5-bromo-4-(difluoromethoxy)-2-methoxypyridine (16B).

[0538] LC-MS, M / Z (ESI): 254.1 (M+H) +

[0539] Step 2: Synthesis of 5-bromo-4-(difluoromethoxy)pyridine-2(1H)-one (16C)

[0540]

[0541] 2.5 g (9.8 mmol) of 5-bromo-4-(difluoromethoxy)-2-methoxypyridine (16B) was dissolved in concentrated hydrochloric acid (100 mL), and the mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 1 / 5) to give 5-bromo-4-(difluoromethoxy)pyridine-2(1H)-one (16C).

[0542] LC-MS, M / Z (ESI): 240.2 (M+H) +

[0543] Step 3: Synthesis of ethyl 2-(5-bromo-4-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16D)

[0544]

[0545] 5-Bromo-4-(difluoromethoxy)pyridin-2(1H)-one (16C) (1.5 g, 6.2 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (2.22 g, 9.3 mmol), and potassium carbonate (1.572 g, 12.4 mmol) were dissolved in acetonitrile (100 mL), and the mixture was slowly heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 5 / 1) to give ethyl 2-(5-bromo-4-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16D).

[0546] LC-MS, M / Z (ESI): 382.2 (M+H) +

[0547] Step 4: Synthesis of ethyl 2-(4-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16E)

[0548]

[0549] Ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16D) (1.25 g, 3.28 mmol), pinacol 1-ethoxyvinyl-2-boronate (1.30 g, 6.56 mmol), potassium carbonate (1.36 g, 9.84 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (240 mg, 0.32 mmol) were dissolved in dioxane (20 mL) and water (2 mL) and reacted at 80 °C for 15 h. After the reaction was complete, the reaction was quenched with water (30 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=3 / 1) to obtain ethyl 2-(4-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16E).

[0550] LC-MS, M / Z (ESI): 374.2 (M+H) +

[0551] Step 5: Synthesis of ethyl 2-(4-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (16F)

[0552]

[0553] Ethyl 2-(4-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16E) (830 mg, 2.22 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 40 °C for 2 h. After the reaction was completed, the solution was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The solution was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 2-(4-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (16F).

[0554] LC-MS, M / Z (ESI): 346.1 (M+H) +

[0555] Step 6: Synthesis of ethyl 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16G)

[0556]

[0557] Ethyl 2-(4-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (16F) (760 mg, 2.2 mmol) and a THF solution of dimethylamine (1.50 mL, 3.3 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (276 mg, 4.40 mmol) was added, and the reaction was continued for 16 h. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain ethyl 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16G).

[0558] LC-MS, M / Z (ESI): 375.2 (M+H) +

[0559] Step 7: Synthesis of 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (16H)

[0560]

[0561] Ethyl 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (16G) (280 mg, 0.80 mmol) and lithium hydroxide monohydrate (101 mg, 2.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (16H).

[0562] LC-MS, M / Z (ESI): 347.1 (M+H) +

[0563] Step 8: Synthesis of (3S)-3-(2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (16J)

[0564]

[0565] 2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (16H) (150 mg, 0.44 mmol), (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1J) (183 mg, 0.52 mmol), N-methylimidazolium (72 mg, 0.87 mmol), and tetramethylchlorourea hexafluorophosphate (183 mg, 0.65 mmol) were dissolved in acetonitrile (6 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH(v / v)=10 / 1) to obtain ethyl (3S)-3-(2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (16J).

[0566] LC-MS, M / Z (ESI): 676.2 (M+H) +

[0567] Step 9: Synthesis of target compounds 16-P1 and 16-P2

[0568]

[0569] Ethyl (3S)-3-(2-(4-(difluoromethoxy)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (16J) (180 mg, 0.27 mmol) and lithium hydroxide monohydrate (57 mg, 1.35 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 58-70) to obtain the target compounds 16-P1 and 16-P2.

[0570] Target compound 16-P1:

[0571] Retention time: 8.05 min

[0572] LC-MS, M / Z (ESI): 648.3 (M+H) +

[0573] 1H NMR (600 MHz, cd3od) δ 7.74 (s, 1H), 7.10 (t, J=71.9 Hz, 1H), 6.85–6.77 (m, 4H), 6.13 (s, 1H), 5.55–5.48 (m, 1H), 5.40 (t, J=5.8 Hz, 1H), 3.27–3.20 (m, 1H), 3.14–3.08 (m, 1H), 2.90–2.85 (m, 2H), 2.72 (s, 6H), 2.64 (dd, J=14.6, 5.2 Hz, 1H), 2.55 (dd, J=14.6, 6.8 Hz, 1H), 2.27 (s, 3H), 2.04–1.98 (m, 1H), 1.97 (s, 3H), 1.93 (dd, J=9.2, 5.5 Hz, 1H), 1.90 (s, 3H), 1.43–1.36 (m, 1H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

[0574] Target compound 16-P2:

[0575] Retention time: 9.91 min

[0576] LC-MS, M / Z (ESI): 648.3 (M+H) +

[0577] 1H NMR (600 MHz, cd3od) δ 7.68 (s, 1H), 7.11 (dd, J=73.0, 70.9 Hz, 1H), 6.87 (d, J=5.3 Hz, 2H), 6.81 (d, J=9.6 Hz, 2H), 6.16 (s, 1H), 5.58 (dd, J=10.2, 3.8 Hz, 1H), 5.56–5.52 (m, 1H), 3.41–3.35 (m, 1H), 3.20 (dt, J=13.1, 4.8 Hz, 1H), 2.95 (dt, J=15.5, 4.6 Hz, 1H), 2.89–2.83 (m, 1H), 2.81 (s, 6H), 2.57 (dd, J=15.1, 3.8 Hz, 1H), 2.41 (dd, J=14.9, 10.3 Hz, 1H), 2.29 (s, 3H), 1.98 (s, 6H), 1.94 (dd, J=14.3, 7.3 Hz, 1H), 1.79–1.72 (m, 1H), 1.41–1.36 (m, 1H), 0.88 (dd, J=9.6, 6.6 Hz, 6H).

[0578] Example 5: Preparation of target compounds 18-P1 and 18-P2

[0579] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2R)-2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanamide)propionic acid

[0580] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2S)-2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanamide)propionic acid

[0581]

[0582] Compound 18-P1 is one of the structures of the two compounds mentioned above, while compound 18-P2 is the other structure.

[0583] The synthetic routes for the target compounds 18-P1 and 18-P2 are as follows:

[0584]

[0585] Step 1: Synthesis of methyl 2-((trifluoromethanesulfonyl)oxy)cyclopent-1-ene-1-carboxylate (18B)

[0586]

[0587] 10 g (70.4 mmol) of 2-cyclopentanone carboxylic acid methyl ester (18A) was dissolved in dichloromethane (80 mL). N,N-diisopropylethylamine (13.64 g, 106 mmol) and trifluoromethanesulfonic anhydride (13.92 mL, 84.4 mmol) were added at -78 °C, and the reaction was carried out at -78 °C for 1 h. After the reaction was complete, water (50 mL) was added to quench the reaction. The mixture was extracted three times with dichloromethane (80 mL), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 10 / 1) to give methyl 2-((trifluoromethanesulfonyl)oxy)cyclopent-1-ene-1-carboxylate (18B).

[0588] LC-MS, M / Z (ESI): 289.2 (M+H) +

[0589] Step 2: Synthesis of methyl 2-((trimethylsilyl)ethynyl)cyclopent-1-ene-1-carboxylate (18C)

[0590]

[0591] 2-((trifluoromethanesulfonyl)oxy)cyclopent-1-ene-1-carboxylate methyl ester (18B) (3.5 g, 12.8 mmol), bis(triphenylphosphine)palladium dichloride (179 mg, 0.26 mmol), cuprous iodide (170 mg, 0.89 mmol), triethylamine (5.33 mL, 38.3 mmol), and trimethylsilylacetylene were dissolved in tetrahydrofuran (40 mL) and reacted at room temperature for 3 h. After the reaction was complete, the solution was concentrated to dryness, and the reaction was quenched with water (30 mL). The solution was extracted three times with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA (v / v) = 10 / 1) to obtain 2-((trimethylsilyl)acetylene)cyclopent-1-ene-1-carboxylate methyl ester (18C).

[0592] Step 3: Synthesis of 2-ethynylcyclopent-1-ene-1-carboxylic acid (18D)

[0593]

[0594] Methyl 2-((trimethylsilyl)ethynyl)cyclopentyl-1-ene-1-carboxylic acid (18C) (10 g, 45 mmol) and lithium hydroxide monohydrate (3.78 g, 90 mmol) were dissolved in tetrahydrofuran (20 mL) and methanol (20 mL) and reacted at 50 °C for 3 h. After the reaction was complete, the solution was concentrated to dryness, and water (50 mL) was added. The pH of the solution was adjusted to about 5 with 1 N hydrochloric acid, and the solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-ethynylcyclopentyl-1-ene-1-carboxylic acid (18D).

[0595] Step 4: Synthesis of 2-ethynylcyclopent-1-ene-1-carboxamide (18E)

[0596]

[0597] 2-Ethynylcyclopent-1-ene-1-carboxylic acid (18D) (6 g, 44.1 mmol), ammonium chloride (11.8 g, 221 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 25.1 g, 66.1 mmol), and N,N-diisopropylethylamine (17.1 g, 132.3 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature for 12 h. After the reaction was complete, the solution was concentrated to dryness, and water (100 mL) was added. The solution was extracted three times with dichloromethane (100 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA (v / v) = 1 / 5) to give 2-ethynylcyclopent-1-ene-1-carboxamide (18E).

[0598] Step 5: Synthesis of 2,5,6,7-tetrahydro-1H-cyclopentan(c)pyridin-1-one (18F)

[0599]

[0600] 2-Ethynylcyclopent-1-ene-1-carboxamide (18E) (4 g, 29.6 mmol) was dissolved in methanol (30 mL), and a tetrahydrofuran solution of dimethylamine (150 mL, 300 mmol) was added. The reaction was carried out at 80 °C for 16 h. After the reaction was completed, the solution was concentrated to dryness, and 1,4-dioxane (80 mL) was added. The reaction was carried out at 110 °C for 6 h. After the reaction was completed, the solution was concentrated to obtain the crude product. The crude product was subjected to column chromatography (dichloromethane DCM / MeOH (v / v) = 10 / 1) to give 2,5,6,7-tetrahydro-1H-cyclopentane(c)pyridin-1-one (18F).

[0601] LC-MS, M / Z (ESI): 136.2 (M+H) +

[0602] Step 6: Synthesis of 4-bromo-2,5,6,7-tetrahydro-1H-cyclopentane(c)pyridin-1-one (18G)

[0603]

[0604] 2,5,6,7-Tetrahydro-1H-cyclopentan(c)pyridin-1-one (18F) (3.4 g, 25.2 mmol) was dissolved in acetic acid (30 mL), and liquid bromine (15.56 mL, 30.2 mmol) was added. The mixture was reacted at 25 °C for 2 h. After the reaction was complete, the solution was concentrated to dryness, and water (30 mL) was added. The mixture was extracted three times with dichloromethane (30 mL), and the organic phases were combined. The solutions were washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to give 4-bromo-2,5,6,7-tetrahydro-1H-cyclopentan(c)pyridin-1-one (18G).

[0605] LC-MS, M / Z (ESI): 214.2 (M+H) +

[0606] Step 7: Synthesis of ethyl 2-(4-bromo-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18H)

[0607]

[0608] 4-Bromo-2,5,6,7-Tetrahydro-1H-cyclopentan(c)pyridin-1-one (18G) (2g, 9.4mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (3.34g, 14.1mmol), and potassium carbonate (3.89g, 28.2mmol) were dissolved in acetonitrile (100mL), and the mixture was slowly heated to 80℃ and reacted for 16h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50mL). The mixture was extracted three times with ethyl acetate (30mL), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=3 / 1) to give ethyl 2-(4-bromo-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18H).

[0609] LC-MS, M / Z (ESI): 356.2 (M+H) +

[0610] Step 8: Synthesis of ethyl 2-(4-((E)-2-ethoxyvinyl-1-yl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18J)

[0611]

[0612] Ethyl 2-(4-bromo-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18H) (2 g, 5.6 mmol), pinacol 1-ethoxyvinyl-2-boronate (2.23 g, 11.2 mmol), potassium carbonate (2.31 g, 16.8 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (409 mg, 0.56 mmol) were dissolved in dioxane (20 mL) and water (2 mL), and reacted at 80 °C for 15 h. After the reaction was complete, the reaction was quenched with water (30 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=2 / 1) to give ethyl 2-(4-((E)-2-ethoxyvinyl-1-yl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18J).

[0613] LC-MS, M / Z (ESI): 348.2 (M+H) +

[0614] Step 9: Synthesis of ethyl 4-methyl-2-(1-oxo-4-(2-oxoethyl)-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)valerate (18K)

[0615]

[0616] Ethyl 2-(4-((E)-2-ethoxyvinyl-1-yl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18J) (1.38 g, 3.98 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 25 °C for 1 h. After the reaction was complete, the solution was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The solution was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 4-methyl-2-(1-oxo-4-(2-oxoethyl)-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)pentanoate (18K).

[0617] LC-MS, M / Z (ESI): 320.1 (M+H) +

[0618] Step 10: Synthesis of ethyl 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoate (18L)

[0619]

[0620] Ethyl 4-methyl-2-(1-oxo-4-(2-oxoethyl)-1,5,6,7-tetrahydro-2H-cyclopentan(c)pyridin-2-yl)valerate (18K) (1.27 g, 3.98 mmol) and a THF solution of dimethylamine (3.98 mL, 7.96 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (373 mg, 5.97 mmol) was added, and the reaction was continued for 16 h. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to give ethyl 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentan(c)pyridin-2-yl)-4-methylvalerate (18 L).

[0621] LC-MS, M / Z (ESI): 349.2 (M+H) +

[0622] Step 11: Synthesis of 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoic acid (18M)

[0623]

[0624] Ethyl 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentan(c)pyridin-2-yl)-4-methylpentanoate (18 L) (416 mg, 1.20 mmol) and lithium hydroxide monohydrate (100 mg, 2.40 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentan(c)pyridin-2-yl)-4-methylpentanoic acid (18 M).

[0625] LC-MS, M / Z (ESI): 321.1 (M+H) +

[0626] Step 12: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentanyl(c)pyridin-2-yl)-4-methylpentamido)propionate (18N)

[0627]

[0628] 2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentanoic acid (18M) (150 mg, 0.48 mmol), (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (200 mg, 0.58 mmol) (1 J), N-methylimidazolium (118 mg, 1.44 mmol), and tetramethylchlorourea hexafluorophosphate (210 mg, 0.72 mmol) were dissolved in acetonitrile (5 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH(v / v)=10 / 1) to give ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentamido)propionate (18N).

[0629] LC-MS, M / Z (ESI): 650.2 (M+H) +

[0630] Step 13: Synthesis of target compounds 18-P1 and 18-P2

[0631]

[0632] Ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(4-(2-(dimethylamino)ethyl)-1-oxo-1,5,6,7-tetrahydro-2H-cyclopentyl(c)pyridin-2-yl)-4-methylpentamido)propionate (18N) (200 mg, 0.31 mmol) and lithium hydroxide monohydrate (65 mg, 1.55 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 55-70) to obtain the target compounds 18-P1 and 18-P2.

[0633] Target compound 18-P1:

[0634] Retention time: 7.08 min

[0635] LC-MS, M / Z (ESI): 622.3 (M+H) +

[0636] 1H NMR (600MHz, CD3OD) δ7.48(s,1H),6.81(d,J=9.7Hz,3H),6.72(d,J=5.6Hz,1H),5.56(s,1H),5.41(t,J=5 .6Hz,1H),3.23–3.16(m,1H),3.15–3.08(m,1H),2.99–2.79(m,4H),2.76–2.70(m,6H),2.66–2.59(m,3H) ,2.54(dd,J=14.7,6.2Hz,1H),2.26(s,3H),2.15–2.07(m,1H),2.07–2.01(m,1H),2.00–1.97(m,1H),1.9 6(s,3H),1.94–1.89(m,1H),1.86(s,3H),1.42–1.33(m,1H),0.91(d,J=6.6Hz,3H),0.88(d,J=6.6Hz,3H).

[0637] Target compound 18-P2:

[0638] Retention time: 8.75 min

[0639] LC-MS, M / Z (ESI): 622.3 (M+H) +

[0640] 1H NMR (600MHz, CD3OD) δ7.47(s,1H),6.86(d,J=5.8Hz,1H),6.84–6.77(m,3H),5.62(dd,J=9.1,6.5Hz,1H),5.54(d d,J=9.3,4.0Hz,1H),3.36–3.31(m,1H),3.23–3.16(m,1H),3.01–2.84(m,4H),2.81(s,6H),2.78–2.71(m,1H),2 .69–2.62(m,1H),2.56(dd,J=15.1,4.1Hz,1H),2.41(dd,J=15.0,9.3Hz,1H),2.29(s,3H),2.16–2.00(m,2H),1. 98(s,3H),1.97–1.93(m,4H),1.86–1.79(m,1H),1.40–1.32(m,1H),0.89(d,J=6.7Hz,3H),0.86(d,J=6.6Hz,3H).

[0641] Example 6: Preparation of target compounds 22-P1 and 22-P2

[0642] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2R)-2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentamido)propionic acid

[0643] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-((2S)-2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentamido)propionic acid

[0644]

[0645] Compound 22-P1 is one of the structures of the two compounds mentioned above, while compound 22-P2 is the other structure.

[0646] The synthetic routes for the target compounds 22-P1 and 22-P2 are as follows:

[0647]

[0648] Step 1: Synthesis of 7-bromopyrazolo(1,5-a)pyrazin-4(5H)-one (22B)

[0649]

[0650] Pyrazolo(1,5-a)pyrazin-4(5H)-one (22A) (2 g, 14.8 mmol) and acetic acid (2.5 mL) were dissolved in DMF (14 mL). N-bromosuccinimide (2.64 g, 14.8 mmol) was added to the solution at 0 °C, and the reaction was carried out at 0 °C for 2 h. After the reaction was completed, the solution was concentrated to dryness, and water (30 mL) was added. The solution was extracted three times with dichloromethane (30 mL), and the organic phases were combined. The solutions were washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to give 7-bromopyrazolo(1,5-a)pyrazin-4(5H)-one (22B).

[0651] LC-MS, M / Z (ESI): 214.2 (M+H) +

[0652] Step 2: Synthesis of ethyl 2-(7-bromo-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22C)

[0653]

[0654] 7-Bromopyrazolo(1,5-a)pyrazin-4(5H)-one (22B) (2.4 g, 11.2 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (3.97 g, 16.8 mmol), and potassium carbonate (4.63 g, 33.6 mmol) were dissolved in acetonitrile (100 mL), and the mixture was slowly heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v) = 3 / 1) to give ethyl 2-(7-bromo-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22C).

[0655] LC-MS, M / Z (ESI): 356.2 (M+H) +

[0656] Step 3: Synthesis of ethyl 2-(7-((E)-2-ethoxyvinyl-1-yl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22D)

[0657]

[0658] Ethyl 2-(7-bromo-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22C) (2 g, 5.6 mmol), pinacol 1-ethoxyvinyl-2-boronate (2.23 g, 11.2 mmol), potassium carbonate (2.31 g, 16.8 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (409 mg, 0.56 mmol) were dissolved in dioxane (20 mL) and water (3 mL), and reacted at 80 °C for 16 h. After the reaction was complete, the reaction was quenched with water (40 mL), and the mixture was extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE / EA(v / v)=3 / 1) to give ethyl 2-(7-((E)-2-ethoxyvinyl-1-yl)-4-oxopyrazo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22D).

[0659] LC-MS, M / Z (ESI): 348.2 (M+H) +

[0660] Step 4: Synthesis of ethyl 4-methyl-2-(4-oxo-7-(2-oxoethyl)pyrazolo(1,5-a)pyrazin-5(4H)-yl)valerate (22E)

[0661]

[0662] Ethyl 2-(7-((E)-2-ethoxyvinyl-1-yl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate ((22D) (1.23 g, 3.54 mmol)) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 25 °C for 1 h. After the reaction was completed, the solution was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The solution was extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 4-methyl-2-(4-oxo-7-(2-oxoethyl)pyrazolo(1,5-a)pyrazin-5(4H)-yl)pentanoate (22E).

[0663] LC-MS, M / Z (ESI): 320.1 (M+H) +

[0664] Step 5: Synthesis of ethyl 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22F)

[0665]

[0666] Ethyl 4-methyl-2-(1-oxo-4-(2-oxoethyl)-1,5,6,7-tetrahydro-2H-cyclopentan(c)pyridin-2-yl)valerate (22E) (1.14 g, 3.54 mmol) and a THF solution of dimethylamine (3.54 mL, 7.08 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (332 mg, 5.31 mmol) was added, and the reaction was continued for 16 h. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to give ethyl 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylvalerate (22F).

[0667] LC-MS, M / Z (ESI): 349.2 (M+H) +

[0668] Step 6: Synthesis of 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoic acid (22G)

[0669]

[0670] Ethyl 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22F) (480 mg, 1.37 mmol) and lithium hydroxide monohydrate (115 mg, 2.74 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoate (22G).

[0671] LC-MS, M / Z (ESI): 321.1 (M+H) +

[0672] Step 7: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentamido)propionate (22H)

[0673]

[0674] 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentanoic acid (22G) (150mg, 0.48mmol), (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1J) (200mg, 0.58mmol), N-methylimidazolium (118mg, 1.44mmol), and tetramethylchlorourea hexafluorophosphate (210mg, 0.72mmol) were dissolved in acetonitrile (10mL) and reacted at 25°C for 2h. After the reaction was complete, the solution was concentrated to dryness, and water (15mL) was added. The solution was extracted three times with ethyl acetate (15mL), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH(v / v)=10 / 1) to give ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentamido)propionate (22H).

[0675] LC-MS, M / Z (ESI): 650.2 (M+H) +

[0676] Step 8: Synthesis of target compounds 22-P1 and 22-P2

[0677]

[0678] Ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)-3-(2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo(1,5-a)pyrazin-5(4H)-yl)-4-methylpentamido)propionate (22H) (180 mg, 0.28 mmol) and lithium hydroxide monohydrate (59 mg, 1.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 58-70) to obtain the target compounds 22-P1 and 22-P2.

[0679] Target compound 22-P1:

[0680] Retention time: 7.71 min

[0681] LC-MS, M / Z (ESI): 622.3 (M+H) +

[0682] 1H NMR (600 MHz, cd3od) δ 7.91 (d, J = 1.9 Hz, 1H), 7.14 (s, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.78 (ddd, J = 27.3, 14.7, 7.0 Hz, 4H), 5.48 (dd, J = 10.8, 5.1 Hz, 1H), 5.38 (t, J = 5.6 Hz, 1H), 3.71–3.64 (m, 1H), 3.40–3.32 (m, 2H), 3.29–3.24 (m, 1H), 2.72 (s, 6H), 2.59 (dd, J = 14.5, 5.3 Hz, 1H), 2.50 (dd, J = 14.4, 5.9 Hz, 1H), 2.26 (s, 3H), 2.08–2.01 (m, 1H), 1.97–1.92 (m, 4H), 1.86 (s, 3H), 1.52–1.44 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H).

[0683] Target compound 22-P2:

[0684] Retention time: 9.21 min

[0685] LC-MS, M / Z (ESI): 622.3 (M+H) +

[0686] 1H NMR (600 MHz, cd3od) δ 7.89 (d, J = 2.1 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.88–6.76 (m, 4H), 5.58–5.52 (m, 2H), 3.77 (t, J = 9.8 Hz, 1H), 3.46 (dt, J = 15.6, 4.5 Hz, 1H), 3.35 (dt, J = 13.1, 4.8 Hz, 1H), 3.27–3.21 (m, 1H), 2.82 (s, 6H), 2.56 (dd, J = 14.7, 4.1 Hz, 1H), 2.38 (dd, J = 14.6, 9.9 Hz, 1H), 2.29 (s, 3H), 2.04–1.96 (m, 4H), 1.93 (s, 3H), 1.89–1.81 (m, 1H), 1.46–1.37 (m, 1H), 0.90 (dd, J = 10.1, 6.6 Hz, 6H).

[0687] Example 7: Preparation of target compounds 37-P1 and 37-P2

[0688] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0689] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0690]

[0691] Compound 37-P1 is one of the structures of the two compounds mentioned above, while compound 37-P2 is the other structure.

[0692] The synthetic routes for target compounds 37-P1 and 37-P2 are as follows:

[0693]

[0694] Step 1: Synthesis of ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (37B)

[0695]

[0696] Ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (37A) (350 mg, 1.01 mmol) and cyclobutamine (87 mg, 1.52 mmol) were dissolved in 1,2-dichloroethane (3.5 mL) and reacted at 25 °C for 30 min. Sodium cyanoborohydride (127 mg, 2.02 mmol) was added to the reaction solution, and the reaction was continued for 18 h. After the reaction was complete, the solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH (V / V) = 1 / 0-10 / 1) to obtain ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (37B).

[0697] LC-MS, M / Z (ESI): 387.3 (M+H) +

[0698] Step 2: Synthesis of 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (37C)

[0699]

[0700] Lithium hydroxide monohydrate (39 mg, 0.93 mmol) was added to a solution of ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (37B) (180 mg, 0.47 mmol) in tetrahydrofuran (1.8 mL) and water (0.6 mL), and the mixture was stirred at room temperature for 3 h. Water (10 mL) was added to the reaction mixture, and the pH was adjusted to 4–5 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate (3 mL × 3). The organic phase was washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to reversed-phase preparative chromatography (column: Phenomenex Synergi C18100×25mm×4μm; solvent: A = water + 0.1 vol% formic acid (99%), B = acetonitrile; gradient: 5%-95%, 7 min) to obtain 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (37C).

[0701] LC-MS, M / Z (ESI): 359.3 (M+H) +

[0702] Step 3: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (37D)

[0703]

[0704] To a solution of 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (37C) (100 mg, 0.28 mmol) in acetonitrile (2 mL), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1 J) (116 mg, 0.33 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (117 mg, 0.42 mmol) were added, and the mixture was stirred at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (V / V) = 1 / 0-10 / 1) to give ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (37D).

[0705] LC-MS, M / Z (ESI): 688.2 (M+H) +

[0706] Compound 37D can be separated into 37D-P1 and 37D-P2 by SFC. Specific SFC separation method: Instrument: Waters 150Q; Column: DAICEL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[0707] The structures of compounds 37D-P1 and 37D-P2 are as follows:

[0708]

[0709] Compound 37D-P1 is one of the structures of the two compounds mentioned above, while compound 37D-P2 is the other structure.

[0710] Step 4: Synthesis of target compounds 37-P1 and 37-P2

[0711]

[0712] Lithium hydroxide monohydrate (40 mg, 0.95 mmol) was added to a solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (37D) (130 mg, 0.19 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL), and then stirred at room temperature for 5 h. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42mL / min; gradient B%: 55-80) to obtain the target compounds 37-P1 and 37-P2.

[0713] Target compound 37-P1:

[0714] Retention time: 8.86 min

[0715] LC-MS, M / Z (ESI): 660.3 (M+H) +

[0716] 1H NMR(600MHz,DMSO-d6)δ9.61(s,1H),7.46(s,1H),7.35(s,1H),7.10(t,J=75.1Hz,1H),6.93 (d,J=9.8Hz,2H),6.89(d,J=5.9Hz,1H),6.80(d,J=6.4Hz,1H),5.36(dd,J=11.9,3.8Hz,1H), 5.21(dd,J=12.5,6.1Hz,1H),3.46(s,2H),3.32(s,2H),2.87(s,2H),2.49–2.30(m,5H),2.24 (s,3H),2.04–1.70(m,10H),1.38–1.30(m,1H),0.86(d,J=6.6Hz,3H),0.78(d,J=6.6Hz,3H).

[0717] Target compound 37-P2:

[0718] Retention time: 10.03 min

[0719] LC-MS, M / Z (ESI): 660.3 (M+H) +

[0720] 1H NMR(600MHz,DMSO-d6)δ9.11(d,J=6.7Hz,1H),7.42(s,1H),7.34(d,J=1.8Hz,1H),7.22-6.98(m,1H), 6.98-6.95(m,2H),6.92(d,J=6.6Hz,1H),6.88(d,J=5.4Hz,1H),5.38(dd,J=13.7,7.6Hz,2H),3.49(d q,J=22.6,7.6Hz,4H),2.94(dd,J=11.7,5.9Hz,1H),2.86–2.80(m,1H),2.48–2.30(m,5H),2.25(s,3H ),2.11–2.03(m,2H),1.94(s,6H),1.77–1.69(m,2H),1.28–1.21(m,1H),0.77(dd,J=12.3,6.6Hz,6H).

[0721] Example 8: Preparation of target compounds 38-P1 and 38-P2

[0722] (3S)-3-((2R)-2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0723] (3S)-3-((2S)-2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamide)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionic acid

[0724]

[0725] Compound 38-P1 is one of the structures of the two compounds mentioned above, while compound 38-P2 is the other structure.

[0726] The synthetic routes for target compounds 38-P1 and 38-P2 are shown below:

[0727]

[0728] Step 1: Synthesis of 4-chloro-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38C)

[0729]

[0730] 5-Bromo-4-chloro-2-methoxypyridine (38A) (20.0 g, 89.90 mmol) was dissolved in 1,4-dioxane (30 mL) and water (3 mL) at 25 °C. 1-ethoxyvinyl-2-borate pinacol ester (38B) (21.37 g, 98.89 mmol) and K3PO4 (38.15 g, 179.80 mmol) were added, followed by 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (6.57 g, 8.99 mmol). The reaction mixture was stirred at 50 °C for 16 hours. LC-MS showed the product as the main peak. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) - 50:1-10:1, gradient elution) to give 4-chloro-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38C).

[0731] LC-MS, M / Z (ESI): 214.1 (M+H) + .

[0732] Step 2: Synthesis of 4-cyclopropyl-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38D)

[0733]

[0734] 4-Chloro-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38C) (10.8 g, 50.55 mmol), cyclopropylboronic acid (5.64 g, 65.71 mmol), and K₂CO₃ (20.93 g, 151.64 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL) at 25 °C. Pd(OAc)₂ (1.13 g, 5.05 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (3.11 g, 7.58 mmol) were added. The reaction mixture was stirred at 85 °C for 3 hours. LC-MS showed that the starting material was not completely reacted, and products were formed. The reaction mixture was directly evaporated to dryness, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V)-50:1-10:1, gradient elution) to give 4-cyclopropyl-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38D).

[0735] LC-MS, M / Z (ESI): 220.2 (M+H) + .

[0736] Step 3: Synthesis of 2-(4-cyclopropyl-6-methoxy-3-pyridyl)acetaldehyde (38E)

[0737]

[0738] 4-Cyclopropyl-5-((E)-2-ethoxyvinyl)-2-methoxypyridine (38D) (1.0 g, 4.56 mmol) was dissolved in trifluoroacetic acid (4 mL) at 0 °C. HCl (665.09 mg, 18.24 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 3 hours. LC-MS showed that the starting material reacted completely and products were formed. The reaction mixture was diluted with dichloromethane (20 mL), evaporated to dryness, diluted again with dichloromethane (20 mL), evaporated to dryness again, and then dried under an oil pump to give 2-(4-cyclopropyl-6-methoxy-3-pyridyl)acetaldehyde (38E).

[0739] LC-MS, M / Z (ESI): 192.2 (M+H) + .

[0740] Step 4: Synthesis of 2-(4-cyclopropyl-6-methoxy-3-pyridyl)-N,N-dimethylethanolamine (38F)

[0741]

[0742] 2-(4-cyclopropyl-6-methoxy-3-pyridyl)acetaldehyde (38E) (820 mg, 4.29 mmol) and dimethylamine in a tetrahydrofuran solution (2.0 M, 5.36 mL) were dissolved in methanol (9.87 mL) at 25 °C, and acetic acid (514.57 mg, 8.58 mmol) was added. The reaction mixture was stirred at 20 °C for 0.5 h. Subsequently, sodium cyanoborohydride (675.38 mg, 10.72 mmol) was added, and the reaction mixture was stirred at 20 °C for 16 h. LC-MS showed that the starting material reacted completely, and a product was formed. The reaction mixture was directly evaporated to dryness, and the crude product was purified by reverse column chromatography (0–70% methanol aqueous solution (1% ammonia)) to give 2-(4-cyclopropyl-6-methoxy-3-pyridyl)-N,N-dimethylethanolamine (38F).

[0743] LC-MS, M / Z (ESI): 221.2 (M+H) + .

[0744] Step 5: Synthesis of 4-cyclopropyl-5-(2-(dimethylamino)ethyl)pyridine-2-ol (38G)

[0745]

[0746] 2-(4-cyclopropyl-6-methoxy-3-pyridyl)-N,N-dimethylethanolamine (38F) (700 mg, 3.18 mmol) was dissolved in HBr·AcOH (8 mL) at 25 °C. The reaction mixture was stirred at 85 °C for 5 hours. LC-MS showed that the starting material was completely reacted. The reaction mixture was directly evaporated to dryness and then purified by reverse column chromatography (C18, 0–50% methanol-water solution (1% ammonia)) to give 4-cyclopropyl-5-(2-(dimethylamino)ethyl)pyridin-2-ol (38G).

[0747] LC-MS, M / Z (ESI): 207.2 (M+H) + .

[0748] Step 6: Synthesis of ethyl 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxo-1-pyridyl)-4-methylpentanoate (38H)

[0749]

[0750] 4-Cyclopropyl-5-(2-(dimethylamino)ethyl)pyridin-2-ol (38g) (450mg, 2.18mmol) was dissolved in acetonitrile (20mL) at 15°C, and K₂CO₃ (903.13mg, 6.54mmol) was added. Then, ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (935.72mg, 3.93mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 85°C for 48 hours. LC-MS showed that the starting material reacted completely. The reaction mixture was directly evaporated to dryness to give the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) - 50:1 - 0:1, gradient elution) to give 500 mg of crude product. The crude product was dissolved in water (2 mL) and purified by reverse column chromatography (C18, 0-60% methanol aqueous solution (0.05% ammonia)) to give ethyl 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxo-1-pyridyl)-4-methylpentanoate (38H).

[0751] 1 H-NMR (400MHz, DMSO-d6) δ7.41(s,1H),5.87(s,1H),5.26(dd,J=11.0,4.7Hz,1H),4.12-4.06(m,2H),2.67-2.63(m,2H),2.42-2.38(m, 2H),2.19(s,6H),2.07-1.99(m,1H),1.84-1.77(m,2H),1.17-1.13(m,3H),1.00-0.94(m,2H),0.87-0.82(m,7H),0.71(q,J=2.4Hz,2H)

[0752] Step 7: Synthesis of 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxo-1-pyridyl)-4-methylpentanoic acid (38J)

[0753]

[0754] Ethyl 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxo-1-pyridyl)-4-methylpentanoate (38H) (300 mg, 860.89 μmol) was dissolved in methanol (3 mL) at 0 °C, and LiOH (103.09 mg, 4.30 mmol) was added. The reaction mixture was stirred at 0 °C to 20 °C for 3 hours. LC-MS showed that the starting material reacted completely, and the pH of the reaction mixture was adjusted to approximately 6 with 1 N HCl. The mixture was separated by reversed-phase high-performance liquid chromatography (column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A = water + 0.01 v / v trifluoroacetic acid (99%), B = acetonitrile; gradient: 5%-45%, 10 min) to give 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxo-1-pyridyl)-4-methylpentanoic acid (38 J).

[0755] 1 H-NMR (400MHz, DMSO-D6) δ10.10(s,1H),7.50(s,1H),5.95(s,1H),5.31(dd,J=11.0,4.7Hz,1H),3.22-3.17(m,2H),2.96-2.90(m,2H),2.86 (s,6H),2.05-1.97(m,1H),1.90-1.83(m,2H),1.33-1.26(m,1H),1.02-0.97(m,2H),0.85(dd,J=6.6,1.1Hz,6H),0.75(dd,J=8.5,5.2Hz,2H)

[0756] LC-MS, M / Z (ESI): 321.4 (M+H) + .

[0757] Step 8: Synthesis of ethyl (3S)-3-(2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (38K)

[0758]

[0759] 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (38J) (320 mg, 1 mmol), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (1J) (347 mg, 1 mmol), tetramethylchlorourea hexafluorophosphate (560 mg, 2 mmol) and N-methylimidazole (246 mg, 3 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the residue was purified by passing it through a silica gel column (DCM:MeOH 4:1) to obtain ethyl (3S)-3-(2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (38K).

[0760] LC-MS, M / Z (ESI): 650.2 (M+H) +

[0761] Step 9: Synthesis of target compounds 38-P1 and 38-P2

[0762]

[0763] Ethyl (3S)-3-(2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate (38K) (320 mg, 0.5 mmol) and lithium hydroxide monohydrate (95 mg, 2.3 mmol) were dissolved in a mixed solution of tetrahydrofuran (4 mL), methanol (1 mL), and water (1 mL), and reacted at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 6-7 with 1N dilute hydrochloric acid. The solvent was removed under vacuum, and the residue was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; gradient B%: 5-95, flow rate: 42mL / min, 13min) to obtain the target compounds 38-P1 and 38-P2.

[0764] Target compound 38-P1:

[0765] Retention time: 6.37 min

[0766] LC-MS, M / Z (ESI): 622.2 (M+H)+

[0767] 1H NMR (400MHz, CD3OD) δ8.11(s,1H),7.36-7.33(m,4H),6.52(s,1H),6.11-6.00(m,2H),3.86-3.15(m,14H),2.80-2.38(m,10H),1.96-1.29(m,11H).

[0768] Target compound 38-P2:

[0769] Retention time: 8-10 min

[0770] LC-MS, M / Z (ESI): 622.2 (M+H) +

[0771] 1H NMR (400MHz, CD3OD) δ7.56(s,1H),6.87-6.80(m,4H),6.06(s,1H),5.60-5.53(m,2H),3.36-2.29(m,15H),1.97-1.84(m,9H),1.34-0.77(m,11H).

[0772] Example 9: Preparation of target compounds 27-P1 and 27-P2

[0773] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]pyridin-1(2H)-yl}-4-methylpentamido]propionic acid

[0774] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]pyridin-1(2H)-yl}-4-methylpentamido]propionic acid

[0775]

[0776] Compound 27-P1 is one of the structures of the two compounds mentioned above, while compound 27-P2 is the other structure.

[0777] The synthetic routes for compounds 27-P1 and 27-P2 are shown below:

[0778]

[0779] Step 1: Synthesis of 5-chloro-2-methoxy-4-[1-(trifluoromethyl)vinyl]pyridine (27B)

[0780]

[0781] At room temperature, 2-bromo-3,3,3-trifluoroprop-1-ene (65.35 g, 373.56 mmol), potassium carbonate (59 g, 426.92 mmol), and bis(triphenylphosphine)palladium(II) dichloride (7.49 g, 10.67 mmol) were added to a solution of (5-chloro-2-methoxy-4-pyridinyl)boronic acid (27A) (20 g, 106.73 mmol) in tetrahydrofuran (280 mL) in a sealed tube, and the mixture was stirred at 70 °C for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (V / V) = 20:1-10:1) to give 5-chloro-2-methoxy-4-[1-(trifluoromethyl)vinyl]pyridine (27B).

[0782] LC-MS, M / Z (ESI): 238.1 [M+H] +

[0783] Step 2: Synthesis of 5-chloro-2-methoxy-4-[1-(trifluoromethyl)cyclopropyl]pyridine (27C)

[0784]

[0785] At -10 °C, sodium bis(trimethylsilyl)amino (8 mL, 16.04 mmol, 2 M tetrahydrofuran solution) was added dropwise to a solution of 5-chloro-2-methoxy-4-[1-(trifluoromethyl)vinyl]pyridine (27B) (3.7 g, 15.57 mmol) and tetrafluoroborate of methyl(diphenyl)sulfonium (4.71 g, 16.35 mmol) in tetrahydrofuran (50 mL). The mixture was then stirred for 1 hour under nitrogen protection. A saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / tetrahydrofuran (V / V) = 10 / 1-8 / 1 / ) to give 5-chloro-2-methoxy-4-[1-(trifluoromethyl)cyclopropyl]pyridine (27C).

[0786] LC-MS, M / Z (ESI): 252.1 [M+H] +

[0787] Step 3: Synthesis of 5-chloro-4-[1-(trifluoromethyl)cyclopropyl]-1H-pyridin-2-one (27D)

[0788]

[0789] 5-Chloro-2-methoxy-4-[1-(trifluoromethyl)cyclopropyl]pyridine (27C) (2.7 g, 10.73 mmol) was dissolved in a 33% hydrobromic acid-acetic acid solution (26.31 g, 107.3 mmol, 33% purity) at room temperature. The reaction solution was stirred at 80 °C for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by C18 reversed-phase preparative chromatography (mobile phase: A = 0.1% formic acid aqueous solution, B = acetonitrile; gradient B%: 20%-45%, 30 min) to give 5-chloro-4-[1-(trifluoromethyl)cyclopropyl]-1H-pyridin-2-one (27D).

[0790] LC-MS, M / Z (ESI): 238.2 [M+H] +

[0791] Step 4: Synthesis of ethyl 2-[5-chloro-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27E)

[0792]

[0793] Potassium carbonate (1.46 g, 10.61 mmol) and ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (1.52 g, 6.36 mmol) were added to a solution of 5-chloro-4-[1-(trifluoromethyl)cyclopropyl]-1H-pyridin-2-one (27D) (1.26 g, 5.30 mmol) in acetonitrile (20 mL). The mixture was then stirred at 80 °C for 16 hours. The reaction solution was concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (V / V) = 5:1-4:1) to give ethyl 2-[5-chloro-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]-4-methylpentanoate (27E).

[0794] LC-MS, M / Z (ESI): 380.3 [M+H] +

[0795] Step 5: Synthesis of ethyl 2-[5-[(E)-2-ethoxyvinyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27F)

[0796]

[0797] To a solution of ethyl 2-[5-chloro-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27E) (660 mg, 1.74 mmol) in N,N-dimethylformamide (10 mL), 1-ethoxyvinyl-2-boronic acid pinacol ester (1.03 g, 5.21 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II) (271 mg, 347.55 μmol) and cesium carbonate (1.13 g, 3.48 mmol) were added. The reaction was carried out under nitrogen protection at 90 °C using microwave for 1 hour. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (V / V) = 5:1-4:1) to give ethyl 2-[5-[(E)-2-ethoxyvinyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27F).

[0798] LC-MS, M / Z (ESI): 416.5 [M+H] +

[0799] Step 6: Synthesis of ethyl 4-methyl-2-[2-oxo-5-(2-oxoethyl)-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]valerate (27G)

[0800]

[0801] At 0 °C, trifluoroacetic acid (4 mL) and two drops of 12 M concentrated hydrochloric acid were added dropwise to a solution of ethyl 2-[5-[(E)-2-ethoxyvinyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27F) (130 mg, 312.9 μmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 mL) and evaporated to dryness using an oil pump at room temperature to give ethyl 4-methyl-2-[2-oxo-5-(2-oxoethyl)-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]pentanoate (27 G).

[0802] LC-MS, M / Z (ESI): 388.2 [M+H] +

[0803] Step 7: Synthesis of ethyl 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27H)

[0804]

[0805] At 0 °C, dimethylamine (1.44 mmol, 0.72 mL, 2 M tetrahydrofuran solution) and two drops of acetic acid were added dropwise to a methanol (4 mL) solution of ethyl 4-methyl-2-[2-oxo-5-(2-oxoethyl)-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]valerate (27 G) (186 mg crude product). The mixture was stirred at room temperature for 16 hours under nitrogen protection. Then, sodium cyanoborohydride (76 mg, 1.20 mmol) was added in portions to the reaction mixture at 0 °C, and the reaction was continued at room temperature for 2 hours under nitrogen protection. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by C18 reversed-phase preparative chromatography (mobile phase: A = 0.1% formic acid aqueous solution, B = acetonitrile; gradient B%: 25%-45%, 30 min) to give ethyl 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoate (27H).

[0806] LC-MS, M / Z (ESI): 417.6 [M+H] +

[0807] Step 8: Synthesis of 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoic acid (27J)

[0808]

[0809] At 0 °C, an aqueous solution (2 mL) of lithium hydroxide (20 mg, 844.83 μmol) was added dropwise to a solution of ethyl 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoic acid (27H) (170 mg, 422.41 μmol) in tetrahydrofuran (2 mL) and methanol (2 mL). The reaction mixture was stirred at 20 °C for half an hour. The pH was adjusted to 5-6 with 1 M hydrochloric acid aqueous solution in an ice bath, and the reaction solution was purified directly by passing it through a C18 reversed-phase preparative chromatography column (mobile phase: A = 0.1% formic acid aqueous solution, B = acetonitrile; gradient B%: 25%-45%, 30 min) to give 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylpentanoic acid (27J).

[0810] LC-MS, M / Z (ESI): 389.3 [M+H] +

[0811] Step 9: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]pyridin-1(2H)-yl}-4-methylpentamido)propionate (27K)

[0812]

[0813] To a solution of 2-[5-[(dimethylamino)methyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]-4-methylvaleric acid (27 J) (100 mg, 0.26 mmol) in acetonitrile (1 mL), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (1 J) (99 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (108 mg, 0.39 mmol) and N-methylimidazole (63 mg, 0.77 mmol). The mixture was stirred at room temperature for 18 h. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]pyridin-1(2H)-yl}-4-methylpentamido)propionate (27K).

[0814] LC-MS, M / Z (ESI): 718.3 [M+H] +

[0815] Step 10: Synthesis of target compounds 27-P1 and 27-P2

[0816]

[0817] Lithium hydroxide monohydrate (35 mg, 0.85 mmol) was added to a solution of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-[1-(trifluoromethyl)cyclopropyl]pyridin-1(2H)-yl}-4-methylpentamido)propionate (27K) (120 mg, 0.17 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 20-80) to obtain the target compounds 27-P1 and 27-P2.

[0818] Target compound 27-P1:

[0819] Retention time: 7.32 min

[0820] 1 H NMR(600MHz,DMSO-d6)δ9.02(d,J=8.0Hz,1H),7.64(s,1H),7.01-6.83(m,4H),6.39(s,1 H),5.53(dd,J=10.4,6.0Hz,1H),5.43(dd,J=14.4,8.0Hz,1H),2.72-2.51(m,5H),2.46-2 .35(m,2H),2.27-2.13(m,9H),1.94(s,3H),1.88-1.78(m,4H),1.74-1.67(m,1H),1.40(d d,J=10.4,5.6Hz,2H),1.33-1.26(m,1H),1.16-1.06(m,2H),0.84(dd,J=31.6,6.8Hz,6H)

[0821] LC-MS, M / Z (ESI): 690.3 [M+H] +

[0822] Target compound 27-P2:

[0823] Retention time: 8.35 min

[0824] 1H NMR(600MHz,DMSO-d6)δ9.16(d,J=6.8Hz,1H),7.66(s,1H),6.96(dd,J=24.8,6.8Hz, 4H),6.45(s,1H),5.59(dd,J=10.4,6.0Hz,1H),5.43(dd,J=14.8,7.6Hz,1H),2.69-2 .58(m,4H),2.48-2.35(m,3H),2.25(s,3H),2.18(s,6H),1.99-1.92(m,6H),1.71-1. 65(m,1H),1.56-1.50(m,1H),1.40(s,2H),1.15(s,3H),0.73(dd,J=6.4,4.0Hz,6H).

[0825] LC-MS, M / Z (ESI): 690.3 [M+H] +

[0826] Example 10: Preparation of target compounds 28-P1 and 28-P2

[0827] (3S)-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionic acid

[0828] (3S)-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionic acid

[0829]

[0830] Compound 28-P1 is one of the structures of the two compounds mentioned above, while compound 28-P2 is the other structure.

[0831] The synthetic routes for the target compounds 28-P1 and 28-P2 are as follows:

[0832]

[0833] Step 1: Synthesis of ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28B)

[0834]

[0835] Ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (28A) (2 g, 5 mmol), pinacol 1-ethoxyvinyl-2-boronate (2.23 g, 11.2 mmol), potassium carbonate (2.31 g, 16.8 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (409 mg, 0.56 mmol) were dissolved in dioxane (20 mL) and water (2 mL) and reacted at 100 °C for 4 h. After the reaction was complete, water (40 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to give ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28B).

[0836] LC-MS, M / Z (ESI): 348.2 [M+H] +

[0837] Step 2: Synthesis of ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (28C)

[0838]

[0839] Ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28B) (1.23 g, 3.54 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 25 °C for 1 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The mixture was extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]pentanoate (28C).

[0840] LC-MS, M / Z (ESI): 320.1 [M+H] +

[0841] Step 3: Synthesis of ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28D)

[0842]

[0843] Ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (28C) (1.14 g, 3.54 mmol), and a THF solution of dimethylamine (3.54 mL, 7.08 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 min, and then sodium cyanoborohydride (332 mg, 5.31 mmol) was added, and the reaction was continued for 1 h. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / V) = 10:1) to obtain ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylvalerate (28D).

[0844] LC-MS, M / Z (ESI): 349.2 [M+H] +

[0845] Step 4: Synthesis of 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (28E)

[0846]

[0847] Ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28D) (480 mg, 1.37 mmol) and lithium hydroxide monohydrate (115 mg, 2.74 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (28E).

[0848] LC-MS, M / Z (ESI): 321.1 [M+H] +

[0849] Step 5: Synthesis of (3S)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (28G)

[0850]

[0851] 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (28E) (150 mg, 0.48 mmol), (3S)-3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (28F) (200 mg, 0.58 mmol), N-methylimidazolium (118 mg, 1.44 mmol), and tetramethylchlorourea hexafluorophosphate (210 mg, 0.72 mmol) were dissolved in acetonitrile (10 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the solution was concentrated to dryness, and water (15 mL) was added. The solution was extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / v) = 10:1) to obtain ethyl (3S)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (28G).

[0852] LC-MS, M / Z (ESI): 654.2 [M+H] +

[0853] Step 6: Synthesis of target compounds 28-P1 and 28-P2.

[0854]

[0855] Ethyl (3S)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(4,4',5-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (28g) (180mg, 0.28mmol) and lithium hydroxide monohydrate (59mg, 1.4mmol) were dissolved in tetrahydrofuran (5mL) and water (1mL) and reacted at 25°C for 5h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile gradient: 20%-70%, flow rate: 42mL / min, 13min) to obtain the target compounds 28-P1 and 28-P2.

[0856] Target compound 28-P1:

[0857] Retention time: 7.93 min

[0858] LC-MS, M / Z (ESI): 626.3 [M+H] +

[0859] 1H NMR(400MHz,CD3OD)δ7.81(s,1H),7.14-7.16(m,1H),7.02-6.65(m,5H),5.48-5.38(m,2H) ,3.64-3.32(m,4H),2.72-2.59(m,8H),2.10-1.80(m,8H),1.56(s,1H),0.96-0.81(m,6H).

[0860] Target compound 28-P2:

[0861] Retention time: 9.66 min

[0862] LC-MS, M / Z (ESI): 626.3 [M+H] +

[0863] 1H NMR (400MHz, CD3OD) δ7.88(s,1H),7.13-6.81(m,6H),5.62-5.55(m,2H),3.74-3. 31(m,4H),2.83-2.43(m,8H),2.01-1.86(m,8H),1.41(s,1H),0.90-0.88(m,6H).

[0864] Example 11: Preparation of target compounds 29-P1 and 29-P2

[0865] (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]propionic acid

[0866] (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[0867]

[0868] Compound 29-P1 is one of the structures of the two compounds mentioned above, while compound 29-P2 is the other structure.

[0869] The synthetic routes for target compounds 29-P1 and 29-P2 are as follows:

[0870]

[0871] Step 1: Synthesis of (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (29B)

[0872]

[0873] 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (28E) (150 mg, 0.48 mmol), (3S)-3-amino-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (29A) (200 mg, 0.58 mmol), N-methylimidazolium (118 mg, 1.44 mmol), and tetramethylchlorourea hexafluorophosphate (210 mg, 0.72 mmol) were dissolved in acetonitrile (10 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the solution was concentrated to dryness, and water (15 mL) was added. The solution was extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / V) = 10:1) to give ethyl (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (29B).

[0874] LC-MS, M / Z (ESI): 670.2 [M+H] +

[0875] Step 2: Synthesis of target compounds 29-P1 and 29-P2

[0876]

[0877] Ethyl (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (29B) (180 mg, 0.28 mmol) and lithium hydroxide monohydrate (59 mg, 1.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile gradient: 30%-80%, flow rate: 42mL / min, 13min) to obtain the target compounds 29-P1 and 29-P2.

[0878] Target compound 29-P1:

[0879] Retention time: 10.00 min

[0880] LC-MS, M / Z (ESI): 642.4 [M+H] +

[0881] 1H NMR (400MHz, CD3OD) δ7.88(s,1H),7.15-6.71(m,6H),5.53-5.44(m,2H),3.55-3. 29(m,4H),2.78-2.59(m,8H),2.03-1.75(m,8H),1.43(s,1H),0.93-0.89(m,6H).

[0882] Target compound 29-P2:

[0883] Retention time: 12.14 min

[0884] LC-MS, M / Z (ESI): 642.4 [M+H] +

[0885] 1H NMR (400MHz, CD3OD) δ7.87(s,1H),7.14-6.81(m,6H),5.59-5.56(m,2H),3.71-3. 21(m,4H),2.82-2.46(m,8H),2.00-1.95(m,8H),1.40(s,1H),0.90-0.87(m,6H).

[0886] Example 12: Preparation of target compounds 30-P1 and 30-P2

[0887] (3S)-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[0888] (3S)-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[0889]

[0890] Compound 30-P1 is one of the structures of the two compounds mentioned above, while compound 30-P2 is the other structure.

[0891] The synthetic routes for target compounds 30-P1 and 30-P2 are as follows:

[0892]

[0893] Step 1: Synthesis of (3S)-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (30B)

[0894]

[0895] 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (28E) (150 mg, 0.48 mmol), (3S)-3-amino-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]propionate ethyl ester (30A) (200 mg, 0.50 mmol), N-methylimidazole (118 mg, 1.44 mmol), and tetramethylchlorourea hexafluorophosphate (210 mg, 0.72 mmol) were dissolved in acetonitrile (10 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the mixture was concentrated to dryness, and water (15 mL) was added. The mixture was extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain ethyl (3S)-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (30B).

[0896] LC-MS, M / Z (ESI): 704.2 [M+H] +

[0897] Step 2: Synthesis of target compounds 30-P1 and 30-P2

[0898]

[0899] Ethyl (3S)-3-[4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (30B) (175 mg, 0.25 mmol) and lithium hydroxide monohydrate (59 mg, 1.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart PrepC187μm 30mm×40cm; solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile gradient: 15%-75%, flow rate: 42mL / min, 13min) to obtain the target compounds 30-P1 and 30-P2.

[0900] Target compound 30-P1:

[0901] Retention time: 7.38 min

[0902] LC-MS, M / Z (ESI): 676.3 [M+H] +

[0903] 1H NMR(400MHz,CD3OD)δ7.89(s,1H),7.28-6.74(m,6H),5.51-5.49(m,2H),3.55-3. 30(m,4H),2.79-2.61(m,8H),2.05-1.94(m,8H),1.45(s,1H),0.93-0.90(m,6H).

[0904] Target compound 30-P2:

[0905] Retention time: 9.38 min

[0906] LC-MS, M / Z (ESI): 676.3 [M+H] +

[0907] 1H NMR (400MHz, CD3OD) δ7.86 (s, 1H), 7.35-6.85 (m, 6H), 5.65-5.57 (m, 2H), 3.71-3. 22(m,4H),2.83-2.51(m,8H),1.99-1.85(m,8H),1.40(s,1H),0.89-0.85(m,6H).

[0908] Example 13: Preparation of target compounds 31-P1 and 31-P2

[0909] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{7-[2-(dimethylamino)-1,1-difluoroethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]propionic acid

[0910] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{7-[2-(dimethylamino)-1,1-difluoroethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]propionic acid

[0911]

[0912] Compound 31-P1 is one of the structures of the two compounds mentioned above, while compound 31-P2 is the other structure.

[0913] The synthetic routes for compounds 31-P1 and 31-P2 are shown below:

[0914]

[0915] Step 1: Synthesis of 7-iodopyrazolo[1,5-a]pyrazin-4(5H)-one (31B)

[0916]

[0917] Pyrazolo[1,5-a]pyrazin-4(5H)-one (31A) (20 g, 148.01 mmol) and N-methylmorpholine (15 g, 147.87 mmol, 16.26 mL) were dissolved in N,N-dimethylformamide (100 mL) at 0 °C. N-iodosuccinimide (46.6 g, 207.22 mmol) was added in portions. The reaction mixture was stirred at 20 °C for 5 hours. Water (500 mL) was added to the reaction mixture at 0 °C, and a large amount of white solid precipitated. The solid was filtered, and the filter cake was dried by an oil pump to obtain 7-iodopyrazolo[1,5-a]pyrazin-4(5H)-one (31B).

[0918] Step 2: Synthesis of 4-chloro-7-iodopyrazolo[1,5-a]pyrazine (31C)

[0919]

[0920] 7-Iodopyrazolo[1,5-a]pyrazin-4(5H)-one (31B) (35 g, 134.09 mmol) was added in portions to phosphorus oxychloride (100 mL) at 0 °C. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was dissolved in ethyl acetate (500 mL), slowly poured into ice water (500 mL), and then the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-5:1) to give 4-chloro-7-iodopyrazolo(1,5-a)pyrazine (31C).

[0921] LC-MS, M / Z (ESI): 280.0 [M+H] +

[0922] Step 3: Synthesis of 7-iodo-4-methoxypyrazolo(1,5-a)pyrazine (31D)

[0923]

[0924] 4-Chloro-7-iodopyrazolo(1,5-a)pyrazine (31C) (31 g, 110.93 mmol) was dissolved in tetrahydrofuran (200 mL) at 0 °C, and sodium methoxide solution (39.9 g, 221.85 mmol, 30% methanol solution) was added in portions. The reaction mixture was stirred at 20 °C for 1 hour. Water (150 mL) was added to the reaction mixture at 0 °C, and a large amount of white solid precipitated. The solid was filtered, and the filter cake was dried by an oil pump to obtain 7-iodo-4-methoxypyrazolo(1,5-a)pyrazine (31D).

[0925] LC-MS, M / Z (ESI): 276.1 [M+H] +

[0926] Step 4: Synthesis of ethyl 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)ethyl acetate (31E)

[0927]

[0928] 7-Iodo-4-methoxypyrazolo(1,5-a)pyrazine (31D) (22 g, 79.99 mmol) and ethyl 2-bromo-2,2-difluoroacetate (32.5 g, 159.97 mmol) were dissolved in dimethyl sulfoxide (60 mL) at 25 °C, and copper powder (25.4 g, 399.93 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and ethyl acetate (125 mL) and water (200 mL) were added to the filtrate. The mixture was extracted with ethyl acetate (150 mL × 2), the organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 50:1-10:1) to give ethyl 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)acetate (31E).

[0929] LC-MS, M / Z (ESI): 272.1 [M+H] +

[0930] Step 5: Synthesis of 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylacetamide (31F)

[0931]

[0932] A solution of dimethylamine (94 mL, 188 mmol, 2 M tetrahydrofuran) was added to a tetrahydrofuran solution of ethyl 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)acetate (31E) (5.1 g, 18.80 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-2:1) to give 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylacetamide (31F).

[0933] LC-MS, M / Z (ESI): 271.3 [M+H] +

[0934] Step 6: Synthesis of 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylethanolamine (31G)

[0935]

[0936] A borane solution (9.6 mL, 9.62 mmol, 1 M tetrahydrofuran solution) was added dropwise to a solution of 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylacetamide (31F) (1.3 g, 4.81 mmol) in 10 mL of tetrahydrofuran at 25 °C. The reaction mixture was stirred at 45 °C for 16 h. Methanol (30 mL) was added dropwise to the reaction mixture at 0 °C, and then the mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-5:1) to give 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylethanolamine (31G).

[0937] LC-MS, M / Z (ESI): 257.2 [M+H] +

[0938] Step 7: Synthesis of 7-[2-(dimethylamino)-1,1-difluoroethyl]pyrazolo[1,5-a]pyrazin-4(5H)-one(31H)

[0939]

[0940] Trimethyliodosilane (2.46 g, 17.56 mmol) was added dropwise to a solution of 2,2-difluoro-2-(4-methoxypyrazolo(1,5-a)pyrazin-7-yl)-N,N-dimethylethanolamine (31 G) (1.8 g, 7.02 mmol) in acetonitrile (30 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. Water (25 mL) was added to the reaction mixture, and the pH was adjusted to approximately 7 with an aqueous sodium bicarbonate solution. Then, an aqueous sodium bisulfite solution was added until the reaction mixture became colorless, and the mixture was extracted with ethyl acetate (55 mL × 2). The organic phases were combined and washed with saturated brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1-1:1) to give 7-[2-(dimethylamino)-1,1-difluoroethyl]pyrazolo[1,5-a]pyrazin-4(5H)-one (31H).

[0941] LC-MS, M / Z (ESI): 243.3 [M+H] +

[0942] Step 8: Synthesis of ethyl 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoate (31J)

[0943]

[0944] 7-[2-(dimethylamino)-1,1-difluoroethyl]pyrazolo[1,5-a]pyrazin-4(5H)-one (31H) (1100 mg, 4.54 mmol) and ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (1.62 g, 6.81 mmol) were dissolved in N,N-dimethylformamide (12 mL) at 25 °C, and then potassium carbonate (689 mg, 5.00 mmol) was added. The reaction mixture was stirred at 85 °C for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to give ethyl 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoate (31J).

[0945] LC-MS, M / Z (ESI): 385.3 [M+H] +

[0946] Step 9: Synthesis of 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoic acid (31K)

[0947]

[0948] Lithium hydroxide (25 mg, 1.04 mmol) was added to a methanol (3 mL) solution of ethyl 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoate (31 J) (200 mg, 0.52 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to approximately 6 with 1 N hydrochloric acid aqueous solution. The mixture was separated by reversed-phase preparative chromatography (column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: A = water + 0.01 v / v trifluoroacetic acid (99%), B = acetonitrile; gradient B%: 5%-35%, 30 min) to give 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoic acid (31K).

[0949] LC-MS, M / Z (ESI): 357.3 [M+H] +

[0950] Step 10: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)-1,1-difluoroethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (31L)

[0951]

[0952] To a solution of 2-(7-(2-(dimethylamino)-1,1-difluoroethyl)-4-oxopyrazolo(1,5-a)pyrazin-5-yl)-4-methylpentanoic acid (31K) (180 mg, 0.51 mmol) in acetonitrile (2 mL), ethyl (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (1 J) (291 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (227 mg, 0.81 mmol) and N-methylimidazole (124 mg, 1.52 mmol). The mixture was stirred at room temperature for 18 h. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)-1,1-difluoroethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (31L).

[0953] LC-MS, M / Z (ESI): 686.3 [M+H] +

[0954] Step 11: Synthesis of target compounds 31-P1 and 31-P2

[0955]

[0956] Lithium hydroxide monohydrate (39 mg, 0.92 mmol) was added to a solution of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)-1,1-difluoroethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (31 L) (210 mg, 0.31 mmol) in tetrahydrofuran (3 mL) and water (1 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 80ml / min; gradient B%: 20-100) to obtain the target compounds 31-P1 and 31-P2.

[0957] Target compound 31-P1:

[0958] Retention time: 10.51 min

[0959] 1 H NMR(600MHz,DMSO-d6)δ9.18(d,J=7.2Hz,1H),8.03(d,J=2.0Hz,1H),7.37(s,1H),7.08(d,J=2.0Hz,1H), 6.93(d,J=8.0Hz,1H),6.88(d,J=6.8Hz,2H),6.80(d,J=9.6Hz,1H),5.53(dd,J=10.4,6.0Hz,1H),5.43(d d,J=14.8,7.6Hz,1H),3.51-3.40(m,1H),3.36-3.28(m,2H),2.63(d,J=7.2Hz,2H),2.21(s,3H),2.11(s, 6H),1.95-1.86(m,4H),1.83-1.74(m,1H),1.65(s,3H),1.38-1.30(m,1H),0.86(dd,J=14.8,6.8Hz,6H).

[0960] LC-MS, M / Z (ESI): 658.3 [M+H] +

[0961] Target compound 31-P2:

[0962] Retention time: 11.51 min

[0963] 1 H NMR(600MHz,DMSO-d6)δ9.32(s,1H),8.04(d,J=2.0Hz,1H),7.43(s,1H),7.17(d,J= 2.0Hz,1H),7.00-6.91(m,4H),5.56(dd,J=10.0,6.0Hz,1H),5.44(dd,J=14.8,7.2H z,1H),3.48-3.33(m,3H),2.60(d,2H),2.26(s,3H),2.13(s,6H),1.96(d,J=3.2Hz, 6H),1.78-1.71(m,1H),1.67-1.60(m,1H),1.24-1.17(m,1H),0.76(t,J=6.4Hz,6H).

[0964] LC-MS, M / Z (ESI): 658.3 [M+H] +

[0965] Example 14: Preparation of target compounds 32-P1 and 32-P2

[0966] (3S)-3-[(2R)-2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[0967] (3S)-3-[(2S)-2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[0968]

[0969] Compound 32-P1 is one of the structures of the two compounds mentioned above, while compound 32-P2 is the other structure.

[0970] The synthetic routes for compounds 32-P1 and 32-P2 are shown below:

[0971]

[0972] Step 1: Synthesis of ethyl 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (32B)

[0973]

[0974] First, 3-fluorozacriane hydrochloride (800 mg, 7 mmol) was dissolved in dichloroethane (15 mL). Then, triethylamine (735 mg, 7.2 mmol) was added to adjust the pH to 8, followed by acetic acid (112 mg, 2 mmol) to adjust the pH to 5. Then, ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (32A) (1.14 g, 3.5 mmol) was added to the reaction solution. After reacting at 25 °C for 10 min, sodium cyanoborohydride (630 mg, 10 mmol) was added, and the reaction continued for 1 h. After the reaction was complete, the solution was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH(V / V)=10:1) to obtain ethyl 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (32B).

[0975] LC-MS, M / Z (ESI): 379.2 [M+H] +

[0976] Step 2: Synthesis of 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (32C)

[0977]

[0978] Ethyl 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (32B) (800 mg, 2.11 mmol) and lithium hydroxide monohydrate (115 mg, 2.74 mmol) were dissolved in tetrahydrofuran (5 mL), methanol (1 mL), and water (1 mL), and reacted at 25 °C for 1 h. After the reaction was complete, the solution was evaporated to dryness, and acetonitrile (10 mL) was added. The pH of the solution was adjusted to approximately 4 with 1 N hydrochloric acid to obtain the crude product. The crude product was subjected to reversed-phase preparative chromatography (HCl system, 50% ACN) to obtain 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (32C).

[0979] LC-MS, M / Z (ESI): 351.1 [M+H] +

[0980] Step 3: Synthesis of (3S)-3-(2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (32E)

[0981]

[0982] To a solution of 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylvaleric acid (32C) (70 mg, 0.22 mmol) in acetonitrile (1 mL), ethyl (3S)-3-amino-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (32D) (132 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (98 mg, 0.35 mmol) and N-methylimidazole (54 mg, 0.66 mmol). The mixture was stirred at room temperature for 18 h. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-(2-{7-[2-(3-fluorozapicyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (32E).

[0983] LC-MS, M / Z (ESI): 668.3 [M+H]+

[0984] Compound 32E can be separated into 32E-P1 and 32E-P2 by SFC. Specific SFC separation method: Instrument: Waters 150Q; Column: DAICEL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[0985] The structures of compounds 32E-P1 and 32E-P2 are as follows:

[0986]

[0987] Compound 32E-P1 is one of the structures of the two compounds mentioned above, while compound 32E-P2 is the other structure.

[0988] Step 4: Synthesis of target compounds 32-P1 and 32-P2

[0989]

[0990] Lithium hydroxide monohydrate (27 mg, 0.65 mmol) was added to a solution of (3S)-3-(2-{7-[2-(3-fluorozacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (32E) (90 mg, 0.13 mmol) in tetrahydrofuran (0.9 mL) and water (0.3 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 10-90) to obtain the target compounds 32-P1 and 32-P2.

[0991] Target compound 32-P1:

[0992] Retention time: 6.52 min

[0993] 1H NMR(600MHz,DMSO-d6)δ8.99(d,J=7.2Hz,1H),7.93(d,J=2.0Hz,1H),7.03-6.92( m,4H),5.53(dd,J=11.2,5.2Hz,1H),5.48(dd,J=14.8,7.2Hz,1H),5.12-5.00(m, 1H),3.56-3.50(m,2H),3.12-3.00(m,3H),2.93-2.70(m,7H),2.16(s,3H),2.00- 1.91(m,4H),1.81-1.70(m,4H),1.35-1.28(m,1H),0.86(dd,J=24.8,6.8Hz,6H).

[0994] LC-MS, M / Z (ESI): 670.2 [M+H] +

[0995] Target compound 32-P2:

[0996] Retention time: 8.33 min

[0997] 1 H NMR(600MHz,DMSO-d6)δ9.07(d,J=6.8Hz,1H),7.94(s,1H),7.08-6.98(m,4H),5.56(dd,J =11.2,5.2Hz,1H),5.48(dd,J=14.4,7.2Hz,1H),5.15-5.02(m,1H),3.60-3.54(m,3H),3. 17-3.03(m,3H),2.92-2.82(m,4H),2.75(dd,J=21.2,14.4Hz,3H),2.22(s,3H),2.01-1.9 2(m,5H),1.86-1.79(m,1H),1.57-1.51(m,1H),1.23(s,1H),0.78(dd,J=16.0,6.4Hz,6H).

[0998] LC-MS, M / Z (ESI): 670.2 [M+H] +

[0999] Example 15: Preparation of target compounds 33-P1 and 33-P2

[1000] (3S)-3-{(2R)-2-[3-(difluoromethoxy)-5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentamido}-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1001] (3S)-3-{(2S)-2-[3-(difluoromethoxy)-5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentamido}-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1002]

[1003] Compound 33-P1 is one of the structures of the two compounds mentioned above, while compound 33-P2 is the other structure.

[1004] The synthetic routes for compounds 33-P1 and 33-P2 are shown below:

[1005]

[1006] Step 1: Synthesis of (3S)-3-{2-[3-(difluoromethoxy)-5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentamido}-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (33A)

[1007]

[1008] To a solution of 2-[3-(difluoromethoxy)-5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentanoic acid (6A) (400 mg, 1.06 mmol) in acetonitrile (4 mL), ethyl (3S)-3-amino-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (32D) (427 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (447 mg, 1.59 mmol) and N-methylimidazole (349 mg, 4.25 mmol). The mixture was stirred at room temperature for 18 h. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-{2-[3-(difluoromethoxy)-5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentamido}-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (33A).

[1009] LC-MS, M / Z (ESI): 724.3 [M+H] +

[1010] Compound 33A can be separated into 33A-P1 and 33A-P2 by SFC. Specific SFC separation method: Instrument: Waters 150Q; Column: DAICEL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[1011] The structures of compounds 33A-P1 and 33A-P2 are as follows:

[1012]

[1013] Compound 33A-P1 is one of the structures of the two compounds mentioned above, while compound 33A-P2 is the other structure.

[1014] Step 2: Synthesis of target compounds 33-P1 and 33-P2

[1015]

[1016] Lithium hydroxide monohydrate (81 mg, 1.93 mmol) was added to a solution of (3S)-3-{2-[3-(difluoromethoxy)-5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxopyridin-1(2H)-yl]-4-methylpentamido}-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (33A) (280 mg, 0.39 mmol) in tetrahydrofuran (3 mL) and water (1 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 80ml / min; gradient B%: 25-100) to obtain the target compounds 33-P1 and 33-P2.

[1017] Target compound 33-P1:

[1018] Retention time: 9.12 min

[1019] 1 H NMR (600MHz, DMSO-d6) δ9.02(d,J=7.0Hz,1H),7.40(d,J=1.5Hz,1H),7.28(d,J=1.9Hz,1H),7.15(d,J=75.3Hz,1H),7.0 3–6.92(m,3H),5.61(dd,J=10.8,5.5Hz,1H),5.48(dd,J=14.9,7.4Hz,1H),5.13–5.02(m,1H),3.55–3.48(m,3H),3.09– 3.00(m,2H),2.91(dd,J=15.8,8.2Hz,1H),2.77(dd,J=16.1,7.0Hz,1H),2.58–2.51(m,2H),2.34(dd,J=17.1,7.1Hz,2H ),2.19(s,3H),1.94(s,3H),1.88(s,4H),1.78–1.71(m,1H),1.25(dd,J=14.0,6.9Hz,1H),0.83(dd,J=22.7,6.6Hz,6H).

[1020] LC-MS, M / Z (ESI): 696.3 [M+H] +

[1021] Target compound 33-P2:

[1022] Retention time: 10.99 min

[1023] 1 H NMR (600MHz, DMSO-d6) δ9.14(d,J=6.8Hz,1H),7.48(s,1H),7.32(d,J=2.0Hz,1H),7.28-7.11(m,1H),7.05-6. 97(m,3H),5.65(dd,J=10.8,5.6Hz,1H),5.46(dd,J=14.4,7.2Hz,1H),5.17-5.02(m,1H),3.56-3.50(m,3H),3. 12-3.01(m,2H),2.89(dd,J=15.6,8.8Hz,1H),2.77-2.71(m,1H),2.63-2.53(m,2H),2.41-2.33(m,2H),2.21(s ,3H),1.99-1.93(m,6H),1.78-1.71(m,1H),1.55-1.48(m,1H),1.16-1.10(m,1H),0.76(dd,J=16.0,6.8Hz,6H)

[1024] LC-MS, M / Z (ESI): 696.3 [M+H] +

[1025] Example 16: Preparation of target compounds 34-P1 and 34-P2

[1026] (3S)-3-[5-(difluoromethyl)-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1027] (3S)-3-[5-(difluoromethyl)-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1028]

[1029] Compound 34-P1 is one of the structures of the two compounds mentioned above, while compound 34-P2 is the other structure.

[1030] The synthetic routes for compounds 34-P1 and 34-P2 are shown below:

[1031]

[1032] Step 1: Synthesis of ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (34B)

[1033]

[1034] 7-Iodopyrazolo[1,5-a]pyrazin-4(5H)-one (34A) (13.3 g, 51.0 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (13D) (18.2 g, 76.5 mmol), and potassium carbonate (14.08 g, 102 mmol) were dissolved in acetonitrile (400 mL), and the mixture was slowly heated to 80 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated to dryness, and the reaction was quenched with water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE:EA(V / V) = 5:1) to obtain ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (34B).

[1035] LC-MS, M / Z (ESI): 404.0 [M+H] +

[1036] Step 2: Synthesis of ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34C)

[1037]

[1038] Ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (34B) (2.5 g, 6.2 mmol), pinacol 1-ethoxyvinyl-2-boronate (2.46 g, 12.4 mmol), potassium carbonate (2.57 g, 18.6 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (480 mg, 0.64 mmol) were dissolved in dioxane (30 mL) and water (3 mL) and reacted at 80 °C for 15 h. After the reaction was complete, the reaction was quenched with water (30 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (PE:EA(V / V)=3:1) to obtain ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34C).

[1039] LC-MS, M / Z (ESI): 348.2 [M+H] +

[1040] Step 3: Synthesis of ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (34D)

[1041]

[1042] Ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34C) (500 mg, 1.44 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and reacted at 40 °C for 2 hours. After the reaction was completed, the mixture was concentrated to dryness, and the reaction was quenched with saturated sodium bicarbonate solution (20 mL). The mixture was extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]pentanoate (34D).

[1043] LC-MS, M / Z (ESI): 320.2 [M+H] +

[1044] Step 4: Synthesis of ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34E)

[1045]

[1046] Ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (34D) (460 mg, 1.44 mmol) and a THF solution of dimethylamine (1.50 mL, 3.3 mmol, 2 mol / L) were dissolved in 10 mL of dichloroethane. The mixture was reacted at 25 °C for 30 minutes, and then sodium cyanoborohydride (276 mg, 4.40 mmol) was added. The reaction was continued for 16 hours. After the reaction was completed, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / V) = 10:1) to obtain ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylvalerate (34E).

[1047] LC-MS, M / Z (ESI): 349.2 [M+H] +

[1048] Step 5: Synthesis of 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (34F)

[1049]

[1050] Ethyl 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34E) (400 mg, 1.15 mmol) and lithium hydroxide monohydrate (101 mg, 2.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 hours. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (34F).

[1051] LC-MS, M / Z (ESI): 321.2 [M+H] +

[1052] Step 6: Synthesis of ethyl propionate ((3S)-3-[5-(difluoromethyl)-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (34H).

[1053]

[1054] 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (34F) (350 mg, 1.10 mmol), (3S)-3-amino-3-[5-difluoromethyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]propionate ethyl ester (34G) (460 mg, 1.32 mmol), N-methylimidazole (180 mg, 2.20 mmol), and tetramethylchlorourea hexafluorophosphate (463 mg, 1.65 mmol) were dissolved in acetonitrile (6 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (3S)-3-[5-(difluoromethyl)-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (34H). No purification was required before proceeding to the next step.

[1055] LC-MS, M / Z (ESI): 685.3 [M+H] +

[1056] Step 7: Synthesis of target compounds 34-P1 and 34-P2

[1057]

[1058] Crude ethyl (3S)-3-[5-(difluoromethyl)-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl]-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (34H) and lithium hydroxide monohydrate (114 mg, 2.70 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 hours. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 58-70) to obtain the target compounds 34-P1 and 34-P2.

[1059] Target compound 34-P1:

[1060] Retention time: 8.05 min

[1061] LC-MS, M / Z (ESI): 658.3 [M+H] +

[1062] 1 H NMR(400MHz, CDCl3)δ7.88(d,1H),7.15(d,1H),7.10(d,1H),7.05-6.87(m,3H),6 .79(dd,1H),6.62(dd,1H),5.62(dd,1H),5.54(dd,1H),4.61(b,2H),3.09-3.04( m,2H),2.83-2.79(m,1H),2.76-2.72(m,1H),2.71-2.59(m,2H),2.32(s,6H),2.0 3-1.99(m,1H),1.95-1.91(s,4H),1.56(s,3H),1.49-1.45(m,1H),0.95(dd,6H).

[1063] Target compound 34-P2:

[1064] Retention time: 9.91 min

[1065] LC-MS, M / Z (ESI): 658.3 [M+H] +

[1066] 1 H NMR(400MHz, CDCl3)δ7.89(d,1H),7.21(d,2H),7.11-6.93(m,3H),6.85(t,2H),5.58-5.56(m,2H),4.61(b,2H),3.42(b,1 H),3.22-3.17(m,2H),2.65(s,6H),2.51(dd,2H),2.03-1.95(m,7H),1.90-1.85(m,1H),1.41-1.37(m,1H),0.90(dd,6H).

[1067] Example 17: Preparation of target compounds 39-P1 and 39-P2

[1068] (3S)-3-(5-Cyclopropyl-4,4'-Difluoro-2',6'-Dimethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1069] (3S)-3-(5-Cyclopropyl-4,4'-Difluoro-2',6'-Dimethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1070]

[1071] Compound 39-P1 is one of the structures of the two compounds mentioned above, while compound 39-P2 is the other structure.

[1072] The synthetic routes for target compounds 39-P1 and 39-P2 are as follows:

[1073]

[1074] Step 1: 4-Bromo-2-cyclopropyl-1-fluorobenzene (39B)

[1075]

[1076] Under argon protection, cyclopropylboronic acid (17.69 g, 0.20 mol), potassium carbonate (21.35 g, 0.15 mol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (7.53 g, 0.0103 mol) were added to a solution of 2-iodo-4-bromofluorobenzene (39A) (15.5 g, 0.051 mol) in 1,4-dioxane (155 mL). The reaction was carried out at 60 °C for 48 hours. The reaction was monitored by TLC. The product and the starting material were at the same point, and the fluorescence was significantly weakened. The reaction solution was cooled to room temperature, filtered with diatomaceous earth to remove insoluble matter, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:0) to give 4-bromo-2-cyclopropyl-1-fluorobenzene (39B).

[1077] Step 2: 5-Bromo-3-cyclopropyl-2-fluorobenzaldehyde (39C)

[1078]

[1079] Under argon protection, a tetrahydrofuran solution (2M) of lithium diisopropylamino in tetrahydrofuran (34.9 mL) was added to a tetrahydrofuran solution (75 mL) of 4-bromo-2-cyclopropyl-1-fluorobenzene (39B) (7.5 g, 0.0349 mol) at -78 °C for 1 hour. Then, N,N-dimethylformamide (5.1 g, 0.0698 mol) was added, and the reaction was continued at -78 °C for 1 hour. The reaction was monitored by TLC. After a small amount of starting material remained, a saturated ammonium chloride solution (100 mL) was added to quench the reaction at -78 °C. After warming to room temperature, ethyl acetate (100 mL) was added. After mixing thoroughly, the mixture was allowed to stand and separate into layers. The organic phase was collected, washed twice with water (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 90:10) to obtain 5-bromo-3-cyclopropyl-2-fluorobenzaldehyde (39C).

[1080] Step 3: (S2R)-N-[(E)-(5-bromo-3-cyclopropyl-2-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide (39D)

[1081]

[1082] Under argon protection, a tetrahydrofuran solution of tetraethyl titanate (10.58 g, 0.046 mol) in 75 mL was added dropwise to a tetrahydrofuran solution of 5-bromo-3-cyclopropyl-2-fluorobenzaldehyde (39C) (7.5 g, 0.031 mol) and (R)-(+)-tert-butylsulfinamide (4.49 g, 0.037 mol) at 0 °C, and the reaction was carried out at 25 °C for 4 hours. The reaction was monitored by LCMS. After no raw material remained, ethyl acetate (100 mL) and water (80 mL) were added to quench the reaction. The reaction solution became turbid. The solution was filtered through diatomaceous earth, and the filtrate was allowed to stand and separate into layers. The organic phase was collected, washed twice with water (60 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 85:15) to obtain (S2R)-N-[(E)-(5-bromo-3-cyclopropyl-2-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide (39D).

[1083] LC-MS, M / Z (ESI): 346.2 [M+H] +

[1084] Step 4: (3S)-3-(5-bromo-3-cyclopropyl-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}ethyl propionate (39E)

[1085]

[1086] Under argon protection at 0°C, trimethylchlorosilane (0.25 g, 0.0023 mol) was added dropwise to a tetrahydrofuran (40 mL) solution of zinc powder (3.79 g, 0.058 mol), and the reaction was carried out at 60°C for 1 hour. After cooling to room temperature, ethyl bromoacetate (4.84 g, 0.029 mol) was added dropwise to the reaction under argon protection at 0°C, and the reaction was carried out at 60°C for 1 hour. After cooling to room temperature, under argon protection at 0°C, a tetrahydrofuran (15 mL) solution of (S2R)-N-[(E)-(5-bromo-3-cyclopropyl-2-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide (39D) (4 g, 0.012 mol) was slowly added dropwise to the reaction, and the reaction was carried out at room temperature for 2 hours after natural warming. The reaction was monitored by LCMS. After no raw materials remained, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by high performance liquid chromatography to obtain ethyl (3S)-3-(5-bromo-3-cyclopropyl-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (39E).

[1087] LC-MS, M / Z (ESI): 434.2 [M+H] +

[1088] Step 5: (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}ethyl propionate (39F)

[1089]

[1090] Ethyl (3S)-3-(5-bromo-3-cyclopropyl-2-fluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (39E) (2.1 g, 4.8 mmol), (4-fluoro-2,6-dimethylphenyl)boronic acid (1.2 g, 7.2 mmol), potassium carbonate (2 g, 14.4 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium(II) chloride (353 mg, 0.48 mmol) in dioxane (20 mL) and water (2 mL) were stirred at 110 °C for 1 hour under a nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was cooled to room temperature. Water (50 mL) was added, and the solution was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 1:1) to give ethyl (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (39F).

[1091] LC-MS, M / Z (ESI): 478.2 [M+H] +

[1092] Step 6: Ethyl (3S)-3-amino-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (39G)

[1093]

[1094] Ethyl (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (39F) (1.5 g, 3.1 mmol) in dichloromethane (5 mL) was added to a solution of dioxane hydrogen chloride (4 M, 6 mL, 24 mmol) and stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by reversed-phase HPLC on a C18 column (mobile phase A: water / 0.01% HCl, mobile phase B: acetonitrile, gradient B%: 0–100%) to give ethyl (3S)-3-amino-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate (39G).

[1095] LC-MS, M / Z (ESI): 374.2 [M+H] +

[1096] Step 7: (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (39H)

[1097]

[1098] 2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (28E) (150 mg, 0.48 mmol), (3S)-3-amino-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate ethyl ester (39G) (200 mg, 0.53 mmol), N-methylimidazolium (118 mg, 1.44 mmol), and tetramethylchlorourea hexafluorophosphate (210 mg, 0.72 mmol) were dissolved in acetonitrile (10 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the mixture was concentrated to dryness, and water (15 mL) was added. The mixture was extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH (V / V) = 10 / 1) to give ethyl (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (39H).

[1099] LC-MS, M / Z (ESI): 676.2 [M+H] +

[1100] Step 8: Synthesis of target compounds 39-P1 and 39-P2

[1101]

[1102] Ethyl (3S)-3-(5-cyclopropyl-4,4'-difluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (39H) (200 mg, 0.3 mmol) and lithium hydroxide monohydrate (59 mg, 1.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-TriartPrep C187μm30mm×40cm; mobile phase: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile gradient: 35%-85%, flow rate: 42mL / min, 13min) to obtain the target compounds 39-P1 and 39-P2.

[1103] Target compound 39-P1:

[1104] Retention time: 9.17 min

[1105] LC-MS, M / Z (ESI): 648.3 [M+H] +

[1106] 1H NMR(400MHz,CD3OD)δ7.89(s,1H),7.15-6.47(m,6H),5.55-5.44(m,2H),3.69-3. 27(m,4H),2.75-2.68(m,8H),2.07-1.75(m,9H),1.49(s,1H),0.94-0.61(m,10H).

[1107] Target compound 39-P2:

[1108] Retention time: 11.48 min

[1109] LC-MS, M / Z (ESI): 648.3 [M+H] +

[1110] 1H NMR (400MHz, CD3OD) δ7.88(s,1H),7.18-6.54(m,6H),5.62-5.57(m,2H),3.71-3. 21(m,4H),2.81-2.42(m,8H),2.13-1.85(m,9H),1.42(s,1H),0.99-0.66(m,10H).

[1111] Example 18: Preparation of target compounds 40-P1 and 40-P2

[1112] (3S)-3-[(2R)-2-{8-[2-(dimethylamino)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoyl]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1113] (3S)-3-[(2S)-2-{8-[2-(dimethylamino)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentamido]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1114]

[1115] Compound 40-P1 is one of the structures of the two compounds mentioned above, while compound 40-P2 is the other structure.

[1116] The synthetic routes for compounds 40-P1 and 40-P2 are shown below:

[1117]

[1118] Step 1: Synthesis of 5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (40B)

[1119]

[1120] Triethylamine (33.3 g, 329.13 mmol) was added to a solution of 5-bromo-2,4-dichloropyrimidine (40A) (50 g, 219.42 mmol) in ethanol (500 mL) at 25 °C, followed by the slow dropwise addition of 2,2-dimethoxyethylamine (35.76 g, 340.1 mmol, 37 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (500 mL × 3), washed with saturated brine (500 mL × 2), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidine-4-amine (40B).

[1121] LC-MS, M / Z (ESI): 296.1 [M+H] +

[1122] Step 2: Synthesis of 8-bromoimidazolo[1,2-c]pyrimidin-5(6H)-one (40C)

[1123]

[1124] 5-Bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (40B) (63 g, 212.44 mmol) was dissolved in concentrated sulfuric acid (63 mL), and the reaction mixture was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction mixture was slowly poured into ice water (300 mL), and then slowly alkalized with 5 M sodium hydroxide aqueous solution to pH ~6. A large amount of solid precipitated out, and the solid was collected by filtration to give 8-bromoimidazolo[1,2-c]pyrimidin-5(6H)-one (40C).

[1125] LC-MS, M / Z (ESI): 214.1 [M+H] +

[1126] Step 3: Synthesis of ethyl 2-(8-bromo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (40D)

[1127]

[1128] Potassium carbonate (6.85 g, 49.53 mmol) was added to a solution of 8-bromoimidazolo[1,2-c]pyrimidin-5(6H)-one (40C) (5.3 g, 24.76 mmol) and ethyl 4-methyl-2-((methanesulfonyl)oxy)valerate (6.49 g, 27.24 mmol) in acetonitrile (60 mL), and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1-3:1) to obtain ethyl 2-(8-bromo-5-oxoimidazolo[1,2-c]pyrimidin-6(5H)-yl)-4-methylvalerate (40D).

[1129] LC-MS, M / Z (ESI): 356.2 [M+H] +

[1130] Step 4: Synthesis of ethyl 2-{8-[(E)-2-ethoxyvinyl-1-yl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (40E)

[1131]

[1132] Ethyl 2-(8-bromo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (40D) (2.5 g, 7.02 mmol) and pinacol 1-ethoxyvinyl-2-boronate (2.78 g, 14.04 mmol) were dissolved in toluene (30 mL) and water (3 mL), followed by the addition of cesium carbonate (6.86 g, 21.05 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (515 mg, 701.82 μmol). After purging with nitrogen, the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (40 mL), and extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (V / V) = 5:1-3:1) to give ethyl 2-{8-[(E)-2-ethoxyvinyl-1-yl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (40E).

[1133] LC-MS, M / Z (ESI): 348.4 [M+H] +

[1134] Step 5: Synthesis of ethyl 4-methyl-2-[5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl]valerate (40F)

[1135]

[1136] Under nitrogen protection, ethyl 2-{8-[(E)-2-ethoxyvinyl-1-yl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (40E) (2.0 g, 5.76 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (8 mL), and then concentrated hydrochloric acid (839 mg, 23.03 mmol) was slowly added under ice bath conditions. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to give ethyl 4-methyl-2-(5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl)pentanoate (40F).

[1137] LC-MS, M / Z (ESI): 320.3 [M+H] +

[1138] Step 6: Synthesis of ethyl 2-(8-(2-(dimethylamino)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (40G)

[1139]

[1140] Ethyl 4-methyl-2-(5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl)valerate (40F) (1.5 g, 4.70 mmol) was dissolved in methanol (15 mL) under nitrogen protection. Dimethylamine (2.0 M, 9.4 mL) and acetic acid (564 mg, 9.39 mmol) were added separately in an ice bath, and the reaction mixture was stirred at 25 °C for 16 hours. Sodium cyanoborohydride (592 mg, 9.39 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to give ethyl 2-(8-(2-(dimethylamino)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylvalerate (40 G).

[1141] LC-MS, M / Z (ESI): 349.4 [M+H] +

[1142] Step 7: Synthesis of 2-(8-(2-(dimethylamino)ethyl)-5-carbonylimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoic acid (40H)

[1143]

[1144] Lithium hydroxide (172 mg, 7.17 mmol) was added to a methanol (12 mL) and water (2.5 mL) solution of ethyl 2-(8-(2-(dimethylamino)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (40 G) (1.0 g, crude), and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to 4-5 with 1M dilute hydrochloric acid. The reaction solution was then purified directly by reversed-phase high-performance liquid chromatography (column: Welch Xtimate 10μm 21.2×250mm; mobile phase: A = water + 0.01% formic acid, B = acetonitrile; gradient 20%-45% B, 35 min) to obtain 2-(8-(2-(dimethylamino)ethyl)-5-carbonylimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoic acid (40H).

[1145] LC-MS, M / Z (ESI): 321.3 [M+H] +

[1146] Step 8: Synthesis of ethyl (3S)-3-(2-{8-[2-(dimethylamino)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (40K)

[1147]

[1148] To a solution of 2-(8-(2-(dimethylamino)ethyl)-5-carbonylimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoic acid (40H) (150 mg, 0.47 mmol) in acetonitrile (1.5 mL), ethyl (3S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (40J) (226 mg, crude hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (197 mg, 0.70 mmol) and N-methylimidazole (115 mg, 1.40 mmol). The mixture was stirred at room temperature for 18 hours. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-(2-{8-[2-(dimethylamino)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (40K).

[1149] LC-MS, M / Z (ESI): 668.3 [M+H] +

[1150] Compound 40K can be resolved into 40K-P1 and 40K-P2 by SFC. Specific SFC resolution method: Instrument: Waters 150Q; Column: DAICL CHIRALCEL OD (250mm × 30mm, 10µm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2ml; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[1151] The structures of compounds 40K-P1 and 40K-P2 are as follows:

[1152]

[1153] Compound 40K-P1 is one of the structures of the two compounds mentioned above, while compound 40K-P2 is the other structure.

[1154] Step 9: Synthesis of target compounds 40-P1 and 40-P2

[1155]

[1156] Lithium hydroxide monohydrate (63 mg, 1.5 mmol) was added to a solution of ethyl (3S)-3-(2-{8-[2-(dimethylamino)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (40K) (200 mg, 0.3 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 20-80) to obtain the target compounds 40-P1 and 40-P2.

[1157] Target compound 40-P1:

[1158] Retention time: 11.97 min

[1159] 1 H NMR (600MHz, DMSO-d6) δ9.16(s,1H),7.76(s,1H),7.39(s,1H),7.34(s,1H),6.97(t,J=10.8Hz,3H),5.40(s,1H),5.34(d,J=6.4Hz, 1H),2.86-2.61(m,7H),2.23(s,6H),2.17(s,3H),2.02-1.93(m,4H),1.86-1.76(m,4H),1.34(s,1H),0.86(dd,J=19.2,6.4Hz,6H).

[1160] LC-MS, M / Z (ESI): 640.2 [M+H] +

[1161] Target compound 40-P2:

[1162] Retention time: 14.45 min

[1163] 1H NMR(600MHz,DMSO-d6)δ8.97(d,J=6.0Hz,1H),7.81(s,1H),7.40(d,J=2.4Hz,2 H),7.01(dd,J=9.2,3.6Hz,3H),5.43(s,1H),5.38-5.32(m,1H),2.93-2.69(m, 6H),2.58(d,J=11.2Hz,1H),2.31(s,6H),2.21(s,3H),1.97(d,J=2.8Hz,6H),1 .89-1.81(m,1H),1.74-1.66(m,1H),1.31-1.20(m,1H),0.80(t,J=6.4Hz,6H).

[1164] LC-MS, M / Z (ESI): 640.2 [M+H] +

[1165] Example 19: Preparation of target compounds 41-P1 and 41-P2

[1166] (3S)-3-[(2R)-2-{5-[2-(dimethylamino)ethyl]-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl}-4-methylpentamido]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1167] (3S)-3-[(2S)-2-{5-[2-(dimethylamino)ethyl]-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl}-4-methylpentamido]-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionic acid

[1168]

[1169] Compound 41-P1 is one of the structures of the two compounds mentioned above, while compound 41-P2 is the other structure.

[1170] The synthetic routes for compounds 41-P1 and 41-P2 are shown below:

[1171]

[1172] Step 1: Synthesis of ethyl 2-(5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylpentanoate (41B)

[1173]

[1174] Potassium carbonate (14.22 g, 102.87 mmol) was added to a solution of 5-bromo-1H-pyrazin-2-one (41A) (9 g, 51.43 mmol) and ethyl 4-methyl-2-methanesulfonyloxyvalerate (13D) (13.48 g, 56.58 mmol) in acetonitrile (150 mL), and the mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, washed with acetonitrile (50 mL), and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1-5:1) to obtain ethyl 2-(5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylvalerate (41B).

[1175] LC-MS, M / Z (ESI): 317.2 [M+H] +

[1176] Step 2: Synthesis of 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41C)

[1177]

[1178] At 0 °C, a solution of ethyl 2-(5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylpentanoate (41B) (5.6 g, 17.66 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (4.14 g, 21.19 mmol) in tetrahydrofuran (10 mL) was added to a suspension of sodium hydride (1.77 g, 44.14 mmol, 60% purity) in anhydrous THF (60 mL). The mixture was stirred at 0 °C for 30 minutes, then slowly increased to 25 °C and stirred for 1.5 hours. After the reaction was complete, the resulting mixture was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41C).

[1179] LC-MS, M / Z (ESI): 328.3 [M+H] +

[1180] Step 3: Synthesis of methyl 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41D)

[1181]

[1182] Potassium carbonate (3.79 g, 27.43 mmol) was added to a solution of 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41C) (6 g, 18.28 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at room temperature for 1 hour, and then iodomethane (5.19 g, 36.57 mmol, 2.3 mL) was slowly added dropwise under ice bath conditions. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (V / V) = 10:1-5:1) to give methyl 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41D).

[1183] LC-MS, M / Z (ESI): 342.2 [M+H] +

[1184] Step 4: Synthesis of methyl (E)-2-(5-(2-ethoxyvinyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41E)

[1185]

[1186] Methyl 2-(5-bromo-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41D) (1.3 g, 3.80 mmol) and pinacol 1-ethoxyvinyl-2-boronate (1.50 g, 7.60 mmol) were dissolved in toluene (13 mL) and water (2 mL), followed by the addition of cesium carbonate (3.71 g, 11.40 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (278 mg, 379.91 μmol). After purging with nitrogen, the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was diluted with water (40 mL), extracted with ethyl acetate (50 mL × 2), the organic phase was washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (V / V) = 5:1-3:1) to obtain methyl (E)-2-(5-(2-ethoxyvinyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41E).

[1187] LC-MS, M / Z (ESI): 334.3 [M+H] +

[1188] Step 5: Synthesis of methyl 4-methyl-2-(8-oxo-5-(2-oxoethyl)imidazo[1,5-a]pyrazin-7(8H)-yl)valerate (41F)

[1189]

[1190] Under nitrogen protection, methyl (E)-2-(5-(2-ethoxyvinyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41E) (1.2 g, 3.60 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (10 mL), and then concentrated hydrochloric acid (525 mg, 14.40 mmol) was slowly added under ice bath conditions. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain methyl 4-methyl-2-(8-oxo-5-(2-oxoethyl)imidazo[1,5-a]pyrazin-7(8H)-yl)pentanoate (41F).

[1191] Step 6: Synthesis of methyl 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41G)

[1192]

[1193] Methyl 4-methyl-2-(8-oxo-5-(2-oxoethyl)imidazo[1,5-a]pyrazin-7(8H)-yl)valerate (41F) (1.0 g, 3.28 mmol) was dissolved in methanol (10 mL) under nitrogen protection. Dimethylamine (2.0 M, 6.5 mL) and acetic acid (393 mg, 6.55 mmol) were added separately in an ice bath, and the reaction mixture was stirred at 25 °C for 16 hours. Sodium cyanoborohydride (516 mg, 8.19 mmol) was then added, and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly purified by reversed-phase high-performance liquid chromatography (column: Welch Xtimate 10μm 21.2×250mm; mobile phase: A = water + 0.01% formic acid, B = acetonitrile; gradient B%: 15%-46%, 28 min) to obtain methyl 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41G).

[1194] LC-MS, M / Z (ESI): 335.4 [M+H] +

[1195] Step 7: Synthesis of 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41H)

[1196]

[1197] Lithium hydroxide (48 mg, 2.02 mmol) was added to a solution of methyl 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoate (41 G) (270 mg, 807.39 μmol) in methanol (1 mL), water (0.3 mL), and tetrahydrofuran (1 mL), and the mixture was stirred at 25 °C for 16 hours. After the reaction was complete, 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 3. The solution was then purified by reversed-phase high-performance liquid chromatography (column: Welch Xtimate 10μm 21.2×250mm; mobile phase: A = water + 0.01% formic acid, B = acetonitrile; gradient B%: 20%-45%, 35 minutes) to obtain 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41H).

[1198] LC-MS, M / Z (ESI): 321.3 [M+H] +

[1199] Step 8: Synthesis of (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (41J)

[1200]

[1201] To a solution of 2-(5-(2-(dimethylamino)ethyl)-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl)-4-methylpentanoic acid (41H) (150 mg, 0.47 mmol) in acetonitrile (1.5 mL), ethyl (3S)-3-amino-3-(2,4-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (40 J) (282 mg, crude hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (197 mg, 0.70 mmol) and N-methylimidazole (115 mg, 1.40 mmol). The mixture was stirred at room temperature for 18 hours. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (41J).

[1202] LC-MS, M / Z (ESI): 668.3 [M+H] +

[1203] Step 9: Synthesis of target compounds 41-P1 and 41-P2

[1204]

[1205] Lithium hydroxide monohydrate (63 mg, 1.5 mmol) was added to a solution of (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-8-oxoimidazo[1,5-a]pyrazin-7(8H)-yl}-4-methylpentamido)-3-(2,4,4'-trifluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)propionate (41 J) (200 mg, 0.3 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 20-80) to obtain the target compounds 41-P1 and 41-P2.

[1206] Target compound 41-P1:

[1207] Retention time: 6.24 min

[1208] 1H NMR(600MHz, DMSO-d6)δ9.01(d,J=6.0Hz,1H),8.36(s,1H),7.80(s,1H),7.02-6.91(m,3H),6.77(s,1H),5.47-5.39(m,2H),2.97-2.76(m ,4H),2.71-2.57(m,3H),2.31-2.10(m,9H),1.94(s,3H),1.90-1.80(m,4H),1.74-1.68(m,1H),1.32(s,1H),0.84(dd,J=23.2,6.4Hz,6H).

[1209] LC-MS, M / Z (ESI): 640.2 [M+H] +

[1210] Target compound 41-P2:

[1211] Retention time: 8.35 min

[1212] 1 H NMR(600MHz,DMSO-d6)δ8.89(d,J=6.4Hz,1H),8.38(s,1H),7.84(s,1H),7 .06-6.96(m,3H),6.85(s,1H),5.50-5.41(m,2H),2.99-2.92(m,2H),2.85- 2.59(m,5H),2.27(s,6H),2.21(s,3H),1.97(d,J=3.6Hz,6H),1.80-1.73( m,1H),1.60-1.53(m,1H),1.26-1.19(m,1H),0.78(dd,J=14.4,6.8Hz,6H).

[1213] LC-MS, M / Z (ESI): 640.2 [M+H] +

[1214] Example 20: Preparation of target compounds 42-P1 and 42-P2

[1215] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentamido]propionic acid

[1216] (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentamido]propionic acid

[1217]

[1218] Compound 42-P1 is one of the structures of the two compounds mentioned above, while compound 42-P2 is the other structure.

[1219] The synthetic routes for compounds 42-P1 and 42-P2 are shown below:

[1220]

[1221] Step 1: Synthesis of ethyl 2-{5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentanoate (42B)

[1222]

[1223] Ethyl 4-methyl-2-[2-oxo-5-(2-oxoethyl)-3-(trifluoromethoxy)pyridin-1(2H)-yl]valerate (42A) (460 mg, 1.27 mmol) and 3-fluorozacriane hydrochloride (423 mg, 3.81 mmol) were dissolved in dichloroethane (10 mL) and reacted at 25 °C for 30 min. Sodium cyanoborohydride (276 mg, 4.40 mmol) was then added, and the reaction continued for 16 h. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / V) = 10:1) to obtain ethyl 2-{5-[2-(3-fluorozacriane-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylvalerate (42B).

[1224] LC-MS, M / Z (ESI): 423.2 [M+H] +

[1225] Step 2: Synthesis of 2-{5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentanoic acid (42C)

[1226]

[1227] Ethyl 2-{5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentanoate (42B) (500 mg, 1.18 mmol) and lithium hydroxide monohydrate (101 mg, 2.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-{5-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentanoic acid (42C).

[1228] LC-MS, M / Z (ESI): 395.2 [M+H] +

[1229] Step 3: Synthesis of (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(3-fluoroazacyclobutane-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42D)

[1230]

[1231] 2-{5-[2-(dimethylamino)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentanoic acid (42C) (400 mg, 1.01 mmol), (3S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl(1,1'-biphenyl)-3-yl)propionate ethyl ester (1J) (460 mg, 1.32 mmol), N-methylimidazolium (180 mg, 2.20 mmol), and tetramethylchlorourea hexafluorophosphate (463 mg, 1.65 mmol) were dissolved in acetonitrile (6 mL) and reacted at 25 °C for 2 h. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42D).

[1232] LC-MS, M / Z (ESI): 724.3 [M+H] +

[1233] Step 4: Synthesis of target compounds 42-P1 and 42-P2

[1234]

[1235] Crude (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl[1,1'-biphenyl]-3-yl)-3-(2-{5-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-2-oxo-3-(trifluoromethoxy)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42D) and lithium hydroxide monohydrate (114 mg, 2.70 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 40-60) to obtain the target compounds 42-P1 and 42-P2.

[1236] Target compound 42-P1:

[1237] Retention time: 9.00 min

[1238] LC-MS, M / Z (ESI): 696.3 [M+H] +

[1239] 1 H NMR(400MHz, CDCl3)δ7.60(s,1H),7.56(s,1H),6.85(d,1H),6.80-6.78(m,3H) ,5.65(t,1H),5.49(t,1H),5.22-5.11(m,1H),4.02-3.85(m,2H),3.66-3.56(m, 2H),3.06-3.00(m,2H),2.75-2.69(m,2H),2.61(t,2H),2.27(s,3H),2.03(s,2H ),1.96-1.93(m,5H),1.86(s,3H),1.42-1.40(m,1H),0.94(d,3H),0.91(d,3H).

[1240] Target compound 42-P2:

[1241] Retention time: 10.15 min

[1242] LC-MS, M / Z (ESI): 696.3 [M+H] +

[1243] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.56(s,1H),6.90(d,2H),6.82(d,2H),5 .64-5.60(m,2H),5.32-5.22(m,1H),4.30-4.20(m,2H),3.95-3.85(m,2H), 3.28(s,2H),2.72-2.68(m,2H),2.61(dd,1H),2.53-2.50(m,1H),2.30(s,3 H),2.03-1.94(m,8H),1.77-1.74(m,1H),1.40-1.35(m,1H),0.88(dd,6H).

[1244] Example 21: Preparation of target compounds 43-P1 and 43-P2

[1245] (3S)-3-(5-Cyclopropyl-2,4,4'-Trifluoro-2',6'-Dimethyl[1,1'-Biphenyl]-3-yl)-3-[(2R)-2-{7-[2-(3-Fluorozycyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1246] (3S)-3-(5-Cyclopropyl-2,4,4'-Trifluoro-2',6'-Dimethyl[1,1'-Biphenyl]-3-yl)-3-[(2S)-2-{7-[2-(3-Fluorozycyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoyl]propionic acid

[1247]

[1248] Compound 43-P1 is one of the structures of the two compounds mentioned above, while compound 43-P2 is the remaining structure.

[1249] The synthetic routes for compounds 43-P1 and 43-P2 are shown below:

[1250]

[1251] Step 1: Synthesis of ethyl 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (43B)

[1252]

[1253] Ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (43A) (460 mg, 1.44 mmol) and 3-fluorozacriane hydrochloride (423 mg, 3.81 mmol) were dissolved in dichloroethane (10 mL) and reacted at 25 °C for 30 min. Sodium cyanoborohydride (276 mg, 4.40 mmol) was then added, and the reaction continued for 16 h. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography (DCM:MeOH (V / V) = 10:1) to give ethyl 2-{7-[2-(3-fluorozacriane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylvalerate (43B).

[1254] LC-MS, M / Z (ESI): 379.2 [M+H] +

[1255] Step 2: Synthesis of 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (43C)

[1256]

[1257] Ethyl 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (43B) (500 mg, 1.32 mmol) and lithium hydroxide monohydrate (101 mg, 2.4 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 hours. After the reaction was complete, water (10 mL) was added, and the pH of the solution was adjusted to about 4 with 1 N hydrochloric acid. The solution was then concentrated to obtain the crude product 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (43C).

[1258] LC-MS, M / Z (ESI): 351.2 [M+H] +

[1259] Step 3: Synthesis of (3S)-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluoroazacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (43E)

[1260]

[1261] 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (43C) (400 mg, 1.14 mmol), (3S)-3-amino-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)propionate ethyl ester (43D) (536 mg, 1.37 mmol), N-methylimidazole (180 mg, 2.20 mmol), and tetramethylchlorourea hexafluorophosphate (463 mg, 1.65 mmol) were dissolved in acetonitrile (6 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (3S)-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluorozacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (43E), which can be directly proceeded to the next step without purification.

[1262] LC-MS, M / Z (ESI): 724.3 [M+H] +

[1263] Step 4: Synthesis of target compounds 43-P1 and 43-P2

[1264]

[1265] Crude (3S)-3-(5-cyclopropyl-2,4,4'-trifluoro-2',6'-dimethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluoroazacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (43E) and lithium hydroxide monohydrate (114 mg, 2.70 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 5 hours. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-TriartPrep C187μm30mm×40cm, mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42ml / min; gradient B%: 40-60) to obtain the target compounds 43-P1 and 43-P2.

[1266] Target compound 43-P1:

[1267] Retention time: 9.00 min

[1268] LC-MS, M / Z (ESI): 696.5 [M+H] +

[1269] 1 H NMR(400MHz, CDCl3)δ7.87(d,1H),7.05(d,1H),6.92(s,1H),6.79(d,1H),6.71(d, 1H),6.47(t,1H),5.70-5.66(m,2H),5.12-5.00(m,1H),3.63-3.60(m,2H),3.26-3. 18(m,2H),2.94-2.90(m,2H),2.88-2.83(m,3H),2.65(dd,1H),2.03-1.88(m,7H), 1.66(s,3H),1.45-1.40(m,1H),0.94(t,6H),0.90-0.86(m,3H),0.56-0.55(m,2H).

[1270] Target compound 43-P2:

[1271] Retention time: 10.15 min

[1272] LC-MS, M / Z (ESI): 696.5 [M+H] +

[1273] 1 H NMR(400MHz, CDCl3)δ7.87(d,1H),7.07(d,1H),7.02(s,1H),6.83(d,2H),6.57(t,1H),5.70-5.65(m,2H),5.15-5.04(m,1H),3.69-3.63(m,2H) ,3.29-3.24(m,1H),2.99-2.92(m,4H),2.86-2.70(m,4H),2.08-1.98(m ,8H),1.83-1.80(m,2H),0.96(dd,2H),0.89(dd,7H),0.67-0.64(m,2H).

[1274] Example 22: Preparation of target compounds 44-P1 and 44-P2

[1275] (3S)-3-[(2R)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,-a]pyridin-5(4H)-yl}-4-methylpentanamide]-3-[2,4,4'-trifluoro-2',6'-methyl-5-(trifluoromethyl)[1,1'-diphenyl]-3-yl]propionic acid

[1276] (3S)-3-[(2S)-2-{7-[2-(dimethylamino)ethyl]-4-oxopyrazolo[1,-a]pyridin-5(4H)-yl}-4-methylpentanamide]-3-[2,4,4'-trifluoro-2',6'-methyl-5-(trifluoromethyl)[1,1'-diphenyl]-3-yl]propionic acid

[1277]

[1278] Compound 44-P1 is one of the structures of the two compounds mentioned above, while compound 44-P2 is the other structure.

[1279] The synthetic routes for compounds 44-P1 and 44-P2 are shown below:

[1280]

[1281] Step 1: Synthesis of 3-bromo-2,6-difluoro-5-(trifluoromethyl)benzaldehyde (44B)

[1282]

[1283] Under nitrogen protection and at -78°C, a solution of LDA in tetrahydrofuran (2.5 M, 4.8 mL) was added dropwise to an anhydrous tetrahydrofuran (50 mL) solution of 1-bromo-2,4-difluoro-5-(trifluoromethyl)benzene (44A) (2.6 g, 10 mmol) and reacted at -78°C for 1 hour. Then, anhydrous DMF (2 mL) was added to the reaction solution. After reacting at -78°C for 20 minutes, the reaction was quenched with a saturated ammonium chloride solution (20 mL). The mixture was extracted three times with ethyl acetate (50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether) to give 3-bromo-2,6-difluoro-5-(trifluoromethyl)benzaldehyde (44B).

[1284] Step 2: Synthesis of (S2R)-N-{[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylmethylene}-2-propane-2-sulfinamide (44C)

[1285]

[1286] Under nitrogen protection and at 0°C, ethyl titanate (Ti(OEt)4, 1.79 g, 7.85 mmol) was added to an anhydrous tetrahydrofuran (25 mL) solution of 3-bromo-2,6-difluoro-5-(trifluoromethyl)benzaldehyde (44B) (1.5 g, 5.23 mmol) and (R)-2-methylpropane-2-sulfinamide (760 mg, 6.27 mmol). The reaction was then carried out at 40°C for 2 hours. The reaction was monitored by LCMS, and the starting material was completely converted. The reaction solution was cooled to room temperature, and water (2 mL) and ethyl acetate (20 mL) were added. The mixture was stirred for 5 minutes, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain (S2R)-N-{[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylmethylene}-2-propane-2-sulfinamide (44C).

[1287] LC-MS, M / Z (ESI): 391.97 [M+H] +

[1288] Step 3: Synthesis of (3S)-3-(3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate ethyl ester (44D)

[1289]

[1290] Under nitrogen protection and at room temperature, trimethylchlorosilane (100 mg, 1.4 mmol) was added dropwise to a suspension of zinc powder (1.6 g, 24.36 mmol) in tetrahydrofuran (25 mL), and the mixture was reacted at 60 °C for 1 hour. The reaction solution was cooled to 20-30 °C, and ethyl bromoacetate (1.74 g, 10.4 mmol) was added. This step of the reaction was exothermic, and the dropping rate was controlled to keep the temperature of the reaction solution below 60 °C. After the addition was complete, the mixture was reacted at 60 °C for 1 hour, and then the reaction solution was cooled to 0 °C. (S2R)-N-{[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylmethylene}-2-propane-2-sulfinamide (44C) (1.9 g, 4.87 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add 25 mL of saturated ammonium chloride solution, extract three times with 30 mL of ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain ethyl (3S)-3-(3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (44D).

[1291] LC-MS, M / Z (ESI): 480.02 [M+H] +

[1292] Step 4: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44E)

[1293]

[1294] Under nitrogen protection, 1,4-dioxane (4 mL) and water (0.4 mL) were added to a mixture of ethyl (3S)-3-(3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (44D) (400 mg, 0.84 mmol), potassium phosphate (531 mg, 2.5 mmol), (4-fluoro-2,6-dimethylphenyl)boric acid (283 mg, 1.68 mmol), and Xphos Pd G2 (80 mg, 0.1 mmol), and the mixture was reacted at 110 °C for 3 hours. After cooling the reaction solution to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44E) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1).

[1295] LC-MS, M / Z(ESI): 524.16[M+H] +

[1296] Step 5: Synthesis of ethyl (3S)-3-amino-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44F)

[1297]

[1298] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 0.5 mL, 2.0 mmol) was added to an anhydrous dichloromethane (4 mL) solution of (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44E) (400 mg, 0.764 mmol). The reaction was then carried out at room temperature, and the reaction was monitored by LCMS. After the substrate was completely converted, the reaction solution was concentrated to obtain crude (3S)-3-amino-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44F), which was then directly used for the next reaction.

[1299] LC-MS, M / Z(ESI): 524.16[M+H] +

[1300] Step 6: Synthesis of ethyl (3S)-3-((S)-2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44G)

[1301]

[1302] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.57 mL, 3.125 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44F) (400 mg, 0.75 mmol), 2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylvaleric acid (28E) (200 mg, 0.625 mmol) and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (428 mg, 1.13 mmol). The reaction was then carried out at room temperature for 2 hours. The reaction was monitored by LCMS, and the substrate conversion was complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution (5 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain ethyl (3S)-3-((S)-2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44 G).

[1303] LC-MS, M / Z(ESI): 722.31[M+H] +

[1304] Step 7: Synthesis of target compounds 44-P1 and 44-P2

[1305]

[1306] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL) of ethyl (3S)-3-((S)-2-(7-(2-(dimethylamino)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4,4'-trifluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propionate (44 G) (350 mg, 0.485 mmol), and the reaction was carried out at room temperature for 3 hours. The substrate conversion was confirmed by LCMS. The pH of the reaction solution was adjusted to 3-4 using 2M hydrochloric acid aqueous solution, and then the reaction solution was concentrated. The crude product was purified by reversed-phase preparative chromatography (YMC-Triart Prep C18 S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80ml / min) to obtain the target compounds 44-P1 and 44-P2.

[1307] Target compound 44-P1:

[1308] Retention time: 11.13 min

[1309] LC-MS, M / Z(ESI): 694.27[M+H] +

[1310] 1 H NMR(400MHz,CD3OD)δ7.96-7.91(m,1H),7.43-7.37(m,1H),7.14-7.10(m,1H),7.07(s,1H) ,6.92-6.84(m,2H),5.61-5.56(m,1H),5.53-5.48(m,1H),3.80-3.71(m,1H),3.44-3.37(m ,1H),3.36-3.26(m,2H),2.79(s,6H),2.70-2.59(m,2H),2.07-1.99(m,1H),2.01(s,3H),1 .98-1.90(m,1H),1.93(s,3H),1.50-1.41(m,1H),1.37-1.25(m,1H),0.96-0.89(m,6H)ppm.

[1311] Target compound 44-P2:

[1312] Retention time: 13.37 min

[1313] LC-MS, M / Z(ESI): 694.27[M+H] +

[1314] 1 H NMR(400MHz,CD3OD)δ7.94-7.90(m,1H),7.47-7.42(m,1H),7.15-7.13(m,1H),7.06(s,1H),6.94 -6.89(m,2H),5.75-5.70(m,1H),5.61-5.56(m,1H),3.78-3.70(m,1H),3.50-3.43(m,1H),3.39-3 .33(m,1H),3.28-3.20(m,1H),2.84(s,6H),2.73-2.67(m,1H),2.56-2.51(m,1H),2.02(s,6H),1 .98-1.92(m,1H),1.88-1.81(m,1H),1.40-1.34(m,1H),1.33-1.24(m,1H),0.93-0.87(m,6H)ppm.

[1315] Example 23: Preparation of target compounds 45-P1 and 45-P2

[1316] (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-[(2R)-2-{7-[2-(3-fluoroazacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]propionic acid

[1317] (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-[(2S)-2-{7-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido]propionic acid

[1318]

[1319] Compound 45-P1 is one of the structures of the two compounds mentioned above, while compound 45-P2 is the other structure.

[1320] The synthetic routes for compounds 45-P1 and 45-P2 are shown below:

[1321]

[1322] Step 1: Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate ethyl ester (45B)

[1323]

[1324] To a solution of ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (45A) (500 mg, 1.17 mmol) and 2,4,6-trimethylphenylboronic acid (769 mg, 4.69 mmol) in dioxane (5 mL) and water (0.5 mL), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (172 mg, 0.23 mmol) and potassium carbonate (486 mg, 3.51 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 h. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), 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 (V / V) = 1:0-0:1) to obtain ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (45B).

[1325] LC-MS, M / Z (ESI): 466.3 [M+H] +

[1326] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)propionate (45C)

[1327]

[1328] To a solution of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (45B) (300 mg, 0.64 mmol) in dioxane (2 mL), hydrochloric acid solution (2 mL, 4 M dioxane solution) was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to obtain (3S)-3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)propionate (45C).

[1329] LC-MS, M / Z (ESI): 362.3 [M+H] +

[1330] Step 3: Synthesis of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluoroazacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (45D)

[1331]

[1332] To a solution of 2-{7-[2-(3-fluorozacricyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylvaleric acid (32C) (200 mg, 0.57 mmol) in acetonitrile (2 mL), ethyl (3S)-3-amino-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)propionate (45C) (206 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (240 mg, 0.86 mmol) and N-methylimidazole (140 mg, 1.71 mmol). The mixture was stirred at room temperature for 18 h. The reaction solution was then concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (45D).

[1333] LC-MS, M / Z (ESI): 694.3 [M+H] +

[1334] Compound 45D can be separated into 45D-P1 and 45D-P2 by SFC. Specific SFC separation method: Instrument: Waters 150Q; Column: DAICEL CHIRALCEL OD (250mm × 30mm, 10μm); Mobile phase: 25% isopropanol (0.2% triethylamine) supercritical carbon dioxide; Flow rate: 150g / min; Cycle time: 2.8min; Total time: 55min; Single injection volume: 2mL; Back pressure: 80bar to maintain carbon dioxide in a supercritical state.

[1335] The structures of compounds 45D-P1 and 45D-P2 are as follows:

[1336]

[1337] Compound 45D-P1 is one of the structures of the two compounds mentioned above, while compound 45D-P2 is the other structure.

[1338] Step 4: Synthesis of target compounds 45-P1 and 45-P2

[1339]

[1340] Lithium hydroxide monohydrate (54 mg, 1.30 mmol) was added to a solution of (3S)-3-(2,4-difluoro-2',4',5,6'-tetramethyl[1,1'-biphenyl]-3-yl)-3-(2-{7-[2-(3-fluoroazacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentamido)propionate (45D) (300 mg, 0.43 mmol) in tetrahydrofuran (3 mL) and water (1 mL), and then stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C187μm 30mm×40cm; mobile phase A: 10mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 80ml / min; gradient B%: 25-100) to obtain the target compounds 45-P1 and 45-P2.

[1341] Target compound 45-P1:

[1342] Retention time: 9.85 min

[1343] 1 H NMR (600MHz, DMSO-d6) δ9.25(d,J=5.6Hz,1H),7.90(d,J=2.0Hz,1H),7.00(d,J=2.0Hz,1H),6.89(d,J=12.0Hz,2H ),6.79(dd,J=22.0,14.0Hz,2H),5.46(dd,J=11.2,5.2Hz,1H),5.25(dd,J=13.6,6.4Hz,1H),5.10-4.97(m,1H),3 .50(dt,J=12.8,6.8Hz,2H),3.07-2.94(m,3H),2.85-2.60(m,5H),2.34(dd,J=14.4,8.0Hz,1H),2.24-2.16(m,4H ),2.09(s,3H),1.96-1.86(m,4H),1.77(ddd,J=14.4,9.6,5.2Hz,1H),1.70(s,3H),0.84(dd,J=18.8,6.8Hz,6H).

[1344] LC-MS, M / Z (ESI): 666.6 [M+H] +

[1345] Target compound 45-P2:

[1346] Retention time: 12.30 min

[1347] 1 H NMR(600MHz,DMSO-d6)δ9.05(d,J=7.2Hz,1H),7.94(d,J=1.6Hz,1H),7.11-7.04(m,2H),7.01-6.92 (m,3H),5.57(dd,J=11.2,5.2Hz,1H),5.50(dd,J=14.8,7.2Hz,1H),5.15-5.03(m,1H),3.58(td,J=1 5.2,8.8Hz,2H),3.17-3.04(m,3H),2.93-2.85(m,4H),2.81-2.72(m,2H),2.27(s,3H),2.22(s,3H), 1.93(s,6H),1.86-1.79(m,1H),1.57-1.51(m,1H),1.25-1.19(m,1H),0.78(dd,J=14.4,6.8Hz,6H).

[1348] LC-MS, M / Z (ESI): 666.6 [M+H] +

[1349] Example 24: Preparation of target compounds 46-P1 and 46-P2

[1350] (3S)-3-((R)-2-(7-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid

[1351] (3S)-3-((S)-2-(7-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionic acid

[1352]

[1353] Compound 46-P1 is one of the structures of the two compounds mentioned above, while compound 46-P2 is the other structure.

[1354] The synthetic routes for compounds 46-P1 and 46-P2 are shown below:

[1355]

[1356] Step 1: Synthesis of (3-fluoro-2,4,6-trimethylphenyl)boronic acid (46B)

[1357]

[1358] Under nitrogen protection and at -78°C, a tetrahydrofuran solution of n-butyllithium (2.0 M, 3 mL) was added dropwise to an anhydrous tetrahydrofuran solution of 2-bromo-4-fluoro-1,3,5-trimethylbenzene (46A) (1.08 g, 5.0 mmol) (25 mL). After reacting at -78°C for 1 hour, triisopropyl borate (1.88 g, 10 mmol) was added to the reaction solution, and the mixture was slowly brought to room temperature. The reaction was quenched with water, and the pH of the reaction solution was adjusted to 4-5 with 2 M hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to give (3-fluoro-2,4,6-trimethylphenyl)boronic acid (46B).

[1359] LC-MS, M / Z(ESI): 183.09[M+H] +

[1360] Step 2: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46D)

[1361]

[1362] Under nitrogen protection, 1,4-dioxane (10 mL) and water (1 mL) were added to a mixture of (3-fluoro-2,4,6-trimethylphenyl)boronic acid (46B) (700 mg, 3.85 mmol), ethyl (S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (46C) (820 mg, 1.92 mmol), potassium phosphate (1.22 g, 5.76 mmol), and Xphos Pd G2 (160 mg, 0.2 mmol), and the mixture was reacted at 110 °C for 3 hours. After cooling the reaction solution to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46D) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1).

[1363] LC-MS, M / Z(ESI): 484.21[M+H] +

[1364] Step 3: Synthesis of ethyl (3S)-3-amino-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46E)

[1365]

[1366] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 1.0 mL, 4.0 mmol) was added to an anhydrous dichloromethane (5 mL) solution of (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46D) (600 mg, 1.24 mmol). The reaction was then carried out at room temperature, and the reaction was monitored by LCMS. After the substrate was completely converted, the reaction solution was concentrated to obtain crude (3S)-3-amino-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46E), which was directly used for the next reaction.

[1367] LC-MS, M / Z(ESI): 380.18[M+H] +

[1368] Step 4: Synthesis of (3S)-3-(2-(7-(2-(3-fluorozacricyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46F)

[1369]

[1370] Under nitrogen protection and at 0°C, ethyl (46E) propionate (230 mg, 0.6 mmol) and 2-(7-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoic acid (32C) (200 mg, 0.57 mmol) in anhydrous acetonitrile (3 mL) were added to a solution of (3S)-3-amino-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (36E) (230 mg, 0.6 mmol) (200 mg, 0.57 mmol). Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 240 mg, 0.855 mmol) were added dropwise to the reaction solution. The reaction was then carried out at room temperature for 2 hours. The reaction was monitored by LCMS, and the substrate conversion was complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution (5 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain ethyl (3S)-3-(2-(7-(2-(3-fluorozacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46F).

[1371] LC-MS, M / Z(ESI): 712.34[M+H] +

[1372] Step 5: Synthesis of target compounds 46-P1 and 46-P2

[1373]

[1374] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL) of ethyl (3S)-3-(2-(7-(2-(3-fluorozacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propionate (46F) (230 mg, 0.32 mmol), and the reaction was carried out at room temperature for 3 hours. The substrate conversion was confirmed by LCMS. The pH of the reaction solution was adjusted to 3-4 using 2M hydrochloric acid aqueous solution, and then the reaction solution was concentrated. The crude product was purified by reversed-phase preparative chromatography (YMC-Triart Prep C18 S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80ml / min) to obtain the target compounds 46-P1 and 46-P2.

[1375] Target compound 46-P1:

[1376] Retention time: 9.71 min

[1377] LC-MS, M / Z(ESI): 684.31[M+H] +

[1378] 1 H NMR (400MHz, CD3OD) δ7.90-7.88(m,1H),7.09-7.07(m,1H),6.94-6.85(m,2H),6.84-6.79(m,1H),5.67 -5.58(m,2H),5.20-5.05(m,1H),3.94-3.78(m,1H),3.56-3.37(m,1H),3.26-3.17(m,2H),3.15-3.09(m ,1H),3.08-3.02(m,1H),3.01-2.94(m,1H),2.82-2.74(m,1H),2.69-2.62(m,1H),2.22(s,3H),2.18(s, 3H),1.99-1.88(m,2H),1.73-1.66(m,2H),1.46-1.37(m,1H),1.05-0.99(m,6H),0.97-0.90(m,6H)ppm.

[1379] Target compound 46-P2:

[1380] Retention time: 12.25 min

[1381] LC-MS, M / Z(ESI): 684.31[M+H] +

[1382] 1 H NMR (400MHz, CD3OD) δ7.90-7.87(m,1H),7.11-7.09(m,1H),6.98(s,1H),6.97-6.93(m,1H),6.90-6.86(m, 1H),5.76-5.71(m,1H),5.65-5.60(m,1H),5.26-5.10(m,1H),4.04-3.87(m,1H),3.67-3.50(m,1H),3.29- 3.11(m,2H),3.03-2.94(m,1H),2.81-2.74(m,1H),2.65-2.58(m,1H),2.26(s,3H),2.25(s,3H),1.97-1.9 3(m,2H),1.92-1.89(m,2H),1.88-1.81(m,1H),1.45-1.32(m,2H),1.05-1.0(m,6H),0.93-0.85(m,6H)ppm.

[1383] Example 25: Preparation of target compounds 47-P1 and 47-P2

[1384] (3S)-3-((R)-2-(7-(2-(3-fluorozacricyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid

[1385] (3S)-3-((S)-2-(7-(2-(3-fluorozazonyl-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionic acid

[1386]

[1387] Compound 47-P1 is one of the structures of the two compounds mentioned above, while compound 47-P2 is the other structure.

[1388] The synthetic routes for compounds 47-P1 and 47-P2 are shown below:

[1389]

[1390] Step 1: Synthesis of (3-fluoro-2,6-dimethylphenyl)boronic acid (47B)

[1391]

[1392] Under nitrogen protection and at -78°C, a tetrahydrofuran solution of n-butyllithium (2.0 M, 3.6 mL) was added dropwise to an anhydrous tetrahydrofuran solution of 2-bromo-4-fluoro-1,3-dimethylbenzene (47A) (1.2 g, 6.0 mmol) in 30 mL. After reacting at -78°C for 1 hour, triisopropyl borate (2.26 g, 12 mmol) was added to the reaction solution, and the mixture was slowly brought to room temperature. The reaction was quenched with water, and the pH of the reaction solution was adjusted to 4-5 with 2 M hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to give (3-fluoro-2,6-dimethylphenyl)boronic acid (47B).

[1393] LC-MS, M / Z(ESI): 169.08[M+H] +

[1394] Step 2: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47C)

[1395]

[1396] Under nitrogen protection, 1,4-dioxane (10 mL) and water (1 mL) were added to a mixture of (3-fluoro-2,6-dimethylphenyl)boronic acid (47B) (600 mg, 3.57 mmol), (S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (46C) (760 mg, 1.78 mmol), potassium phosphate (1.13 g, 5.34 mmol), and Xphos Pd G2 (160 mg, 0.2 mmol), and the mixture was reacted at 110 °C for 3 hours. After cooling the reaction solution to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47C) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 2:1).

[1397] LC-MS, M / Z(ESI): 470.19[M+H] +

[1398] Step 3: Synthesis of ethyl (3S)-3-amino-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47D)

[1399]

[1400] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 1.0 mL, 4.0 mmol) was added to an anhydrous dichloromethane (5 mL) solution of (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47C) (500 mg, 1.06 mmol). The reaction was then carried out at room temperature, and the reaction was monitored by LCMS. After the substrate was completely converted, the reaction solution was concentrated to obtain crude (3S)-3-amino-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47D), which was then directly used for the next reaction.

[1401] LC-MS, M / Z(ESI): 366.16[M+H] +

[1402] Step 4: Synthesis of (3S)-3-(2-(7-(2-(3-fluorozacricyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47E)

[1403]

[1404] Under nitrogen protection and at 0°C, ethyl (47D) propionate (220 mg, 0.6 mmol) and 2-(7-(2-(3-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (220 mg, 0.6 mmol) and 2-(7-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoic acid (32C) (200 mg, 0.57 mmol) in anhydrous acetonitrile (3 mL) were added to a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 240 mg, 0.855 mmol). The reaction was then carried out at room temperature for 2 hours. The reaction was monitored by LCMS, and the substrate conversion was complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution (5 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to obtain ethyl (3S)-3-(2-(7-(2-(3-fluorozacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47E).

[1405] LC-MS, M / Z(ESI): 698.33[M+H] +

[1406] Step 5: Synthesis of target compounds 47-P1 and 47-P2

[1407]

[1408] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of (3S)-3-(2-(7-(2-(3-fluorozacyclobutan-1-yl)ethyl)-4-oxopyrazo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,3',4-trifluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propionate (47E) (240 mg, 0.32 mmol) in tetrahydrofuran (3 mL) and water (1 mL), and the reaction was carried out at room temperature for 3 hours. The substrate conversion was confirmed by LCMS. The pH of the reaction solution was adjusted to 3-4 using 2M hydrochloric acid aqueous solution, and then the reaction solution was concentrated. The crude product was purified by reversed-phase preparative chromatography (YMC-TriartPrep C18 S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80ml / min) to obtain the target compounds 47-P1 and 47-P2.

[1409] Target compound 47-P1:

[1410] Retention time: 11.40 min

[1411] LC-MS, M / Z(ESI): 670.29[M+H] +

[1412] 1 H NMR (400MHz, CD3OD) δ7.93-7.90(m,1H),7.12-7.10(m,1H),7.09-7.03(m,1H),6.98-6.92(m,2H),6.91-6.86(m, 1H),5.61-5.55(m,2H),5.26-5.11(m,1H),4.17-4.07(m,1H),4.04-3.96(m,1H),3.80-3.71(m,1H),3.68-3.60(m ,1H),3.55-3.46(m,1H),3.22-3.15(m,2H),3.06-2.99(m,1H),2.78-2.66(m,2H),2.22(s,3H),2.03-1.92(m,1H) ,1.96(s,3H),1.91-1.87(m,2H),1.85-1.81(m,2H),1.79-1.77(m,1H),1.48-1.40(m,1H),0.97-0.80(m,6H)ppm.

[1413] Target compound 47-P2:

[1414] Retention time: 13.45 min

[1415] LC-MS, M / Z(ESI): 670.29[M+H] +

[1416] 1 H NMR (400MHz, CD3OD) δ7.91-7.88(m,1H),7.13-7.12(m,1H),7.11-7.08(m,1H),6.99-6.92(m,3H),5.80-5.75(m,1H),5 .62-5.57(m,1H),5.32-5.18(m,1H),4.33-4.24(m,1H),4.21-4.13(m,1H),3.94-3.86(m,1H),3.85-3.77(m,1H),3.60- 3.55(m,1H),3.39-3.31(m,1H),3.25-3.20(m,1H),3.03-2.97(m,1H),2.77-2.70(m,1H),2.57-2.51(m,1H),2.27(s,3H ),2.0-1.96(m,3H),1.95-1.88(m,4H),1.86-1.79(m,1H),1.69-1.62(m,1H),1.44-1.34(m,1H),0.93-0.87(m,6H)ppm.

[1417] Example 26: Preparation of target compounds 48-P1 and 48-P2

[1418] (3S)-3-(2,4-difluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((R)-2-(7-(2-(3-fluoroazacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyr...

Claims

1. A compound, said compound being a compound of formula (II), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of formula (II): in: R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; Ring E is selected from R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3; R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5. R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups; R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5; R 10 Selected from hydrogen or C 1-6 alkyl; R 11 Selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more groups selected from halogens, cyano groups, hydroxyl groups, and C6 groups. 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; And the compound is not 2. The compound according to claim 1, wherein its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, are characterized in that, The compound satisfies one or more of the following conditions: (1) R1 and R2 are each independently selected from halogens and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; (2) R1 and R2 are each independently selected from halogens and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogens; (3) R1 and R2 are each independently selected from halogen, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one or more substituents selected from halogen; (4) R1 and R2 are each independently selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more substituents selected from F and Cl; (5) R1 is selected from F, Cl, -CH3, -CHF2, -CF3, and cyclopropyl; (6) R2 is selected from F; (7) R4 is selected from H, halogens, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; (8) R4 is selected from H, halogens, and methyl groups; (9) R4 is selected from H and F; (10) R4 is selected from H; (11)R 11 Selected from H, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; (12)R 11 Selected from H, halogens, and methyl groups; (13)R 11 Selected from H and F; (14)R 11 Selected from H; (15) Selected from 3. The compound according to claim 1, wherein its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, are characterized in that, The compound is the compound shown in formula (I): in: R1, R2, and R3 are each independently selected from halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O-(3- to 6-membered heterocycloalkyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; p is an integer selected from 0, 1, 2, 3, 4, 5; R4 is selected from hydrogen or halogen; R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; Ring E is selected from R 6a R 7a Each is independently selected from H, -(CR) 8c R 8d ) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3; R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5. R9 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R 8c R 8d Each is independently selected from H, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from halogen, cyano, and hydroxyl groups; R 6b R 6c R 6d R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl), and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -O- (3- to 6-membered heterocycloalkyl) optionally separated by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; q is an integer selected from 0, 1, 2, 3, 4, and 5; R 10 Selected from hydrogen or C 1-6 alkyl.

4. The compound according to claim 3, wherein its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, are characterized in that, The compound satisfies one or more of the following conditions: (1) R1 and R2 are each independently selected from halogens and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; (2) R1 and R2 are each independently selected from halogens and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogens; (3) R1 and R2 are each independently selected from halogen, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one or more substituents selected from halogen; (4) R1 and R2 are each independently selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more substituents selected from F and Cl; (5) R1 is selected from F, Cl, -CH3, -CHF2, -CF3, and cyclopropyl; (6) R2 is selected from F; (7) R4 is selected from H and F; (8) R4 is selected from H; (9) Selected from 5. The compound according to claim 1, wherein its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, are characterized in that, The compound satisfies one or more of the following conditions: (1) R3 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; (2) R3 is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogens; (3) R3 is independently selected from halogen, cyano, methyl, methoxy, cyclopropyl, wherein the methyl, methoxy, cyclopropyl are optionally substituted by one or more substituents selected from halogen; (4) R3 is independently selected from F, methyl, and methoxy; <5 Selected from <6) Selected from 6. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1) R5 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; (2) R5 is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 cycloalkyl, -C 1-3 Alkyl-(3 to 6-membered heterocyclic alkyl), the C 1-4 Alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogens; (3) R5 is selected from C 1-4 Alkyl, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 3-6 cycloalkyl; (4) R5 is selected from 7. The compound according to claim 1, wherein its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, are characterized in that, The compound satisfies one or more of the following conditions: (1)R 8a R 8b Each is independently selected from hydrogen or C substituted with m R9 atoms. 1-6 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, 3, 4, and 5; R9 is independently selected from halogen, cyano, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally substituted by one or more substituents selected from halogen, cyano, or hydroxyl; the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, or S; (2)R 8a R 8b Each is independently selected from hydrogen or C. 1-3 Alkyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0, 1, 2, and 3; R9 is independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy group; the heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O or S; (3)R 8a R 8b Selected from methyl; or R 8a and R 8b Together with the N atom it is attached to, it forms a 4- to 5-membered heterocyclic alkyl group substituted with m R9 atoms; m is an integer selected from 0 and 1; R9 is independently selected from F, methyl, and methoxy; the heterocyclic alkyl group contains 1 N atom; (4)R 8c R 8d Each is independently selected from H, halogen, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more substituents selected from halogens; (5)R 6a R 7a Each is independently selected from -(CH2) n -N(R 8a )R 8b -CF2-CH2-N(R) 8a )R 8b n is an integer selected from 0, 1, 2, and 3; (6)R 6a R 7a Each is independently selected from -(CH2) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3; (7)R 6a R 7a Each independently selected (8)R 8c R 8d Each is independently selected from H and F; (9)R 7a Independently selected from H, -(CR 8c R 8d ) n -N(R 8a )R 8b n is an integer selected from 0, 1, 2, and 3; (10)R 7a Independently selected from H, (11)R 7a Selected independently from H.

8. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1)R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-6 Alkoxy, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkyl groups; (2)R 6b R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic alkyl, and R 6b R 6c R 6d At least one of them is selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocycloalkyl groups, are optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; (3)R 6b Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6c R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; (4)R 6c Selected from C 1-3 Alkoxy, C 3-6 cycloalkyl, R 6b R 6d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is optionally surrounded by one or more elements selected from halogens, C 1-3 Substituents of haloalkyl groups; (5)R 6b Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6c R 6d Selected from hydrogen; (6)R 6c Selected from cyclopropyl, methoxy, -OCF3, -OCHF2, R 6b R 6d Selected from hydrogen.

9. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1)R 7b Each is independently selected from hydrogen, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3 to 6-membered heterocyclic alkyl groups, are optionally surrounded by one or more elements selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; (2)R 7b Each is independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or 3- to 6-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from halogens; (3)R 7b Each group is independently selected from hydrogen, F, cyano, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more F groups; (4)R 7b Selected from hydrogen.

10. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that: Ring E is selected from 11. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound mentioned is the compound shown in formula (II-A): R1, R2, R3, R4, R5, R 10 R 11 The definitions of ring E and p are as described in claim 1.

12. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound mentioned is the compound shown in formula (II-B): Where p' is an integer selected from 3 or 4; Ring E' is selected from R' 6a 、R' 7a Each is independently selected from H and -(CH2). n -N(R' 8a )R' 8b The -(CH2) mentioned above n -N(R' 8a )R' 8b Optionally selected by one or more halogens, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; n is an integer selected from 0, 1, 2, 3; R' 8a 、R' 8b Each is independently selected from hydrogen or C. 1-3 Alkyl; or R' 8a and R' 8b Together with the N atom it is attached to, it forms a 3- to 6-membered heterocyclic alkyl group, wherein the 3- to 6-membered heterocyclic alkyl group is optionally bonded by one or more atoms selected from halogens, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R' 6b Selected from H, C 3-6 cycloalkyl, C 1-6 Alkoxy, the C 3-6 cycloalkyl, C 1-6 Alkyl groups are optionally surrounded by one or more elements selected from halogens, C 1-6 Substituents of haloalkyl groups; R' 6c Selected from H, C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens; R' 6b and R' 6c At least one of them is selected from C 1-6 Alkoxy or C 3-6 cycloalkyl; R1, R3, R4, R 10 R 11 The definition is as described in claim 1.

13. The compound according to claim 12, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1)R' 8a 、R' 8b Each is independently selected from methyl; or R' 8a and R' 8b Together with the N atom to which it is attached, it forms a 4- to 5-membered heterocyclic alkyl group, wherein the 4- to 5-membered heterocyclic alkyl group is optionally substituted by one or more substituents selected from F, methyl, and methoxy; (2)R' 6a 、R' 7a Each is independently selected from -(CH2)2-N(R' 8a )R' 8b -CF2-CH2-N(R' 8a )R' 8b ; (3)R' 6a 、R' 7a Each is independently selected from H, (4)R' 6b Selected from cyclopropyl, -OCHF2, R' 6c Selected from hydrogen; (5)R' 6c Selected from -OCF3, -OCHF2, R' 6b Selected from hydrogen; (6) Ring E' is selected from 14. The compound according to claim 12, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound is the compound shown in formula (II-C): R1, R3, R4, R 10 R 11 The definitions of ring E' and p' are as described in claim 12.

15. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound is the compound shown in formula (II-D): Wherein, X is selected from F, methyl, and methoxy; R'4 is selected from H or F; R” 6a 、R” 7a Each is independently selected from -(CH2) n -N(R” 8a )R” 8b n is an integer selected from 1, 2, and 3; R” 8a 、R” 8b Each was independently selected from C 1-3 Alkyl; or R” 8a and R” 8b Together with the N atom to which it is attached, it forms a 4-membered heterocyclic alkyl group, which is optionally substituted by one or more substituents selected from halogens; R” 6c Selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens.

16. The compound according to claim 15, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1)R” 6a 、R” 7a Each independently selected (2)R” 6c Selected from -OCF3 and -OCHF2; (3) Ring E1 is selected from 17. The compound according to claim 15, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound mentioned is the compound shown in formula (II-E): The definitions of X, R'4, and ring E1 are as described in claim 15.

18. The compound according to claim 1, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound mentioned is the compound shown in formula (III): Wherein, X is selected from F, methyl, and methoxy; R'4 is selected from H or F; Ring E1 is selected from R” 6a 、R” 7a Each is independently selected from -(CH2) n -N(R” 8a )R” 8b n is an integer selected from 1, 2, and 3; R” 8a 、R” 8b Each was independently selected from C 1-3 Alkyl; or R” 8a and R” 8b Together with the N atom to which it is attached, it forms a 4-membered heterocyclic alkyl group, which is optionally substituted by one or more substituents selected from halogens; R” 6c Selected from C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens.

19. The compound according to claim 18, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound satisfies one or more of the following conditions: (1)R” 6a 、R” 7a Each independently selected (2)R” 6c Selected from -OCF3 and -OCHF2; (3) Ring E1 is selected from 20. The compound according to claim 18, wherein the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug is characterized in that, The compound mentioned is the compound shown in formula (III-A): The definitions of X, R'4, and ring E1 are as described in claim 18.

21. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

22. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

23. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: the compound as described in any one of claims 1 to 22, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs; and optionally a pharmaceutically acceptable carrier.

24. Use of the compound of any one of claims 1 to 22, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition of claim 23 in the preparation of a medicament for the treatment or prevention of diseases related to integrin α4β7.

25. The use according to claim 24, characterized in that, The integrin α4β7-related diseases mentioned above are selected from: (1) Autoimmune diseases; (2) Inflammatory bowel disease; (3) Ulcerative colitis and Crohn's disease.

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