Thiophene compound as integrin α4β7 antagonist and use thereof

Abstract

Provided are a compound that effectively antagonizes integrin α4β7, which is a compound represented by formula (Y), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of the compound represented by formula (Y).

Description

Thiophene compounds as integrin α4β7 antagonists and their uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to thiophene compounds as integrin α4β7 antagonists, and more specifically, this invention relates to thiophene compounds as integrin α4β7 antagonists and their use in the preparation of pharmaceuticals. 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 (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 then MAdCAM-1 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] The role of integrins as drug targets has long been recognized, and they can be used to treat a variety of 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 at least partially solve one of the above-mentioned technical problems or at least provide a useful commercial option.

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

[0007] in:

[0008] L is selected from and -SF5;

[0009] Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S; the ring E is selected from

[0010] R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0011] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0012] R8 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0013] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0014] R5 is selected from substituted or unsubstituted C.1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0015] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0016] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(CR c 2) 0-3 NR a R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0017] R 7a Selected from H, -(CR) c 2) 0-3 NR d R e ;

[0018] R 7b Selected from H, -OH, -CN, halogens, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted -OC 3-6 Cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclic alkyl, substituted or unsubstituted -O- (3-6-membered heterocyclic alkyl), wherein the heteroatom of the heterocyclic alkyl is selected from 1, 2 or 3 of N, O and S, and the substituent is selected from -OH, -CN, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups;

[0019] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0020] R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0021] m is selected from 0, 1, 2, 3, and 4;

[0022] n is selected from 0, 1, 2, and 3;

[0023] q is selected from 0, 1, 2, 3, 4, and 5;

[0024] When L is selected At that time, at least one of R1 and R2 is not H.

[0025] The alkyl group includes straight-chain alkyl and branched-chain alkyl;

[0026] The halogen is selected from fluorine, chlorine, bromine, and iodine; preferably, the halogen is selected from fluorine, chlorine, and bromine.

[0027] This invention provides a compound, which is a compound of formula (Y), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (Y):

[0028] in:

[0029] L is selected from and -SF5;

[0030] Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S;

[0031] Ring E is selected from

[0032] R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0033] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0034] R8 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0035] R4 is selected from H, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0036] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0037] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0038] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0039] R 7a Selected from H, -(C(R) c )2) 0-3 N(R d )R e ;

[0040] R 7b Selected from H, -OH, -CN, halogens, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted -OC 3-6 Cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclic alkyl, substituted or unsubstituted -O- (3-6-membered heterocyclic alkyl), wherein the heteroatom of the heterocyclic alkyl is selected from 1, 2 or 3 of N, O and S, and the substituent is selected from -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups;

[0041] Each Rc Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0042] R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, or R d Re and its attached N atom cyclize together to form a substituted or unsubstituted 3-10 membered heterocyclic group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0043] m is selected from 0, 1, 2, 3, and 4;

[0044] n is selected from 0, 1, 2, and 3;

[0045] q is selected from 0, 1, 2, 3, 4, and 5;

[0046] When L is selected At that time, at least one of R1 and R2 is not H.

[0047] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0048] According to certain embodiments of the present invention, the R8 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0049] According to certain embodiments of the present invention, R8 is selected from H, -OH, -CN, -NH2, halogens, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0050] According to certain embodiments of the present invention, R8 is selected from H, halogens, and methyl groups; undefined groups are as described in any embodiment of the present invention.

[0051] According to certain embodiments of the present invention, R8 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0052] According to certain embodiments of the present invention, R8 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0053] According to certain embodiments of the present invention, R8 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0054] This invention provides a compound, said compound being a compound of formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (II):

[0055] in:

[0056] L is selected from and -SF5;

[0057] Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S;

[0058] R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0059] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0060] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0061] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0062] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0063] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(CR c 2) 0-3 NR a R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0064] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C1-6 alkyl;

[0065] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0066] m is selected from 0, 1, 2, 3, and 4;

[0067] n is selected from 0, 1, 2, and 3;

[0068] When L is selected At that time, at least one of R1 and R2 is not H.

[0069] According to certain embodiments of the present invention, the compound is a compound of formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (II):

[0070] in:

[0071] L is selected from and -SF5;

[0072] Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S;

[0073] R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0074] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0075] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0076] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0077] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0078] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0079] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0080] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0081] m is selected from 0, 1, 2, 3, and 4;

[0082] n is selected from 0, 1, 2, and 3;

[0083] When L is selected At that time, at least one of R1 and R2 is not H.

[0084] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0085] According to certain embodiments of the present invention, the ring G is selected from... 5-membered heteroaryl, 5-8-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; undefined groups are as described in any embodiment of the present invention.

[0086] According to certain embodiments of the present invention, the ring G is selected from... A 5-membered heteroaryl group, or a 5-7-membered heterocyclic alkyl group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the heterocyclic alkyl group is a bridged ring; undefined groups are as described in any embodiment of the present invention.

[0087] According to certain embodiments of the present invention, the ring G is selected from... Thiophene group Undefined groups are as described in any embodiment of this invention.

[0088] According to certain embodiments of the present invention, the ring G is selected from... Thiophene group Undefined groups are as described in any embodiment of this invention.

[0089] This invention provides a compound, which is a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):

[0090] in:

[0091] Cyclone G is selected from thienyl groups;

[0092] R1 and R2 are each independently selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0093] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0094] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0095] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0096] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0097] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(CR c 2) 0-3 NR a R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0098] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0099] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C.1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0100] m is selected from 0, 1, 2, 3, and 4;

[0101] n is selected from 0, 1, 2, and 3.

[0102] According to certain embodiments of the present invention, the compound is a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):

[0103] in:

[0104] Cyclone G is selected from thienyl groups;

[0105] R1 and R2 are each independently selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0106] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0107] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6Alkoxy;

[0108] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0109] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0110] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy;

[0111] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0112] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R bTogether with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0113] m is selected from 0, 1, 2, 3, and 4;

[0114] n is selected from 0, 1, 2, and 3.

[0115] According to certain embodiments of the present invention, the ring G is selected from... Undefined groups are as described in any embodiment of this invention.

[0116] According to certain embodiments of the present invention, the ring G is selected from... Undefined groups are as described in any embodiment of this invention.

[0117] According to certain embodiments of the present invention, the ring G is selected from... Undefined groups are as described in any embodiment of this invention.

[0118] According to certain embodiments of the present invention, the ring G is selected from... Undefined groups are as described in any embodiment of this invention.

[0119] According to certain embodiments of the present invention, the ring G is selected from... Undefined groups are as described in any embodiment of this invention.

[0120] According to certain embodiments of the present invention, the Selected from n is selected from 1 and 2; undefined groups are as described in any of the embodiments of the present invention.

[0121] According to certain embodiments of the present invention, the Selected from n is selected from 1; undefined groups are as described in any embodiment of this invention.

[0122] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0123] According to certain embodiments of the present invention, the Selected from n is selected from 1, 2, and 3; undefined groups are as described in any of the embodiments of the present invention.

[0124] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0125] According to certain embodiments of the present invention, the Selected from n is selected from 1, 2, and 3; undefined groups are as described in any of the embodiments of the present invention.

[0126] According to certain embodiments of the present invention, the Selected from n is selected from 2 and 3; undefined groups are as described in any of the embodiments of the present invention.

[0127] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0128] According to certain embodiments of the present invention, the Selected from n is selected from 1 and 2; undefined groups are as described in any of the embodiments of the present invention.

[0129] According to certain embodiments of the present invention, the Selected from n is selected from 2; undefined groups are as described in any embodiment of this invention.

[0130] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0131] According to certain embodiments of the present invention, the Selected from n is selected from 1 and 2; undefined groups are as described in any of the embodiments of the present invention.

[0132] According to certain embodiments of the present invention, the Selected from n is selected from 1; undefined groups are as described in any embodiment of this invention.

[0133] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0134] According to certain embodiments of the present invention, the R4 is selected from -CN, -NH2, halogens, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0135] According to certain embodiments of the present invention, R4 is selected from -CN, -NH2, halogens, and C. 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen-substituted 3-7 membered heterocyclic alkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heteroatom of the heterocyclic alkyl is selected from 1, 2 or 3 of N, O and S; undefined groups are as described in any embodiment of the present invention.

[0136] According to certain embodiments of the present invention, R4 is selected from halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0137] According to certain embodiments of the present invention, R4 is selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0138] According to certain embodiments of the present invention, R4 is selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F; undefined groups are as described in any embodiment of the present invention.

[0139] According to certain embodiments of the present invention, R4 is selected from F, Cl, -CH3, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0140] According to certain embodiments of the present invention, R4 is selected from F, Cl, -CH3; undefined groups are as described in any embodiment of the present invention.

[0141] According to certain embodiments of the present invention, R4 is selected from -CH3; undefined groups are as described in any embodiment of the present invention.

[0142] According to certain embodiments of the present invention, L is selected from...

[0143] Undefined groups are as described in any embodiment of this invention.

[0144] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0145] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0146] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0147] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

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

[0149] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0150] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0151] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0152] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0153] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0154] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0155] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0156] According to certain embodiments of the present invention, the L is selected from -SF5; undefined groups are as described in any embodiment of the present invention.

[0157] This invention provides a compound, said compound being a compound of formula (III), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (III):

[0158] The rings E, R1, R2, R4, R5, R6, and R8 are defined as described in any embodiment of this invention.

[0159] According to certain embodiments of the present invention, R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0160] According to certain embodiments of the present invention, R1 and R2 are each independently selected from H, halogens, and C. 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen-substituted 3-7 membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; undefined groups are as described in any embodiment of the present invention.

[0161] According to certain embodiments of the present invention, R1 and R2 are each independently selected from H, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0162] According to certain embodiments of the present invention, R1 and R2 are each independently selected from H, F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0163] According to certain embodiments of the present invention, R1 is selected from H, F, Cl, -CH3, -CHF2, -CF3, cyclopropyl, and R2 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0164] According to certain embodiments of the present invention, R1 is selected from -CH3, and R2 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0165] According to certain embodiments of the present invention, the R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0166] According to certain embodiments of the present invention, R3 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0167] According to certain embodiments of the present invention, R3 is selected from H, -OH, -CN, -NH2, halogens, C1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0168] According to certain embodiments of the present invention, R3 is selected from -OH, -CN, -NH2, halogens, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0169] According to certain embodiments of the present invention, R3 is selected from H, halogens, and methyl groups; undefined groups are as described in any embodiment of the present invention.

[0170] According to certain embodiments of the present invention, R3 is selected from halogens and methyl groups; undefined groups are as described in any embodiment of the present invention.

[0171] According to certain embodiments of the present invention, R3 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0172] According to certain embodiments of the present invention, R3 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0173] According to certain embodiments of the present invention, R3 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0174] According to certain embodiments of the present invention, R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0175] According to certain embodiments of the present invention, R5 is selected from C. 1-6 Alkyl groups, halogenated C 1-6 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heteroatom of the heterocyclic alkyl is selected from 1, 2 or 3 of N, O and S; undefined groups are as described in any embodiment of the present invention.

[0176] 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.

[0177] According to certain embodiments of the present invention, R5 is selected from... Undefined groups are as described in any embodiment of this invention.

[0178] According to certain embodiments of the present invention, R6 is selected from H and C. 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0179] According to certain embodiments of the present invention, R6 is selected from H and methyl; undefined groups are as described in any embodiment of the present invention.

[0180] According to certain embodiments of the present invention, R6 is selected from H and ethyl; undefined groups are as described in any embodiment of the present invention.

[0181] According to certain embodiments of the present invention, R6 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0182] According to certain embodiments of the present invention, R6 is selected from ethyl groups; undefined groups are as described in any embodiment of the present invention.

[0183] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0184] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0185] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0186] According to certain embodiments of the present invention, R7 is selected from -OH, -CN, -NH2, halogens, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic alkyl, -(CH2) 0-3 NR a R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy;

[0187] R a and R b Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together they cyclize to form a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[0188] Undefined groups are as described in any embodiment of this invention.

[0189] According to certain embodiments of the present invention, R7 is selected from -OH, -CN, -NH2, halogens, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic alkyl, -(CH2) 0-3 N(R a )R bThe heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy;

[0190] R a and R b Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together with the N atom it is attached to, they cyclize to form a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[0191] Undefined groups are as described in any embodiment of this invention.

[0192] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, -(CH2) 0-3 NR a R b ;

[0193] R a and R b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Cyclization forms a substituted or unsubstituted 4-6 membered heterocyclic alkyl group, wherein the heteroatom is selected from one or two of N, O, and S, and the substituent is selected from -OH, -CN, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[0194] Undefined groups are as described in any embodiment of this invention.

[0195] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, -(CH2) 0-3 N(R a )R b ;

[0196] R a and R b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[0197] Undefined groups are as described in any embodiment of this invention.

[0198] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, and -(CH2). 2-3 NR a R b ;

[0199] R a and R b Each is independently selected from H, methyl, or R. a and R b Cyclization is performed to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy.

[0200] Undefined groups are as described in any embodiment of this invention.

[0201] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, and -(CH2). 2-3 N(R a )R b ;

[0202] R a and R b Each is independently selected from H, methyl, or R. a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy.

[0203] Undefined groups are as described in any embodiment of this invention.

[0204] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, -(CH2)2N(R a )R b ;

[0205] R a and R b Each is independently selected from H, methyl, or R. a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy.

[0206] Undefined groups are as described in any embodiment of this invention.

[0207] According to certain embodiments of the present invention, R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, -(CH2)2NR a R b ;

[0208] R a and R b Each is independently selected from H, methyl, or R. a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy.

[0209] Undefined groups are as described in any embodiment of this invention.

[0210] According to certain embodiments of the present invention, R7 is selected from F, -CH3, -CF3, -CHF2, -OCHF2, -OCF3, cyclopropyl, Undefined groups are as described in any embodiment of the invention. According to certain embodiments of the invention, R7 is selected from F, -CH3, -CF3, -CHF2, -OCHF2, -OCF3, cyclopropyl, ... Undefined groups are as described in any embodiment of the invention. According to certain embodiments of the invention, R7 is selected from F, -CH3, -CF3, -CHF2, -OCHF2, -OCF3, cyclopropyl, ... Undefined groups are as described in any embodiment of this invention.

[0211] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0212] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0213] According to certain embodiments of the present invention, the Selected from Undefined groups are as described in any embodiment of this invention.

[0214] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0215] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0216] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0217] According to certain embodiments of the present invention, the R 7a Selected from -(CH2) 0-3 N(R d )R e ;R d and R e Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C1-3 alkoxy, or R d and R e Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0218] According to certain embodiments of the present invention, the R 7a Selected from -(CH2) 0-3 NR d R e ;R d and R e Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R d and R e Cyclization forms a substituted or unsubstituted 4-6 membered heterocyclic alkyl group, wherein the heteroatom is selected from one or two of N, O, and S, and the substituent is selected from -OH, -CN, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0219] According to certain embodiments of the present invention, the R 7a Selected from -(CH2) 2-3 N(R d )R e ;R d and R e Each is independently selected from H, methyl, or R. d and R e Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 member nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, methylmethoxy; undefined groups are as described in any embodiment of the present invention.

[0220] According to certain embodiments of the present invention, the R 7a Selected from -(CH2) 2-3 NR d R e ;R d and R e Each is independently selected from H, methyl, or R. d and R eCyclization is performed to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy; undefined groups are as described in any embodiment of the present invention.

[0221] According to certain embodiments of the present invention, the R 7a Selected from Undefined groups are as described in any embodiment of this invention.

[0222] According to certain embodiments of the present invention, the R 7b Selected from H, -OH, -CN, halogens, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic alkyl groups, wherein the heteroatoms of the heterocyclic alkyl group are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, -CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0223] According to certain embodiments of the present invention, the R 7b Selected from H, -CN, halogens, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic alkyl groups, wherein the heteroatoms of the heterocyclic alkyl group are selected from 1 or 2 of N, O and S, and the substituents are selected from halogens; undefined groups are as described in any embodiment of the invention.

[0224] According to certain embodiments of the present invention, the R 7b Selected from H, -CN, F, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl; undefined groups are as described in any of the embodiments of this invention.

[0225] According to certain embodiments of the present invention, the R 7b Selected from H; undefined groups are as described in any embodiment of this invention.

[0226] According to certain embodiments of the present invention, q is selected from 0, 1, 2 and 3; undefined groups are as described in any embodiment of the present invention.

[0227] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0228] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0229] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0230] According to certain embodiments of the present invention, the ring E is selected from... Undefined groups are as described in any embodiment of this invention.

[0231] According to certain embodiments of the present invention, the compound has the structure shown in formula (Y-1):

[0232] The rings E, L, R1, R2, R3, R5, and R8 are defined as described in any embodiment of this invention.

[0233] According to certain embodiments of the present invention, the compound has the structure shown in formula (II-1):

[0234] The definitions of L, R1, R2, R3, R5, R7, and m are as described in any of the embodiments of this invention.

[0235] According to certain embodiments of the present invention, the compound has the structure shown in formula (III-1):

[0236] The definitions of rings E, R1, R2, R4, R5, and R8 are as described in any embodiment of this invention.

[0237] According to certain embodiments of the present invention, the compound has the structure shown in formula (YA):

[0238] The rings E, L, R1, R2, R3, R5, R6, and R8 are defined as described in any embodiment of this invention.

[0239] According to certain embodiments of the present invention, the compound has the structure shown in formula (II-A):

[0240] The definitions of L, R1, R2, R3, R5, R6, R7, and m are as described in any of the embodiments of this invention.

[0241] According to certain embodiments of the present invention, the compound has the structure shown in formula (IA):

[0242] The rings G, R1, R2, R3, R4, R5, R6, R7, m, and n are defined as described in any embodiment of this invention.

[0243] According to certain embodiments of the present invention, the compound has the structure shown in formula (III-A):

[0244] The rings E, R1, R2, R4, R5, R6, and R8 are defined as described in any embodiment of this invention.

[0245] According to certain embodiments of the present invention, the compound has the structure shown in formula (Y-1A):

[0246] The rings E, L, R1, R2, R3, R5, and R8 are defined as described in any embodiment of this invention.

[0247] According to certain embodiments of the present invention, the compound has the structure shown in formula (II-1A):

[0248] The definitions of L, R1, R2, R3, R5, R7, and m are as described in any of the embodiments of this invention.

[0249] According to certain embodiments of the present invention, the compound has the structure shown in formula (III-1A):

[0250] The definitions of rings E, R1, R2, R4, R5, and R8 are as described in any embodiment of this invention.

[0251] This invention provides a compound, which is a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):

[0252] in:

[0253] Cyclone G is selected from thiophene;

[0254] R1 and R2 are selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0255] R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0256] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 1-6 Alkyl-heterocyclic group, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0257] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 1-6 Alkyl-heterocyclic alkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0258] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0259] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, -(CR c 2) 0-3 NR a R b The substituents are selected from -OH, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0260] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0261] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b They cyclize together to form substituted or unsubstituted heterocyclic groups, wherein the substituents are selected from -OH, -CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0262] m is selected from 0, 1, 2, 3, and 4;

[0263] n is selected from 0, 1, 2, and 3.

[0264] This invention provides a compound, which is a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (I):

[0265] in:

[0266] Cyclone G is selected from thiophene;

[0267] R1 and R2 are selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0268] R3 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0269] R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 1-6 Alkyl-heterocyclic group, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0270] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted C 1-6 Alkyl-heterocyclic alkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0271] R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0272] R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, -(CR c 2) 0-3 NR a R b The substituents are selected from -OH, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0273] Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0274] R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C1-6 Alkyl-C 1-6 alkoxy, or R a and R b They cyclize together to form substituted or unsubstituted heterocyclic groups, wherein the substituents are selected from -OH, -CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy;

[0275] m is selected from 0, 1, 2, 3, and 4;

[0276] n is selected from 0, 1, 2, and 3.

[0277] According to certain embodiments of the present invention, in the compound shown in formula (I), the ring G 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), the... Selected from n is selected from 1, 2, and 3; undefined groups are as described in any of the embodiments of the present invention.

[0279] According to certain embodiments of the present invention, in the compound shown in formula (I), the... Selected from n is selected from 1 and 2; undefined groups are as described in any of the embodiments of the present invention.

[0280] According to certain embodiments of the present invention, in the compound shown in formula (I), the... Selected from Undefined groups are as described in any embodiment of this invention.

[0281] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7 membered heterocyclic group), wherein the substituent is selected from -OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0282] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from -CN, -NH2, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl group (3-7 membered heterocyclic alkyl); undefined groups as described in any embodiment of the invention.

[0283] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from halogen, methyl, halogen-substituted methyl, -CH3-OCH3, halogen-substituted -CH3-OCH3, cyclopropyl, halogen-substituted cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0284] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F; undefined groups are as described in any embodiment of the present invention.

[0285] According to certain embodiments of the present invention, in the compound shown in formula (I), R4 is selected from F, Cl, -CH3; undefined groups are as described in any embodiment of the present invention.

[0286] According to certain embodiments of the present invention, in the compound shown in formula (I), the... Selected from Undefined groups are as described in any embodiment of this invention.

[0287] According to certain embodiments of the present invention, in the compound represented by formula (I), R1 and R2 are selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0288] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are selected from halogens, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-7 membered heterocyclic alkyl, halogen-substituted 3-7 membered heterocyclic alkyl; undefined groups as described in any embodiment of the present invention.

[0289] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are selected from halogens, methyl groups, halogen-substituted methyl groups, methoxy groups, halogen-substituted methoxy groups, cyclopropyl groups, and halogen-substituted cyclopropyl groups; undefined groups are as described in any embodiment of the present invention.

[0290] According to certain embodiments of the present invention, in the compound shown in formula (I), R1 and R2 are selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, cyclopropyl; undefined groups are as described in any embodiment of the present invention.

[0291] 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.

[0292] According to certain embodiments of the present invention, in the compound represented by formula (I), R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0293] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from H, -OH, -CN, -NH2, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0294] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from H, halogen, methyl; undefined groups are as described in any embodiment of the present invention.

[0295] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from H and F; undefined groups are as described in any embodiment of the present invention.

[0296] According to certain embodiments of the present invention, in the compound represented by formula (I), R3 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0297] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from -OH, -CN, -NH2, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0298] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from halogens and methyl groups; undefined groups are as described in any embodiment of the present invention.

[0299] According to certain embodiments of the present invention, in the compound shown in formula (I), R3 is selected from F; undefined groups are as described in any embodiment of the present invention.

[0300] According to certain embodiments of the present invention, in the compound represented by formula (I), R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy groups; 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), R5 is selected from C 1-6 Alkyl groups, halogenated C 1-6 Alkyl, C 1-3 Alkyl-C1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), wherein the substituent is selected from -OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy groups; undefined groups as described in any of the embodiments of the present invention.

[0302] 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.

[0303] 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.

[0304] According to certain embodiments of the present invention, in the compound shown in formula (I), R6 is selected from H, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0305] According to certain embodiments of the present invention, in the compound shown in formula (I), R6 is selected from H and methyl; 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), R6 is selected from H; undefined groups are as described in any embodiment of the present invention.

[0307] According to certain embodiments of the present invention, in the compound shown in formula (I), the... Selected from Undefined groups are as described in any embodiment of this invention.

[0308] According to certain embodiments of the present invention, in the compound shown in formula (I), R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic alkyl, -(CH2) 0-3 NR a R b The substituents are selected from -OH, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy;

[0309] R a and R b Independently selected from H, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, wherein the substituents are selected from -OH, -CN, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[0310] 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), R7 is selected from -CN, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, -(CH2) 0-3 NR a R b ;

[0312] R a and R b Independently selected from H and C 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R a and R bCyclization is performed to form substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, wherein the substituents are selected from -OH, -CN, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy;

[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), R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, -(CH2)2NR a R b ;

[0315] R a and R b Selected independently from H, methyl, or R a and R b Cyclization is performed to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from -halogen, methyl, methoxy, and methylmethoxy.

[0316] Undefined groups are as described in any embodiment of this invention.

[0317] According to certain embodiments of the present invention, in the compound shown in formula (I), R7 is selected from F, -CH3, -CF3, -CHF2, -OCHF2, cyclopropyl, Undefined groups are as described in any embodiment of this invention.

[0318] According to certain embodiments of the present invention, in the compound shown in formula (I), the... Selected from Undefined groups are as described in any embodiment of this invention.

[0319] According to certain embodiments of the present invention, the compound represented by formula (I) has the structure represented by formula (IA):

[0320] The rings G, R1, R2, R3, R4, R5, R6, R7, m, and n are defined as described in any embodiment of this invention.

[0321] According to certain embodiments of the present invention,

[0322] The L is selected from and -SF5;

[0323] The ring G is selected from 5-membered heteroaryl, 5-7-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S;

[0324] The ring E is selected from

[0325] R1 and R2 are each independently selected from H, halogens, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 alkyl;

[0326] The R3 is selected from H and halogens;

[0327] The R4 is selected from halogenated, substituted, or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 alkyl;

[0328] R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 alkyl;

[0329] R6 is selected from -H, C 1-3 Alkyl groups, halogenated C 1-3 alkyl;

[0330] The R7 is selected from substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, -(C(R) c )2) 0-3 N(R a )R b The substituents are selected from -OH, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy;

[0331] The R 7a Selected from H, -(C(R) c )2) 0-3 N(R d )R eThe R 7b Selected from H, halogens, substituted or unsubstituted C 1-3 Alkyl; each R c Each is independently selected from H;

[0332] The R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 Alkyl, C 1-3 Alkoxy;

[0333] The R8 is selected from H, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 Alkyl group; m is selected from 0, 1, 2, 3;

[0334] The value of n is selected from 0, 1, 2, and 3;

[0335] The value of q is selected from 0, 1, and 2.

[0336] According to certain embodiments of the present invention, L is selected from... and -SF5;

[0337] The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S;

[0338] The ring E is selected from

[0339] R1 is selected from H, halogens, and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl;

[0340] The R2 is selected from H and halogens;

[0341] The R3 is selected from H and halogens;

[0342] The R4 is selected from halogenated, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0343] R5 is selected from C. 1-6 alkyl;

[0344] R6 is selected from H and C. 1-6 alkyl;

[0345] The R7 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl;

[0346] The R 7a Selected from H, -(CH2) 0-3 N(R d )R e ;

[0347] The R 7b Selected from H;

[0348] The R8 is selected from H and halogens;

[0349] The R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 alkyl;

[0350] The m is selected from 2 and 3;

[0351] The n is selected from 0, 1, 2 and 3; undefined groups are as described in any embodiment of the present invention.

[0352] According to certain embodiments of the present invention, R1 is selected from H, Cl, methyl, -CF3;

[0353] R2 is selected from H and F;

[0354] R3 is selected from H and F;

[0355] R4 is selected from methyl, F, Cl, and cyclopropyl;

[0356] R5 is selected from

[0357] R6 is selected from H and ethyl;

[0358] R7 is selected from -CF3, -OCHF2,

[0359] The R 7a Selected from

[0360] The R8 is selected from H and F; undefined groups are as described in any of the embodiments of the present invention.

[0361] According to certain embodiments of the present invention, L is selected from... and -SF5;

[0362] The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S;

[0363] The ring E is selected from

[0364] R1 is selected from H and C. 1-6 alkyl;

[0365] The R2 is selected from H and halogens;

[0366] The R3 is selected from H and halogens;

[0367] The R4 is selected from halogenated, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0368] R5 is selected from C. 1-6 alkyl;

[0369] R6 is selected from H and C. 1-6 alkyl;

[0370] The R7 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl;

[0371] The R 7a Selected from H, -(CH2) 0-3 N(Rd )R e ;

[0372] The R 7b Selected from H;

[0373] The R8 is selected from H and halogens;

[0374] The R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 alkyl;

[0375] The m is selected from 2 and 3;

[0376] The n is selected from 0, 1, 2 and 3; undefined groups are as described in any embodiment of the present invention.

[0377] According to certain embodiments of the present invention, R1 is selected from H and methyl;

[0378] R2 is selected from H and F;

[0379] R3 is selected from H and F;

[0380] R4 is selected from F, methyl, and cyclopropyl;

[0381] R5 is selected from

[0382] R6 is selected from H and ethyl;

[0383] R7 is selected from -CF3, -OCHF2,

[0384] The R 7a Selected from

[0385] The R8 is selected from H and F; undefined groups are as described in any of the embodiments of the present invention.

[0386] According to certain embodiments of the present invention, L is selected from...

[0387] The ring E is selected from

[0388] R1 is selected from C 1-6 alkyl;

[0389] The R2 is selected from halogens;

[0390] The R3 is selected from H and halogens;

[0391] R4 is selected from halogens, C 1-6 alkyl;

[0392] R5 is selected from C. 1-6 alkyl;

[0393] R6 is selected from H and C. 1-6 alkyl;

[0394] The R7 is selected from substituted or unsubstituted C. 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl;

[0395] The R8 is selected from H and halogens;

[0396] The R a and R b Each was independently selected from C 1-3 Alkyl, or R a and R b Together with the N atom to which it is attached, they cyclize to form a substituted or unsubstituted 4-5 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and S. 1-3 alkyl;

[0397] The m is selected from 2 and 3; undefined groups are as described in any embodiment of the present invention.

[0398] According to certain embodiments of the present invention, L is selected from...

[0399] The ring E is selected from

[0400] R1 is selected from methyl;

[0401] R2 is selected from F;

[0402] R3 is selected from H and F;

[0403] R5 is selected from

[0404] R6 is selected from H and ethyl;

[0405] R8 is selected from H and F;

[0406] Undefined groups are as described in any embodiment of this invention.

[0407] According to certain embodiments of the present invention, the L is selected from -SF5;

[0408] The ring E is selected from

[0409] R1 and R2 are each independently selected from H, halogens, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 Alkyl groups; preferably, R1 and R2 are hydrogen;

[0410] R3 is selected from H;

[0411] R5 is selected from substituted or unsubstituted C. 1-6 alkyl;

[0412] R6 is selected from H and C. 1-3 alkyl;

[0413] The R7 is selected from substituted or unsubstituted C. 1-3 Alkyl group, -(CH2) 0-3 NR a R b The substituents are selected from halogens;

[0414] The R a R b Each is independently selected from H, substituted or unsubstituted C. 1-3 alkyl;

[0415] R8 is selected from H;

[0416] The m is selected from 1, 2, 3; undefined groups are as described in any embodiment of this invention.

[0417] According to certain embodiments of the present invention, L is selected from...

[0418] The ring G is selected from thienyl groups;

[0419] The ring E is selected from

[0420] R1 and R2 are each independently selected from H, halogens, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 alkyl;

[0421] R3 and R8 are selected from H; undefined groups are as described in any embodiment of the present invention.

[0422] According to certain embodiments of the present invention, L is selected from...

[0423] The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from S or both S and N;

[0424] The ring E is selected from

[0425] R1 and R2 are each independently selected from halogenated, substituted, or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 alkyl;

[0426] One of R3 and R8 is H, and the other is a halogen;

[0427] R7 is selected from -(C(R) c )2) 0-3 NR a R b ;

[0428] The R a and R b Together with the N atom to which it is attached, they cyclize to form a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and S. 1-3 alkyl;

[0429] The n is 3; undefined groups are as described in any embodiment of this invention.

[0430] According to certain embodiments of the present invention, L is selected from...

[0431] The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from one or two of S and N;

[0432] The ring E is selected from

[0433] R1 and R2 are each independently selected from halogens, C 1-3 alkyl;

[0434] One of R3 and R8 is H, and the other is a halogen;

[0435] The R4 is selected from substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 alkyl;

[0436] R7 is selected from -(C(R) c )2) 0-3 NRa R b ;

[0437] The R a and R b Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 alkyl;

[0438] The n is 3; undefined groups are as described in any embodiment of this invention.

[0439] According to certain embodiments of the present invention, L is selected from... Undefined groups are as described in any embodiment of this invention.

[0440] This invention provides a compound, said compound being a compound of formula (V), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (V):

[0441] The definitions of L, ring E, R1, R2, R3, R5, and R8 are as described in any embodiment of this invention.

[0442] This invention provides a compound, said compound being a compound of formula (VA), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (VA):

[0443] The definitions of L, ring E, R1, R2, R3, R5, and R8 are as described in any embodiment of this invention.

[0444] According to certain embodiments of the present invention, the present invention provides any of the following compounds or stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs of any of the following compounds:

[0445] According to certain embodiments of the present invention, the present invention provides any of the following compounds or stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs of any of the following compounds:

[0446] In a second aspect, the present invention also provides a pharmaceutical composition comprising the compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of the compound.

[0447] In the pharmaceutical composition described herein, the compound, or a pharmaceutical composition of the compound's stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs, may be a therapeutically effective dose.

[0448] The present invention also provides a pharmaceutical composition comprising the compound of formula (I) above, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound of formula (I).

[0449] In the pharmaceutical composition described herein, the compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of the compound of formula (I), may be a therapeutically effective dose.

[0450] In a third aspect, the present invention also provides the use of the said compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the said compound, in the preparation of a medicament for the treatment or prevention of diseases related to integrin α4β7.

[0451] The integrin α4β7-related diseases mentioned are selected from autoimmune diseases.

[0452] The integrin α4β7-related diseases mentioned are selected from inflammatory bowel disease.

[0453] The integrin α4β7-related diseases mentioned are selected from ulcerative colitis and Crohn's disease.

[0454] The present invention also provides the use of the compound of formula (I) above, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound of formula (I) in the preparation of a medicament for the treatment or prevention of diseases related to integrin α4β7.

[0455] The integrin α4β7-related diseases mentioned are selected from autoimmune diseases.

[0456] The integrin α4β7-related diseases mentioned are selected from inflammatory bowel disease.

[0457] The integrin α4β7-related diseases mentioned are selected from ulcerative colitis and Crohn's disease.

[0458] 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 stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound, or a pharmaceutical composition as described in the second aspect.

[0459] The integrin α4β7-related diseases mentioned are selected from autoimmune diseases.

[0460] The integrin α4β7-related diseases mentioned are selected from inflammatory bowel disease.

[0461] The integrin α4β7-related diseases mentioned are selected from ulcerative colitis and Crohn's disease.

[0462] 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 stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound of formula (I), or a pharmaceutical composition as described in the second aspect.

[0463] The integrin α4β7-related diseases mentioned are selected from autoimmune diseases.

[0464] The integrin α4β7-related diseases mentioned are selected from inflammatory bowel disease.

[0465] The integrin α4β7-related diseases mentioned are selected from ulcerative colitis and Crohn's disease.

[0466] In a fifth aspect of the invention, a compound described in the first aspect of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound, or a pharmaceutical composition as described in the second aspect, is provided for the treatment or prevention of diseases related to integrin α4β7.

[0467] The compound of the first aspect of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound, 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 autoimmune diseases.

[0468] The compound of the first aspect of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound, 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.

[0469] The compound of the first aspect of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of the compound, 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 ulcerative colitis and Crohn's disease.

[0470] The present invention also provides a compound of formula (I) as described in the first aspect of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug of a compound of formula (I), or a pharmaceutical composition as described in the second aspect, for the treatment or prevention of diseases related to integrin α4β7.

[0471] The compound of formula (I) of the first aspect of the present invention, or a stereoisomer, tautomer, 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, wherein the integrin α4β7-related diseases are selected from autoimmune diseases.

[0472] The compound of formula (I) of the first aspect of the present invention, or a stereoisomer, tautomer, 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.

[0473] The compound of formula (I) of the first aspect of the present invention, or a stereoisomer, tautomer, 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.

[0474] Terminology Definitions and Explanations

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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.

[0483] 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.

[0484] 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 forms of α-methylbenzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a 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.

[0485] 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.

[0486] 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.

[0487] 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.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents.

[0492] The terms "halogenated" and "halogen" are used interchangeably, referring to fluorine, chlorine, bromine, and iodine.

[0493] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, including deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the substituted compound is stable. Examples of substituents include, but are not limited to, -OH, -CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6Alkyl group.

[0494] Term "C" 1-6 "Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, 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, or their isomers. "C" 1-3 "Alkyl" is, for example, methyl, ethyl, n-propyl or isopropyl, or their isomers.

[0495] The term “halogen-substituted alkyl” or “halogenated alkyl” should be understood as a straight-chain or branched saturated monovalent hydrocarbon group having a specific number of carbon atoms and being substituted with one or more halogens (e.g., -CvFw, where v = 1 to 6 and w = 1 to (2v+1)).

[0496] Term "C" 1-6 "Alkoxy" should be understood to represent a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms and an oxygen atom, or to represent a C1-C6 alkyl group. The definition of -O-C1-C6 alkyl is as described in this specification, where the oxygen atom may be attached to any carbon atom of the straight chain or the straight chain of the C1-C6 alkyl group. This includes, but is not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-), and butoxy (C4H9-O-). The term "C..." 1-3 "Alkoxy" should be understood as representing a straight-chain or branched saturated hydrocarbon group with 1, 2, or 3 carbon atoms and an oxygen atom, or represented as C 1-3 Alkyl-O-,C 1-3 Alkyl groups are defined as described in this specification, and oxygen atoms may be attached to C. 1-3 On any carbon atom of the straight chain or straight chain of an alkyl group. Including but not limited to: methoxy (CH3-O-), ethoxy (C2H5-O-), propoxy (C3H7-O-).

[0497] The terms “halogen-substituted alkoxy” or “haloalkoxy” should be understood as an alkoxy group having one or more hydrogen atoms substituted by a halogen, wherein the definition of alkoxy is as described above.

[0498] Term "C" 3-8"Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms, including fused or bridged polycyclic systems. The term "C"... 3-6 "Cycloalkyl" should be understood as referring to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 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.

[0499] The terms “halogen-substituted cycloalkyl” or “halogenated cycloalkyl” should be understood as having one or more hydrogen atoms attached to a cycloalkyl group that are substituted with halogens, wherein the definition of cycloalkyl is as described above.

[0500] The term "heterocyclic group" should be understood as a saturated, unsaturated, or partially saturated monocyclic, bicyclic, or tricyclic ring in which one, two, three, four, or five ring atoms are selected from N, O, and S. Unless otherwise specified, it may be linked by carbon or nitrogen, wherein -CH 2- The group may optionally be replaced by -C(O)-; and unless otherwise stated to the contrary, the cyclic nitrogen atom or cyclic sulfur atom may optionally be oxidized to form an N-oxide or S-oxide, or the cyclic nitrogen atom may optionally be quaternized; wherein the -NH in the ring may optionally be replaced by an acetyl, formyl, methyl, or methanesulfonyl group; and the ring may optionally be replaced by one or more halogens. 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. The term "3-10 membered heterocyclic group" should be understood to mean a saturated, unsaturated, or partially saturated monocyclic, bicyclic, or tricyclic ring having 3 to 10 atoms, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S. The term "3-7 membered heterocyclic group" should be understood to mean a saturated, unsaturated, or partially saturated monocyclic, bicyclic, or tricyclic ring having 3 to 7 atoms, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S.

[0501] The term "heterocyclic alkyl" should be understood as a saturated cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, and S. "Heterocyclic alkyl" can be monocyclic, bicyclic, or tricyclic, including bridged and spirocyclic structures. The term "3-10-membered heterocyclic alkyl" should be understood as a saturated monocyclic, bicyclic, or tricyclic group having 3 to 10 atoms, wherein the heteroatoms are preferably N, O, and S. 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. The term "3-7-membered heterocyclic alkyl" should be understood as a saturated monocyclic, bicyclic, or tricyclic group having 3 to 7 atoms, wherein the heteroatoms are preferably N, O, and S. 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. The term "4-6 membered heterocyclic alkyl" should be understood as a saturated monocyclic, bicyclic, or tricyclic ring having 4 to 6 atoms, wherein the heteroatoms are preferably selected from N, O, and S. 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. The term "4-5 membered nitrogen-containing heterocyclic alkyl" should be understood as a saturated monocyclic, bicyclic, or tricyclic ring having 4 to 5 atoms, wherein at least one ring's heteroatom is selected from N. Including but not limited to:

[0502] The terms “halogen-substituted heterocyclic alkyl” or “halogenated heterocyclic alkyl” should be understood as having one or more hydrogen atoms attached to a heterocyclic alkyl group that are substituted with halogens, wherein the definition of heterocyclic alkyl is as described above.

[0503] The term "heteroaryl" refers to a monocyclic aromatic ring group containing at least one, two, or three heteroatoms independently selected from (C=O), N, O, S, NO, (S=O), and S(=O)2. This includes, but is not limited to, pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and triazinyl. For example, "5-membered heteroaryl".

[0504] The term "bicyclic" refers to a group having two connecting rings. Bicyclic compounds include (a) spirocyclic compounds, where the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0505] (b) Compounds with fused rings, wherein the two rings share two adjacent atoms. In other words, the rings share a single covalent bond, i.e., the bridgehead atoms are directly connected. Examples of fused ring compounds include, but are not limited to:

[0506] (c) Bridged ring compounds, wherein two rings share three or more atoms and are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclic [2.2.1]heptane, can be considered as a pair of cyclopentane rings, each ring sharing three of its five carbon atoms. Examples of bridged ring compounds include, but are not limited to: Beneficial effects

[0507] According to a specific example of the present invention, the compound of formula (I) of the present invention, its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, have good antagonistic effects on integrin α4β7.

[0508] According to a specific example of the present invention, the compounds of the present invention, their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, have good antagonistic effects on integrin α4β7 and good pharmacokinetic properties, good drug-likeness, and low risk of drug-drug interactions.

[0509] 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

[0510] Those skilled in the art will understand that the embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed in accordance with the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0511] The embodiments of the present invention provide compounds of formula (I), their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the present invention in the preparation of pharmaceuticals.

[0512] The embodiments of the present invention provide the compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions, and the use of the compounds and pharmaceutical compositions of the present invention in the preparation of pharmaceuticals.

[0513] 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.

[0514] 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).

[0515] 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.

[0516] The abbreviations in this invention are defined as follows: Reagents: PE: Petroleum ether; EA: Ethyl acetate; DCM: Dichloromethane; DMF: N,N-dimethylformamide; n-BuLi: n-butyllithium; dioxane: Dioxane; LiOH: Lithium hydroxide; DCM: Dichloromethane; MeOH: Methanol; LDA: Lithium diisopropylaminodimethylamine; MeI: Iodomethane; NFSI: N-fluorobis(benzenesulfonamide); Pd(dppf)Cl2: 1,1-bis(diphenylphosphine)ferrocene palladium chloride; THF: Tetrahydrofuran; HATU: (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; Ti(OEt)4: Ethyl titanate; TMSCl: Trimethylchlorosilane; TCFH: N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; NMI: Azomethylimidazolium; MeCN / ACN: Acetonitrile

[0517] Symbols or units:

[0518] IC 50 The half-maximum inhibitory concentration (MCC) refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0519] M: mol / L, molar concentration, e.g., 1M hydrochloric acid represents a 1 mol / L hydrochloric acid solution.

[0520] N: Equivalent concentration, for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution.

[0521] RT: Retention Time

[0522] Test method:

[0523] LC-MS: Liquid chromatography-mass spectrometry

[0524] Example 1: Preparation of target compounds 1-P1 and 1-P2

[0525] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionic acid

[0526] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionic acid

[0527] Compound 1-P1 is one of the structures of the two compounds mentioned above, while compound 1-P2 is the other structure.

[0528] The synthetic routes for the target compounds 1-P1 and 1-P2 are as follows:

[0529] Synthesis of intermediate 1B: Synthesis of ethyl (3S)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1B)

[0530] Ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1A) (500 mg, 1.23 mmol), 3-methylthiophene-2-boronate (551 mg, 2.46 mmol), potassium carbonate (510 mg, 3.69 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL) and reacted at 110 °C for 5 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were 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 (PE / EA(v / v)=3 / 1) to obtain ethyl (3S)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1B).

[0531] LC-MS, M / Z (ESI): 426.1 (M+H) +

[0532] Synthesis of intermediate 1C: Synthesis of ethyl (3S)-3-amino-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate (1C)

[0533] Ethyl (3S)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1B) (400 mg, 0.93 mmol) was dissolved in dioxane (2 mL), and dioxane chloride solution (5 mL, 4 mol / L) was added. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, the solution was concentrated, and the reaction was quenched with water (10 mL). The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate (1C).

[0534] LC-MS, M / Z (ESI): 322.1 (M+H) +

[0535] Step 1: Synthesis of ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E)

[0536] Ethyl 2-hydroxy-4-methylpentanoate (1D) (10 g, 62.4 mmol) and triethylamine (12.63 g, 124.8 mmol) were dissolved in dichloromethane (100 mL). Methanesulfonyl chloride (10.7 g, 9.36 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 (100 mL) was added to quench the reaction. The mixture was extracted three times with dichloromethane (50 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) = 5 / 1) to obtain the target compound, ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E).

[0537] Step 2: Synthesis of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1G)

[0538] 5-Bromo-2-hydroxy-4-trifluoromethylpyridine (1F) (3 g, 12.4 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E) (3.54 g, 14.9 mmol), and potassium carbonate (3.43 g, 24.8 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 obtain the target compound ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridine-1(2H)-yl)-4-methylpentanoate (1G).

[0539] LC-MS, M / Z (ESI): 384.2 (M+H) +

[0540] Step 3: Synthesis of ethyl 2-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1H)

[0541] Ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1g) (3.0g, 7.81mmol), pinacol 1-ethoxyvinyl-2-boronate (3.09g, 15.62mmol), potassium carbonate (3.24g, 23.43mmol), and 1,1-bis(diphenylphosphine)dipyridylferric palladium dichloride (570mg, 0.78mmol) were dissolved in dioxane (30mL) and water (3mL), and reacted at 80℃ for 15h. After the reaction was complete, the reaction was quenched with water (50mL), and the mixture was extracted three times with ethyl acetate (50mL). The combined organic phases were washed with saturated brine (50mL), 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-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1H).

[0542] LC-MS, M / Z (ESI): 376.2 (M+H) +

[0543] Step 4: Synthesis of ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)valerate (1J)

[0544] Ethyl 2-(5-((E)-2-ethoxyvinyl-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1H) (2.0 g, 5.33 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 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 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-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoate (1J).

[0545] LC-MS, M / Z (ESI): 348.1 (M+H) +

[0546] Step 5: Synthesis of ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1K)

[0547] Ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)valerate (1J) (1.35 g, 3.89 mmol) and aziridine (333 mg, 5.83 mmol) were dissolved in dichloroethane (10 mL) and reacted at 25 °C for 30 min. Sodium cyanoborohydride (490 mg, 7.78 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-(5-(2-(aziridine-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylvalerate (1K).

[0548] LC-MS, M / Z (ESI): 389.2 (M+H) +

[0549] Step 6: Synthesis of 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M)

[0550] Ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (1K) (786 mg, 2.02 mmol) and lithium hydroxide (97 mg, 4.04 mmol) were dissolved in tetrahydrofuran (10 mL) and water (2 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 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 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1 M).

[0551] LC-MS, M / Z (ESI): 361.1 (M+H) +

[0552] Step 7: Synthesis of ethyl (1N)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate.

[0553] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (100 mg, 0.28 mmol), (3S)-3-amino-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate (1C) (109 mg, 0.34 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (118 mg, 0.42 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-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate (1N).

[0554] LC-MS, M / Z (ESI): 664.1 (M+H) +

[0555] Step 8: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionic acid (target compounds 1-P1, 1-P2)

[0556] Ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(3-methylthiophen-2-yl)phenyl)propionate (1N) (146 mg, 0.22 mmol) and lithium hydroxide (21.2 mg, 0.88 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C18, 7 μm 30 mm × 40 cm, mobile phase A: 10 mM NH4HCO3; mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient B%: 56-64) to obtain the target compounds 1-P1 and 1-P2.

[0557] Target compound 1-P1:

[0558] The retention time RT of 1-P1 was 8.23 ​​min.

[0559] LC-MS, M / Z (ESI): 636.3 (M+H) +

[0560] 1H NMR (400MHz, CD3OD) δ7.79(s,1H),7.23(d,J=5.1Hz,1H),7.16(d,J=6.7Hz,2H),6.89(d,J=5.1Hz,1H) ,6.82(s,1H),5.67(t,J=8.0Hz,1H),5.52(t,J=6.7Hz,1H),3.94(t,J=8.1Hz,4H),3.23(dt,J=13.2,6 .4Hz,2H),2.81(t,J=6.7Hz,2H),2.67(d,J=6.8Hz,2H),2.34(p,J=8.0Hz,2H),2.26(d,J=1.8Hz,3H), 2.22(s,3H),1.99(dd,J=12.5,4.5Hz,3H),1.41(dt,J=13.5,6.8Hz,1H),0.93(dd,J=6.6,4.0Hz,6H).

[0561] Target compound 1-P2:

[0562] The retention time RT of 1-P2 was 9.74 min.

[0563] LC-MS, M / Z (ESI): 636.3 (M+H) +

[0564] 1 H NMR(400MHz, CD3OD)) δ7.70(s,1H),7.26–7.22(m,2H),7.20(dd,J=6.8,1.7Hz,1H),6.90(d,J=4.8Hz,2H),5.7 0(dd,J=10.9,3.6Hz,1H),5.63(t,J=7.6Hz,1H),4.11(t,J=8.0Hz,4H),3.44–3.31(m,2H),2.91(dt,J=15.8,4. 7Hz,1H),2.82–2.74(m,1H),2.60(dd,J=15.4,3.7Hz,1H),2.53–2.39(m,3H),2.30(d,J=1.8Hz,3H),2.26(s,3H ),2.04–1.92(m,2H),1.66(dt,J=14.0,7.2Hz,1H),1.39(dt,J=13.4,6.6Hz,1H),0.89(dd,J=10.3,6.6Hz,6H).

[0565] Example 2: Preparation of target compounds 2-P1 and 2-P2

[0566] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionic acid

[0567] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionic acid

[0568] The synthetic routes for the target compounds 2-P1 and 2-P2 are as follows:

[0569] Compound 2-P1 is one of the structures of the two compounds mentioned above, while compound 2-P2 is the other structure.

[0570] Step 1: Synthesis of ethyl (3S)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (2B)

[0571] Ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1A) (500 mg, 1.23 mmol), 4-methylthiophene-3-boronate (551 mg, 2.46 mmol), potassium carbonate (510 mg, 3.69 mmol), and 1,1-bis(diphenylphosphine)dipyridylferric palladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL) and reacted at 110 °C for 5 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were 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 (PE / EA(v / v)=3 / 1) to obtain ethyl (3S)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (2B).

[0572] LC-MS, M / Z (ESI): 426.1 (M+H) +

[0573] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionate (2C)

[0574] Ethyl (3S)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (2B) (390 mg, 0.91 mmol) was dissolved in dioxane (2 mL), and dioxane chloride solution (5 mL, 4 mol / L) was added. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, the solution was concentrated, and the reaction was quenched with water (10 mL). The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionate (2C).

[0575] LC-MS, M / Z (ESI): 322.1 (M+H) +

[0576] Step 3: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)ethyl propionate (2D)

[0577] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (100 mg, 0.28 mmol), (3S)-3-amino-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionate (2C) (109 mg, 0.34 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (118 mg, 0.42 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 obtain (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionic acid ethyl ester (2D).

[0578] LC-MS, M / Z (ESI): 664.1 (M+H) +

[0579] Step 4: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophen-3-yl)phenyl)propionic acid (target compounds 2-P1, 2-P2)

[0580] (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2-fluoro-3-methyl-5-(4-methylthiophene-3-yl)phenyl)propionate ethyl ester (2D) (120 mg, 0.18 mmol), lithium hydroxide (21.6 mg, 0.90 mmol), were dissolved in tetrahydrofuran (5 mL) and water (1 mL), and reacted at 25 °C for 2 h. After the reaction was completed, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C18, 7 μm 30 mm × 40 cm, mobile phase A: 10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 42 mL / min; gradient B%: 56-64) to obtain the target compounds 2-P1 and 2-P2.

[0581] Target compound 2-P1:

[0582] The retention time RT of 2-P1 was 8.32 min.

[0583] LC-MS, M / Z (ESI): 636.3 (M+H) +

[0584] 1 H NMR (400MHz, CD3OD) δ7.82(s,1H),7.18(d,J=3.2Hz,1H),7.14(d,J=6.3Hz,1H),7.11(d,J=6.5H z,1H),7.06(d,J=2.4Hz,1H),6.81(s,1H),5.69–5.64(m,1H),5.55(t,J=6.7Hz,1H),3.95(t,J= 8.0Hz,4H),3.27–3.17(m,2H),2.80(t,J=6.9Hz,2H),2.68(d,J=6.7Hz,2H),2.36(p,J=8.0Hz,2 H),2.26(s,3H),2.18(s,3H),2.06–1.92(m,3H),1.45–1.36(m,1H),0.94(dd,J=6.2,5.1Hz,6H).

[0585] Target compound 2-P2:

[0586] The retention time RT of 2-P2 was 9.78 min.

[0587] LC-MS, M / Z (ESI): 636.3 (M+H) +

[0588] 1H NMR (400MHz, CD3OD) δ7.71(s,1H),7.23(d,J=3.2Hz,1H),7.21–7.18(m,1H),7.16(d,J=6.7Hz,1H),7.09(d,J=3.1Hz,1H), 6.91(s,1H),5.71(dd,J=10.7,3.6Hz,1H),5.63(t,J=7.7Hz,1H),4.09(s,4H),3.42–3.36(m,1H),3.33(dd,J=8.7,3.7Hz,1 H),2.90(dt,J=15.3,4.2Hz,1H),2.83–2.75(m,1H),2.60(dd,J=15.3,3.7Hz,1H),2.50(dd,J=15.3,10.8Hz,1H),2.46–2.4 0(m,2H),2.30(s,3H),2.22(s,3H),2.05–1.94(m,2H),1.72–1.65(m,1H),1.43–1.35(m,1H),0.90(dd,J=11.9,6.6Hz,6H).

[0589] Example 3: Preparation of target compounds 3-P1 and 3-P2

[0590] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionic acid

[0591] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionic acid

[0592] Compound 3-P1 is one of the structures of the two compounds mentioned above, while compound 3-P2 is the other structure.

[0593] The synthetic routes for the target compounds 3-P1 and 3-P2 are as follows:

[0594] Step 1: Synthesis of 3-bromo-2,4-dimethylthiophene (3B)

[0595] 3-Bromo-4-methylthiophene (3A) (5 g, 28.2 mmol) was dissolved in tetrahydrofuran (30 mL). Diisopropylaminolithium (34.2 mL, 34.2 mmol) was slowly added dropwise at -78 °C. After reacting for 1 h at this temperature, iodomethane (4.3 g, 37.6 mmol) was slowly added dropwise. The mixture was then slowly brought to room temperature and stirred overnight. After the reaction was complete, water (30 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined. The extract was 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 (PE as eluent) to give 3-bromo-2,4-dimethylthiophene (3B).

[0596] Step 2: Synthesis of 2-(2,4-dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3C)

[0597] 3-Bromo-2,4-dimethylthiophene (3B) (1.8 g, 9.4 mmol), pinacol diboronate (4.78 g, 18.8 mmol), potassium acetate (2.65 g, 28.2 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (688 mg, 0.94 mmol) were dissolved in dioxane (30 mL) and reacted at 90 °C for 16 h. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 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 (PE / EA (v / v) = 3 / 1) to give 2-(2,4-dimethylthiophene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3C).

[0598] Step 3: Synthesis of ethyl (3S)-3-(5-(2,4-dimethylthiophene-3-yl)-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (3D)

[0599] Ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1A) (500 mg, 1.23 mmol), 2-(2,4-dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3C) (585 mg, 2.46 mmol), potassium carbonate (510 mg, 3.69 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and reacted at 110 °C for 5 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 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 (PE / EA (v / v) = 3 / 1) to obtain ethyl (3S)-3-(5-(2,4-dimethylthiophene-3-yl)-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (3D).

[0600] LC-MS, M / Z (ESI): 440.1 (M+H) +

[0601] Step 4: Synthesis of ethyl (3S)-3-amino-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3E)

[0602] Ethyl (3S)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (3D) (320 mg, 0.73 mmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (5 mL, 4 mol / L) was added. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, the solution was concentrated, and the reaction was quenched with water (10 mL). The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3E).

[0603] LC-MS, M / Z (ESI): 336.1 (M+H) +

[0604] Step 5: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3F)

[0605] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (100 mg, 0.28 mmol), ethyl (3S)-3-amino-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3E) (114 mg, 0.34 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (118 mg, 0.42 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 obtain ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3F).

[0606] LC-MS, M / Z (ESI): 678.1 (M+H) +

[0607] Step 6: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionic acid (target compounds 3-P1, 3-P2)

[0608] Ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(5-(2,4-dimethylthiophen-3-yl)-2-fluoro-3-methylphenyl)propionate (3F) (150 mg, 0.22 mmol) and lithium hydroxide (21.1 mg, 0.88 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the reaction solution was subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C18, 7μm 30mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 42mL / min; gradient B%: 50%-67%) to obtain the target compounds 3-P1 and 3-P2.

[0609] Target compound 3-P1:

[0610] The retention time RT of 3-P1 was 7.94 min.

[0611] LC-MS, M / Z (ESI): 650.3 (M+H) +

[0612] 1 H NMR (400MHz, CD3OD) δ7.81(s,1H),6.97(d,J=5.3Hz,1H),6.93(d,J=6.4Hz,1H),6.80(s,1H) ,6.78(s,1H),5.65(dd,J=9.8,6.3Hz,1H),5.57(t,J=6.7Hz,1H),3.98–3.89(m,4H),3.22(t ,J=6.2Hz,2H),2.82(t,J=6.8Hz,2H),2.68(d,J=6.6Hz,2H),2.38(p,J=7.9Hz,2H),2.27(s, 3H),2.21(s,3H),2.05–1.97(m,3H),1.95(s,3H),1.43–1.35(m,1H),0.93(t,J=7.3Hz,6H).

[0613] Target compound 3-P2:

[0614] The retention time RT of 3-P2 was 9.46 min.

[0615] LC-MS, M / Z (ESI): 650.3 (M+H) +

[0616] 1H NMR (400MHz, CD3OD) δ7.72(s,1H),7.02(d,J=5.6Hz,1H),6.98(d,J=6.6Hz,1H),6.90(s,1H),6.80(s,1H),5.73(d d,J=10.8,3.3Hz,1H),5.62(t,J=7.2Hz,1H),4.08(s,4H),3.40–3.35(m,1H),3.32(d,J=3.0Hz,1H),2.93–2.87(m ,1H),2.82–2.74(m,1H),2.61(dd,J=15.3,3.3Hz,1H),2.54–2.46(m,1H),2.46–2.40(m,2H),2.31(s,3H),2.25(s ,3H),2.05–1.94(m,5H),1.66(dt,J=14.0,7.2Hz,1H),1.39(td,J=13.3,6.6Hz,1H),0.88(dd,J=8.5,6.8Hz,6H).

[0617] Example 4: Preparation of target compounds 29-P1 and 29-P2

[0618] (3S)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)-3-(3-methyl-5-(pentafluoro-λ) 6 -Thioalkyl)phenyl)propionic acid

[0619] (3S)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)-3-(3-methyl-5-(pentafluoro-λ) 6 -Thioalkyl)phenyl)propionic acid

[0620] Compound 29-P1 is one of the structures of the two compounds mentioned above, while compound 29-P2 is the other structure.

[0621] The synthetic routes for target compounds 29-P1 and 29-P2 are as follows:

[0622] Step 1: (S) 2 R)-2-methyl-N-{[3-methyl-5-(pentafluoro-λ) 6 Synthesis of 2-thio[phenyl]methylmethylene]propane-2-sulfinamide (29B)

[0623] Under nitrogen protection and at 0°C, 3-methyl-5-(pentafluoro-λ) 6 (-Thioalkyl)benzaldehyde (29A) (600 mg, 2.4 mmol) and (R)-2-methylpropane-2-sulfinamide (32C) (349 mg, 2.88 mmol) in anhydrous tetrahydrofuran (12 mL) solution were added to ethyl titanate (Ti(OEt)4, 822 mg, 3.6 mmol). The reaction was then carried out at 40 °C for 2 hours. LC-MS analysis confirmed complete conversion of the starting material. The reaction mixture was cooled to room temperature, and water (1 mL) and ethyl acetate (10 mL) were added. The mixture was stirred for 5 minutes, filtered, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 4:1) to obtain (S 2 R)-2-methyl-N-{[3-methyl-5-(pentafluoro-λ) 6 [-thioyl]phenyl]methylmethylene}propane-2-sulfinamide (29B).

[0624] LC-MS, M / Z (ESI): 350.06 [M+H] +

[0625] Step 2: (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-methyl-5-(pentafluoro-λ) 6 Synthesis of ethyl thioalkyl)phenyl)propionate (29C)

[0626] Under nitrogen protection and at room temperature, trimethylchlorosilane (42 mg, 0.38 mmol) was added dropwise to a suspension of zinc powder (630 mg, 9.6 mmol) in tetrahydrofuran (40 mL), and the mixture was reacted at 60 °C for 1 hour. The reaction solution was cooled to 20-30 °C, and ethyl bromoacetate (818 mg, 4.9 mmol) was added. This step of the reaction was exothermic, and the dropping rate was controlled to keep the reaction solution temperature below 60 °C. After the addition was complete, the reaction was continued at 60 °C for 1 hour, and then the reaction solution was cooled to 0 °C. (S...) 2 R)-2-methyl-N-{[3-methyl-5-(pentafluoro-λ) 6[-thioyl]phenyl]methylmethylene]propane-2-sulfinamide (29B) (670 mg, 1.92 mmol), and then reacted at room temperature for 2 hours. A saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 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 (eluent: petroleum ether: ethyl acetate (V / V) = 3:1) to give (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-methyl-5-(pentafluoro-λ) 6 ethyl thioalkyl)phenyl)propionate (29C).

[0627] LC-MS, M / Z (ESI): 438.11 [M+H] +

[0628] Step 3: (3S)-3-amino-3-(3-methyl-5-(pentafluoro-λ) 6 Synthesis of ethyl thioalkyl)phenyl)propionate (29D)

[0629] Under nitrogen protection and at 0°C, (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-methyl-5-(pentafluoro-λ) 6 Ethyl (29C)-(3-thioalkyl)phenyl)propionate (400 mg, 0.92 mmol) was added to anhydrous dichloromethane (4 mL) solution in 1,4-dioxane hydrochloric acid (4 M, 0.5 mL, 2.0 mmol), and the reaction was carried out at room temperature. The reaction was monitored by LCMS. After the substrate was completely converted, the reaction solution was concentrated to obtain the crude product (3S)-3-amino-3-(3-methyl-5-(pentafluoro-λ) 6 ethyl thioalkyl)phenyl)propionate (29D) proceeds directly to the next reaction.

[0630] LC-MS, M / Z(ESI): 334.08[M+H] +

[0631] Step 4: (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-methyl-5-(pentafluoro-λ) 6 Synthesis of ethyl thioalkyl)phenyl)propionate (29E)

[0632] Under nitrogen protection and at 0°C, (3S)-3-amino-3-(3-methyl-5-(pentafluoro-λ) 6Ethyl thioalkyl)phenyl)propionate (29D) (200 mg, 0.6 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (191 mg, 0.55 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (314 mg, 0.83 mmol) were added to anhydrous dichloromethane (3 mL) along with N,N-diisopropylethylamine (0.4 mL, 2.2 mmol). The reaction was then carried out at room temperature for 2 hours. The reaction was monitored by LCMS. The substrate conversion was complete. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL). 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 product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-methyl-5-(pentafluoro-λ) 6 ethyl thioalkyl)phenyl)propionate (29E).

[0633] LC-MS, M / Z(ESI): 664.24[M+H] +

[0634] Step 5: Synthesis of target compounds 29-P1 and 29-P2

[0635] (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-methyl-5-(pentafluoro-λ) 6 Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL) containing ethyl thioalkylphenyl propionate (29E) (270 mg, 0.4 mmol) at room temperature for 3 hours. LCMS analysis confirmed complete substrate conversion. The pH of the reaction solution was adjusted to 3-4 with 2 M hydrochloric acid aqueous solution, and the solution was then concentrated. The crude product was purified by reverse-phase chromatography (YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80 mL / min, gradient B%: 35%-65%) to obtain the target compounds 29-P1 and 29-P2.

[0636] The retention time RT of 29-P1 was 9.602 min.

[0637] LC-MS, M / Z (ESI): 636.2 [M+H] +

[0638] 1 H NMR(400MHz,CD3OD)δ7.86(s,1H),7.52(s,1H),7.47(s,1H),7.39(s,1H),6.86(s,1H),5.74-5.69(m,1H),5.32-5.27(m,1H),3.10-3.05(m,2H) ,2.97-2.85(m,2H),2.75(s,6H),2.72-2.61(m,2H),2.36(s,3H),2.01- 1.96(m,2H),1.48-1.40(m,1H),1.37-1.26(m,1H),1.0-0.93(m,6H)ppm.

[0639] The retention time RT of 29-P2 was 12.001 min.

[0640] LC-MS, M / Z (ESI): 636.2 [M+H] +

[0641] 1 H NMR(400MHz,CD3OD)δ7.81(s,1H),7.58(s,1H),7.53(s,1H),7.41(s,1H),6.91(s ,1H),5.68-5.63(m,1H),5.42-5.37(m,1H),3.29-3.23(m,1H),3.22-3.16(m,1H), 2.99-2.95(m,2H),2.81(s,6H),2.62-2.49(m,2H),2.42(s,3H),2.02-1.94(m,1H ),1.77-1.70(m,1H),1.43-1.35(m,1H),1.34-1.25(m,1H),0.95-0.88(m,6H)ppm.

[0642] Example 5: Preparation of target compounds 30-P1 and 30-P2

[0643] (3S)-3-(3-chloro-5-(pentafluoro-λ) 6 -Thioalkyl)phenyl)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0644] (3S)-3-(3-chloro-5-(pentafluoro-λ) 6-Thioalkyl)phenyl)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0645] Compound 30-P1 is one of the structures of the two compounds mentioned above, while compound 30-P2 is the other structure.

[0646] The synthetic routes for target compounds 30-P1 and 30-P2 are as follows:

[0647] Step 1: (S) 2 R)-N-{(Z)-[3-chloro-5-(pentafluoro-λ] 6 Synthesis of 30B: [thioalkyl]phenyl]methylene}-2-methylpropane-2-sulfinamide

[0648] Under nitrogen atmosphere, 3-chloro-5-(pentafluoro-λ) 6 Tetraethoxytitanium (912 mg, 4 mmol) was added dropwise to a tetrahydrofuran (5 mL) solution of (R)-2-methylpropane-2-sulfinamide (32C) (480 mg, 4 mmol) and (S-methylpropane-2-sulfinamide) (30A) (530 mg, 2 mmol), while maintaining the temperature below 30 °C. The reaction mixture was warmed to 35 °C and stirred for 1 hour. Water (5 mL) and ethyl acetate (100 mL) were added to the mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was separated and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1) to give (S 2 R)-N-{(Z)-[3-chloro-5-(pentafluoro-λ] 6 [-thioalkyl)phenyl]methylene}-2-methylpropane-2-sulfinamide (30B).

[0649] LC-MS, M / Z (ESI): 370.2 [M+H] +

[0650] Step 2: (3S)-3-[3-chloro-5-(pentafluoro-λ)] 6 Synthesis of ethyl propionate (30C)[(R)-2-methylpropane-2-sulfinyl]amino]propionate

[0651] Trimethylchlorosilane (30 mg, 0.3 mmol) was added dropwise to a mixture of Zn (360 mg, 5.6 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture was heated to 50 °C and stirred for 1 hour, then cooled to room temperature. Ethyl 2-bromoacetate (32E) (580 mg, 3.5 mmol) was added dropwise at room temperature, then the mixture was heated to 60 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature. (S...) 2 R)-N-{(Z)-[3-chloro-5-(pentafluoro-λ] 6 A solution of (3S)-3-[3-chloro-5-(pentafluoro-λ)-2-methylpropane-2-sulfinamide (30B) (500 mg, 1.4 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture and stirred at room temperature for 1 hour. Water (5 mL) and ethyl acetate (50 mL) were added to the mixture and stirred at room temperature for 10 minutes. The mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was separated and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to give (3S)-3-[3-chloro-5-(pentafluoro-λ)-2-methylpropane-2-sulfinamide (30B) (500 mg, 1.4 mmol)). 6 [-thioalkyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}ethyl propionate (30C).

[0652] LC-MS, M / Z (ESI): 458.2 [M+H] +

[0653] Step 3: (3S)-3-amino-3-[3-chloro-5-(pentafluoro-λ) 6 Synthesis of ethyl 30D [thioalkyl]phenyl]propionate

[0654] (3S)-3-[3-chloro-5-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate ethyl ester (30C) (400 mg, 0.87 mmol) in dichloromethane (2 mL) was added to a solution of dioxane hydrogen chloride (4 M, 3 mL, 12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, adjusted to alkalinity with sodium bicarbonate solution, extracted with ethyl acetate, dried over the organic phase and concentrated to obtain a crude product. The crude product was purified by reversed-phase chromatography on a C18 / 40 g column (mobile phase A: water / 0.1% HCl, mobile phase B: CH3CN) to obtain (3S)-3-amino-3-[3-chloro-5-(pentafluoro-λ) 6 [-thioalkyl)phenyl]ethyl propionate (30D).

[0655] LC-MS, M / Z (ESI): 354.2 [M+H] +

[0656] Step 4: (3S)-3-[3-chloro-5-(pentafluoro-λ)] 6 Synthesis of ethyl propionate (30E)[-thioalkyl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate

[0657] 2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentanoic acid (32H) (100 mg, 0.28 mmol), (3S)-3-amino-3-[3-chloro-5-(pentafluoro-λ 6 Ethyl 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (192 mg, 0.50 mmol) was dissolved in dichloromethane (3 mL), and then diisopropylethylamine (181 mg, 1.4 mmol) was slowly added dropwise. The reaction was carried out at 25 °C for 1 h. After the reaction was completed, 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. The crude product was purified by reversed-phase chromatography using a C18 / 20 g column (mobile phase A: water / 0.1% HCl, mobile phase B: CH3CN) to obtain (3S)-3-[3-chloro-5-(pentafluoro-λ] 6 [-thioalkyl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (30E).

[0658] LC-MS, M / Z (ESI): 684.1 [M+H] +

[0659] Step 5: Synthesis of target compounds 30-P1 and 30-P2

[0660] (3S)-3-[3-chloro-5-(pentafluoro-λ) 6[-thioalkyl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (30E) (140 mg, 0.20 mmol), LiOH-H2O (95 mg, 2.3 mmol) was 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 prepared by preparative reversed-phase chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 30mm×40cm; solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile gradient: 25%-75%, flow rate: 42mL / min, 13min) to obtain the target compounds 30-P1 and 30-P2.

[0661] Target compound 30-P1:

[0662] The retention time RT of 30-P1 was 7.93 min.

[0663] LC-MS, M / Z (ESI): 656.2 [M+H] +

[0664] 1 H NMR(400MHz,MeOD)δ7.94-7.64(m,4H),6.85(s,1H),5.74-5.71(m,1H),5.36-5.34( m,1H),3.07-1.97(m,12H),2.01-1.97(m,2H),1.45-1.42(m,1H),0.96-0.93(m,6H).

[0665] Target compound 30-P2:

[0666] The retention time RT of 30-P2 was 8.80 min.

[0667] LC-MS, M / Z (ESI): 656.2 [M+H] +

[0668] 1 H NMR(400MHz,MeOD)δ7.85-7.66(m,4H),6.90(m,1H),5.72-5.69(m,1H),5.39-5.35( m,1H),3.20-2.59(m,12H),1.97-1.78(m,2H),1.37-1.35(m,1H),0.91-0.87(m,6H).

[0669] Example 6: Preparation of target compounds 32-P1 and 32-P2

[0670] (3S)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(pentafluoro-λ) 6 -Thioalkyl)phenyl)propionic acid

[0671] (3S)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(pentafluoro-λ) 6 -Thioalkyl)phenyl)propionic acid

[0672] Compound 32-P1 is one of the structures of the two compounds mentioned above, while compound 32-P2 is the other structure.

[0673] The synthetic routes for target compounds 32-P1 and 32-P2 are as follows:

[0674] Step 1: 3-(pentafluoro-λ) 6 Synthesis of 32B (thioalkyl)benzaldehyde

[0675] 1-bromo-3-(pentafluoro-λ) 6 3-(thioalkyl)benzene (32A) (5 g, 17.7 mmol) and N,N-dimethylformamide (6.5 g, 88.5 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), purged with nitrogen, and cooled to -78 °C. Then, n-butyllithium (2.5 M, 10 mL, 25 mmol) was slowly added dropwise while stirring for 10 min. The reaction was quenched with water, and then extracted with ethyl acetate (50 mL) and a saturated ammonium chloride solution (200 mL). The organic phase was evaporated to dryness, and the residue was purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to give 3-(pentafluoro-λ)benzene (32A) (5 g, 17.7 mmol) and N,N-dimethylformamide (6.5 g, 88.5 mmol). 6 -Thioalkyl)benzaldehyde (32B).

[0676] LC-MS, M / Z (ESI): 233.2 [M+H] +

[0677] Step 2: (S) 2 R)-2-methyl-N-((Z)-(3-(pentafluoro-λ) 6 Synthesis of 2-sulfinamide (32D) with thioalkyl)phenyl)methylene)propane

[0678] Under nitrogen atmosphere, towards 3-(pentafluoro-λ) 6 Tetraethoxytitanium (3.7 g, 16.2 mmol) was added dropwise to a solution of (R)-2-methylpropane-2-sulfinamide (32C) (1.4 g, 11.8 mmol) in tetrahydrofuran (20 mL), and the temperature was maintained below 30 °C. The reaction mixture was warmed to 35 °C and stirred for 1 hour. Water (5 mL) and ethyl acetate (100 mL) were added to the mixture, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was separated and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to give (S 2 R)-2-methyl-N-((Z)-(3-(pentafluoro-λ) 6 -Thioalkyl)phenyl)methylene)propane-2-sulfinamide (32D).

[0679] LC-MS, M / Z (ESI): 336.2 [M+H] +

[0680] Step 3: (3S)-3-(((R)-2-methylpropane-2-sulfinyl)amino)-3-(3-(pentafluoro-λ) 6 Synthesis of ethyl thioalkyl)phenyl)propionate (32F)

[0681] Trimethylchlorosilane (67 mg, 0.6 mmol) was added dropwise to a mixture of Zn (0.8 g, 12 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen atmosphere. The mixture was heated to 50 °C and stirred for 1 hour, then cooled to room temperature. Ethyl 2-bromoethyl acetate (32E) (1.2 g, 7.5 mmol) was added dropwise at room temperature, then the mixture was heated to 60 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature. (S...) 2 R)-2-methyl-N-((Z)-(3-(pentafluoro-λ) 6A solution of (3S)-3-(((R)-2-methylpropane-2-sulfinyl)amino)-3-(3-(pentafluoro-λ)-2-sulfinamide (32D) (1 g, 3 mmol) dissolved in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture and stirred at room temperature for 1 hour. Water (5 mL) and ethyl acetate (50 mL) were added to the mixture and stirred at room temperature for 10 minutes. The mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was separated and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to give (3S)-3-(((R)-2-methylpropane-2-sulfinyl)amino)-3-(3-(pentafluoro-λ) ... 6 ethyl thioalkyl)phenyl)propionate (32F).

[0682] LC-MS, M / Z (ESI): 424.2 [M+H] +

[0683] Step 4: (3S)-3-amino-3-[3-(pentafluoro-λ) 6 Synthesis of ethyl 3-thioalkyl)phenyl]propionate (32G)

[0684] (3S)-3-(((R)-2-methylpropane-2-sulfinyl)amino)-3-(3-(pentafluoro-λ) 6 Ethyl thioalkyl)phenyl)propionate (32F) (500 mg, 1.18 mmol) dissolved in dichloromethane (2 mL) was mixed with dioxane solution (4 M, 3 mL, 12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, adjusted to alkalinity with sodium bicarbonate solution, extracted with ethyl acetate, dried and concentrated to obtain crude product. The crude product was purified by reversed-phase chromatography on a C18 / 40 g column (mobile phase A: 0.1% NH3·H2O + water, mobile phase B: acetonitrile) to obtain (3S)-3-amino-3-[3-(pentafluoro-λ)propionate. 6 [-thioalkyl)phenyl]ethyl propionate (32G).

[0685] LC-MS, M / Z (ESI): 320.2 [M+H] +

[0686] Step 5: Ethyl(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(pentafluoro-λ) 6 Synthesis of thioalkyl)phenyl)propionate (32J)

[0687] 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (100 mg, 0.28 mmol), (3S)-3-amino-3-[3-(pentafluoro-λ) 6 Ethyl [-thioalkyl)phenyl]propionate (32g) (100mg, 0.32mmol), N-methylimidazole (46mg, 0.56mmol), and tetramethylchlorourea hexafluorophosphate (118mg, 0.42mmol) were dissolved in acetonitrile (5mL) and reacted at 25°C for 2h. After the reaction was complete, water (10mL) was added, and the mixture was extracted three times with ethyl acetate (10mL). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reversed-phase chromatography on a C18 / 40g column (mobile phase A: 0.1% NH3·H2O + water, mobile phase B: acetonitrile) to obtain ethyl(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(pentafluoro-λ) 6 -Thioalkyl)phenyl)propionate (32J).

[0688] LC-MS, M / Z (ESI): 650.1 [M+H] +

[0689] Step 6: Synthesis of target compounds 32-P1 and 32-P2

[0690] Ethyl(3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(pentafluoro-λ) 6 32-(thioalkyl)phenyl)propionate (32J) (150 mg, 0.23 mmol) and LiOH-H2O (95 mg, 2.3 mmol) were dissolved in a mixture 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 prepared by preparative reversed-phase chromatography (column: YMC-Triart Prep C18, 7 μm 30 mm × 40 cm, solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; gradient B%: 5%-95%, flow rate: 42 mL / min, 13 min) to give the target compounds 32-P1 and 32-P2.

[0691] Target compound 32-P1:

[0692] The retention time RT of 32-P1 was 6.86 min.

[0693] LC-MS, M / Z (ESI): 622.2 [M+H] +

[0694] 1 H NMR (400MHz, CD3OD) δ7.88-7.41(m,5H),6.85(s,1H),6.73-6.71(m,1H),6.36-6.34( m,1H),3.05-2.68(m,12H),2.02-1.97(m,2H),1.45-1.42(m,1H),0.96-0.93(m,6H).

[0695] Target compound 32-P2:

[0696] The retention time RT of 32-P2 was 7.63 min.

[0697] LC-MS, M / Z (ESI): 622.2 [M+H]+

[0698] 1 H NMR (400MHz, CD3OD) δ7.88-7.49(m,5H),6.88(m,1H),5.72-5.69(m,1H),5.43-5.40( m,1H),3.10-2.59(m,12H),1.92-1.81(m,2H),1.37-1.35(m,1H),0.91-0.87(m,6H).

[0699] Example 7: Preparation of target compounds 33-P1 and 33-P2

[0700] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionic acid

[0701] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionic acid

[0702] Compound 33-P1 is one of the structures of the two compounds mentioned above, while compound 33-P2 is the other structure.

[0703] The synthetic routes for target compounds 33-P1 and 33-P2 are as follows:

[0704] Step 1: Synthesis of 3-bromo-2,4-dimethylthiophene (3B)

[0705] Under nitrogen protection and at -78°C, a solution of LDA in tetrahydrofuran (1.0 M, 25 mL) was added dropwise to an anhydrous tetrahydrofuran (50 mL) solution of 3-bromo-4-methylthiophene (3A) (4 g, 23 mmol) and reacted at -78°C for 1 hour. Iodomethane (3.6 g, 25 mmol) was then added to the reaction mixture. The reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was complete, a saturated ammonium chloride solution (50 mL) was added to quench the reaction. 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-2,4-dimethylthiophene (3B).

[0706] Step 2: Synthesis of 3-bromo-5-fluoro-2,4-dimethylthiophene (33C)

[0707] Under nitrogen protection and at -78°C, a solution of LDA in tetrahydrofuran (1.0 M, 15 mL) was added dropwise to an anhydrous tetrahydrofuran (50 mL) solution of 3-bromo-2,4-dimethylthiophene (3B) (1.9 g, 10 mmol), and the reaction was carried out at -78°C for 1 hour. Then, N-fluorobis(benzenesulfonamide) (3.78 g, 12 mmol) was added to the reaction mixture. The reaction mixture was heated to room temperature and stirred for 16 hours. After the reaction was completed, a saturated ammonium chloride solution (50 mL) was added to quench the reaction. 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-5-fluoro-2,4-dimethylthiophene (33C).

[0708] 1 H NMR (400MHz, CDCl3) δ2.28 (d, J = 2.6 Hz, 3H), 2.04 (d, J = 2.3 Hz, 3H) ppm.

[0709] Step 3: Synthesis of 2-(5-fluoro-2,4-dimethylthiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (33D)

[0710] Under nitrogen protection, an anhydrous 1,4-dioxane solution of 3-bromo-5-fluoro-2,4-dimethylthiophene (33C) (2.07 g, 10 mmol), potassium acetate (2.94 g, 30 mmol), pinacol diboronate (5.08 g, 20 mmol), and Pd(dppf)Cl2 (725 mg, 1 mmol) was heated to 80 °C and reacted for 16 hours. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL), and the mixture was extracted three times with ethyl acetate (50 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 (eluent: petroleum ether: ethyl acetate = 10:1) to give 2-(5-fluoro-2,4-dimethylthiophene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (33D).

[0711] 1 H NMR (400MHz, CDCl3) δ2.52 (d, J = 2.6Hz, 3H), 2.14 (d, J = 2.3Hz, 3H) 1.31 (s, 12H) ppm.

[0712] Step 4: Synthesis of ethyl (3S)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophene-3-yl)-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33E)

[0713] Under nitrogen protection, 1,4-dioxane (10 mL) and water (2 mL) were added to a mixture of 2-(5-fluoro-2,4-dimethylthiophene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (33D) (600 mg, 2.34 mmol), potassium carbonate (970 mg, 7.03 mmol), ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33A) (664 mg, 1.56 mmol) and Pd(dppf)Cl2 (167 mg, 0.23 mmol), and the mixture was then reacted at 85 °C for 16 hours. After the reaction solution was cooled to room temperature, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (20 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: ethyl acetate = 4:1) to obtain ethyl (3S)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophene-3-yl)-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33E).

[0714] LC-MS, M / Z(ESI): 478.15[M+H] +

[0715] Step 5: Synthesis of ethyl (3S)-3-amino-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionate (33F)

[0716] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 0.7mL, 2.8mmol) was added to an anhydrous dichloromethane (7mL) solution of (3S)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33E) (600mg, 1.4mmol). 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-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionate (33F), which was then directly used for the next reaction.

[0717] LC-MS, M / Z(ESI): 372.12[M+H] +

[0718] Step 6: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionate (33G)

[0719] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.4 mL, 2.2 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophene-3-yl)-5-methylphenyl)propionate (33F) (220 mg, 0.6 mmol), 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylvaleric acid (1M) (200 mg, 0.55 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (314 mg, 0.83 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 (eluent: dichloromethane: methanol = 10:1) to obtain ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionate (33 G).

[0720] LC-MS, M / Z(ESI): 714.17[M+H] +

[0721] Compound 33G was resolved into 64-P1 and 64-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.

[0722] The structures of 64-P1 and 64-P2 are as follows:

[0723] Compound 64-P1 is one of the structures of the two compounds mentioned above, while compound 64-P2 is the other structure.

[0724] LC-MS, M / Z(ESI): 714.17[M+H] +

[0725] Step 7: Synthesis of target compounds 33-P1 and 33-P2

[0726] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-(5-fluoro-2,4-dimethylthiophen-3-yl)-5-methylphenyl)propionate (33 G) (270 mg, 0.37 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 30%-80%) to obtain the target compounds 33-P1 and 33-P2.

[0727] The retention time RT of 33-P1 was 10.534 min.

[0728] LC-MS, M / Z(ESI): 686.24[M+H] +

[0729] 1 H NMR(400MHz,CD3OD)δ7.79(s,1H),7.0–6.94(m,1H),6.87–6.83(m,1H),5.76–5.65 (m,2H),4.60(s,1H),4.05–3.93(m,4H),3.30–3.20(m,2H),2.94–2.86(m,1H),2.8 5–2.79(m,2H),2.67–2.61(m,1H),2.46–2.37(m,2H),2.23(s,3H),2.15–2.06(m,3 H),2.04–1.93(m,2H),1.85–1.74(m,3H),1.42–1.32(m,1H),0.97–0.89(m,6H)ppm.

[0730] The retention time RT of 33-P2 was 13.072 min.

[0731] LC-MS, M / Z(ESI): 686.24[M+H] +

[0732] 1 H NMR(400MHz,CD3OD)δ7.67(s,1H),7.06–7.0(m,1H),6.92(s,1H),5.92–5.87(m,1H),5.64–5 .59(m,1H),4.6(s,1H),4.16–4.03(m,4H),3.43–3.37(m,1H),3.35–3.28(m,1H),2.95–2.87 (m,1H),2.86–2.71(m,2H),2.52–2.47(m,1H),2.47–2.41(m,2H),2.27(s,3H),2.14(s,3H), 1.96–1.89(m,1H),1.83(s,3H),1.76–1.70(m,1H),1.38–1.30(m,1H),0.92–0.83(m,6H)ppm.

[0733] Example 8: Preparation of target compounds 34-P1 and 34-P2

[0734] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionic acid

[0735] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionic acid

[0736] Compound 34-P1 is one of the structures of the two compounds mentioned above, while compound 34-P2 is the other structure.

[0737] The synthetic routes for the target compounds 34-P1 and 34-P2 are as follows:

[0738] Step 1: Synthesis of ethyl (3S)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (34A)

[0739] Under nitrogen protection, 1,4-dioxane (15 mL) and water (3 mL) were added to a mixture of 2-(5-fluoro-2,4-dimethylthiophene-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (33D) (1 g, 3.9 mmol), potassium carbonate (1.62 g, 11.7 mmol), (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (1A) (768 mg, 3 mmol), and Pd(dppf)Cl2 (218 mg, 0.3 mmol), and the mixture was reacted at 85 °C for 16 hours. After cooling the reaction solution to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution (20 mL), and 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. Ethyl (3S)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (34A) was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1).

[0740] LC-MS, M / Z(ESI): 458.16[M+H] +

[0741] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34B)

[0742] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 0.5mL, 2.0mmol) was added to an anhydrous dichloromethane (5mL) solution of (3S)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (34A) (457mg, 1.0mmol). 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-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34B), which was then directly used for the next reaction.

[0743] LC-MS, M / Z(ESI): 354.13[M+H] +

[0744] Step 3: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34C)

[0745] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.4 mL, 2.2 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34B) (212 mg, 0.6 mmol), 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (200 mg, 0.55 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (314 mg, 0.83 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 (eluent: dichloromethane: methanol = 10:1) to give ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34C) (300 mg, yield: 78.5%).

[0746] LC-MS, M / Z(ESI): 696.28[M+H] + Step 4: Synthesis of target compounds 34-P1 and 34-P2

[0747] Lithium hydroxide monohydrate (110 mg, 2.6 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-5-(5-fluoro-2,4-dimethylthiophen-3-yl)-3-methylphenyl)propionate (34C) (300 mg, 0.43 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 subjected to reversed-phase preparative chromatography (column: YMC-Triart Prep C18 S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 25%-75%) to obtain the target compounds 34-P1 and 34-P2.

[0748] The retention time RT of 34-P1 was 10.582 min.

[0749] LC-MS, M / Z(ESI): 668.25[M+H] +

[0750] 1 H NMR(400MHz,CD3OD)δ7.8(s,1H),6.98–6.92(m,2H),6.79(s,1H),5.68–5.62(m,1H) ),5.57–5.52(m,1H),4.63–4.55(m,1H),3.94–3.83(m,4H),3.22–3.12(m,2H),2.8 3–2.74(m,2H),2.71–2.61(m,2H),2.40–2.32(m,2H),2.27(s,3H),2.15–2.11(m,3 H),2.05–1.95(m,2H),1.81–1.77(m,3H),1.44–1.35(m,1H),0.97–0.91(m,6H)ppm.

[0751] The retention time RT of 34-P2 was 12.904 min.

[0752] LC-MS, M / Z(ESI): 668.25[M+H] +

[0753] 1H NMR(400MHz,CD3OD)δ7.71(s,1H),7.04–6.97(m,2H),6.90(s,1H),5.72–5.67(m,1H),5.65–5.59 (m,1H),4.70–4.50(m,1H),4.10–3.97(m,4H),3.37–3.23(m,2H),2.92–2.85(m,1H),2.80–2.73(m ,1H),2.64–2.57(m,1H),2.53–2.46(m,1H),2.46–2.37(m,2H),2.30(s,3H),2.20–2.15(m,3H),2 .01–1.94(m,1H),1.88–1.83(m,3H),1.71–1.64(m,1H),1.43–1.33(m,1H),0.92–0.85(m,6H)ppm.

[0754] Example 9: Preparation of target compounds 37-P1 and 37-P2

[0755] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionic acid

[0756] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionic acid

[0757] Compound 37-P1 is one of the structures of the two compounds mentioned above, while compound 37-P2 is the other structure.

[0758] The synthetic routes for target compounds 37-P1 and 37-P2 are as follows:

[0759] Step 1: Synthesis of ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (37B)

[0760] Ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33A) (300 mg, 0.704 mmol), (1,3,5-trimethyl-1H-pyrazole-4-yl)boronic acid (217 mg, 1.41 mmol), potassium carbonate (292 mg, 2.12 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and the mixture was microwaved at 90 °C for 40 min. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were 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 (PE / EA(v / v)=3 / 1) to obtain ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (37B).

[0761] LC-MS, M / Z (ESI): 456.2 (M+H) +

[0762] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37C)

[0763] Ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (37B) (250 mg, 0.549 mmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (5 mL, 4 mol / L) was added. The mixture was reacted at 25 °C for 5 h. After the reaction was complete, the mixture was concentrated, and water (10 mL) was added to quench the reaction. The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37C).

[0764] LC-MS, M / Z (ESI): 352.2 (M+H) +

[0765] Step 3: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37D)

[0766] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (200 mg, 0.56 mmol), (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37C) (192 mg, 0.55 mmol), N-methylimidazolium (92 mg, 1.12 mmol), and tetramethylchlorourea hexafluorophosphate (236 mg, 0.84 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-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37D).

[0767] LC-MS, M / Z (ESI): 694.3 (M+H) + Step 4: Synthesis of target compounds 37-P1 and 37-P2

[0768] Ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,6-difluoro-3-methyl-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)propionate (37D) (200 mg, 0.288 mmol) and lithium hydroxide (21.2 mg, 0.88 mmol) were dissolved in tetrahydrofuran (5 mL) and water (1 mL) and reacted at 25 °C for 2 h. After the reaction was complete, the reaction solution was prepared by reverse phase chromatography (column: YMC-Triart Prep C18, 7μm 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 37-P1 and 37-P2.

[0769] Target compound 37-P1:

[0770] The retention time RT of 37-P1 was 8.56 min.

[0771] LC-MS, M / Z (ESI): 666.3 (M+H) +

[0772] 1 H NMR(400MHz,CD3OD)δ7.81(s,1H),6.98(t,1H),6.85(s,1H),5.76-5.69(m,2H),3.94(t,4H),3.74(s,3H),3.29-3.25(m,2H),2.83(dd,1H) ,2.76(t,2H),2.66(dd,1H),2.41-2.38(m,2H),2.23(s,3H),2.12(s,3H),2.05(s,3H),2.04-1.98(m,2H),1.38-1.35(m,1H),0.93(d,6H).

[0773] Target compound 37-P2:

[0774] The retention time RT for 37-P2 was 10 min.

[0775] LC-MS, M / Z (ESI): 666.3 (M+H) +

[0776] 1H NMR(400MHz,CD3OD)δ7.68(s,1H),7.03(t,1H),6.93(s,1H),5.90(dd,1H), 5.63(t,1H),4.09(b,4H),3.75(s,3H),3.38–3.31(m,2H),2.91-2.89(m,1H ),2.78–2.74(m,2H),2.51-2.43(m,3H),2.27(s,3H),2.15(s,3H),2.09(s, 3H),1.93–1.90(m,1H),1.77-1.74(m,1H),1.35-1.33(m,1H),0.89(dd,6H).

[0777] Example 10: Preparation of target compounds 38-P1 and 38-P2

[0778] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0779] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0780] Compound 38-P1 is one of the structures of the two compounds mentioned above, while compound 38-P2 is the other structure.

[0781] The synthetic routes for target compounds 38-P1 and 38-P2 are as follows:

[0782] Step 1: Synthesis of ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (38B)

[0783] Ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33A) (500 mg, 1.2 mmol), 4,4,5,5-tetramethyl-2-(2,4,5-trimethylthiophene-3-yl)-1,3,2-dioxaborane (38A) (565 mg, 2.4 mmol), potassium carbonate (500 mg, 3.6 mmol), and 1,1-bis(diphenylphosphine)diferropalladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and reacted at 110 °C for 2 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 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 (PE / EA(v / v) = 3 / 1) to obtain ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (38B).

[0784] LC-MS, M / Z (ESI): 472.1 (M+H) +

[0785] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (38C)

[0786] Ethyl (3S)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (38B) (300 mg, 0.6 mmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (5 mL, 4 mol / L) was added. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, the solution was concentrated, and the reaction was quenched with water (10 mL). The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (38C).

[0787] LC-MS, M / Z (ESI): 368.2 (M+H) +

[0788] Step 3: Synthesis of ethyl(3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (38D)

[0789] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (100 mg, 0.27 mmol), ethyl (3S)-3-amino-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (38C) (110 mg, 0.30 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (118 mg, 0.42 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-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (38D).

[0790] LC-MS, M / Z (ESI): 710.1 (M+H) +

[0791] Compound 38D was resolved into 65-P1 and 65-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.

[0792] The structures of 65-P1 and 65-P2 are as follows:

[0793] Compound 65-P1 is one of the structures of the two compounds mentioned above, while compound 65-P2 is the other structure.

[0794] LC-MS, M / Z (ESI): 710.1 (M+H) +

[0795] Step 4: Synthesis of target compounds 38-P1 and 38-P2

[0796] Ethyl(3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(2,6-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (38D) (130 mg, 0.18 mmol) and LiOH-H2O (95 mg, 2.3 mmol) were dissolved in a mixture 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 prepared by preparative reverse-phase chromatography (column: YMC-Triart Prep C18, 7μm 30mm×40cm, solvent: A = water + 0.1 vol% ammonium bicarbonate (99%), B = acetonitrile; acetonitrile B%: 5%-95%, flow rate: 42mL / min, 13min) to obtain the target compounds 38-P1 and 38-P2.

[0797] Target compound 38-P1:

[0798] The retention time RT of 38-P1 was 7.52 min.

[0799] LC-MS, M / Z (ESI): 682.2 [M+H]+

[0800] 1 H NMR (400MHz, CD3OD) δ7.80(s,1H),6.92-6.85(m,2H),5.74-5.68(m,2H),3.92(s,4H),3.20-1.76(m,22H),1.37-1.29(m,1H),0.96-0.93(m,6H).

[0801] Target compound 38-P2:

[0802] The retention time RT of 38-P2 was 9.30 min.

[0803] LC-MS, M / Z (ESI): 682.2 [M+H]+

[0804] 1 H NMR (400MHz, CD3OD) δ7.72(s,1H),6.97-6.92(m,2H),5.91-5.62(m,2H),4.06(s,4H),3.34-1.83(m,22H),1.34-1.29(m,1H),0.90-0.81(m,6H).

[0805] Example 11: Preparation of target compounds 39-P1 and 39-P2

[0806] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[0807] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[0808] Compound 39-P1 is one of the structures of the two compounds mentioned above, while compound 39-P2 is the other structure.

[0809] The synthetic routes for target compounds 39-P1 and 39-P2 are as follows:

[0810] Step 1: Synthesis of 2-(3,5-dimethylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (39B)

[0811] 2-Bromo-3,5-dimethylthiophene (39A) (1.8 g, 9.4 mmol), pinacol diboronate (4.78 g, 18.8 mmol), potassium acetate (2.65 g, 28.2 mmol), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (688 mg, 0.94 mmol) were dissolved in dioxane (30 mL) and reacted at 90 °C for 1 h. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 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 (PE / EA (v / v) = 3 / 1) to give 2-(3,5-dimethylthiophene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (39B).

[0812] LC-MS, M / Z (ESI): 239.1 (M+H) +

[0813] Step 2: Synthesis of ethyl (3S)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (39C)

[0814] Ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33A) (500 mg, 1.2 mmol), 2-(3,5-dimethylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (39B) (565 mg, 2.4 mmol), potassium carbonate (500 mg, 3.6 mmol), and 1,1-bis(diphenylphosphine)diferro-palladium dichloride (88 mg, 0.12 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and reacted at 110 °C for 2 h. After the reaction was complete, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 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 (PE / EA (v / v) = 3 / 1) to obtain ethyl (3S)-3-(3-(3,5-dimethylthiophene-2-yl)-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (39C).

[0815] LC-MS, M / Z (ESI): 458.1 (M+H) +

[0816] Step 3: Synthesis of ethyl (3S)-3-amino-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39D)

[0817] Ethyl (3S)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (39C) (300 mg, 0.6 mmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (5 mL, 4 mol / L) was added. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, the solution was concentrated, and the reaction was quenched with water (10 mL). The pH was adjusted to about 8 with saturated sodium bicarbonate solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl (3S)-3-amino-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39D).

[0818] LC-MS, M / Z (ESI): 354.2 (M+H) +

[0819] Step 4: Synthesis of ethyl(3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39E)

[0820] 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (100 mg, 0.27 mmol), (3S)-3-amino-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39D) (110 mg, 0.32 mmol), N-methylimidazolium (46 mg, 0.56 mmol), and tetramethylchlorourea hexafluorophosphate (118 mg, 0.42 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-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39E).

[0821] LC-MS, M / Z (ESI): 696.1 (M+H) +

[0822] Step 5: Synthesis of target compounds 39-P1 and 39-P2

[0823] Ethyl(3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamide)-3-(3-(3,5-dimethylthiophen-2-yl)-2,6-difluoro-5-methylphenyl)propionate (39E) (140 mg, 0.2 mmol), LiOH-H2O (95 mg, 2.3 mmol) was 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 prepared by preparative reverse-phase chromatography (column: YMC-Triart Prep C18, 7μm 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 39-P1 and 39-P2.

[0824] Target compound 39-P1:

[0825] The retention time RT of 39-P1 was 9.27 min.

[0826] LC-MS, M / Z (ESI): 668.2 [M+H] +

[0827] 1 H NMR (400MHz, CD3OD) δ7.80(s,1H),7.08-6.59(m,3H),5.74-5.70(m,2H),3.94(s,4H),3.30-1.96(m,19H),1.37-1.36(m,1H),0.94-0.93(m,6H).

[0828] Target compound 39-P2:

[0829] The retention time RT of 39-P2 was 10.88 min.

[0830] LC-MS, M / Z (ESI): 668.2 [M+H] +

[0831] 1 H NMR (400MHz, CD3OD) δ7.69(s,1H),7.14-6.61(m,3H),5.91-5.62(m,2H),4.09(s,4H),3.38-1.91(m,19H),1.34-1.32(m,1H),0.90-0.86(m,6H).

[0832] Example 12: Preparation of target compounds 40-P1 and 40-P2

[0833] (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)propionic acid

[0834] (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)propionic acid

[0835] Compound 40-P1 is one of the structures of the two compounds mentioned above, while compound 40-P2 is the other structure.

[0836] The synthetic routes for the target compounds 40-P1 and 40-P2 are as follows:

[0837] Step 1: Synthesis of ethyl (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (40A)

[0838] To a solution of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (200 mg, 0.57 mmol) in acetonitrile (2 mL), ethyl (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47F) (301 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (242 mg, 0.86 mmol) and N-methylimidazole (94 mg, 1.15 mmol). The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain the product (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (40A).

[0839] LC-MS, M / Z (ESI): 698.3 [M+H] +

[0840] Compound 40A was resolved into 66-P1 and 66-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.

[0841] The structures of 66-P1 and 66-P2 are as follows:

[0842] Compound 66-P1 is one of the structures of the two compounds mentioned above, while compound 66-P2 is the other structure.

[0843] LC-MS, M / Z (ESI): 698.3 [M+H] +

[0844] Step 2: Synthesis of target compounds 40-P1 and 40-P2

[0845] Lithium hydroxide monohydrate (54 mg, 1.3 mmol) was added to a solution of (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (40A) (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 reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, 7μm 30mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 20%-70%) to obtain the target compounds 40-P1 and 40-P2.

[0846] Target compound 40-P1:

[0847] The retention time RT of 40-P1 was 9.3 min.

[0848] LC-MS, M / Z (ESI): 670.2 [M+H] +

[0849] 1 H NMR(600MHz,DMSO-d6)δ9.03(d,J=7.6Hz,1H),7.78(s,1H),7.00(dd,J=12.8,8.0Hz,1H),6.65(d, J=8.8Hz,1H),5.54(dd,J=10.8,5.6Hz,1H),5.38(dd,J=14.8,7.2Hz,1H),2.66(d,J=7.2Hz,2H),2 .61-2.50(m,2H),2.33(d,J=7.6Hz,2H),2.26(d,J=10.4Hz,3H),2.18-2.08(m,11H),1.99-1.85(m ,3H),1.81-1.67(m,3H),1.63(s,1H),1.29(dt,J=13.6,6.8Hz,1H),0.83(dd,J=26.8,6.8Hz,6H).

[0850] Target compound 40-P2:

[0851] The retention time RT of 40-P2 was 11.3 min.

[0852] LC-MS, M / Z (ESI): 670.2 [M+H] +

[0853] 1 H NMR (600MHz, DMSO-d6) δ9.13 (s, 1H), 7.79 (s, 1H), 7.07 (t, J = 7.6Hz, 1H), 6.7 5(s,1H),5.60-5.55(m,1H),5.42(dd,J=14.8,7.6Hz,1H),2.67-2.52(m,5H), 2.42(dd,J=14.0,6.8Hz,2H),2.29(s,3H),2.19(s,9H),2.13(d,J=3.6Hz,3H) ,1.85-1.75(m,4H),1.66-1.59(m,1H),1.21-1.14(m,1H),0.79-0.72(m,6H).

[0854] Example 13: Preparation of target compounds 41-P1 and 41-P2

[0855] (3S)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl)propionic acid

[0856] (3S)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl)propionic acid

[0857] Compound 41-P1 is one of the structures of the two compounds mentioned above, while compound 41-P2 is the other structure.

[0858] The synthetic routes for target compounds 41-P1 and 41-P2 are as follows:

[0859] Step 1: Synthesis of 3,5-dimethyl-1,2-thiazole (41B)

[0860] To a solution of 5-bromo-3-methyl-1,2-thiazole (41A) (1 g, 5.6 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (1.05 g, 8.4 mmol) in dioxane (10 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (804 mg, 1.1 mmol) and potassium phosphate (3.56 g, 16.8 mmol) were added, purging with argon three times, and then stirred at 90 °C for 18 hours. Water (50 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 (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) = 1:0-10:1) to give 3,5-dimethyl-1,2-thiazole (41B).

[0861] LC-MS, M / Z (ESI): 114.2 [M+H] +

[0862] Step 2: Synthesis of 4-iodo-3,5-dimethyl-1,2-thiazole (41C)

[0863] 3,5-Dimethyl-1,2-thiazole (41B) (200 mg, 1.77 mmol) was dissolved in concentrated nitric acid (2 mL). Elemental iodine (673 mg, 2.65 mmol) was slowly added to the reaction solution at 0 °C, and the mixture was stirred at 80 °C for 2 hours. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium thiosulfate solution (20 mL × 2), followed by washing with saturated brine (20 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) = 1:0-10:1) to obtain 4-iodo-3,5-dimethyl-1,2-thiazole (41C).

[0864] LC-MS, M / Z (ESI): 240.2 [M+H] +

[0865] Step 3: Synthesis of ethyl (3S)-3-[2,4-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41D)

[0866] To a solution of (3S)-3-(5-bromo-2,4-difluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (47D) (500 mg, 1.2 mmol) in dioxane (5 mL), pinacol borate (596 mg, 2.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (86 mg, 0.12 mmol), and potassium acetate (348 mg, 3.5 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 hours. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 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) = 1:0-0:1) to obtain ethyl (3S)-3-[2,4-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41D).

[0867] LC-MS, M / Z (ESI): 474.3 [M+H] +

[0868] Step 4: Synthesis of ethyl (3S)-3-[5-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,4-difluoro-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41E)

[0869] To a solution of (3S)-3-[2,4-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41D) (150 mg, 0.63 mmol) and 4-iodo-3,5-dimethyl-1,2-thiazole (297 mg, 0.63 mmol) in dioxane (3 mL) and water (0.3 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (46 mg, 0.06 mmol) and potassium carbonate (260 mg, 1.89 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 hours. Water (50 mL) was added to the reaction solution, and then the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and 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-[5-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,4-difluoro-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41E).

[0870] LC-MS, M / Z (ESI): 459.3 [M+H] +

[0871] Step 5: Synthesis of ethyl (3S)-3-amino-3-[5-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,4-difluoro-3-methylphenyl]propionate (41F)

[0872] Ethyl (41E) propionate (4S)-3-[5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41E) (150 mg, 0.33 mmol) in dioxane (1 mL) was added to a solution of dioxane (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 1:0-10:1) to obtain ethyl (4S)-3-amino-3-[5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl]propionate (41F, hydrochloride).

[0873] LC-MS, M / Z (ESI): 355.3 [M+H] +

[0874] Step 6: Synthesis of ethyl (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[5-(3,5-dimethyl-1,2-thiazolyl)-2,4-difluoro-3-methylphenyl]propionate (41G)

[0875] To a solution of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (80 mg, 0.23 mmol) in acetonitrile (1 mL), ethyl (3S)-3-amino-3-[5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl]propionate (41F) (81 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (97 mg, 0.34 mmol) and N-methylimidazole (56 mg, 0.69 mmol). The mixture was stirred at room temperature for 3 hours. The reaction solution was 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 ethyl (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[5-(3,5-dimethyl-1,2-thiazo-4-yl)-2,4-difluoro-3-methylphenyl]propionate (41G).

[0876] LC-MS, M / Z (ESI): 685.3 [M+H] +

[0877] Step 7: Synthesis of target compounds 41-P1 and 41-P2

[0878] Lithium hydroxide monohydrate (18 mg, 0.45 mmol) was added to a solution of ethyl (3S)-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[5-(3,5-dimethyl-1,2-thiazolyl)-2,4-difluoro-3-methylphenyl]propionate (41 G) (100 mg, 0.15 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 chromatography (column: YMC-Triart Prep C18, 7μm 30mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 30%-80%, 13min) to obtain the target compounds 41-P1 and 41-P2.

[0879] Target compound 41-P1:

[0880] The retention time RT of 41-P1 was 7.1 min.

[0881] LC-MS, M / Z (ESI): 657.2 [M+H] +

[0882] 1 H NMR(600MHz,DMSO-d6)δ9.08(d,J=7.6Hz,1H),7.80(s,1H),7.12(t,J=8.0Hz,1H),6.64(s,1H), 5.54(dd,J=10.8,5.6Hz,1H),5.39(dd,J=14.8,7.2Hz,1H),2.69(d,J=7.2Hz,2H),2.57(ddd,J=2 8.8,14.8,7.6Hz,3H),2.34(dd,J=18.0,9.4Hz,4H),2.24-2.00(m,13H),1.95(t,J=10.0Hz,1H) ,1.75(ddd,J=14.4,9.2,5.6Hz,1H),1.31(dt,J=13.6,6.8Hz,1H),0.85(dd,J=30.0,6.8Hz,6H).

[0883] Target compound 41-P2:

[0884] The retention time RT of 41-P2 was 8.3 min.

[0885] LC-MS, M / Z (ESI): 657.2 [M+H] +

[0886] 1 H NMR(600MHz,DMSO-d6)δ9.10(d,J=7.6Hz,1H),7.80(s,1H),7.21(t,J=8.0Hz,1 H),6.76(s,1H),5.57(dd,J=10.4,5.6Hz,1H),5.44(dd,J=15.2,7.6Hz,1H),2.7 2-2.52(m,5H),2.45(dd,J=16.0,10.0Hz,3H),2.34(s,3H),2.21(s,11H),1.82- 1.76(m,1H),1.67-1.60(m,1H),1.20-1.14(m,1H),0.76(dd,J=9.6,6.8Hz,6H).

[0887] Example 14: Preparation of target compounds 42-P1 and 42-P2

[0888] (3S)-3-(2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)propionic acid

[0889] (3S)-3-(2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoyl)propionic acid

[0890] Compound 42-P1 is one of the structures of the two compounds mentioned above, while compound 42-P2 is the other structure.

[0891] The synthetic routes for target compounds 42-P1 and 42-P2 are shown below:

[0892] Step 1: Synthesis of 3-bromo-4-fluoro-2,5-dimethylthiophene (42B)

[0893] 3,4-Dibromo-2,5-dimethylthiophene (42A) (500 mg, 1.85 mmol) was dissolved in tetrahydrofuran (5 mL), and the mixture was purged with argon three times. At -78 °C, n-butyllithium (1.1 mL, 2.76 mmol, 2.5 M n-hexane solution) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 0.5 hours. Then, a tetrahydrofuran (5 mL) solution of N-fluorobis(benzenesulfonamide) (619 mg, 1.96 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred for another 2 hours. A saturated ammonium chloride solution (30 mL) was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 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) = 1:0-10:1) to obtain 3-bromo-4-fluoro-2,5-dimethylthiophene (42B).

[0894] Step 2: Synthesis of (3S)-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophene-3-yl)-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}ethyl propionate (42C)

[0895] To a solution of 3-bromo-4-fluoro-2,5-dimethylthiophene (42B) (200 mg, 0.96 mmol) and ethyl (3S)-3-[2,4-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (41D) (679 mg, 1.43 mmol) in dioxane (3 mL) and water (0.3 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (140 mg, 0.19 mmol) and potassium carbonate (397 mg, 2.87 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 hours. Water (50 mL) was added to the reaction mixture, and then it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and 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-5-(4-fluoro-2,5-dimethylthiophene-3-yl)-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (42C).

[0896] LC-MS, M / Z (ESI): 476.3 [M+H] +

[0897] Step 3: Synthesis of ethyl (3S)-3-amino-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]propionate (42D)

[0898] Ethyl (42C) propionate (300 mg, 0.63 mmol) of (3S)-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (42C) was added to a 2 mL solution of dioxane and stirred at room temperature for 1 hour. The reaction solution was 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 ethyl (42D, hydrochloride) propionate (4S)-3-amino-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]propionate.

[0899] LC-MS, M / Z (ESI): 372.2 [M+H] +

[0900] Step 4: Synthesis of (3S)-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42E)

[0901] To a solution of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (50 mg, 0.14 mmol) in acetonitrile (1 mL), ethyl (3S)-3-amino-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]propionate (42D) (64 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (60 mg, 0.22 mmol) and N-methylimidazole (35 mg, 0.43 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was 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-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42E).

[0902] LC-MS, M / Z (ESI): 702.3 [M+H]+

[0903] Step 5: Synthesis of target compounds 42-P1 and 42-P2

[0904] Lithium hydroxide monohydrate (10 mg, 0.23 mmol) was added to a solution of (3S)-3-[2,4-difluoro-5-(4-fluoro-2,5-dimethylthiophen-3-yl)-3-methylphenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (42E) (55 mg, 0.078 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 reverse-phase preparation (column: ASAYMC-Triart Prep C18, 7μm 30mm×40cm; mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 42ml / min, gradient B%: 20%-100%) to obtain the target compounds 42-P1 and 42-P2.

[0905] Target compound 42-P1:

[0906] The retention time RT of 42-P1 was 8.33 min.

[0907] LC-MS, M / Z (ESI): 674.2 [M+H] +

[0908] 1 H NMR(600MHz,DMSO-d6)δ9.06(t,J=6.8Hz,1H),7.77(s,1H),7.13(dd,J=18.8,8.4Hz,1H ),6.69-6.62(m,1H),5.56(dd,J=10.4,5.6Hz,1H),5.39(dd,J=13.6,6.0Hz,1H),2.74- 2.50(m,6H),2.41-2.25(m,5H),2.21-2.12(m,11H),1.92(ddd,J=14.6,10.0,4.8Hz,1H ),1.76(ddd,J=14.4,8.8,5.6Hz,1H),1.35-1.28(m,1H),0.85(dd,J=24.8,6.4Hz,6H).

[0909] Target compound 42-P2:

[0910] The retention time RT of 42-P2 was 9.49 min.

[0911] LC-MS, M / Z (ESI): 674.2 [M+H] +

[0912] 1 H NMR(600MHz,DMSO-d6)δ9.15-9.10(m,1H),7.81-7.77(m,1H),7.21-7.16(m,1H),6.76 -6.65(m,1H),5.60(dd,J=10.8,5.6Hz,1H),5.40(dd,J=7.2,4.4Hz,1H),2.71-2.51(m, 5H),2.42(dd,J=16.4,9.6Hz,4H),2.29-2.23(m,4H),2.19(s,8H),2.04-1.94(m,1H), 1.87-1.79(m,1H),1.67(dt,J=14.4,6.0Hz,1H),1.21-1.17(m,1H),0.85-0.73(m,6H).

[0913] Example 15: Preparation of target compounds 43-P1 and 43-P2

[0914] (3S)-3-(2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0915] (3S)-3-(2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0916] Compound 43-P1 is one of the structures of the two compounds mentioned above, while compound 43-P2 is the remaining structure.

[0917] The synthetic routes for target compounds 43-P1 and 43-P2 are shown below:

[0918] Step 1: Synthesis of 5-bromo-2,4-difluoro-3-(trifluoromethyl)benzaldehyde (43B)

[0919] 1-Bromo-2,4-difluoro-3-(trifluoromethyl)benzene (43A) (2 g, 7.7 mmol) was dissolved in tetrahydrofuran (20 mL), and argon gas was purged three times. A solution of lithium diisopropylamino (16 mL, 16 mmol, 2 M tetrahydrofuran) was slowly added dropwise to the solution at -78 °C, and the mixture was stirred for 1 hour at -78 °C. Then, N,N-dimethylformamide (0.6 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred for another 1 hour at -78 °C. A saturated ammonium chloride solution (20 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5-bromo-2,4-difluoro-3-(trifluoromethyl)benzaldehyde (43B). The crude product was used directly in the next reaction step.

[0920] Step 2: (S) 2 Synthesis of S)-N-{(E)-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide (43C)

[0921] R-tert-butylsulfinamide (1.1 g, 9 mmol) and tetraethyl titanate (4.7 g, 20.7 mmol) were added to a tetrahydrofuran (20 mL) solution of 5-bromo-2,4-difluoro-3-(trifluoromethyl)benzaldehyde (43B), and the mixture was stirred at 40 °C for 3 h. 1 mL of water was added to the reaction mixture, and the mixture was then 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 (S 2 S)-N-{(E)-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide (43C).

[0922] LC-MS, M / Z (ESI): 394.2 [M+H] +

[0923] Step 3: Synthesis of ethyl (3S)-3-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (43D)

[0924] Add zinc powder (500 mg, 7.6 mmol) and trimethylchlorosilane (33 mg, 0.3 mmol) to tetrahydrofuran (3 mL), purging the argon atmosphere, and then stir at 60 °C for 1 hour. Add ethyl bromoacetate (639 mg, 3.8 mmol) to the reaction mixture at -20 °C, raise the temperature to 50 °C, and continue stirring for 1 hour. Then add (S) to the reaction mixture at -20 °C. 2 (3S)-N-{(E)-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide (43C) (600 mg, 1.5 mmol), stirred at room temperature for 1 hour. The reaction solution was 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 give ethyl (3S)-3-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (43D).

[0925] LC-MS, M / Z (ESI): 482.2 [M+H] +

[0926] Step 4: Synthesis of (3S)-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate ethyl ester (43E)

[0927] To a solution of (3S)-3-[5-bromo-2,4-difluoro-3-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (43D) (300 mg, 0.6 mmol) and 4,4,5,5-tetramethyl-2-(2,4,5-trimethylthiophene-3-yl)-1,3,2-dioxaborane (38A) (394 mg, 1.6 mmol) in dioxane (3 mL) and water (0.3 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (91 mg, 0.12 mmol) and potassium carbonate (259 mg, 1.8 mmol) were added, purging with argon three times, and then stirred at 90 °C for 18 hours. Water (50 mL) was added to the reaction solution, and then the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and 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-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (43E).

[0928] LC-MS, M / Z (ESI): 526.3 [M+H] +

[0929] Step 5: Synthesis of ethyl (3S)-3-amino-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]propionate (43F)

[0930] To a solution of (3S)-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophen-3-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (43E) (120 mg, 0.23 mmol) in dioxane (1 mL), hydrochloric acid solution (1 mL, 4 M dioxane solution) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain (3S)-3-amino-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophen-3-yl)phenyl]propionate (43F, hydrochloride).

[0931] LC-MS, M / Z (ESI): 422.2 [M+H] +

[0932] Step 6: Synthesis of (3S)-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (43G)

[0933] To a solution of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (32H) (70 mg, 0.2 mmol) in dichloromethane (1 mL), O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (115 mg, 0.3 mmol) and diisopropylethylamine (98 mg, 0.8 mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Then, ethyl (3S)-3-amino-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]propionate (43F) (93 mg, hydrochloride) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture 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 ethyl (3S)-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophene-3-yl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (43G).

[0934] LC-MS, M / Z (ESI): 752.2 [M+H] +

[0935] Step 7: Synthesis of target compounds 43-P1 and 43-P2

[0936] Lithium hydroxide monohydrate (7 mg, 0.168 mmol) was added to a solution of ethyl (3S)-3-[2,4-difluoro-3-(trifluoromethyl)-5-(2,4,5-trimethylthiophen-3-yl)phenyl]-3-(2-{5-[2-(dimethylamino)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)propionate (43 G) (42 mg, 0.056 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 reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, 7μm 30mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 20%-70%) to obtain the target compounds 43-P1 and 43-P2.

[0937] Target compound 43-P1:

[0938] The retention time RT of 43-P1 was 12.7 min.

[0939] LC-MS, M / Z (ESI): 724.2 [M+H] +

[0940] 1 H NMR(600MHz,DMSO-d6)δ9.28(s,1H),7.78(s,1H),7.53(dd,J=12.8,7.6Hz,1H),6.65( d,J=11.2Hz,1H),5.52(dd,J=10.4,5.6Hz,1H),5.37(dd,J=14.0,7.2Hz,1H),2.90(s,1 H),2.71-2.62(m,2H),2.60-2.50(m,3H),2.36-2.22(m,5H),2.14(s,7H),1.99-1.91(m ,2H),1.82-1.74(m,2H),1.64(s,1H),1.33-1.21(m,2H),0.85(dd,J=25.2,6.4Hz,6H).

[0941] Target compound 43-P2:

[0942] The retention time RT of 43-P2 was 14.7 min.

[0943] LC-MS, M / Z (ESI): 724.2 [M+H] +

[0944] 1H NMR(600MHz, DMSO-d6)δ9.25(s,1H),7.79(s,1H),7.61(t,J=7.6Hz,1H),6.75(s,1H),5.58-5.52(m,1H),5.42-5.37(m,1H),2.77-2.51(m,6H), 2.47-2.39(m,2H),2.30(s,3H),2.17(d,J=20.8Hz,8H),1.86-1.74(m,4 H),1.68-1.61(m,1H),1.21-1.15(m,1H),0.77(dd,J=12.4,6.4Hz,6H).

[0945] Example 16: Preparation of target compounds 44-P1 and 44-P2

[0946] (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2R)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0947] (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-((2S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionic acid

[0948] Compound 44-P1 is one of the structures of the two compounds mentioned above, while compound 44-P2 is the other structure.

[0949] The synthetic routes for target compounds 44-P1 and 44-P2 are shown below:

[0950] Step 1: Synthesis of ethyl (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (44B)

[0951] Under nitrogen protection and at 0°C, ethyl (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47F) (220 mg, 0.6 mmol) and 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (44A) (217 mg, 0.6 mmol) in anhydrous acetonitrile (3 mL) were added to a solution of N-methylimidazolium (246 mg, 3 mmol). Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 336 mg, 1.2 mmol) was 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 (eluent: dichloromethane: methanol (v / v) = 10:1) to give ethyl (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (44B).

[0952] LC-MS, M / Z(ESI): 712.31[M+H] +

[0953] Step 2: Synthesis of target compounds 44-P1 and 44-P2

[0954] Lithium hydroxide monohydrate (105 mg, 2.5 mmol) was added to a mixed solution of (3S)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)-3-(2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)propionate (44B) (310 mg, 0.43 mmol) in tetrahydrofuran (2 mL) and water (0.6 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 42mL / min, gradient B%: 30%-70%) to obtain the target compounds 44-P1 and 44-P2.

[0955] Target compound 44-P1:

[0956] The retention time RT of 44-P1 was 7.33 min.

[0957] LC-MS, M / Z(ESI): 683.28[M+H] +

[0958] 1 H NMR(400MHz,CD3OD)δ7.78(s,1H),6.96(t,J=8.2Hz,1H),6.76(d,J=4.8Hz,1H) ,5.75–5.69(m,1H),5.54–5.49(m,1H),3.10–3.00(m,2H),2.78(s,6H),2.70–2. 61(m,4H),2.29(d,J=4.5Hz,3H),2.19(d,J=1.9Hz,3H),2.14(s,1H),2.07–1.88 (m,7H),1.82(s,1H),1.71(s,1H),1.40–1.27(m,2H),0.93(d,J=6.6Hz,6H)ppm.

[0959] Target compound 44-P2:

[0960] The retention time RT of 44-P2 was 9.06 min.

[0961] LC-MS, M / Z(ESI): 683.28[M+H] +

[0962] 1H NMR (400MHz, CD3OD) δ7.80(s,1H),6.96(td,J=8.3,2.7Hz,1H),6.85(s,1H),5.65(dd,J=9.9,4.1Hz,1H),5.59( td,J=7.6,2.1Hz,1H),3.05–2.96(m,2H),2.77(s,6H),2.66(dt,J=14.9,6.3Hz,1H),2.59(dt,J=15.4,4.2Hz,2H ),2.52(dd,J=15.4,9.9Hz,1H),2.30(d,J=2.6Hz,3H),2.23(d,J=1.7Hz,3H),2.13(d,J=2.4Hz,3H),2.06–1.93 (m,3H),1.82(d,J=3.6Hz,3H),1.65(dt,J=14.1,7.2Hz,1H),1.38–1.28(m,2H),0.86(dt,J=6.1,2.8Hz,6H)ppm.

[0963] Example 17: Preparation of target compounds 45-P1 and 45-P2

[0964] (3S)-3-((2R)-2-(5-(3-(azacyclobutan-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0965] (3S)-3-((2S)-2-(5-(3-(azacyclobutan-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0966] Compound 45-P1 is one of the structures of the two compounds mentioned above, while compound 45-P2 is the other structure.

[0967] The synthetic routes for target compounds 45-P1 and 45-P2 are shown below:

[0968] Step 1: Synthesis of ethyl (3S)-3-(2-(5-(3-(azacyclobutan-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (45B)

[0969] Under nitrogen protection and at 0°C, ethyl (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47F) (200 mg, 0.54 mmol) and anhydrous acetonitrile (3 mL) of 2-(5-(3-(azacyclobutane-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (45A) (202 mg, 0.54 mmol) were added to the reaction mixture. Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 302 mg, 1.08 mmol) was added dropwise to the reaction mixture. 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 (eluent: dichloromethane: methanol (v / v) = 10:1) to give ethyl (3S)-3-(2-(5-(3-(azacyclobutan-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (45B).

[0970] LC-MS, M / Z(ESI): 724.31[M+H] +

[0971] Step 2: Synthesis of target compounds 45-P1 and 45-P2

[0972] Lithium hydroxide monohydrate (57 mg, 1.35 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(3-(azacyclobutan-1-yl)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (45B) (200 mg, 0.27 mmol) in tetrahydrofuran (2 mL) and water (0.6 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reversed-phase preparative chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 42mL / min, gradient B%: 30%-70%) to obtain the target compounds 45-P1 and 45-P2.

[0973] Target compound 45-P1:

[0974] The retention time RT of 45-P1 was 7.51 min.

[0975] LC-MS, M / Z(ESI): 696.28[M+H] +

[0976] 1 H NMR (400MHz, CD3OD) δ7.78(s,1H),6.96(t,J=8.2Hz,1H),6.75(d,J=4.7Hz,1H),5.71(dt,J= 10.7,5.5Hz,1H),5.54–5.50(m,1H),4.05(t,J=8.2Hz,4H),3.16–3.10(m,2H),2.69–2.58(m, 4H),2.47–2.39(m,2H),2.29(d,J=4.7Hz,3H),2.19(d,J=1.8Hz,3H),2.14(s,1H),2.06–1.9 4(m,4H),1.89–1.80(m,2H),1.77–1.69(m,2H),1.39–1.27(m,3H),0.93(d,J=6.6Hz,6H)ppm.

[0977] Target compound 45-P2:

[0978] The retention time RT of 45-P2 was 9.16 min.

[0979] LC-MS, M / Z(ESI): 696.28[M+H] +

[0980] 1 H NMR (400MHz, CD3OD) δ7.78(s,1H),6.95(td,J=8.2,3.7Hz,1H),6.83(s,1H),5.66(dd,J=9.9,4.1Hz,1H),5.57(td,J=7. 6,1.6Hz,1H),4.10–3.98(m,4H),3.10(td,J=11.6,5.6Hz,1H),3.02(td,J=11.8,4.5Hz,1H),2.69–2.51(m,4H),2.47–2. 38(m,2H),2.30(d,J=2.5Hz,3H),2.23(d,J=1.7Hz,3H),2.13(d,J=3.7Hz,3H),2.04–1.93(m,1H),1.88(tq,J=11.8,6.0 Hz,1H),1.82(d,J=4.8Hz,3H),1.80–1.69(m,1H),1.67–1.58(m,1H),1.37–1.27(m,2H),0.85(dt,J=6.3,3.0Hz,6H)ppm.

[0981] Example 18: Preparation of target compounds 47-P1 and 47-P2

[0982] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0983] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[0984] Compound 47-P1 is one of the structures of the two compounds mentioned above, while compound 47-P2 is the other structure.

[0985] The synthetic routes for target compounds 47-P1 and 47-P2 are shown below:

[0986] Step 1: Synthesis of 5-bromo-2,4-difluoro-3-methylbenzaldehyde (47B)

[0987] 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-3-methylbenzene (47A) (2.1 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 (petroleum ether:ethyl acetate (V / V) = 1:0) to give 5-bromo-2,4-difluoro-3-methylbenzaldehyde (47B).

[0988] Step 2: Synthesis of (R)-N-[(Z)-(5-bromo-2,4-difluoro-3-methylphenyl)methylene]-2-methylpropane-2-sulfinamide (47C)

[0989] Under nitrogen protection and at 0°C, ethyl titanate (Ti(OEt)4, 2.64 g, 11.6 mmol) was added to an anhydrous tetrahydrofuran (30 mL) solution of 5-bromo-2,4-difluoro-3-methylbenzaldehyde (47B) (1.8 g, 7.7 mmol) and (R)-2-methylpropane-2-sulfinamide (32C) (1.12 g, 9.27 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 give (R)-N-[(Z)-(5-bromo-2,4-difluoro-3-methylphenyl)methylene]-2-methylpropane-2-sulfinamide (47C).

[0990] LC-MS, M / Z (ESI): 337.99 [M+H] +

[0991] Step 3: Synthesis of ethyl (3S)-3-(5-bromo-2,4-difluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (47D)

[0992] Under nitrogen protection and at room temperature, trimethylchlorosilane (150 mg, 1.4 mmol) was added dropwise to a suspension of zinc powder (3.1 g, 46.8 mmol) in tetrahydrofuran (50 mL), and the mixture was reacted at 60 °C for 1 hour. The reaction solution was cooled to 20-30 °C, and ethyl bromoacetate (32E) (2.9 g, 17.34 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 reaction was continued at 60 °C for 1 hour, and then the reaction solution was cooled to 0 °C. (R)-N-[(Z)-(5-bromo-2,4-difluoro-3-methylphenyl)methylene]-2-methylpropane-2-sulfinamide (47C) (2.3 g, 6.84 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add saturated ammonium chloride solution (50 mL), extract three times with ethyl acetate (50 mL), combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain crude product. Purify by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain ethyl (3S)-3-(5-bromo-2,4-difluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (47D).

[0993] LC-MS, M / Z (ESI): 426.05 [M+H] +

[0994] Step 4: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47E)

[0995] Under nitrogen protection, 1,4-dioxane (18 mL) and water (1.8 mL) were added to a mixture of (3S)-3-(5-bromo-2,4-difluoro-3-methylphenyl)-3-(((R)-tert-butylsulfinyl)amino)propionate (47D) (800 mg, 1.88 mmol), potassium carbonate (780 mg, 5.64 mmol), 4,4,5,5-tetramethyl-2-(2,4,5-trimethylthiophen-3-yl)-1,3,2-dioxaborane (38A) (568 mg, 2.26 mmol) and Pd(dppf)Cl2 (167 mg, 0.23 mmol), and the mixture was then reacted at 85 °C for 16 hours. After the reaction solution was cooled to room temperature, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (20 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 (petroleum ether:ethyl acetate (V / V) = 4:1) to give ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47E).

[0996] LC-MS, M / Z(ESI): 472.17[M+H] +

[0997] Step 5: Synthesis of ethyl (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47F)

[0998] 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-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (47E) (471 mg, 1.0 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-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (47F), which was then directly used for the next reaction.

[0999] LC-MS, M / Z(ESI): 368.14[M+H] +

[1000] Step 6: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (47G)

[1001] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.4 mL, 2.2 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (47F) (220 mg, 0.6 mmol), 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (200 mg, 0.55 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (314 mg, 0.83 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 give ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (47 G).

[1002] LC-MS, M / Z(ESI): 710.30[M+H] +

[1003] Compound 47G was resolved into 67-P1 and 67-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.

[1004] The structures of 67-P1 and 67-P2 are as follows:

[1005] Compound 67-P1 is one of the structures of the two compounds mentioned above, while compound 67-P2 is the other structure.

[1006] LC-MS, M / Z(ESI): 710.30[M+H] +

[1007] Step 7: Synthesis of target compounds 47-P1 and 47-P2

[1008] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (47 G) (240 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 25%-75%) to obtain the target compounds 47-P1 and 47-P2.

[1009] Target compound 47-P1:

[1010] The retention time RT of 47-P1 was 12.125 min.

[1011] LC-MS, M / Z(ESI): 682.27[M+H] +

[1012] 1 H NMR(400MHz,CD3OD)δ7.77(s,1H),6.96-6.89(m,1H),6.75-6.71(m,1H), 5.74-5.68(m,1H),5.51-5.46(m,1H),3.47-3.39(m,4H),2.76-2.69(m,2H ),2.68-2.55(m,4H),2.31-2.26(m,3H),2.21-2.12(m,7H),2.05-1.93(m ,4H),1.82(s,1H),1.65(s,1H),1.48-1.35(m,2H),0.99-0.91(m,6H)ppm.

[1013] Target compound 47-P2:

[1014] The retention time RT of 47-P2 was 14.373 min.

[1015] LC-MS, M / Z(ESI): 682.27[M+H] +

[1016] 1 H NMR(400MHz,CD3OD)δ7.74(s,1H),7.04-6.98(m,1H),6.87(s,1H),5.66-5.59(m,2H) ,3.96-3.77(m,4H),3.21-3.06(m,2H),2.84-2.76(m,1H),2.75-2.67(m,1H),2.65-2 .49(m,2H),2.39-2.29(m,2H),2.30(s,3H),2.23(s,3H),2.15(s,3H),1.97-1.90(m, 1H),1.85-1.81(m,3H),1.75-1.67(m,1H),1.41-1.29(m,2H),0.93-0.84(m,6H)ppm.

[1017] Example 19: Preparation of target compounds 48-P1 and 48-P2

[1018] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[1019] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[1020] Compound 48-P1 is one of the structures of the two compounds mentioned above, while compound 48-P2 is the other structure.

[1021] The synthetic routes for target compounds 48-P1 and 48-P2 are as follows:

[1022] Step 1: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48B)

[1023] Under nitrogen protection, ethyl (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (33A) (500 mg, 1.18 mmol), potassium carbonate (489 mg, 3.54 mmol), Pd(dppf)Cl2 (145 mg, 0.2 mmol), and 1,4-dimethylpyrazole-5-boronic acid pinacol ester (48A) (393 mg, 1.77 mmol) were added to a mixture of 1,4-dioxane (6 mL) and water (0.6 mL), and the mixture was reacted overnight at 85 °C. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20 mL), and the mixture was extracted three times with ethyl acetate (30 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-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48B) was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:3).

[1024] LC-MS, M / Z(ESI): 442.19[M+H] +

[1025] Step 2: Synthesis of ethyl (3S)-3-amino-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48C)

[1026] 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 (5 mL) solution of (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(1,4-dimethyl-1H-pyrazole-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48B) (450 mg, 1.02 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-(3-(1,4-dimethyl-1H-pyrazole-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48C), which was then directly used for the next reaction.

[1027] LC-MS, M / Z(ESI): 338.16[M+H] +

[1028] Step 3: Synthesis of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48D)

[1029] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.55 mL, 3 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48C) (203 mg, 0.6 mmol), 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (216 mg, 0.6 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (302 mg, 0.8 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 (eluent: dichloromethane: methanol = 10:1) to obtain ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48D).

[1030] LC-MS, M / Z(ESI): 680.32[M+H] +

[1031] Step 4: Synthesis of target compounds 48-P1 and 48-P2

[1032] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,6-difluoro-5-methylphenyl)propionate (48D) (230 mg, 0.31 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reverse-phase preparative chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 15%-65%) to obtain the target compounds 48-P1 and 48-P2.

[1033] Target compound 48-P1:

[1034] The retention time RT of 48-P1 was 9.879 min.

[1035] LC-MS, M / Z(ESI): 652.28[M+H] +

[1036] 1 H NMR(400MHz,CD3OD)δ7.78(s,1H),7.34(s,1H),7.13–7.08(m,1H),6.83(s,1H),5.75–5.6 7(m,2H),3.90–3.84(m,3H),3.64–3.61(m,3H),3.19–3.09(m,2H),3.03-2.97(m,1H),2.9 2–2.86(m,1H),2.80–2.75(m,2H),2.72–2.66(m,1H),2.40–2.32(m,2H),2.25(s,3H),2.0 5–1.99(m,1H),1.98–1.93(m,1H),1.90(s,3H),1.37–1.34(m,2H),0.95–0.91(m,6H)ppm.

[1037] Target compound 48-P2:

[1038] The retention time RT of 48-P2 was 11.268 min.

[1039] LC-MS, M / Z(ESI): 652.28[M+H]+

[1040] 1 H NMR(400MHz,CD3OD)δ7.68(s,1H),7.37(s,1H),7.19–7.14(m,1H),6.91(s,1H),5.89–5.84( m,1H),5.66–5.61(m,1H),4.04–3.94(m,3H),3.67(s,3H),3.03–2.97(m,1H),2.90–2.82(m,1 H),2.82–2.74(m,3H),2.60–2.53(m,1H),2.43–2.36(m,2H),2.30(s,3H),1.95(s,3H),1.94– 1.88(m,2H),1.78–1.71(m,1H),1.36–1.30(m,2H),0.90–0.88(m,3H),0.87–0.85(m,3H)ppm.

[1041] Example 20: Preparation of target compounds 49-P1 and 49-P2

[1042] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1043] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1044] Compound 49-P1 is one of the structures of the two compounds mentioned above, while compound 49-P2 is the other structure.

[1045] The synthetic routes for target compounds 49-P1 and 49-P2 are as follows:

[1046] Step 1: Synthesis of ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (49A)

[1047] Under nitrogen protection, ethyl (1A) of ((3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-2-methylpropane-2-sulfinyl)amino)propionate (820 mg, 2.0 mmol), 4,4,5,5-tetramethyl-2-(2,4,5-trimethylthiophen-3-yl)-1,3,2-dioxaborane (38A) (756 mg, 3.0 mmol), potassium carbonate (828 mg, 6 mmol), and Pd(dppf)Cl2 (145 mg, 0.2 mmol) was added. Dioxane (10 mL) and water (2 mL) were reacted at 85 °C for 16 hours. After the reaction solution was cooled to room temperature, the reaction was quenched by adding 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. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give ethyl (3S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (49A).

[1048] LC-MS, M / Z(ESI): 454.18[M+H] +

[1049] Step 2: Synthesis of ethyl (3S)-3-amino-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (49B)

[1050] 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-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (49A) (453 mg, 1.0 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-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (49B), which was then directly used for the next reaction.

[1051] LC-MS, M / Z(ESI): 350.15[M+H] +

[1052] Step 3: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (49C)

[1053] Under nitrogen protection and at 0°C, N,N-diisopropylethylamine (0.4 mL, 2.2 mmol) was added to anhydrous dichloromethane containing (3S)-3-amino-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (49B) (210 mg, 0.6 mmol), 2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (1M) (200 mg, 0.55 mmol), and (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (314 mg, 0.83 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 give ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (49C).

[1054] LC-MS, M / Z(ESI): 692.31[M+H] +

[1055] Compound 49C was resolved into 68-P1 and 68-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.

[1056] The structures of 68-P1 and 68-P2 are as follows:

[1057] Compound 68-P1 is one of the structures of the two compounds mentioned above, while compound 68-P2 is the other structure.

[1058] LC-MS, M / Z(ESI): 692.31[M+H] +

[1059] Step 4: Synthesis of target compounds 49-P1 and 49-P2

[1060] Lithium hydroxide monohydrate (93 mg, 2.22 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(2-fluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (49C) (240 mg, 0.35 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reverse-phase preparative chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 25%-75%) to obtain the target compounds 49-P1 and 49-P2.

[1061] Target compound 49-P1:

[1062] The retention time RT of 49-P1 was 9.30 min.

[1063] LC-MS, M / Z(ESI): 664.28[M+H] +

[1064] 1H NMR(400MHz,CD3OD)δ7.81(s,1H),6.95-6.88(m,2H),6.82(s,1H),5.69-5.63(m, 1H),5.59-5.53(m,1H),4.61(brs,1H),4.0-3.88(m,4H),3.27-3.19(m,2H),2.85- 2.78(m,2H),2.69-2.65(m,2H),2.42-2.33(m,2H),2.28(s,3H),2.27(s,3H),2.14 (s,3H),2.04-1.94(m,2H),1.81(s,3H),1.44-1.34(m,1H),0.96-0.90(m,6H)ppm.

[1065] Target compound 49-P2:

[1066] The retention time RT of 49-P2 was 10.80 min.

[1067] LC-MS, M / Z(ESI): 664.28[M+H] +

[1068] 1 H NMR(400MHz,CD3OD)δ7.74(s,1H),7.01-6.93(m,2H),6.90(s,1H),5.74-5.68(m,1H),5.66-5.61(m, 1H),4.62(brs,1H),4.23-4.06(m,4H),3.46-3.40(m,1H),3.39-3.32(m,1H),2.95-2.87(m,1H),2.84 -2.77(m,1H),2.68-2.60(m,1H),2.58-2.50(m,1H),2.49-2.42(m,2H),2.30(s,3H),2.29(s,3H),2.1 8(s,3H),1.99-1.92(m,1H),1.87(s,3H),1.72-1.65(m,1H),1.42-1.34(m,1H),0.92-0.86(m,6H)ppm

[1069] Example 21: Preparation of target compounds 50-P1 and 50-P2

[1070] (3S)-3-((2R)-2-(7-(2-(azacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1071] (3S)-3-((2S)-2-(7-(2-(azacyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1072] Compound 50-P1 is one of the structures of the two compounds mentioned above, while compound 50-P2 is the other structure.

[1073] The synthetic routes for the target compounds 50-P1 and 50-P2 are as follows:

[1074] Step 1: Synthesis of ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (50B)

[1075] 7-Iodopyrazolo[1,5-a]pyrazin-4(5H)-one (50A) (13.3 g, 51.0 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E) (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 (50B).

[1076] LC-MS, M / Z (ESI): 404.0 [M+H] +

[1077] Step 2: Synthesis of ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (50D)

[1078] Ethyl 2-(7-iodo-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentanoate (50B) (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 (50D).

[1079] LC-MS, M / Z (ESI): 348.2 [M+H] +

[1080] Step 3: Synthesis of ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (50E)

[1081] Ethyl 2-{7-[(E)-2-ethoxyvinyl-1-yl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (50D) (1.23 g, 3.54 mmol) was dissolved in dichloromethane (5 mL) and hydrogen chloride / dioxane solution (7 mL, 4 M), and reacted at 25 °C for 1 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 mixture 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 (50E).

[1082] LC-MS, M / Z (ESI): 320.1 [M+H] +

[1083] Step 4: Synthesis of ethyl 2-{7-[2-(azacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (50F)

[1084] Ethyl 4-methyl-2-[4-oxo-7-(2-oxoethyl)pyrazolo[1,5-a]pyrazin-5(4H)-yl]valerate (50E) (1.14 g, 3.5 mmol) was dissolved in dichloroethane (15 mL), and acetic acid (112 mg, 2 mmol) was added to adjust the pH to 5. Then, aziridine (600 mg, 10.5 mmol) was added dropwise to the reaction solution. After reacting at 25 °C for 3 min, sodium cyanoborohydride (1.1 g, 17.5 mmol) was added, and the reaction was continued for 1 h. After the reaction was complete, the mixture was extracted with dichloromethane (15 mL × 3), and the concentrated organic phases were combined 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-(azacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (50F).

[1085] LC-MS, M / Z (ESI): 361.2 [M+H] +

[1086] Step 5: Synthesis of 2-{7-[2-(azacyclobutane-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (50G)

[1087] Ethyl 2-{7-[2-(azacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoate (50F) (800 mg, 2.2 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 about 4 with 1 N hydrochloric acid to obtain the crude product. The crude product was passed through a reverse-phase column (HCl system, 30% ACN) and lyophilized to obtain 2-{7-[2-(azacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (50 G).

[1088] LC-MS, M / Z (ESI): 333.1 [M+H] +

[1089] Step 6: Synthesis of ethyl (3S)-3-(2-(7-(2-(azacyclobutane-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (50H)

[1090] Under nitrogen protection and at 0°C, ethyl (47F) propionate (220 mg, 0.6 mmol) and 2-{7-[2-(azacyclobutan-1-yl)ethyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl}-4-methylpentanoic acid (50 G) (200 mg, 0.6 mmol) in anhydrous acetonitrile (3 mL) were added to a solution of (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-propionate (47F) (220 mg, 0.6 mmol) (200 mg, 0.6 mmol). Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 240 mg, 0.855 mmol) was 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 (eluent: dichloromethane: methanol (v / v) = 10:1) to give ethyl (3S)-3-(2-(7-(2-(azacyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (50H).

[1091] LC-MS, M / Z(ESI): 682.32[M+H] +

[1092] Step 7: Synthesis of target compounds 50-P1 and 50-P2

[1093] Lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added to a mixed solution of tetrahydrofuran (3 mL) and water (1 mL) of ethyl (3S)-3-(2-(7-(2-(azacyclobutan-1-yl)ethyl)-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (50H) (230 mg, 0.33 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 obtained was purified by reverse-phase preparative chromatography (column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 30%-70%) to obtain the target compounds 50-P1 and 50-P2.

[1094] Target compound 50-P1:

[1095] The retention time RT of 50-P1 was 10.823 min.

[1096] LC-MS, M / Z(ESI): 654.28[M+H] +

[1097] 1 H NMR (400MHz, CD3OD) δ7.92(d,J=2.2Hz,1H),7.06(dd,J=13.1,2.2Hz,1H),7.04–6.99(m,1H),6.88(t,J=8.1Hz,1H),5. 51–5.45(m,1H),5.40–5.35(m,1H),4.07–3.97(m,2H),3.86(dt,J=17.8,9.2Hz,2H),3.76(d,J=10.8Hz,1H),3.47(q,J =7.0Hz,1H),3.37–3.33(m,1H),3.13–3.06(m,1H),2.64–2.52(m,2H),2.36–2.25(m,5H),2.21(d,J=2.0Hz,3H),2.14( s,1H),2.10–1.93(m,4H),1.78(d,J=9.0Hz,3H),1.47(q,J=9.8Hz,1H),1.31(d,J=17.4Hz,1H),0.97–0.91(m,6H)ppm.

[1098] Target compound 50-P2:

[1099] The retention time RT of 50-P2 was 13.465 min.

[1100] LC-MS, M / Z(ESI): 654.28[M+H] +

[1101] 1 H NMR (400MHz, CD3OD) δ7.90(t,J=1.9Hz,1H),7.09(t,J=1.9Hz,1H),6.98(d,J=2.2Hz,1H),6.93(dd,J=9.2,7.0H z,1H),5.62–5.54(m,2H),4.21–4.04(m,3H),3.76(t,J=11.8Hz,1H),3.52(d,J=13.5Hz,1H),3.42(d,J=16.1Hz, 1H),3.02–2.93(m,1H),2.62–2.56(m,1H),2.50–2.38(m,3H),2.31(d,J=10.2Hz,3H),2.23(s,3H),2.15(s,1H), 2.10(s,1H),2.05–1.96(m,1H),1.85–1.77(m,4H),1.45–1.37(m,1H),1.35–1.25(m,3H),0.94–0.87(m,6H)ppm.

[1102] Example 22: Preparation of target compounds 53-P1 and 53-P2

[1103] (3S)-3-((2R)-2-(8-(2-(azacyclobutan-1-yl)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1104] (3S)-3-((2S)-2-(8-(2-(azacyclobutan-1-yl)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionic acid

[1105] Compound 53-P1 is one of the two compounds mentioned above, and compound 53-P2 is the remaining structure. The synthetic routes for the target compounds 53-P1 and 53-P2 are shown below:

[1106] Step 1: Synthesis of 5-bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (53B)

[1107] Triethylamine (33.3 g, 329.13 mmol) was added to an ethanol (500 mL) solution of 5-bromo-2,4-dichloropyrimidine (53A) (50 g, 219.42 mmol) 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 (53B).

[1108] LC-MS, M / Z (ESI): 296.1 [M+H] +

[1109] Step 2: Synthesis of 8-bromoimidazolo[1,2-c]pyrimidine-5(6H)-one (53C)

[1110] 5-Bromo-2-chloro-N-(2,2-dimethoxyethyl)pyrimidin-4-amine (53B) (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 (53C).

[1111] LC-MS, M / Z (ESI): 214.1 [M+H] +

[1112] Step 3: Synthesis of ethyl 2-(8-bromo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (53D)

[1113] Potassium carbonate (6.85 g, 49.53 mmol) was added to a solution of 8-bromoimidazolo[1,2-c]pyrimidin-5(6H)-one (53C) (5.3 g, 24.76 mmol) and ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E) (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-methylpentanoate (53D).

[1114] LC-MS, M / Z (ESI): 356.2 [M+H] +

[1115] Step 4: Synthesis of ethyl 2-{8-[(E)-2-ethoxyvinyl-1-yl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (53E)

[1116] Ethyl 2-(8-bromo-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentanoate (53D) (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). Cesium carbonate (6.86 g, 21.05 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (515 mg, 701.82 μmol) were then added. 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 (53E).

[1117] LC-MS, M / Z (ESI): 348.4 [M+H] +

[1118] Step 5: Synthesis of ethyl 4-methyl-2-[5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl]valerate (53F)

[1119] Ethyl 2-{8-[(E)-2-ethoxyvinyl-1-yl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (53E) (1.2 g, 3.5 mmol) was dissolved in dichloromethane (5 mL) and hydrogen chloride / dioxane solution (10 mL, 4 M), and reacted at 25 °C for 1 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 mixture 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-[5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl]pentanoate (53F).

[1120] LC-MS, M / Z (ESI): 320.1 [M+H] +

[1121] Step 6: Synthesis of ethyl 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (53G)

[1122] Ethyl 4-methyl-2-[5-oxo-8-(2-oxoethyl)imidazo[1,2-c]pyrimidin-6(5H)-yl]valerate (53F) (1.1 g, 3.5 mmol) was dissolved in dichloroethane (15 mL), and acetic acid (112 mg, 2 mmol) was added to adjust the pH to 5. Then, aziridine (600 mg, 10.5 mmol) was added dropwise to the reaction solution. After reacting at 25 °C for 3 min, sodium cyanoborohydride (1.1 g, 17.5 mmol) was added, and the reaction was continued for 1 h. After the reaction was completed, the mixture was extracted with dichloromethane (15 mL × 3), and the concentrated organic phases were combined to obtain the crude product. The crude product was subjected to column chromatography (DCM / MeOH(v / v)=10 / 1) to give ethyl 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (53G).

[1123] LC-MS, M / Z (ESI): 361.2 [M+H] +

[1124] Step 7: Synthesis of 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoic acid (53H)

[1125] Ethyl 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoate (53G) (800mg, 2.2mmol) and lithium hydroxide monohydrate (115mg, 2.74mmol) were dissolved in tetrahydrofuran (5mL), methanol (1mL), and water (1mL), and reacted at 25°C for 1h. After the reaction was complete, the solution was evaporated to dryness, and acetonitrile (10mL) was added. The pH of the solution was adjusted to about 4 with 1N hydrochloric acid to obtain the crude product. The crude product was passed through a reverse-phase column (HCl system, 30% ACN) and lyophilized to obtain 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoic acid (53H).

[1126] LC-MS, M / Z (ESI): 333.1 [M+H] +

[1127] Step 8: Synthesis of ethyl (3S)-3-(2-(8-(2-(azacyclobutan-1-yl)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (53J)

[1128] Under nitrogen protection and at 0°C, ethyl (47F) propionate (170 mg, 0.46 mmol) and 2-{8-[2-(azacyclobutan-1-yl)ethyl]-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl}-4-methylpentanoic acid (53H) (153 mg, 0.46 mmol) in anhydrous acetonitrile (2 mL) were added to a solution of (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-)-4-methylpentanoic acid (53H) (153 mg, 0.46 mmol). Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 256 mg, 0.92 mmol) was 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 (eluent: dichloromethane: methanol (v / v) = 10:1) to give ethyl (3S)-3-(2-(8-(2-(azacyclobutan-1-yl)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (53 J).

[1129] LC-MS, M / Z(ESI): 682.32[M+H] +

[1130] Step 9: Synthesis of target compounds 53-P1 and 53-P2

[1131] Lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added to a mixed solution of (3S)-3-(2-(8-(2-(azacyclobutan-1-yl)ethyl)-5-oxoimidazo[1,2-c]pyrimidin-6(5H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (53J) (200 mg, 0.29 mmol) in tetrahydrofuran (2 mL) and water (0.6 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 obtained was purified by reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 80mL / min, gradient B%: 30%-70%) to obtain the target compounds 53-P1 and 53-P2.

[1132] Target compound 53-P1:

[1133] The retention time RT of 53-P1 was 9.833 min.

[1134] LC-MS, M / Z(ESI): 654.28[M+H] +

[1135] 1 H NMR (400MHz, CD3OD) δ7.72–7.65(m,1H),7.44-7.38(m,2H),6.87(t,J=8.1Hz,1H),5.40(q,J=6.0Hz,1H),5.36(dt,J= 10.7,4.9Hz,1H),4.60(s,1H),4.10–3.94(m,4H),3.64–3.56(m,1H),3.50–3.42(m,1H),3.08–3.00(m,1H),2.96–2.88 (m,1H),2.66–2.60(m,1H),2.56(dt,J=14.7,6.0Hz,1H),2.40–2.32(m,2H),2.33–2.30(m,3H),2.20(d,J=2.0Hz,3H) ,2.13–2.06(m,3H),2.03–1.95(m,1H),1.76(s,3H),1.52–1.44(m,1H),1.31(d,J=17.5Hz,1H),0.97–0.92(m,6H)ppm.

[1136] Target compound 53-P2:

[1137] The retention time RT of 53-P2 was 12.453 min.

[1138] LC-MS, M / Z(ESI): 654.28[M+H] +

[1139] 1 H NMR (400MHz, CD3OD) δ7.80(s,1H),7.41(s,1H),7.34(d,J=2.6Hz,1H),6.94(td,J=8.3,3.3Hz,1H),5.60(d,J=10.3Hz,1H),5. 43(t,J=7.7Hz,1H),4.60(s,1H),4.24–4.04(m,3H),3.63(t,J=11.6Hz,1H),3.54–3.48(m,1H),3.17–3.10(m,1H),2.86–2.77( m,1H),2.59(dd,J=14.9,3.9Hz,1H),2.43(dd,J=15.0,10.2Hz,3H),2.31(d,J=8.2Hz,3H),2.23(s,3H),2.17–2.10(m,3H),2. 02(dt,J=15.2,7.6Hz,1H),1.85–1.77(m,4H),1.41(dd,J=13.7,6.9Hz,1H),1.31(d,J=17.3Hz,1H),0.91(d,J=6.3Hz,6H)ppm.

[1140] Example 23: Preparation of target compounds 54-P1 and 54-P2

[1141] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionic acid

[1142] (3S)-3-((2S)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionic acid

[1143] Compound 54-P1 is one of the structures of the two compounds mentioned above, while compound 54-P2 is the other structure.

[1144] The synthetic routes for the target compounds 54-P1 and 54-P2 are as follows:

[1145] Step 1: Synthesis of 5-bromo-3-(difluoromethoxy)pyridine-2(1H)-one (54B)

[1146] 3-(difluoromethoxy)pyridine-2(1H)-one (54A) (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 (PE / EA(v / v) = 1 / 1) to give 5-bromo-3-(difluoromethoxy)pyridine-2(1H)-one (54B).

[1147] LC-MS, M / Z (ESI): 240.2 [M+H] +

[1148] Step 2: Synthesis of ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (54D)

[1149] 5-Bromo-3-(difluoromethoxy)pyridin-2(1H)-one (54B) (1.35 g, 5.6 mmol), ethyl 2-((methanesulfonyl)oxy)-4-methylpentanoate (1E) (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 (54D).

[1150] LC-MS, M / Z (ESI): 382.2 [M+H] +

[1151] Step 3: Synthesis of ethyl 2-(3-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (54E)

[1152] Ethyl 2-(5-bromo-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (54D) (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 (54E).

[1153] LC-MS, M / Z (ESI): 374.2 [M+H] +

[1154] Step 4: Synthesis of ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (54F)

[1155] Ethyl 2-(3-(difluoromethoxy)-5-((E)-2-ethoxyvinyl-1-yl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (54E) (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 (54F).

[1156] LC-MS, M / Z (ESI): 346.1 [M+H] +

[1157] Step 5: Synthesis of ethyl 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (54G)

[1158] Ethyl 2-(3-(difluoromethoxy)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (54F) (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 (54G).

[1159] LC-MS, M / Z (ESI): 387.3 [M+H] +

[1160] Step 6: Synthesis of 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (54H)

[1161] 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 (54 g) (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 C18, 100×25mm×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 (54H).

[1162] LC-MS, M / Z (ESI): 359.3 [M+H] +

[1163] Step 7: Synthesis of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (54J)

[1164] Under nitrogen protection and at 0°C, ethyl (47F) propionate (220 mg, 0.6 mmol) and 2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (54H) (217 mg, 0.6 mmol) in anhydrous acetonitrile (3 mL) were added to a solution of (3S)-3-amino-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)-4-methylpentanoic acid (54H) (217 mg, 0.6 mmol). Then, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 336 mg, 1.2 mmol) was 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 (eluent: dichloromethane: methanol (v / v) = 10:1) to give ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophene-3-yl)phenyl)propionate (54 J).

[1165] LC-MS, M / Z(ESI): 708.30[M+H] +

[1166] Step 8: Synthesis of target compounds 54-P1 and 54-P2

[1167] Lithium hydroxide monohydrate (105 mg, 2.5 mmol) was added to a mixed solution of ethyl (3S)-3-(2-(5-(2-(azacyclobutan-1-yl)ethyl)-3-(difluoromethoxy)-2-oxopyridin-1(2H)-yl)-4-methylpentamido)-3-(2,4-difluoro-3-methyl-5-(2,4,5-trimethylthiophen-3-yl)phenyl)propionate (54 J) (350 mg, 0.5 mmol) in tetrahydrofuran (3 mL) and water (1 mL). The reaction was then carried out at room temperature for 3 hours, and 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 obtained was purified by reverse-phase preparation (chromatographic column: YMC-Triart Prep C18, S-12nm S-7μm 50mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 42mL / min, gradient B%: 30%-70%) to obtain the target compounds 54-P1 and 54-P2.

[1168] Target compound 54-P1:

[1169] The retention time RT of 54-P1 was 8.31 min.

[1170] LC-MS, M / Z(ESI): 680.27[M+H] +

[1171] 1 H NMR (400MHz, CD3OD) δ7.48–7.42(m,1H),7.38(d,J=2.1Hz,1H),7.08–6.78(m,2H),5.57(t,J=7.8Hz, 1H),5.38(dt,J=11.0,5.7Hz,1H),4.60(s,1H),4.00(q,J=8.9Hz,2H),3.92–3.81(m,2H),3.42–3.33 (m,1H),2.80–2.69(m,2H),2.66–2.54(m,2H),2.37–2.26(m,5H),2.21(s,3H),2.16–2.10(m,3H),2. 04–1.93(m,2H),1.80(d,J=3.2Hz,3H),1.45–1.38(m,1H),1.35–1.27(m,1H),0.95–0.88(m,6H)ppm.

[1172] Target compound 54-P2:

[1173] The retention time RT of 54-P2 was 10.06 min.

[1174] LC-MS, M / Z(ESI): 680.27[M+H] +

[1175] 1 H NMR (400MHz, CD3OD) δ7.42(d,J=2.2Hz,1H),7.33(d,J=2.2Hz,1H),7.05–6.78(m,2H),5.6 3–5.55(m,2H),4.14–4.02(m,4H),3.45–3.36(m,2H),2.79–2.66(m,2H),2.62–2.56(m,1H) ,2.48–2.38(m,3H),2.30(d,J=2.4Hz,3H),2.23(d,J=1.9Hz,3H),2.14(d,J=2.7Hz,3H),2. 01–1.94(m,1H),1.82(s,3H),1.80–1.73(m,1H),1.43–1.27(m,2H),0.92–0.87(m,6H)ppm.

[1176] Example 24: Preparation of target compounds 56-P1 and 56-P2

[1177] (3S)-3-((2R)-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[1178] (3S)-3-((2S)-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentamido)-3-(3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl)propionic acid

[1179] Compound 56-P1 is one of the structures of the two compounds mentioned above, while compound 56-P2 is the other structure.

[1180] The synthetic routes for the target compounds 56-P1 and 56-P2 are as follows:

[1181] Step 1: Synthesis of ethyl (3S)-3-[2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (56A)

[1182] To a solution of (3S)-3-(3-bromo-2,6-difluoro-5-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (33A) (1.5 g, 3.5 mmol) in dioxane (15 mL), pinacol borate (2.2 g, 8.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (256 mg, 0.35 mmol), and potassium acetate (1.0 g, 10.5 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 hours. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 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) = 1:0-0:1) to obtain ethyl (3S)-3-[2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (56A).

[1183] LC-MS, M / Z (ESI): 474.3 [M+H] +

[1184] Step 2: Synthesis of ethyl (3S)-3-[3-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,6-difluoro-5-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (56B)

[1185] To a solution of 4-iodo-3,5-dimethyl-1,2-thiazole (350 mg, 1.46 mmol) and (3S)-3-[2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (56A) (1.0 g, 2.20 mmol) in dioxane (5 mL) and water (0.5 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (214 mg, 0.29 mmol) and potassium carbonate (607 mg, 4.39 mmol) were added, purging with argon three times, and then stirred at 100 °C for 18 hours. Water (50 mL) was added to the reaction solution, and then the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and 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-[3-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,6-difluoro-5-methylphenyl]-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (56B).

[1186] LC-MS, M / Z (ESI): 459.3 [M+H] +

[1187] Step 3: Synthesis of ethyl (3S)-3-amino-3-[3-(3,5-dimethyl-1,2-thiazolyl-4-yl)-2,6-difluoro-5-methylphenyl]propionate (56C)

[1188] Ethyl (56B) propionate (56B) (600 mg, 1.3 mmol) in a solution of dioxane (3 mL) was added to a solution of dioxane (3 mL) in hydrochloric acid (3 mL, 4 M dioxane solution), and the mixture was stirred at room temperature for 1 hour. The reaction solution was 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 ethyl (56C, hydrochloride) propionate (56C).

[1189] LC-MS, M / Z (ESI): 355.2 [M+H] +

[1190] Step 4: Synthesis of (3S)-3-(2-{5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl]propionate (56D)

[1191] To a solution of 2-{5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentanoic acid (1M) (200 mg, 0.56 mmol) in acetonitrile (2 mL), ethyl (3S)-3-amino-3-[3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl]propionate (56C) (282 mg, hydrochloride) was added, followed by tetramethylchlorourea hexafluorophosphate (234 mg, 0.83 mmol) and N-methylimidazole (137 mg, 1.68 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was 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-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl]propionate (56D).

[1192] LC-MS, M / Z (ESI): 697.3 [M+H] +

[1193] Step 5: Synthesis of target compounds 56-P1 and 56-P2

[1194] Lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added to a solution of ethyl (3S)-3-(2-{5-[2-(azacyclobutan-1-yl)ethyl]-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl}-4-methylpentamido)-3-[3-(3,5-dimethyl-1,2-thiazo-4-yl)-2,6-difluoro-5-methylphenyl]propionate (56D) (280 mg, 0.4 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 reverse-phase preparation (column: ASAYMC-Triart Prep C18, 7μm 30mm×40cm, mobile phase A: 10mM NH4HCO3, mobile phase B: acetonitrile, flow rate: 42mL / min, gradient B%: 15%-100%) to obtain the target compounds 56-P1 and 56-P2.

[1195] Target compound 56-P1:

[1196] The retention time RT of 56-P1 was 7.92 min.

[1197] LC-MS, M / Z (ESI): 669.3 [M+H] +

[1198] 1 H NMR (600MHz, DMSO-d6) δ9.15(s,1H),7.74(s,1H),7.20(t,J=7.2Hz,1H),6.70(s,1H),5.59(dd,J=10.8,4.8 Hz,1H),5.48(dd,J=14.0,7.2Hz,1H),3.28(dd,J=15.2,7.2Hz,1H),3.20-3.11(m,4H),2.90(dd,J=16.0,8.0 Hz,1H),2.76(dd,J=16.0,6.4Hz,1H),2.49-2.43(m,3H),2.41-2.35(m,1H),2.29(d,J=32.8Hz,3H),2.22-2. 07(m,6H),2.01-1.91(m,3H),1.81-1.75(m,1H),1.30(td,J=12.4,6.8Hz,1H),0.85(dd,J=34.0,6.4Hz,6H).

[1199] Target compound 56-P2:

[1200] The retention time RT of 56-P2 was 8.93 min.

[1201] LC-MS, M / Z (ESI): 669.3 [M+H] +

[1202] 1 H NMR (600MHz, DMSO-d6) δ9.03(s,1H),7.72(s,1H),7.21(t,J=8.0Hz,1H),6.76(s,1H),5.59(dd,J= 10.8,5.3Hz,1H),5.50(dd,J=14.8,6.8Hz,1H),3.29-3.20(m,5H),2.82(dd,J=15.6,9.2Hz,1H),2 .70-2.52(m,4H),2.46(dd,J=15.2,7.6Hz,2H),2.33(d,J=6.0Hz,3H),2.25-2.16(m,5H),2.02-1. 95(m,2H),1.86-1.80(m,1H),1.66-1.59(m,1H),1.24-1.19(m,1H),0.78(dd,J=24.0,6.4Hz,6H).

[1203] Example 25: Preparation of target compounds 57-P1 and 57-P2

[1204] (3S)-3-((2R)-2-(5-(2-(azacyclobutan-1-yl)ethyl)-2-oxo-4-(tri...

Claims

1. A compound, said compound being a compound of formula (Y), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (Y): in: L is selected from and -SF5; Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; Ring E is selected from R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R8 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R4 is selected from H, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl; R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy; R 7a Selected from H, -(C(R) c )2) 0-3 N(R d )R e ; R 7b Selected from H, -OH, -CN, halogens, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted -OC 3-6 Cycloalkyl, substituted or unsubstituted 3-6-membered heterocyclic alkyl, substituted or unsubstituted -O- (3-6-membered heterocyclic alkyl), wherein the heteroatom of the heterocyclic alkyl is selected from 1, 2 or 3 of N, O and S, and the substituent is selected from -OH, -CN, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups; Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl; R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, or R d Re and its attached N atom cyclize together to form a substituted or unsubstituted 3-10 membered heterocyclic group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, and 3; q is selected from 0, 1, 2, 3, 4, and 5; When L is selected At that time, at least one of R1 and R2 is not H.

2. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1a) R8 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy; (2a) R8 is selected from H, -OH, -CN, -NH2, halogens, and C. 1-3 Alkyl groups, halogenated C 1-3 alkyl; (3a) R8 is selected from H, halogens, and methyl groups; (4a) R8 is selected from H and F; (5a) R8 is selected from H; (6a)R8 is selected from F.

3. The compound according to claim 1, wherein the compound is a compound of formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (II): in: L is selected from and -SF5; Ring G is selected from 5-membered heteroaryl, 5-10-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl; R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy; Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl; R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, and 3; When L is selected At that time, at least one of R1 and R2 is not H.

4. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1b)L is selected from (2b) Ring G is selected from 5-membered heteroaryl, 5-8-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; (3b) Ring G is selected from 5-membered heteroaryl, 5-7-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the heterocyclic alkyl is a bridged ring; (4b) Ring G is selected from Thiophene group 5. The compound according to claim 1, wherein the compound is a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (I): in: Cyclone G is selected from thienyl groups; R1 and R2 are each independently selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R5 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 1-6 Alkyl-C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C 1-6 Alkyl-(3-10-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; R6 is selected from H and C. 1-6 Alkyl groups, halogenated C 1-6 alkyl; R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, -(C(R c )2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy; Each R c Each is independently selected from H, halogen, C 1-6 Alkyl groups, halogenated C 1-6 alkyl; R a and R b Independently selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl-C 1-6 alkoxy, or R a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 3-10 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy; m is selected from 0, 1, 2, 3, and 4; n is selected from 0, 1, 2, and 3.

6. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1c) Ring G is selected from (2c) Ring G is selected from (3c) Ring G is selected from (4c) Ring G is selected from (5c) Ring G is selected from (6c) Selected from n is selected from 1 and 2; (7c) Selected from n is selected from 1; (8c) Selected from (9c) Selected from n is selected from 1, 2, and 3; (10c) Selected from (11c) Selected from n is selected from 1, 2, and 3; (12c) Selected from n is selected from 2 and 3; (13c) Selected from (14c) Selected from n is selected from 1 and 2; (15c) Selected from n is selected from 2; (16c) Selected from (17c) Selected from n is selected from 1 and 2; (18c) Selected from n is selected from 1; (19c) Selected from (20c)R4 is selected from -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7 membered heterocyclic group), wherein the heteroatom of the heterocyclic group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C 1-3 Alkyl, C 1-3 Alkoxy; (21c)R4 is selected from -CN, -NH2, halogens, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heteroatoms of the heterocyclic alkyl are selected from 1, 2 or 3 of N, O and S; (22c) R4 is selected from halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl. (23c)R4 is selected from F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl; (24c)R4 is selected from F, Cl, -CH3, and cyclopropyl; (25c)R4 is selected from -CH3; (26c)L is selected from (27c)L is selected from -SF5.

7. The compound according to claim 1, wherein the compound is a compound of formula (III), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug of a compound of formula (III): The definitions of rings E, R1, R2, R4, R5, R6, and R8 are as described in claim 1.

8. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1d) R1 and R2 are each independently selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy; (2d) R1 and R2 are each independently selected from H, halogens, and C. 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S; (3d) R1 and R2 are each independently selected from H, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl. (4d) R1 and R2 are each independently selected from H, F, Cl, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl; (5d) R1 is selected from H, F, Cl, -CH3, -CHF2, -CF3, cyclopropyl, and R2 is selected from H and F; (6d) R1 is selected from -CH3, and R2 is selected from F.

9. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1e) R3 is selected from H, -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from -OH, halogens, C 1-3 Alkyl, C 1-3 Alkoxy; (2e)R3 is selected from H, -OH, -CN, -NH2, halogens, and C. 1-3 Alkyl groups, halogenated C 1-3 alkyl; (3e)R3 is selected from H, halogens, and methyl groups; (4e)R3 is selected from H and F; (5e)R3 is selected from H; (6e)R3 is selected from F.

10. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1f) R5 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-3 Alkyl-C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic groups, substituted or unsubstituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heterocyclic group and the heteroatom of the heterocyclic alkyl group are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; (2f)R5 is selected from C 1-6 Alkyl groups, halogenated C 1-6 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy groups, halogenated C 1-3 Alkyl-C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-3 Alkyl-C 3-6 cycloalkyl, halogenated C 1-3 Alkyl-C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogen-substituted 3-7 membered heterocycloalkyl, C 1-3 Alkyl-(3-7 membered heterocyclic alkyl), halogen-substituted C 1-3 Alkyl-(3-7-membered heterocyclic alkyl), wherein the heteroatoms of the heterocyclic alkyl are selected from 1, 2 or 3 of N, O and S; (3f)R5 is selected from C 1-6 Alkyl, C 1-3 Alkyl-C 1-3 Alkoxy, C 1-3 Alkyl-C 3-6 cycloalkyl; (4f)R5 is selected from 11. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1g)R6 is selected from H, C 1-3 Alkyl groups, halogenated C 1-3 alkyl; (2g) R6 is selected from H and methyl groups; (3g)R6 is selected from H.

12. The compound according to claim 1, wherein: The compound satisfies one or more of the following conditions: (1h) Ring E is selected from (2h) Ring E is selected from (3h)R7 is selected from -OH, -CN, -NH2, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-7 membered heterocyclic alkyl, -(CH2) 0-3 N(R a )R b The heteroatom of the heterocyclic alkyl group is selected from 1, 2, or 3 of N, O, and S, and the substituent is selected from -OH, halogen, C. 1-3 Alkyl, C 1-3 Alkoxy; R a and R b Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together with the N atom it is attached to, they cyclize to form a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the substituents are selected from -OH, -CN, halogens, C, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy; (4h)R7 is selected from -CN, halogen, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl, C 1-3 Alkoxy groups, halogenated C 1-3 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, -(CH2) 0-3 N(R a )R b ; R a and R b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy; (5h)R7 is selected from -CN, halogen, methyl, halogen-substituted methyl, methoxy, halogen-substituted methoxy, cyclopropyl, halogen-substituted cyclopropyl, -(CH2). 2-3 N(R a )R b ; R a and R b Each is independently selected from H, methyl, or R. a and R b Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy. (6h)R7 is selected from F, -CH3, -CF3, -CHF2, -OCHF2, -OCF3, cyclopropyl, (7h)R7 is selected from (8h) Ring E is selected from (9h)R 7a Selected from -(CH2) 0-3 N(R d )R e ;R d and R e Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkyl-C 1-3 alkoxy, or R d and R e Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-6 membered heterocyclic alkyl groups, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from -OH, -CN, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl-C 1-3 Alkoxy; (10h)R 7a Selected from -(CH2) 2-3 N(R d )R e ;R d and R e Each is independently selected from H, methyl, or R. d and R e Together with the N atom to which it is attached, they cyclize to form substituted or unsubstituted 4-5 membered nitrogen-containing heterocyclic alkyl groups, wherein the substituents are selected from halogens, methyl, methoxy, and methylmethoxy. (11h)R 7a Selected from (12h)R 7b Selected from H, -OH, -CN, halogens, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic alkyl groups, wherein the heteroatoms of the heterocyclic alkyl group are selected from 1, 2 or 3 of N, O and S, and the substituents are selected from -OH, -CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy; (13h)R 7b Selected from H, -CN, halogens, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, wherein the heteroatom of the heterocycloalkyl is selected from 1 or 2 of N, O and S, and the substituent is selected from halogens; (14h)R 7b Selected from H, -CN, F, -CH3, -CF3, -CHF2, -CH2F, -OCH3, -OCF3, -OCHF2, -OCH2F, and cyclopropyl; (15h)R 7b Selected from H; (16h)q is selected from 0, 1, 2 and 3; (17h) Ring E is selected from (18h) Ring E is selected from 13. The compound according to claim 1, wherein: The compound has the structure shown in formula (YA): The definitions of rings E, L, R1, R2, R3, R5, R6, and R8 are as described in claim 1.

14. The compound according to claim 1, wherein: The compound has the structure shown in formula (II-A): The definitions of L, R1, R2, R3, R5, R6, R7, and m are as described in claim 1.

15. The compound according to claim 5, wherein: The compound has the structure shown in formula (IA): The rings G, R1, R2, R3, R4, R5, R6, R7, m, and n are defined as described in claim 5.

16. The compound according to claim 1, wherein: The compound has the structure shown in formula (III-A): The definitions of rings E, R1, R2, R4, R5, R6, and R8 are as described in claim 1.

17. The compound according to claim 1, wherein: L is selected from and -SF5; Ring G is selected from 5-membered heteroaryl, 5-7-membered heterocyclic alkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S; Ring E is selected from R1 and R2 are each independently selected from H, halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 Alkyl group; R3 is selected from H, halogen; R4 is selected from halogen, substituted or unsubstituted C. 1-3 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 Alkyl; R5 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-3 Alkyl-C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 3-6 cycloalkyl, wherein the substituent is selected from halogens, C 1-3 Alkyl group; R6 is selected from -H, C 1-3 Alkyl groups, halogenated C 1-3 Alkyl group; R7 is selected from substituted or unsubstituted C4 groups. 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Alkyl-C 1-6 Alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, -(C(R) c )2) 0-3 N(R a )R b The substituents are selected from -OH, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy; R 7a Selected from H, -(C(R) c )2) 0-3 N(R d )R e ;R 7b Selected from H, halogens, substituted or unsubstituted C 1-3 Alkyl; each R c Each is independently selected from H; R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 Alkyl, C 1-3 Alkoxy; R8 is selected from H, halogen, substituted or unsubstituted C. 1-3 Alkyl groups, wherein the substituents are selected from halogens, C 1-3 Alkyl group; m is selected from 0, 1, 2, 3; n is selected from 0, 1, 2, and 3; q is selected from 0, 1, and 2.

18. The compound according to claim 1, wherein: L is selected from and -SF5; The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S; Ring E is selected from R1 is selected from H, halogens, C 1-6 Alkyl groups, halogenated C 1-6 alkyl; R2 is selected from H or halogens; R3 is selected from H and halogens; R4 is selected from halogenated, substituted, or unsubstituted C4. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R5 is selected from C 1-6 alkyl; R6 is selected from H and C. 1-6 alkyl; R7 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl; R 7a Selected from H, -(CH2) 0-3 N(R d )R e ; R 7b Selected from H; R8 is selected from H and halogens; R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 alkyl; m is selected from 2 and 3; n is selected from 0, 1, 2, and 3.

19. The compound according to claim 1, wherein: L is selected from and -SF5; The ring G is selected from a 5-membered heteroaryl group, wherein the heteroatom is selected from 1, 2 or 3 of N, O and S; Ring E is selected from R1 is selected from H and C. 1-6 alkyl; R2 is selected from H or halogens; R3 is selected from H and halogens; R4 is selected from halogenated, substituted, or unsubstituted C4. 1-6 Alkyl, substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from -OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; R5 is selected from C 1-6 alkyl; R6 is selected from H and C. 1-6 alkyl; R7 is selected from substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl; R 7a Selected from H, -(CH2) 0-3 N(R d )R e ; R 7b Selected from H; R8 is selected from H and halogens; R a R b R d and R e Each is independently selected from H, substituted or unsubstituted C. 1-3 Alkyl, or R a and R b Together with the N atom it is attached to, they cyclize to form substituted or unsubstituted 3-7 membered heterocyclic groups, or R d Together with Re and its attached N atom, cyclization forms a substituted or unsubstituted 3-7 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and C. 1-3 alkyl; m is selected from 2 and 3; n is selected from 0, 1, 2, and 3.

20. The compound according to claim 1, wherein: L is selected from Ring E is selected from R1 is selected from C 1-6 alkyl; R2 is selected from halogens; R3 is selected from H and halogens; R4 is selected from halogens, C 1-6 alkyl; R5 is selected from C 1-6 alkyl; R6 is selected from H and C. 1-6 alkyl; R7 is selected from substituted or unsubstituted C. 1-6 Alkyl group, -(CH2) 0-3 N(R a )R b The substituents are selected from halogens, C 1-6 alkyl; R8 is selected from H and halogens; R a and R b Each was independently selected from C 1-3 Alkyl, or R a and R b Together with the N atom to which it is attached, they cyclize to form a substituted or unsubstituted 4-5 membered heterocyclic group, wherein the heteroatoms are selected from one or two of N, O, and S, and the substituents are selected from halogens, C, and S. 1-3 alkyl; m is selected from 2 and 3.

21. The compound shown in the following formula, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs:

22. The compound shown in the following formula, or its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs:

23. A pharmaceutical composition comprising an effective dose of any one of claims 1 to 22.

24. Use of the compound according to any one of claims 1 to 22, or the pharmaceutical composition according to claim 23, wherein the use includes at least one of the following: Use in the preparation of medicaments for the treatment or prevention of diseases related to integrin α4β7; Use in the treatment or prevention of diseases related to integrin α4β7.

25. The use according to claim 24, wherein, The integrin α4β7-related diseases mentioned are selected from: (1) Autoimmune diseases; (2) Inflammatory bowel disease; (3) Ulcerative colitis and Crohn's disease.

26. A method for treating or preventing integrin α4β7-related diseases, wherein, include: Apply an effective amount of the compound of any one of claims 1 to 22 or the pharmaceutical composition of claim 23 to the desired object.

27. The method according to claim 26, wherein, The integrin α4β7-related diseases mentioned are selected from: (1) Autoimmune diseases; (2) Inflammatory bowel disease; (3) Ulcerative colitis and Crohn's disease.

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