Small-molecule compound having GLP-1 receptor agonist activity and use thereof

Abstract

A GLP-1 receptor agonist having a structure of formula I, a pharmaceutically acceptable salt or a stereoisomer. Compared with LY3502970, the compound has excellent drug-like properties.

Description

A small molecule compound having GLP-1 receptor agonist effect and its use Technical Field

[0001] The present invention belongs to the technical field of chemical medicines, and specifically relates to a small molecule compound having GLP-1 receptor agonist effect and its use. Background Art

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin hormone synthesized by L cells in the distal small intestine and colon. It exerts its effects by binding to the GLP-1 receptor (GLP-1R) on the surface of target cell membranes. Its therapeutic effects in type 2 diabetes include glucose-dependent insulin synthesis and secretion, inhibition of postprandial glucagon secretion, protection of pancreatic β cells, appetite suppression, delayed gastric emptying, reduced hepatic glucose output, increased insulin sensitivity, and weight loss. GLP-1R agonists (GLP-1RAs) have the advantage of avoiding rapid degradation by dipeptidyl peptidase IV (DPP-IV) in the body, making them a hot topic in diabetes research and treatment. GLP-1RAs currently feature prominently in the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2013 Edition)" and other guidelines published by the Chinese Medical Association's Diabetes Society.

[0003] Studies have found that GLP-1 receptors are not only expressed in the pancreas, but also widely expressed in extra-pancreatic tissues, including the gastrointestinal tract, cardiovascular system, central nervous system, lungs, kidneys, bones, skin, etc. GLP-1 receptor agonists can not only be used to treat type 2 diabetes, but also have the potential to become drugs for the treatment of obesity, fatty liver, polycystic ovary syndrome and other diseases.

[0004] LY3502970 is a known GLP-1 receptor agonist that can be used to treat diseases such as type 2 diabetes and obesity. However, the drugability of LY3502970 needs to be further improved. Summary of the Invention

[0005] The purpose of the present invention is to provide a small molecule compound having GLP-1 receptor agonist effect and its use.

[0006] The present invention provides a compound represented by Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0007] in,

[0008] Ring A is selected from aryl, heteroaryl, fused cycloalkyl, and heterofused cycloalkyl;

[0009] The E ring is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;

[0010] The C ring is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;

[0011] Ring D is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0012] Z1 is selected from N, CH;

[0013] f is a substituent R Z1 The number of is selected from integers from 0 to 6;

[0014] R Z1 Each independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, halogen; or two adjacent R Z1 Connected to form a 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; or two non-adjacent R Z1 Connection formation m is 1, 2, or 3;

[0015] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0016] Z2 is selected from NR z2 、CHR z2 ;

[0017] R z2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0018] X is selected from O, S;

[0019] i is selected from 0 or 1;

[0020] W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N;

[0021] Y1 and Y2 are each independently selected from C=O, C=S, N or CR 14 ; R 14 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, halogen, hydroxy, carboxyl, substituted or unsubstituted 3-10 membered cycloalkyl;

[0022] The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2;

[0023] h is an integer selected from 0 to 3;

[0024] g is the number of substituents R, selected from an integer of 0-3;

[0025] R is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, and halogen;

[0026] Ring B is selected from null, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0027] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: deuterium, halogen, hydroxyl, cyano, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)R1', -NR2'R3';

[0028] The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are selected from the following groups: substituted or unsubstituted C1-C8 alkyl, halogen, cyano, hydroxyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C1-C8 ester, substituted or unsubstituted C1-C8 amide, amino, carboxyl, substituted or unsubstituted C1-C8 aldehyde, substituted or unsubstituted C1-C8 amine, =O; or the substituents on the same carbon atom in the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups form =O or =S;

[0029] R1', R2', and R3' are independently selected from hydrogen, C1-C8 alkyl;

[0030] The compound is not:

[0031] Furthermore, the compound is shown in Formula I-1:

[0032] in,

[0033] Ring A is selected from aryl, heteroaryl, fused cycloalkyl, and heterofused cycloalkyl;

[0034] The E ring is selected from substituted or unsubstituted 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocycloalkyl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen;

[0035] The C ring is selected from substituted or unsubstituted 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocycloalkyl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen;

[0036] Ring D is selected from aryl and heteroaryl;

[0037] Z1 is selected from N, CH;

[0038] f is an integer selected from 0 to 6;

[0039] R Z1 Each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen; or two adjacent R Z1 Connected to form a 3-8 membered saturated cycloalkyl, a 3-8 membered saturated heterocycloalkyl; or two non-adjacent R Z1 Connection formation m is 1, 2, or 3;

[0040] Z2 is selected from NR z2 、CHR z2 ;

[0041] R z2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocycloalkyl;

[0042] X is selected from O, S;

[0043] Selected from

[0044] when for When Y1 is selected from C=O, C=S;

[0045] when for When Y1 is selected from N or CR 14 ; R 14 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen, and hydroxy;

[0046] g is an integer selected from 0 to 3;

[0047] R is independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen;

[0048] Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents are each independently selected from C1-C8 alkyl, deuterated C1-C8 alkyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, and halogen;

[0049] The compound is not:

[0050] Furthermore, the structure of the compound is shown in Formula II-1:

[0051] in,

[0052] A is

[0053] R1 is selected from hydrogen, C1-C5 alkyl, halogen;

[0054] R2 is selected from hydrogen, C1-C5 alkyl, halogen;

[0055] R3 is selected from hydrogen, C1-C5 alkyl, halogen;

[0056] R4 is selected from hydrogen, C1-C5 alkyl, halogen;

[0057] R5 is selected from hydrogen, C1-C5 alkyl, halogen;

[0058] R6 is selected from hydrogen, C1-C5 alkyl, halogen;

[0059] R7 is selected from hydrogen, C1-C5 alkyl, halogen;

[0060] R8 is selected from hydrogen, C1-C5 alkyl, halogen;

[0061] R9 is selected from hydrogen, C1-C5 alkyl, halogen;

[0062] R 10 Selected from hydrogen, C1-C5 alkyl, halogen;

[0063] Alternatively, R5 and R6 are linked to form a 3-6 membered saturated cycloalkyl group;

[0064] Alternatively, R5 and R9 are connected to form m1 is 1, 2, or 3;

[0065] Alternatively, R5 and R7 are connected to form m2 is 1, 2 or 3;

[0066] R 11Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0067] R 12 Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0068] R 13 Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0069] X is selected from O, S;

[0070] Selected from

[0071] when for When Y1 is C=O or C=S;

[0072] when for When Y1 is N or CR 14 ; R 14 Selected from hydrogen, C1-C5 alkyl, halogen, hydroxyl;

[0073] R 15 Selected from hydrogen, C1-C5 alkyl, halogen;

[0074] R 16 Selected from C1~C5 alkyl, deuterated C1~C5 alkyl.

[0075] Furthermore, the structure of the compound is shown in Formula III-1:

[0076] in,

[0077] A is

[0078] R1 is selected from hydrogen, C1-C3 alkyl, halogen;

[0079] R2 is selected from hydrogen, C1-C3 alkyl, halogen;

[0080] R3 is selected from hydrogen, C1-C3 alkyl, halogen;

[0081] R4 is selected from hydrogen, C1-C3 alkyl, halogen;

[0082] R5 is selected from hydrogen, C1-C3 alkyl, halogen;

[0083] R6 is selected from hydrogen, C1-C3 alkyl, halogen;

[0084] R7 is selected from hydrogen, C1-C3 alkyl, halogen;

[0085] R9 is selected from hydrogen, C1-C3 alkyl, halogen;

[0086] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0087] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0088] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0089] X is selected from O, S;

[0090] Selected from

[0091] when for When Y1 is C=O or C=S;

[0092] when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0093] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0094] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0095] Furthermore, the structure of the compound is as shown in Formula III-1-1, Formula III-2-1, Formula III-3-1, Formula III-4-1, Formula III-5-1, Formula III-6-1, Formula III-7-1, Formula III-8-1, Formula III-9-1 or Formula III-10-1:

[0096] in,

[0097] A is

[0098] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0099] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0100] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0101] X is selected from O, S;

[0102] R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0103] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0104] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0105] Furthermore, the structures of the compounds are shown in Formula III-11-1, Formula III-12-1, and Formula III-13-1:

[0106] in,

[0107] A is

[0108] R9 is selected from hydrogen, C1-C3 alkyl, halogen;

[0109] R 10 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0110] Or, R9 and R 10 Connected to form a 3-6 membered saturated cycloalkyl group;

[0111] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0112] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0113] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0114] X is selected from O, S;

[0115] R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0116] R 15 Selected from hydrogen, C1-C5 alkyl, halogen;

[0117] R 16 Selected from C1~C5 alkyl, deuterated C1~C5 alkyl.

[0118] Furthermore, the structure of the compound is shown in Formula IV-1 or Formula IV'-1:

[0119] in,

[0120] A is

[0121] R1 is selected from hydrogen, C1-C3 alkyl, halogen;

[0122] R2 is selected from hydrogen, C1-C3 alkyl, halogen;

[0123] R3 is selected from hydrogen, C1-C3 alkyl, halogen;

[0124] R4 is selected from hydrogen, C1-C3 alkyl, halogen;

[0125] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0126] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0127] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0128] X is selected from O, S;

[0129] Selected from

[0130] when for When Y1 is C=O or C=S;

[0131] when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0132] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0133] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0134] Furthermore, the structure of the compound is as shown in Formula IV-1-1, Formula IV-2-1, Formula IV-3-1, Formula IV-4-1, Formula IV-5-1, Formula IV-6-1, Formula IV-7-1 or Formula IV-8-1:

[0135] in,

[0136] A is

[0137] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0138] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0139] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0140] X is selected from O, S;

[0141] R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0142] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0143] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0144] Furthermore, the structure of the compound is shown in Formula V-1:

[0145] in,

[0146] A is

[0147] R1 is selected from hydrogen, C1-C3 alkyl, halogen;

[0148] R2 is selected from hydrogen, C1-C3 alkyl, halogen;

[0149] R3 is selected from hydrogen, C1-C3 alkyl, halogen;

[0150] R4 is selected from hydrogen, C1-C3 alkyl, halogen;

[0151] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0152] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0153] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0154] X is selected from O, S;

[0155] Selected from

[0156] when for When Y1 is C=O or C=S;

[0157] when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0158] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0159] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0160] Furthermore, the structure of the compound is shown in Formula V-1-1, Formula V-2-1, Formula V-3-1 or Formula V-4-1:

[0161] in,

[0162] A is

[0163] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0164] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0165] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0166] X is selected from O, S;

[0167] R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl;

[0168] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0169] R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

[0170] Furthermore, the structure of the compound is shown in Formula I-2, Formula I-3, Formula I-4 or Formula I-5:

[0171] in,

[0172] A is

[0173] R5 is selected from hydrogen, C1-C3 alkyl, halogen;

[0174] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0175] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0176] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0177] X is selected from O, S;

[0178] Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy;

[0179] h is 0 or 1;

[0180] R 15 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen;

[0181] in,

[0182] A is

[0183] R5 is selected from hydrogen, C1-C3 alkyl, halogen;

[0184] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0185] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0186] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0187] X is selected from O, S;

[0188] Y2 is selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl;

[0189] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0190] R 16 Selected from C1-C3 alkyl, deuterated C1-C3 alkyl;

[0191] in,

[0192] A is

[0193] R5 is selected from hydrogen, C1-C3 alkyl, halogen;

[0194] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0195] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0196] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0197] X is selected from O, S;

[0198] W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N;

[0199] Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl;

[0200] The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2;

[0201] R 15 is selected from hydrogen, C1-C3 alkyl, and halogen;

[0202] R 16 Selected from C1-C3 alkyl, deuterated C1-C3 alkyl;

[0203] in,

[0204] A is

[0205] R5 is selected from hydrogen, C1-C3 alkyl, halogen;

[0206] R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0207] R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0208] R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl;

[0209] X is selected from O, S;

[0210] W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N;

[0211] Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl;

[0212] The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2;

[0213] R 15 Selected from hydrogen, C1-C3 alkyl, and halogen.

[0214] Furthermore, the compound is shown in Formula I-6:

[0215] in,

[0216] R 12 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0217] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0218] R 141 、R142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0219] R1, R5, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0220] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0221] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0222] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0223] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0224] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0225] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0226] Furthermore, the structure of the compound is shown in Formula II-6:

[0227] in,

[0228] R 12 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0229] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0230] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0231] R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0232] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0233] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0234] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0235] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0236] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0237] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0238] Furthermore, the structure of the compound is shown in Formula III-6:

[0239] in,

[0240] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0241] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0242] R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0243] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0244] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0245] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0246] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0247] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0248] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0249] Furthermore, the structure of the compound is shown in Formula IV-6:

[0250] in,

[0251] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0252] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0253] R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0254] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0255] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0256] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0257] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0258] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0259] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0260] Furthermore, the structure of the compound is shown in Formula Va-6:

[0261] in,

[0262] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0263] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0264] R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0265] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0266] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0267] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0268] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0269] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0270] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0271] Furthermore, the structure of the compound is shown in Formula Vb-6:

[0272] in,

[0273] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0274] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0275] R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0276] X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2;

[0277] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0278] The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0279] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0280] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0281] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0282] Further,

[0283] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0284] The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3';

[0285] The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy;

[0286] R1', R2', and R3' are independently selected from hydrogen, C1-C6 alkyl;

[0287] The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl and indolyl are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen and hydroxyl.

[0288] Further,

[0289] for

[0290] Further,

[0291] for

[0292] Furthermore, the structure of the compound is shown in Formula VIa-6:

[0293] in,

[0294] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0295] The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3';

[0296] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0297] R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0298] The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl, and indolyl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0299] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0300] The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy;

[0301] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0302] Furthermore, the structure of the compound is shown in Formula VIa-6-1:

[0303] in,

[0304] R 13 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogen.

[0305] Furthermore, the structure of the compound is shown in Formula VIb-6:

[0306] in,

[0307] R 11 、R 13are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl;

[0308] The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3';

[0309] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0310] R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0311] The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl, and indolyl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0312] The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1';

[0313] The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy;

[0314] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0315] Furthermore, the compound is as shown in Formula I-7:

[0316] in,

[0317] R 11 、R 12 、R 13are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide;

[0318] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0319] R 15 、R 16 、R 17 、R 18 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0320] R1, R5, R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0321] V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4;

[0322] n is 0 or 1;

[0323] U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R 23 are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key;

[0324] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0325] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0326] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0327] Furthermore, the structure of the compound is shown in Formula II-A-7 or Formula II-B-7:

[0328] in,

[0329] R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide;

[0330] R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen;

[0331] R 15 、R 16 、R 17 、R 18 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0332] R1, R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen;

[0333] n is 0 or 1;

[0334] U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R 23are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key;

[0335] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0336] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0337] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0338] Furthermore, the structure of the compound is shown in Formula III-A-7 or Formula III-B-7:

[0339] in,

[0340] R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide;

[0341] R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen;

[0342] n is 0 or 1;

[0343] U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R23 are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key;

[0344] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3';

[0345] The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl;

[0346] R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

[0347] Furthermore,

[0348] Selected from

[0349] R 21 、R 22 、R 23 are independently selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, and O=;

[0350] The substituents of the alkyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

[0351] The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl.

[0352] Furthermore,

[0353] Selected from

[0354] R 22 Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

[0355] Furthermore, the structure of the compound is shown in Formula IV-7:

[0356] in,

[0357] R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide;

[0358] R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen;

[0359] R 22 Selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=;

[0360] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester, and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy;

[0361] The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, hydroxyl;

[0362] Preferably, R 22Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

[0363] Furthermore, the structure of the compound is shown in Formula V-7:

[0364] in,

[0365] R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide;

[0366] R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen;

[0367] R 22 Selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=;

[0368] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester, and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy;

[0369] The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, hydroxyl;

[0370] Preferably, R 22 Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

[0371] Furthermore, the structure of the compound is shown in Formula V-7-1:

[0372] in,

[0373] R 11 、R 13are independently selected from C1 to C6 alkyl;

[0374] R 22 Selected from hydrogen, R is selected from C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0375] Furthermore, the compound is one of the compounds with the following structures:

[0376] The present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a GLP-1 receptor agonist.

[0377] The present invention also provides use of the aforementioned compound, a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of a drug for preventing and / or treating diseases associated with the GLP-1 receptor.

[0378] Furthermore, the diseases related to GLP-1 receptor are diabetes, obesity, fatty liver, and polycystic ovary syndrome;

[0379] Preferably, the diabetes is type 2 diabetes.

[0380] The present invention also provides a medicine, which is a preparation prepared by using the aforementioned compound, its pharmaceutically acceptable salt or its stereoisomer as an active ingredient, and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0381] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0382] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0383] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0384] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkyl; "C1-C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkoxy.

[0385] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, among others.

[0386] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. An alkenyl group can be straight-chain or branched.

[0387] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. Alkynyl groups can be straight or branched.

[0388] "Halogen" is fluorine, chlorine, bromine or iodine.

[0389] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0390] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to: wait.

[0391] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to wait.

[0392] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, such as but not limited to thienyl, furyl, isothiazolyl, etc.

[0393] "Ester group" refers to a group that is connected to the attachment site through a carbon chain and contains at least one ester bond (i.e., -COO-). R is a C1-C6 alkyl group.

[0394] "Amide" refers to a group that is connected to the attachment site through a carbon chain and contains at least one amide bond (i.e., -CONH-). R is a C1-C6 alkyl group.

[0395] "Amine" refers to a group that is connected to a linking site through a carbon chain or nitrogen and contains at least one nitrogen in the carbon chain.

[0396] "Aldehyde" refers to a group attached to a linking site via a carbon chain containing at least one -CHO group.

[0397] The substituent is selected from "O=", which means that the oxygen atom is connected to the attachment site through a double bond.

[0398] In the ring containing X1, X2, X3 and X4 and the ring containing Y1, Y2, Y3 and Y4, the absence of a dotted line indicates a single bond, and the presence of a dotted line indicates a double bond.

[0399] R 12 、R 13 and R 14 When it is None, it means that no group is connected.

[0400] The pharmaceutically acceptable salts of the present invention include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate, quaternary ammonium salt or succinate, etc.

[0401] Compared with the prior art, the present invention has the following beneficial effects:

[0402] The present invention provides a new class of small molecule compounds that can be used as GLP-1 receptor agonists for the preparation of medicaments for preventing and / or treating diseases such as diabetes, obesity, fatty liver disease, and polycystic ovary syndrome. Compared with LY3502970, the compounds of the present invention have superior drugability, as demonstrated by improved pharmacokinetic (PK) properties, improved oral bioavailability, lower toxicity, improved permeability, and improved efficacy. Therefore, the compounds of the present invention have broad application prospects.

[0403] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0404] The following is a further detailed description of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0405] The raw materials and equipment used in the specific embodiments of the present invention are all known products, which are synthesized according to literature methods or obtained by purchasing commercial products.

[0406] The synthetic methods of some common intermediates of the present invention are as follows:

[0407] 1. Synthesis of Compound (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 1)

[0408] Synthesis of Intermediate (3-bromo-4-fluoro-5-methylphenyl)hydrazine hydrochloride (Int 1-2)

[0409] 3-Bromo-4-fluoro-5-methylaniline Int 1-1 (7.8 g, 38 mmol), water (78 mL) and concentrated hydrochloric acid (40 mL) were added to the reaction flask. An aqueous solution of NaNO2 (3.97 g, 57 mmol) (8 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour. Then, a concentrated hydrochloric acid solution of SnCl2 (21 g, 110 mmol) (40 mL) was added dropwise at the same temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filter cake was dried and slurried with ethyl acetate (20 mL). After filtration, the crude solid compound Int 1-2 (9.9 g, 39 mmol) was obtained in a yield of 103%. Ms: 219, 221 (M+H + )

[0410] Synthesis of Intermediate (S)-tert-butyl 3-amino-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Int 1-3)

[0411] To the reaction flask were added (3-bromo-4-fluoro-5-methylphenyl)hydrazine hydrochloride Int 1-2 (9.9 g, 39 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (8.31 g, 35 mmol), N,N-diisopropylethylamine (9 g, 69 mmol) and ethanol (100 mL). The solution was heated to 80°C and stirred overnight. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was rotary evaporated and purified by column chromatography to obtain solid compound Int 1-3 (7 g, 16 mmol) in a yield of 46.6%. Ms: 439, 441 (M+H + )

[0412] Synthesis of Intermediate (S)-tert-butyl 2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Int 1-4)

[0413] To the reaction flask, (S)-3-amino-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester Int 1-3 (4.9 g, 11.2 mmol), pyridine (2.7 g, 33.6 mmol) and 2-methyltetrahydrofuran (50 mL) were added dropwise under ice bath. 2,2,2-trichloroethyl chloroformate (3.6 g, 16.8 mmol) was added dropwise. After the addition was complete, the reaction was continued. After the reaction was complete, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3 times). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and then purified by column chromatography to obtain solid compound Int 1-4 (6 g, 9.8 mmol) with a yield of 88%. Ms: 613, 615, 617 (M+H + )

[0414] Synthesis of Intermediate (S)-tert-butyl 2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(2,2-dimethoxyethyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Int 1-5)

[0415] To the reaction flask was added tert-butyl (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate Int 1-4 (6 g, 9.8 mmol), N-(2,2-dimethoxyethyl)-4-fluoro-1-methyl-1H-indazol-5-amine (5 g, 19.8 mmol), pyridine (23.2 g 294 mmol) and N,N-dimethylformamide (120 mL). The solution was heated to 90°C for reaction. After completion of the reaction, it was cooled to room temperature, ethyl acetate (200 mL) was added, and the mixture was extracted with water (120 mL x 5 times). The organic layer was dried over anhydrous sodium sulfate, and the solvent was rotary evaporated and purified by column chromatography to obtain solid compound Int1-5 (5.4 g, 7.5 mmol) in a yield of 77%. Ms: 718, 720 (M+H + )

[0416] Synthesis of Compound (S)-tert-butyl 2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Int 1)

[0417] To the reaction flask, (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(2,2-dimethoxyethyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester Int 1-5 (5.4 g, 7.5 mmol) and tetrahydrofuran (60 mL) were added, and methanesulfonic acid (7.4 g, 75 mmol) was added at room temperature. The solution was heated to 60 ° C for reaction. After the reaction was completed, it was cooled to room temperature and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7-8. After the adjustment was completed, di-tert-butyl dicarbonate (6.5 g, 30 mmol) was added. After the reaction was completed, water (50 mL) was added and the mixture was washed with ethyl acetate (50 mL X 40 mL). 3 times) extraction, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was rotary evaporated and then purified by column to obtain solid compound Int1 (4.3 g, 6.6 mmol) with a yield of 88%. Ms: 654, 656 (M+H + )

[0418] 2. Synthesis of Intermediate (S)-1-(-2-(3,5-diethynyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (Int 2)

[0419] Step 1: Synthesis of intermediate (3,5-dibromo-4-fluorophenyl)hydrazine (Int 2-1)

[0420] Procedure: Dissolve 3,5-dibromo-4-fluoroaniline (5.0 g, 18.6 mmol) in 6N hydrochloric acid (50 mL), cool to 0°C, add dropwise a solution of sodium nitrite (1.9 g, 27.9 mmol) in water (4 mL), react at 0°C for 0.5 h, add dropwise a solution of stannous chloride (7.1 g, 37.2 mmol) in concentrated hydrochloric acid (7 mL), warm to room temperature naturally, react for 2 h, filter, and slurry the filter cake with methyl tert-butyl ether (15 mL), filter, and dry the filter cake to obtain 3.5 g of the product (Int 2-1) hydrochloride, yield: 58.7%. Ms: 284.9 / 282.9 / 286.9 (M+H+ ).

[0421] Step 2: Synthesis of intermediate (S)-3-amino-2-(3,5-dibromo-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 2-2)

[0422] Procedure: Intermediate Int 2-1 hydrochloride (3.5 g, 10.9 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.6 g, 10.9 mmol), and N,N-diisopropylethylamine (2.8 g, 21.8 mmol) were added to ethanol (35 mL) in sequence. The mixture was reacted at 80°C overnight, concentrated under reduced pressure, and purified by column chromatography to obtain 2.5 g of the product (Int 2-2) in a yield of 45.4%. Ms: 505.0 / 503.0 / 507.0 (M+H + ).

[0423] Step 3: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-4-methyl-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 2-3)

[0424] Procedure: Intermediate Int 2-2 (2.5 g, 5.0 mmol) and pyridine (0.8 g, 9.9 mmol) were added sequentially to tetrahydrofuran (50 mL). The temperature was lowered to 0°C, and a solution of 2,2,2-trichloroethyl chloroformate (1.6 g, 7.4 mmol) in tetrahydrofuran (16 mL) was added dropwise. The temperature was naturally raised to room temperature and the mixture was reacted overnight. Saturated aqueous potassium carbonate (25 mL) was added and stirred for 4 hours. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed once with saturated brine (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.9 g of the product (Int 2-3) in a yield of 86.1%. Ms: 678.8 / 680.8 / 682.8 (M+H + ).

[0425] Step 4: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 2-4)

[0426] Procedure: Intermediate Int 2-3 (2.9 g, 4.3 mmol), N-(2,2-dimethoxyethyl)-4-fluoro-1-methyl-1H-indazol-5-amine (2.2 g, 8.5 mmol), and pyridine (10.1 g, 128 mmol) were added to N,N-dimethylformamide (30 mL) in sequence and reacted at 90°C for 3 hours. The mixture was diluted with ethyl acetate (50 mL), washed once with water (60 mL) and once with saturated brine (60 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 2.5 g of the product (Int 2-4) in a yield of 74.8%. Ms: 784.0 / 782.0 / 786.0 (M+H + ).

[0427] Step 5: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 2-5)

[0428] Procedure: Intermediate Int 2-4 (2.5 g, 3.2 mmol) and methanesulfonic acid (3.1 g, 31.9 mmol) were added sequentially to tetrahydrofuran (30 mL) and reacted at 60°C for 1 hour. The mixture was cooled to room temperature and N,N-diisopropylethylamine (5.4 g, 41.5 mmol) and di-tert-butyl dicarbonate (1.4 g, 6.4 mmol) were added sequentially. The mixture was reacted at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL), washed once with water (50 mL) and once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.1 g of the product (Int 2-5) in a yield of 91.5%. Ms: 720.0 / 717.9 / 722.0 (M+H + ).

[0429] Step 6: Synthesis of intermediate (S)-2-(3,5-diethynyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 2-6)

[0430] Procedure: Intermediate Int 2-5 (320 mg, 0.44 mmol), triisopropylsilyl acetylene (811 mg, 4.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (62 mg, 0.09 mmol), cuprous iodide (17 mg, 0.09 mmol), and triethylamine (450 mg, 4.4 mmol) were added sequentially to dimethyl sulfoxide (6 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 80°C for 8 hours. The mixture was cooled to room temperature and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 5 mL) was added. The mixture was stirred at room temperature for 1 hour and filtered. The filter cake was slurried with ethyl acetate (20 mL × 2). The filtrates were combined, washed with water (20 mL × 3), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 140 mg of the product (Int 2-6) in a yield of 51.6%. Ms: 610.2 (M+H + ).

[0431] Step 7: Synthesis of intermediate (S)-1-(-2-(3,5-diethynyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (Int 2)

[0432] Procedure: Add intermediate Int 2-6 (140 mg, 0.25 mmol) to a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 mL) and react at room temperature for 2 hours. Adjust the pH to >7 with saturated sodium bicarbonate aqueous solution and extract with ethyl acetate (20 mL x 2). Combine the organic layers, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 100 mg of the product (Int 2). Yield: 85.5%. Ms: 510.1 (M+H + ).

[0433] 3. Synthesis of Intermediate (S)-1-(-2-(3,5-divinyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (Int 3)

[0434] Step 1: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 3-3)

[0435] Procedure: Intermediate Int 2-2 (8.0 g, 15.9 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide, and potassium tert-butoxide (5.35 g, 47.7 mmol) were added to N,N-dimethylacetamide (80 mL) in sequence and reacted at 20°C for 2 hours. 200 mL of water was added to the system and extracted with ethyl acetate (50 x 3 mL). The organic layer was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 9.1 g of the product (Int 3-3) in a yield of 91.1%. Ms: 636 / 634 / 638 (M+H + ).

[0436] Step 2: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 3-4)

[0437] Procedure: Intermediate Int 3-3 (9.1 g, 14.3 mmol) and methanesulfonic acid (2.8 g, 27.6 mmol) were added to tetrahydrofuran (300 mL) in sequence and reacted at 60°C for 2 hours. The system was diluted with water (150 mL) and extracted with ethyl acetate (50 mL*3). The mixture was washed once with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.0 g of the product (Int 3-4) in a yield of 61.1%. Ms: 572 / 570 / 573 (M+H + ).

[0438] Step 3: Synthesis of intermediate (S)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 3-5)

[0439] Procedure: Intermediate Int 3-4 (5.0 g, 8.75 mmol), allylboronic acid pinacol ester (6.76 g, 43.8 mmol), 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (0.64 g, 0.87 mmol), and potassium carbonate (24.1 g, 17.5 mmol) were added sequentially to N,N-dimethylformamide / water (100 mL, 10:1) and reacted at 105°C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (300 mL). The mixture was washed three times with water (50 mL) and once with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.8 g of the product (Int 3-5) in a yield of 70.0%. Ms: 466 (M+H + ).

[0440] Step 4: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 3-6)

[0441] Procedure: Intermediate Int 3-5 (1.8 g, 3.87 mmol), 4-fluoro-5-iodo-1-methyl-1H-indole (1.50 g, 5.41 mmol), cuprous iodide (0.29 g, 1.93 mmol), (1S, 2S)-N 1 , N 2 1,2-Dimethylcyclohexane-1,2-diamine (550 mg, 3.87 mmol) and potassium carbonate (1.1 g, 7.74 mmol) were added to dimethyl sulfoxide (40 mL) in sequence. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 125°C for 28 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with water (20 mL × 3) and saturated brine (20 mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.0 g of the product (Int 3-6) in a yield of 42.2%. Ms: 613 (M+H + ).

[0442] Step 5: Synthesis of intermediate (S)-1-(-2-(3,5-divinyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (Int 3)

[0443] Procedure: Intermediate Int 3-6 (1.0 g, 1.63 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL) and reacted at room temperature for 0.5 h. The pH was adjusted to >7 with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 600 mg of the product (Int 3) in a yield of 71.1%. Ms: 513 (M+H + ).

[0444] 4. Synthesis of Intermediate (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (Int 4)

[0445] Step 1: Synthesis of intermediate (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 4-1)

[0446] Procedure: Dissolve the intermediate (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (20 g, 84.0 mmol) in ethanol (200 mL), add (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (17.5 g, 92.4 mmol) and N,N-diisopropylethylamine (21.7 g, 168.0 mmol) in sequence, heat to 80°C, react overnight, concentrate under reduced pressure, and purify by column chromatography to obtain 23 g of the product (Int 4-1) in a yield of 73.2%. Ms: 375.2 (M+H + ).

[0447] Step 2: Synthesis of intermediate (S)-3-(3-(2,2-dimethoxyethyl)urea)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 4-2)

[0448] Procedure: Intermediate Int 4-1 (2 g, 5.35 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (1.38 g, 6.42 mmol), and potassium tert-butoxide (0.9 g, 8.03 mmol) were added to DMAc (10 mL) in sequence. The mixture was stirred at room temperature and monitored by TLC. After the reaction, the reaction solution was cooled to room temperature, added dropwise to water, filtered, and purified by solid column chromatography to obtain 1.1 g of the product (Int 4-2) in a yield of 40.7%. Ms: 506.1 (M+H + ).

[0449] Step 3: Synthesis of intermediate (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 4-3)

[0450] Procedure: Dissolve intermediate Int 4-2 (1.1 g, 2.17 mmol) in tetrahydrofuran (22 mL), add methanesulfonic acid (0.21 g, 2.17 mmol) dropwise, stir at 60°C, monitor by TLC, add water (110 mL), extract with ethyl acetate (50 mL x 3), wash the organic layer once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 0.92 g of the product (Int 4-3) in a yield of 96.1%. Ms: 442.1 (M+H + ).

[0451] Step 4: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 4-4)

[0452] Procedure: Intermediate Int 4-3 (0.92 g, 2 mmol), 4-fluoro-5-iodo-1-methyl-1H-indazole (1.1 g, 4 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (0.28 g, 2 mmol), cuprous iodide (0.38 g, 2 mmol), potassium carbonate (0.82 g, 6 mmol), and molecular sieves (0.92 g) were added sequentially to NMP (10 mL) under N2(g) protection. The mixture was reacted at 130°C for 12 hours, diluted with ethyl acetate (50 mL), washed once with water (10 mL) and once with saturated brine (60 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 680 mg of the product (Int 4-4) in a yield of 57.7%. Ms: 590.1 (M+H + ).

[0453] Step 5: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (Int 4)

[0454] Procedure: Intermediate Int 4-4 (680 mg, 1.15 mmol) was added to a solution of dichloromethane (7 ml) and hydrogen chloride in 1,4-dioxane (4 M, 3 mL). The mixture was reacted at room temperature for 2 hours. The pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 511 mg of the product (Int 4). Yield: 91%. Ms: 490.1 (M+H + ).

[0455] 5. Synthesis of intermediate (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (Int 5)

[0456] Step 1: Synthesis of intermediate 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (Int 5-1)

[0457] Procedure: Tetrahydro-2,2-dimethyl-4H-pyran-4-one (25.6 g, 200.0 mmol) was dissolved in tetrahydrofuran (250 mL), cooled to -70°C in a dry ice bath, and a solution of LiHMDS (1 M, 240 mL) in tetrahydrofuran was slowly added dropwise. The reaction was carried out at -70°C for 0.5 h. N-phenylbis(trifluoromethanesulfonyl)imide (77 g, 220 mmol) was dissolved in tetrahydrofuran (250 mL) and slowly added dropwise to the reaction solution, maintaining the temperature not exceeding -60°C. After the addition was completed, the temperature was naturally raised to react overnight. Saturated aqueous ammonium chloride (500 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (500 mL × 2). The organic layers were combined and dried over anhydrous sodium sulfate to obtain 100.0 g of a crude product (Int 5-1), which was used directly in the next step.

[0458] Step 2: Synthesis of intermediate 5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (Int 5-2)

[0459] Procedure: Ethyl 5-bromoindole-2-carboxylate (26.8 g, 100.0 mmol), diboron pinacol ester (50.8 g, 200.0 mmol), potassium acetate (19.6 g, 200.0 mmol), and PdCl2(dppf) (7.3 g, 10.0 mmol) were added sequentially to dioxane / water (v / v = 10:1, 500 mL). The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 80°C overnight. The mixture was cooled to room temperature, filtered through celite, and the filter cake was rinsed with ethyl acetate (100 mL). The filtrate was added to water (500 mL) and extracted with ethyl acetate (300 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 20.0 g of the product (Int 5-2) in a yield of 63.0%. Ms: 318.4 (M+H + ).

[0460] Step 3: Synthesis of intermediate 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (Int 5-3)

[0461] Procedure: Intermediate Int 5-2 (19.0 g, 60.0 mmol), crude intermediate Int 5-1 (100 g, 200.0 mmol), potassium carbonate (17.0 g, 120.0 mmol), and PdCl2(dppf) (4.4 g, 6.0 mmol) were added to dioxane / water (v / v=10:1, 500 mL) in sequence, replaced with nitrogen three times, reacted at 80°C overnight, cooled to room temperature, filtered through celite, and the filter cake was rinsed with ethyl acetate (100 mL). Water (500 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (300 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A tetrahydrofuran / methanol (v / v=5:1, 200 mL) solution was added, and 10% Pd / C (1.0 g) was added, replaced with nitrogen three times, replaced with hydrogen three times, and reacted at room temperature overnight. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 11.0 g of the product (Int 5-3). The yield was 60.9%. Ms: 302.2 (M+H + ).

[0462] Step 4: Separation of intermediate 5-3-P1 and intermediate 5-3-P2

[0463] Procedure: Intermediate Int 5-3 (10.0 g, 33.2 mmol) was purified by SFC (column: DAICEL AD-H (30×250 mm, 5 μm; mobile phase: A=CO 2 , Co-Solvent B=IPA / CAN, Co-Solvent B%=35%; flow rate: 45 mL; wavelength: 215 nm; temperature: 35° C.) to give intermediate Int 5-3-P1 (3.8 g) and intermediate Int 5-3-P2 (4.5 g).

[0464] Step 5: Synthesis of intermediate (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (Int 5-4)

[0465] Procedure: Dissolve the intermediate Int 5-3-P2 (4 g, 13.3 mmol) in N,N-dimethylformamide (40 mL) and stir on ice for 10 min. Then, add NaH (479 mg, 19.95 mmol) in portions and warm to room temperature and stir for 2 hours. Then, add chloroacetonitrile (5 g, 66.67 mmol) on ice and warm to room temperature and stir for 2 hours. After the reaction is complete, add 40 mL of aqueous ammonium chloride solution and extract with ethyl acetate (25 mL x 3). Combine the organic layers, wash twice with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 3.8 g of the product (Int 5-4) in a yield of 84.4%. Ms: 341.2 (M+H + ).

[0466] Step 6: Synthesis of intermediate (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (Int 5-5)

[0467] Procedure: Intermediate Int 5-4 (1.45 g, 4.3 mmol) and vinyl sulfate (1.6 g, 12.8 mmol) were dissolved in tetrahydrofuran (20 mL). Stirred on ice for ten minutes, a solution of LiHMDS in tetrahydrofuran (1 M, 22 mL) was slowly added, and the mixture was stirred on ice for 1 hour. After completion of the reaction, aqueous ammonium chloride (50 mL) was added, followed by extraction with ethyl acetate (25 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 1.14 g of the product (Int 5-5) in a yield of 73.1%. Ms: 367.2 (M+H + ).

[0468] Step 7: Synthesis of intermediate (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (Int 5)

[0469] Procedure: Dissolve intermediate Int 5-5 (1.14 g, 3.1 mmol) and potassium trimethylsilanol (1.6 g, 12.4 mmol) in tetrahydrofuran (11 mL) and stir at room temperature for 4 hours. After the reaction is complete, add 2N HCl to adjust the pH to 1, then extract with ethyl acetate (25 mL x 3). The combined organic layers are dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC to obtain 840 mg of Int 5 in a yield of 83.0%. Ms: 339.1 (M+H + ).

[0470] 6. Synthesis of intermediate 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (Int 6)

[0471] Step 1: Synthesis of ethyl 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (Int 6-1)

[0472] Procedure: Intermediate Int 5-4 (1.45 g, 4.3 mmol) and (4S)-4-propyl-[1,3-2]dioxothioethane-2,2-oxide (1.8 g, 12.8 mmol) were dissolved in N,N-dimethylpropyleneurea (9 mL). Stirred on ice for 10 minutes, a solution of LiHMDS in tetrahydrofuran (1 M, 22 mL) was slowly added, and the mixture was stirred on ice for 1 hour. After completion of the reaction, aqueous ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.0 g of the product (Int 6-1) in a yield of 62.0%. Ms: 381.2 (M+H + ).

[0473] Step 2: Synthesis of the intermediate 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (Int 6)

[0474] Procedure: Dissolve the intermediate Int 6-1 (1.0 g, 2.6 mmol) and potassium trimethylsilanol (1.3 g, 10.4 mmol) in tetrahydrofuran (9 mL) and stir at room temperature for 4 hours. After the reaction is complete, add 2N HCl to adjust the pH to 1, then extract with ethyl acetate (25 mL x 3). The combined organic layers are dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC to obtain 880 mg of Int 6 in a yield of 95.0%. Ms: 353.1 (M+H + ).

[0475] 7. Synthesis of Intermediate (S)-2-(3-bromo-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 7)

[0476] Step 1: Synthesis of intermediate (3-bromo-4-fluorophenyl)hydrazine hydrochloride (Int 7-2)

[0477] At room temperature, Int 7-1 (6.0 g, 38 mmol), water (70 mL) and concentrated hydrochloric acid (30 mL) were added dropwise at 0°C with an aqueous solution of NaNO2 (2.4 g, 34.73 mmol) (6 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour. Then, a concentrated hydrochloric acid solution of SnCl2 (11.97 g, 63.15 mmol) (20 mL) was added dropwise at the same temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was dried and slurried with water (10 mL). After filtration, the white solid compound Int 7-2 (6.0 g, 24.85 mmol) was obtained in a yield of 78%. M / S: 205.1 (M+H + ).

[0478] Step 2: Synthesis of intermediate (S)-3-amino-2-(3-bromo-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 7-3)

[0479] A mixture of intermediate Int7-2 (7.0 g, 28.99 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.87 g, 24.64 mmol), N,N-diisopropylethylamine (7.49 g, 57.97 mmol) and ethanol (100 mL) was heated to 80°C and stirred overnight. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3 times). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was rotary evaporated and purified by column chromatography to obtain solid compound Int 7-3 (11 g, 25.86 mmol) with a yield of 89%. Ms: 425.1 (M+H + ).

[0480] Step 3: Synthesis of intermediate (S)-2-(3-bromo-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 7-4)

[0481] At room temperature, the intermediate Int7-3 (11.0 g, 25.86 mmol) was dissolved in DMA (150 mL), and N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (10.3 g, 51.73 mmol) was added. After nitrogen replacement, potassium tert-butoxide (7.26 g, 64.66 mmol) was slowly added dropwise in an ice bath. The mixture was stirred at room temperature for 2 hours. TLC monitoring confirmed the complete reaction of the starting material. The reaction solution was diluted with 200 mL of water and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the light yellow solid product Int 7-4 (9.0 g, 16.17 mmol) in a yield of 62%. M / S: 556.1 (M+H + ).

[0482] Step 4: Synthesis of compound (S)-2-(3-bromo-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int 7)

[0483] Intermediate Int 7-4 (9.0 g, 16.17 mmol) and methanesulfonic acid (1.87 g, 19.41 mmol) were dissolved in THF (200 mL) at room temperature and stirred at 60°C for 1 h. TLC monitored the complete reaction of the starting materials. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (150 mL × 3). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a light yellow solid product Int7 (4.0 g, 0.52 mmol) in a yield of 50%. M / S: 492.1 (M+H + ).

[0484] Example 1. Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-one (Compound R):

[0485] Step 1: Synthesis of the first intermediate N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (ref-2):

[0486] Procedure: CDI (1.55 g, 9.5 mmol) was added to a reaction flask, followed by EA (10 mL). After stirring for 10 min under an ice bath, ref-1 (1 g, 9.5 mmol) was slowly added dropwise, followed by stirring at room temperature for 2 h. After the reaction was completed, 20 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with 20 mL of saturated brine and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the intermediate ref-2 (1.47 g, yield: 77.8%). Ms: 200 (M+H + )

[0487] Step 2: Synthesis of the second intermediate (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (ref-3):

[0488] Procedure: At room temperature, intermediate ref-2 (200 mg, 1.01 mmol) and (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (400 mg, 0.84 mmol) were added to a solution of t-BuOK (282 mg, 2.52 mmol) in N,N-dimethylacetamide (20 mL). The resulting system was stirred at room temperature for 2 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with 50 mL of saturated brine and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate ref-3 (450.0 mg, yield: 83.3%). Ms: 506 (M+H + )

[0489] Step 3: Synthesis of the third intermediate (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (ref-4):

[0490] Procedure: Compound ref-3 (450 mg, 0.89 mmol) was placed in a 50 mL single-necked flask. Tetrahydrofuran (20 mL) was added, followed by methanesulfonic acid (41 mg, 0.44 mmol). The mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and K₃PO₄ aqueous solution was added to adjust the pH to 9. Di-tert-butyl dicarbonate (78 mg, 0.356 mmol) was added and stirred for 1 hour. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield intermediate ref-4 (340 mg, yield: 86.5%). Ms: 442 (M+H + )

[0491] Step 4: Synthesis of the fourth intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (ref-5):

[0492] Procedure: In a three-necked flask, compound ref-4 (100 mg, 0.159 mmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (104 mg, 0.317 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (17 mg, 0.079 mmol) were dissolved in N-methylpyrrolidone (10 mL). Cuprous iodide (9 mg, 0.032 mmol) and potassium carbonate (94 mg, 0.476 mmol) were then added. The reaction mixture was stirred at 130°C under nitrogen for 2 h. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield intermediate ref-5 (50 mg, yield: 38%). Ms: 590 (M+H + )

[0493] Step 5: Synthesis of the fifth intermediate (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (compound ref-6):

[0494] Procedure: Compound ref-5 (50 mg, 0.085 mmol) was placed in a 25 mL single-necked flask, and a 4 M 1,4-dioxane hydrochloride solution (5 mL) was added. The mixture was stirred at room temperature for 1 h. A K2CO3 aqueous solution was then added to adjust the pH to 11. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford intermediate ref-6 (40 mg, yield: 97%). Ms: 490 (M+H + )

[0495] Step 6: Synthesis of the product 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-one (Compound R):

[0496] Procedure: Compound ref-6 (40 mg, 0.12 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 0.12 mmol) were dissolved in DMF (0.5 mL). HATU (68 mg, 0.18 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) were added, respectively, and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with 20 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield the title compound (Compound R) (13 mg, 18% yield). 883(M+H+)

[0497] 1H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.31(s,1H),7.64(d,J=8.9Hz,1H),7.53(s,1H),7.49(d,J= 7.9Hz,1H),7.39(d,J=8.5Hz,1H),7.26(d,J=8.5Hz,1H),7.18(d,J=6.2Hz,2H),7.09(s,1H),6.95 (s,2H),4.10(d,J=10.7Hz,3H),3.71(d,J=8.4Hz,2H),3.18(s,1H),3.02(d,J=12.1Hz,1H),2.88( d,J=14.9Hz,1H),2.26(s,6H),1.66(d,J=12.2Hz,7H),1.43(d,J=6.7Hz,2H),1.28–1.17(m,13H).

[0498] Example 2. Synthesis of Compound 3-((1S,2S)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 1)

[0499] Step 1: Synthesis of intermediate N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (ref-2)

[0500] Procedure: Add N,N'-carbonyldiimidazole (3.3 g, 20.0 mmol) to ethyl acetate (40 mL), add aminoacetaldehyde dimethyl acetal (2.1 g, 20.0 mmol) dropwise, react at room temperature overnight, add ethyl acetate (100 mL), wash once with water (50 mL), wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.5 g of the product with a yield of 39.6%. Ms: 200 (M+H + ).

[0501] Step 2: Synthesis of intermediate 3-fluoro-4-iodo-2-methylaniline (1-2)

[0502] Procedure: Dissolve 3-fluoro-2-methylaniline (50.0 g, 0.4 mol) in 500 mL of acetonitrile, control the temperature below 5°C, add N-iodosuccinimide (99.0 g, 0.44 mol) in batches, control the temperature below 10°C and react for 2 h. Add sodium hydroxide aqueous solution to adjust the pH to 9-10, extract with ethyl acetate (500 mL x 2), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 99 g of the product with a yield of 98.7%. Ms: 251.9 (M+H + ).

[0503] Step 3: Synthesis of intermediate 4-fluoro-5-iodo-1H-indazole (1-3)

[0504] Procedure: Dissolve intermediate 1-2 (50 g, 0.2 mol) in acetic acid (500 mL), add sodium nitrite (27.6 g, 0.4 mol) in portions, react at room temperature for 4 hours, cool to -10°C, add sodium hydroxide aqueous solution (30%) dropwise with vigorous stirring until pH = 7-8, extract with ethyl acetate (500 mL × 3), combine the organic layers, wash once with saturated brine (500 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 26 g of the product, yield: 49.8%. Ms: 262.9 (M+H + ).

[0505] Step 4: Synthesis of intermediate 4-fluoro-5-iodo-1-methyl-1H-indazole (1-4)

[0506] Procedure: Sodium hydride (4.8 g, 0.11 mol) was added to N,N-dimethylacetamide (160 mL). Under N2 protection, the mixture was cooled to 0°C in an ice-water bath. A solution of intermediate 1-3 (26.0 g, 0.1 mol) in N,N-dimethylacetamide (100 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. Methyl iodide (7.5 mL, 0.12 mol) was slowly added dropwise. The mixture was reacted at room temperature for 4 hours. The mixture was slowly poured into ice water (1000 mL) for quenching. The mixture was extracted with ethyl acetate (500 mL × 3). The organic layers were combined, washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 19 g of the product (intermediate 1-4) in a yield of 69.3%. Ms: 277.0 (M+H + ).

[0507] Step 5: Synthesis of intermediate (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1-5)

[0508] Procedure: (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (2.0 g, 7.3 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (4.1 g, 14.6 mmol), and N-methylimidazole (1.8 g, 21.9 mmol) were added to acetonitrile (40 mL) in sequence and stirred at room temperature for 0.5 hour. N-methylaniline (1.2 g, 11.0 mmol) was added and reacted at room temperature for 1 hour. The mixture was filtered, and the filter cake was rinsed with acetonitrile (10 mL). The filter cake was dried to obtain 2.5 g of the product with a yield of 94.2%. Ms: 363.2 (M+H + ).

[0509] Step 6: Synthesis of intermediate (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1-6)

[0510] Procedure: Sodium hydride (0.42 g, 10.4 mmol) was added to N,N-dimethylformamide (20 mL), and the mixture was cooled to 0°C in an ice-water bath under N2 protection. A solution of intermediate 1-5 (2.5 g, 6.9 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Chloroacetonitrile (0.79 mg, 10.4 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was slowly poured into ice water (50 mL) for quenching, and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.5 g of the product with a yield of 90.0%. Ms: 402.1 (M+H + ).

[0511] Step 7: Synthesis of intermediate 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1-7)

[0512] Procedure: Intermediate 1-6 (500 mg, 1.25 mmol) and (4R)-4-methyl-1,3,2-dithiolane (430 mg, 3.12 mmol) were added to N,N-dimethylpropyleneurea (5 mL) in sequence. The mixture was cooled to 0°C in an ice-water bath under N2 protection. Sodium bis(trimethylsilyl)amide (2.5 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 0°C for 4 hours. Saturated aqueous ammonium chloride (10 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 400 mg of the product in a yield of 72.7%. Ms: 442.2 (M+H + ).

[0513] Step 8: Synthesis of intermediate 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (1-8)

[0514] Procedure: Intermediate 1-7 (300 mg, 0.68 mmol), hydroxylamine hydrochloride (235 mg, 3.4 mmol), and potassium carbonate (516 mg, 3.74 mmol) were added to ethanol (6 mL) in sequence, reacted at 100 ° C for 3 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (10 mL × 2), combined the organic layers, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was dissolved in dimethyl sulfoxide (5 mL) L), N,N'-carbonyldiimidazole (162 mg, 1.0 mmol) and 1,8-diazacyclo[5,4,0]undec-7-ene (213 mg, 1.4 mmol) were added in sequence, reacted at 80°C for 3 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (10 mL × 2), combined organic layers, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 250 mg of the product with a yield of 73.4%. Ms: 501.2 (M+H + ).

[0515] Step 9: Synthesis of intermediate 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (1-9)

[0516] Procedure: Intermediate 1-8 (250 mg, 0.5 mmol) and potassium hydroxide (280 mg, 5.0 mmol) were added to 2-methoxyethanol (10 mL) in sequence. The mixture was reacted at 125°C for 1 hour, cooled to room temperature, and 2N hydrochloric acid was added dropwise to adjust the pH to 3. Water (10 mL) was added to precipitate the solid, which was filtered and dried to obtain 150 mg of the product. Yield: 73.0%. Ms: 412.2 (M+H + ).

[0517] Step 10: Synthesis of intermediate 3-cyclopropyl-4-fluoroaniline (1-10)

[0518] Procedure: 3-Bromo-4-fluoroaniline (100 g, 526 mmol), cyclopropylboronic acid (58.8 g, 684 mmol), potassium phosphate (391 g, 1.84 mol), tricyclohexylphosphine (14.8 g, 52.6 mol), and palladium (II) acetate (5.96 g, 26.3 mmol) were added to toluene / water (20:1, 2000 mL) in sequence. The atmosphere was replaced with nitrogen three times. The oil bath was heated to 100°C and reacted overnight. The temperature was then lowered to room temperature and filtered. The filter cake was rinsed with ethyl acetate (500 mL). The filtrates were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 70 g of the product in an 88% yield. Ms: 152.2 (M+H + ).

[0519] Step 11: Synthesis of intermediate (3-cyclopropyl-4-fluorophenyl)hydrazine (1-11)

[0520] Procedure: Dissolve intermediate 1-10 (50 g, 331 mmol) in 6N hydrochloric acid (500 mL), cool to 0°C, add dropwise a solution of sodium nitrite (34.2 g, 496 mmol) in water (70 mL), react at 0°C for 0.5 hours, add dropwise a solution of stannous chloride (125 g, 661 mmol) in concentrated hydrochloric acid (150 mL), naturally warm to react for 3 hours, filter, and slurry the filter cake with methyl tert-butyl ether (200 mL), filter, and dry the filter cake to obtain 30 g of the product hydrochloride, yield: 45%. Ms: 167.1 (M+H + ).

[0521] Step 12: Synthesis of intermediate (S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1-12)

[0522] Procedure: Intermediate 1-11 hydrochloride (19 g, 93.7 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (22.3 g, 93.7 mmol), and N,N-diisopropylethylamine (24.2 g, 187 mmol) were added to ethanol (200 mL) in sequence. The mixture was reacted at 80°C overnight, concentrated under reduced pressure, and purified by column chromatography to obtain 21 g of the product in a yield of 58%. Ms: 387.2 (M+H + ).

[0523] Step 13: Synthesis of intermediate (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1-13)

[0524] Procedure: Intermediate 1-12 (1.5 g, 3.9 mmol), intermediate ref-2 (1.6 g, 7.8 mmol), and potassium tert-butoxide (1.3 g, 11.6 mmol) were added to N,N-dimethylacetamide (15 mL) in sequence and reacted at room temperature for 2 hours. The mixture was diluted with ethyl acetate (150 mL), washed once with water (100 mL), and once with saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.4 g of the product in a yield of 69.7%. Ms: 518.3 (M+H + ).

[0525] Step 14: Synthesis of intermediate (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1-14)

[0526] Procedure: Intermediate 1-13 (1.4 g, 2.7 mmol) and methanesulfonic acid (0.26 g, 2.7 mmol) were added to tetrahydrofuran (30 mL) in sequence and reacted at 60°C for 2 hours. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed once with saturated sodium bicarbonate aqueous solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.1 g of the product in a yield of 89.7%. Ms: 454.2 (M+H + ).

[0527] Step 15: Synthesis of intermediate (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1-15)

[0528] Procedure: Intermediate 1-14 (1.1 g, 2.4 mmol), intermediate 1-4 (1.3 g, 4.8 mmol), (1S,2S)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (0.35 g, 2.4 mmol), cuprous iodide (0.47 g, 2.4 mmol), and potassium carbonate (1.0 g, 7.3 mmol) were added to N,N-dimethylacetamide (15 mL) in sequence. The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 120°C overnight. The mixture was cooled to room temperature and filtered. The filter cake was slurried with ethyl acetate (50 mL × 2). The filtrates were combined, washed with water (50 mL × 2), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.0 g of the product in a yield of 68.5%. Ms: 602.3 (M+H + ).

[0529] Step 16: Synthesis of intermediate (S)-1-(2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (1-16)

[0530] Procedure: Add intermediate 1-15 (1.0 g, 1.7 mmol) to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL) and react at room temperature for 2 hours. Adjust the pH to >7 with saturated sodium bicarbonate aqueous solution and extract with ethyl acetate (20 mL x 2). Combine the organic layers, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 750 mg of the product with a yield of 90%. Ms: 502.2 (M+H + ).

[0531] Step 17: Synthesis of compound 3-((1S,2S)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0532] Procedure: Intermediate 1-16 (50 mg, 0.1 mmol), Intermediate 1-9 (49 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL), and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 51 mg of the product in a yield of 57%. Ms: 894.6 (M+H + ). 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.29(s,1H),7.64(d,J=8.8Hz,1H),7.53(s,1H),7.51–7.46(m,1H),7.44 –7.33(m,2H),7.32–7.21(m,2H),7.18–7.09(m,2H),7.04–6.92(m,2H),5.69–5.61(m,1H),4.15–4.00(m,4H),3 .75–3.64(m,2H),3.39(d,J=11.0Hz,1H),3.00–2.86(m,1H),2.77–2.65(m,1H),2.14–2.01(m,1H),1.74–1.59( m,4H),1.49(q,J=12.8Hz,1H),1.34(d,J=6.6Hz,3H),1.28–1.13(m,9H),1.04–0.92(m,5H),0.81–0.61(m,2H).

[0533] Example 3. Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 4)

[0534] Step 1: Synthesis of intermediate N-(1,1-dimethoxyprop-2-yl)-1H-imidazole-1-carboxamide (4-2)

[0535] Dissolve CDI (1.55 g, 9.5 mmol) in ethyl acetate (10 mL). Slowly add compound 4-1 (1 g, 8.4 mmol) dropwise under ice-cooling. Stir at room temperature for 2 h. After the reaction is complete, dilute with 20 mL of water and extract with ethyl acetate (20 mL x 3). The organic phase is washed with 20 mL of saturated brine, dried over sodium sulfate, and filtered. Concentrate under reduced pressure and purify the concentrate by silica gel column chromatography to obtain intermediate 4-2 (1.5 g, yield: 84%). M / S: 214.1 (M+H + ).

[0536] Step 2: Synthesis of the intermediate (4S)-3-(3-(1,1-dimethoxyprop-2-yl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (4-3)

[0537] At room temperature, intermediate 4-2 (215 mg, 1.01 mmol), (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (400 mg, 0.84 mmol) and t-BuOK (282 mg, 2.52 mmol) were added to a solution of N,N-dimethylacetamide (20 mL) and stirred at room temperature for 4 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 4-3 (450.0 mg, yield: 83.3%). M / S: 520.2 (M+H + ).

[0538] Step 3: Synthesis of the intermediate ((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (4-4)

[0539] Compound 4-3 (460 mg, 0.89 mmol) was placed in a 50 mL single-necked flask, tetrahydrofuran (20 mL) was added, and then methanesulfonic acid (41 mg, 0.44 mmol) was added. The mixture was stirred at 60°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of water was added. The pH was adjusted to 7 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield intermediate 4-4 (340 mg, yield: 75%). Ms: 456.1 (M+H+).

[0540] Step 4: Synthesis of compound (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (4-5).

[0541] Compound 4-4 (75 mg, 0.16 mmol), 5-iodo-1-methyl-1H-indazole (104 mg, 0.317 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (17 mg, 0.079 mmol) were dissolved in N-methylpyrrolidone (10 mL). Cuprous iodide (9 mg, 0.032 mmol) and potassium carbonate (94 mg, 0.476 mmol) were then added. The reaction mixture was stirred at 130°C under nitrogen for 3 h. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, and filtered. The mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate 4-5 (50 mg, 0.085 mmol) in a 53% yield. M / S: 586.2 (M+H + ).

[0542] Step 5: Synthesis of intermediate (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-4-methyl-3-(1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (4-6)

[0543] Compound 4-5 (50 mg, 0.085 mmol) was placed in a 25 mL single-necked bottle at room temperature, and a 1,4-dioxane hydrochloride solution (5 mL, 4 N) was added. The mixture was stirred at room temperature for 2 h. Aqueous potassium carbonate solution was added to adjust the pH to 11, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 4-6 (40 mg, 0.084 mmol). The yield was 97%. M / S: 485.1 (M+H + ).

[0544] Step 6: Synthesis of compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (4)

[0545] Intermediate 1-9 (33 mg, 0.08 mmol) was dissolved in DMF (10 mL), and HATU (46 mg, 0.12 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) were added. After stirring for 10 minutes, compound 4-6 (40 mg, 0.08 mmol) was added. The reaction was stirred at room temperature for 5 hours. 20 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain compound 4 (20 mg, 0.023 mmol). The yield was 28%. M / S: 879 (M+H + ). 1HNMR (400MHz, DMSO-d6) δ11.76(s,1H),8.31(s,1H),7.64(d,J=8.8Hz,1H),7.50(dd,J=17.5,9. 6Hz,2H),7.40(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),7.18(d,J=6.4Hz,1H),7.09(d,J=3.2Hz,1 H),6.95(s,2H),4.11(s,3H),3.71(d,J=8.4Hz,2H),3.17(d,J=12.4Hz,1H),3.06–2.99(m,1H), 2.92–2.86(m,1H),2.26(s,6H),1.99(s,1H),1.54(dd,J=89.6,9.6Hz,13H),1.30–1.14(m,11H).

[0546] Example 4. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptane[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 18)

[0547] Step 1: Synthesis of the intermediate (4R,7S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carboxylic acid tert-butyl ester (18-1)

[0548] Dissolve tert-butyl (1R,5S)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylate (2.5 g, 10 mmol) and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (2.29 g, 12 mmol) in ethanol (50 mL). Add N,N-diisopropylethylamine (2.84 g, 22 mmol) and stir at 80°C for 12 h. After the reaction, dilute with 50 mL of water and extract with ethyl acetate (50 mL x 3). The organic phase is washed with 30 mL of saturated brine, dried over sodium sulfate, and filtered. Concentrate under reduced pressure and purify the concentrate by silica gel column chromatography to obtain Intermediate 18-1 (2 g, yield: 52%). M / S: 387.2 (M+H + ).

[0549] Step 2: Synthesis of the intermediate (4R,7S)-3-(3-(2,2-dimethoxyethyl)urea)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester (18-2).

[0550] At room temperature, intermediate 18-1 (872 mg, 2.26 mmol), ref-2 (900 mg, 4.25 mmol), and t-BuOK (633 mg, 5.65 mmol) were added to a solution of N,N-dimethylacetamide (20 mL) and stirred at room temperature for 2 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 18-2 (995 mg, yield: 85%). M / S: 518.3 (M+H + ).

[0551] Step 3: Synthesis of the intermediate (4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester (18-3).

[0552] Compound 18-2 (880 mg, 1.70 mmol) was placed in a 50 mL single-necked flask, tetrahydrofuran (20 mL) was added, and then methanesulfonic acid (254 mg, 2.55 mmol) was added. The mixture was stirred at 60°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, 50 mL of water was added, and the pH was adjusted to 7 with saturated sodium carbonate aqueous solution. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate 18-3 (710 mg, yield: 92%). Ms: 454.1 (M+H + ).

[0553] Step 4: Synthesis of compound (4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester (18-4)

[0554] Compound 18-3 (680 mg, 1.50 mmol), 5-iodo-1-methyl-1H-indazole (705 mg, 2.56 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (214 mg, 1.50 mmol) were dissolved in N-methylpyrrolidone (10 mL), followed by the addition of cuprous iodide (115 mg, 0.6 mmol) and potassium carbonate (478 mg, 2.26 mmol). The reaction mixture was stirred at 130°C for 2 h. After cooling to room temperature, 20 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford intermediate 18-4 (225 mg, 0.38 mmol) in a 25% yield. M / S: 602.3 (M+H + ).

[0555] Step 5: Synthesis of 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (18-5)

[0556] Compound 18-4 (225 mg, 0.38 mmol) was placed in a 25 mL single-necked bottle at room temperature, and a 1,4-dioxane hydrochloride solution (10 mL, 4 N) was added. The mixture was stirred at room temperature for 1 h. Aqueous potassium carbonate solution was added to adjust the pH to 11, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 18-5 (184 mg, 0.37 mmol). The yield was 97%. M / S: 502.3 (M+H + ).

[0557] Step 6: Synthesis of compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18)

[0558] Intermediate 1-9 (40 mg, 0.1 mmol) was dissolved in DMAc (10 mL), and HATU (44 mg, 0.12 mmol) and N,N-diisopropylethylamine (20 mg, 0.015 mmol) were added. After stirring for 10 minutes, compound 18-5 (50 mg, 0.1 mmol) was added. The reaction was stirred at room temperature for 2 h. 20 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain compound 18 (44 mg, 0.049 mmol). The yield was 49%. M / S: 895.4 (M+H + ).

[0559] Example 5. Synthesis of Compound 3-((1S,2S)-1-(2-((4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptane[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (19)

[0560] Step 1: Synthesis of the intermediate (4R,7S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester (19-1).

[0561] Tert-butyl (1R,5S)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylate (3.5 g, 13.98 mmol) and (3-cyclopropyl-4-fluorophenyl)hydrazine hydrochloride (3.4 g, 16.78 mmol) were dissolved in ethanol (50 mL). N,N-diisopropylethylamine (3.61 g, 27.97 mmol) was added and stirred at 80°C for 12 h. After the reaction, the mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 30 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography. After chiral resolution, intermediate 19-1 (1.2 g, yield: 21%) was obtained. M / S: 403.2 (M+H + ).

[0562] Step 2: Synthesis of the intermediate (4R,7S)-(2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester (19-2)

[0563] At room temperature, intermediate 19-1 (900 mg, 2.26 mmol), intermediate ref-2 (900 mg, 4.25 mmol) and t-BuOK (633 mg, 5.65 mmol) were added to N,N-dimethylacetamide (20 mL) solution and stirred at room temperature for 2 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 19-2 (1.0 g, yield: 83%). M / S: 530.3 (M+H + ).

[0564] Step 3: Synthesis of the intermediate (4R,7S)-(2-(3-cyclopropyl-4-fluorophenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester (19-3).

[0565] Compound 19-2 (900 mg, 1.70 mmol) was placed in a 50 mL single-necked flask, tetrahydrofuran (20 mL) was added, and then methanesulfonic acid (254 mg, 2.55 mmol) was added. The mixture was stirred at 60°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of water was added. The pH was adjusted to 7 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford intermediate 19-3 (700 mg, yield: 88%). Ms: 466.1 (M+H+).

[0566] Step 4: Synthesis of compound (4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-3(-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester (19-4)

[0567] Compound 19-3 (700 mg, 1.50 mmol), 5-iodo-1-methyl-1H-indazole (705 mg, 2.56 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (214 mg, 1.50 mmol) were dissolved in N-methylpyrrolidone (10 mL). Cuprous iodide (115 mg, 0.6 mmol) and potassium carbonate (478 mg, 2.26 mmol) were then added. The reaction mixture was stirred at 130°C for 2 h. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, and filtered. The mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain intermediate 19-4 (230 mg, 0.38 mmol) in a 25% yield. M / S: 614.3 (M+H + ).

[0568] Step 5: Synthesis of intermediate 1-((4R,7S)-(2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazol-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (19-5).

[0569] Compound 19-4 (230 mg, 0.37 mmol) was placed in a 25 mL single-necked bottle at room temperature, and a 1,4-dioxane hydrochloride solution (10 mL, 4 N) was added. The mixture was stirred at room temperature for 1 h. Aqueous potassium carbonate solution was added to adjust the pH to 11, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 19-5 (180 mg, 0.35 mmol). The yield was 97%. M / S: 514.3 (M+H + ).

[0570] Step 6: Synthesis of compound 3-((1S,2S)-1-(2-((4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (19)

[0571] Intermediate 1-9 (38 mg, 0.09 mmol) was dissolved in DMAc (10 mL), and HATU (44 mg, 0.12 mmol) and N,N-diisopropylethylamine (20 mg, 0.015 mmol) were added. After stirring for 10 minutes, compound 19-5 (40 mg, 0.077 mmol) was added. The reaction was stirred at room temperature for 2 hours. 20 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain compound 19 (40 mg, 0.044 mmol). The yield was 56%. M / S: 907.4 (M+H + ).

[0572] Example 6. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30)

[0573] A similar method to Example 4 was used, except that (1S,5R)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was substituted for (1R,5S)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to obtain compound 30 in a yield of 49%. M / S: 895.4 (M+H + ).

[0574] Example 7. Synthesis of Compound 3-((1S,2S)-1-(2-((4S,7R)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptane[c]pyrazole-9-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (31)

[0575] A similar method to Example 5 was used, except that (1S,5R)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was substituted for (1R,5S)-2-cyano-3-oxo-8-azacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to obtain compound 31 in a yield of 56%. M / S: 907.4 (M+H + ).

[0576] Example 8. Synthesis of Compound 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indol-3-yl)cyclopropyl)-1,2,4-oxazol-5(4H)-one (41)

[0577] Step 1: Synthesis of intermediate (S)-3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indole-2-carboxylic acid ethyl ester (41-1)

[0578] Ethyl (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indole-2-carboxylate (1.1 g, 3.65 mmol), 2-bromoacetonitrile (482 mg, 4.01 mmol), FeSO4 hydrate (508 mg, 1.82 mmol), and NaI (547 mg, 3.65 mmol) were added to DMF (10 mL). The mixture was cooled to 0°C in an ice-water bath under N2 protection. Hydrogen peroxide (1.88 mL, 30%) was added dropwise. The mixture was stirred at 0°C for 20 minutes and then slowly poured into ice water (20 mL) for quenching. The mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 530 mg of the product in a yield of 43%. Ms: 341.3 (M+H + ).

[0579] Step 2: Synthesis of intermediate (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indole-2-carboxylic acid ethyl ester (41-2)

[0580] Intermediate 41-1 (425 mg, 1.25 mmol) and 1,3,2-dioxathiolane (387 mg, 3.12 mmol) were added to N,N-dimethylpropyleneurea (4 mL) in sequence. The mixture was cooled to 0°C in an ice-water bath under N2 protection. Sodium bis(trimethylsilyl)amide (2.5 mL, 5.0 mmol) was added dropwise. The mixture was reacted at 0°C for 4 hours. Saturated aqueous ammonium chloride solution (10 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 330 mg of the product in a yield of 75%. Ms: 367.2 (M+H + ).

[0581] Step 3: Synthesis of intermediate (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indole-2-carboxylic acid ethyl ester (41-3)

[0582] Intermediate 41-2 (249 mg, 0.68 mmol), hydroxylamine hydrochloride (235 mg, 3.4 mmol), and potassium carbonate (516 mg, 3.74 mmol) were added to ethanol (6 mL) in sequence and refluxed for 3 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was dissolved in dimethyl sulfoxide (5 mL). N,N'-carbonyldiimidazole (162 mg, 1.0 mmol) and 1,8-diazacyclo[5,4,0]undec-7-ene (213 mg, 1.4 mmol) were added in sequence and reacted at 80°C for 3 hours. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The organic layers were combined and washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 205 mg of the product with a yield of 73.4%. Ms: 426.2 (M+H + ).

[0583] Step 4: Synthesis of intermediate (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indole-2-carboxylic acid (41-4)

[0584] Intermediate 41-3 (212 mg, 0.5 mmol) and potassium hydroxide (280 mg, 5.0 mmol) were added to 2-methoxyethanol (10 mL) in sequence. The mixture was reacted at 125°C for 1 hour. The mixture was cooled to room temperature and 2N hydrochloric acid was added dropwise to adjust the pH to 3. Water (10 mL) was added to precipitate the solid, which was filtered and dried to obtain 151 mg of the product. The yield was 76.0%. Ms: 398.2 (M+H + ).

[0585] Step 5: Synthesis of compound 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indol-3-yl)cyclopropyl)-1,2,4-oxazol-5(4H)-one (41)

[0586] Intermediate 41-4 (49 mg, 0.1 mmol), intermediate Int 4 (49 mg, 0.1 mmol), HATU (46 mg, 0.12 mmol), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL) and once with saturated brine (10 mL), and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 42 mg of the product in a yield of 47.7%. Ms: 880.6 (M+H + ).

[0587] 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.30(s,1H),8.16(d,J=7.3Hz,1H),7.64(d,J=8.9Hz,1H),7.48–7.41(m,1H),7.33–7. 20(m,3H),7.10(d,J=3.2Hz,1H),7.02–6.90(m,2H),6.72(dd,J=7.3,1.8Hz,1H),6.42(s,1H),5.69–5.61(m,1H),4.15–4.00( m,4H),3.75–3.64(m,2H),3.39(d,J=11.0Hz,1H),3.00–2.86(m,1H),2.77–2.65(m,1H),2.14–2.01(m,1H),1.74–1.59(m,4H ),1.49(q,J=12.8Hz,1H),1.34(d,J=6.6Hz,3H),1.28–1.13(m,9H),1.04–0.92(m,2H),0.87–0.80(m,1H),0.71–0.58(m,2H).

[0588] Example 9. Synthesis of Compound 3-(1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (42)

[0589] Procedure: Intermediate 1-16 (50 mg, 0.1 mmol), intermediate 41-4 (40 mg, 0.1 mmol), HATU (46 mg, 0.12 mmol), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL), and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 42 mg of the product in a yield of 47.7%. Ms: 880.6 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.30(s,1H),8.16(d,J=7.3Hz,1H),7.64(d,J=8.9Hz,1H),7.48–7.41(m,1H),7.33–7. 20(m,3H),7.10(d,J=3.2Hz,1H),7.02–6.90(m,2H),6.72(dd,J=7.3,1.8Hz,1H),6.42(s,1H),5.69–5.61(m,1H),4.15–4.00( m,4H),3.75–3.64(m,2H),3.39(d,J=11.0Hz,1H),3.00–2.86(m,1H),2.77–2.65(m,1H),2.14–2.01(m,1H),1.74–1.59(m,4H ),1.49(q,J=12.8Hz,1H),1.34(d,J=6.6Hz,3H),1.28–1.13(m,9H),1.04–0.92(m,2H),0.87–0.80(m,1H),0.71–0.58(m,2H).

[0590] Example 10. Synthesis of Compound 3-(1-(7-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indole-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-bridged cyclohepta[c]pyrazole-9-carbonyl)indole-3-yl)cyclopropyl)-1,2,4-oxazol-5(4H)-one (59)

[0591] Compounds 18-8 (60 mg, 0.12 mmol) and 41-4 (53 mg, 0.13 mmol) were dissolved in DMA (3 mL), and HATU (69 mg, 0.18 mmol) and DIPEA (31 mg, 0.24 mmol) were added. The mixture was allowed to react at room temperature for 6 h and monitored by TLC. The reaction was quenched by adding water (20 mL), and extracted with EA (10 mL × 3). The EA was combined, washed with water (20 mL × 2), and then washed with saturated brine (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 45 mg of a white solid with a yield of 42.7%. M / S: 881 (M+H + ). 1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.39–8.21(m,1H),8.13(dd,J=32.7,7.2Hz,1H),7.68–7 .45(m,1H),7.35–7.11(m,3H),6.99(dd,J=49.9,21.3Hz,3H),6.69(d,J=32.3Hz,1H),6.61–6. 36(m,1H),5.06(d,J=35.1Hz,1H),4.10(s,3H),3.79–3.35(m,4H),2.97–2.57(m,2H),2.42-2. 16(m,7H),2.06(d,J=9.5Hz,3H),1.83–1.34(m,6H),1.35–1.11(m,6H),1.08(d,J=6.9Hz,2H).

[0592] Example 11. Synthesis of Compound 3-(1-(2-((4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-epiaminocycloheptane[c]pyrazole-9-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (60):

[0593] Step 1: Synthesis of the intermediate (4R,7S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester:

[0594] Compound 18-3 (3.2 g, 12.8 mmol) and (3-cyclopropyl-4-fluorophenyl)hydrazine hydrochloride (2.9 g, 14.2 mmol) were dissolved in ethanol (50 mL) and stirred at 50°C for 12 hours. After the reaction, the mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography afforded intermediate 60-1 (2.8 g, 5.3 mmol). Yield: 55%. M / S: 399 (M+H + ).

[0595] Step 2: Synthesis of the intermediate (4R,7S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carboxylic acid tert-butyl ester (60-2).

[0596] At room temperature, intermediate 60-1 (2.8 g, 7.1 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (3 g, 14.2 mmol), and potassium tert-butoxide (2.9 g, 21.3 mmol) were dissolved in N,N-dimethylacetamide (30 mL) and stirred at room temperature for 4 hours. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. Concentrated under reduced pressure and purified by column chromatography to give intermediate 60-2 (2.5 g, 4.7 mmol) in a yield of 67.6%. M / S: 530 (M+H + ).

[0597] Step 3: Synthesis of the intermediate (4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carboxylic acid tert-butyl ester (60-3).

[0598] Compound 60-2 (2.5 g, 4.7 mmol) was placed in a 100 mL single-necked flask, tetrahydrofuran (50 mL) was added, and then methanesulfonic acid (454 mg, 4.7 mmol) was added. The mixture was stirred at 60°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, 50 mL of water was added, and the pH was adjusted to 7 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography afforded intermediate 60-3 (1.9 g, 2.4 mmol) in an 86.4% yield. Ms: 466 (M+H + ).

[0599] Step 4: Synthesis of the intermediate (4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazole-9-carboxylic acid tert-butyl ester (60-4).

[0600] Compound 60-3 (1.9 g, 4.1 mmol), 5-iodo-4-fluoro-1-methyl-1H-indazole (2.2 g, 8.2 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (581 mg, 4.1 mmol) were dissolved in N-methylpyrrolidone (20 mL), followed by the addition of cuprous iodide (779 mg, 4.1 mmol) and potassium carbonate (1698 mg, 12.3 mmol). The reaction mixture was stirred at 130°C under nitrogen for 3 h. The mixture was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography afforded intermediate 60-4 (1349 mg, 2.2 mmol) in a 54% yield. M / S: 614 (M+H + ).

[0601] Step 5: Synthesis of intermediate 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((4R,7S)-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-cycloheptane[c]pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one (60-5):

[0602] Compound 60-4 (1.35 mg, 2.2 mmol) was dissolved in DCM (4 mL) at room temperature, and a 1,4-dioxane hydrochloride solution (6 mL, 4 N) was added. The reaction was stirred at room temperature for 1 h and monitored by TLC. Sodium bicarbonate solution was added to adjust the pH to 10, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 60-5 (1 g, 1.95 mmol). Yield: 90%. M / S: 514 (M+H + ).

[0603] Step 6: Synthesis of compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(3-cyclopropyl-4-fluorophenyl)-2,4,5,6,7,8-hexahydro-4,7-bridged cycloheptyl[c]pyrazole-9-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (60).

[0604] Intermediate 60-5 (62 mg, 0.12 mmol) and intermediate 41-4 (54 mg, 0.13 mmol) were dissolved in DMA (5 mL), and HATU (91 mg, 0.24 mmol) and DIPEA (31 mg, 0.24 mmol) were added. The reaction was stirred at room temperature for 2 h. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated. Compound 60 (40 mg, 0.045 mmol) was purified by column chromatography. The yield was 36.5%. M / S: 907 M+H + ). 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.36–8.22(m,1H),8.10(dd,J=22.1,7.3Hz,1H),7.58(ddd,J=28.5,19. 5,8.4Hz,1H),7.30(s,1H),7.15(dt,J=12.6,6.3Hz,2H),7.10–6.83(m,3H),6.79–6.57(m,1H),6.57–6.29(m, 1H),5.06(d,J=36.8Hz,1H),4.10(t,J=4.0Hz,3H),3.59(dd,J=92.6,9.0Hz,3H),3.11–2.73(m,2H),2.38-2.1 6(m,7H),2.17–1.89(m,3H),1.73–1.35(m,5H),1.29-1.13(m,6H),0.96(d,J=18.6Hz,2H),0.89–0.78(m,2H).

[0605] Example 12. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-7-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxazol-5(4H)-one (118)

[0606] Step 1: Synthesis of the intermediate (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-7-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (118-1):

[0607] The intermediate (5S)-3-cyano-5-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (20 g, 84.0 mmol) was dissolved in ethanol (200 mL), and (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride (17.5 g, 92.4 mmol) and N,N-diisopropylethylamine (21.7 g, 168.0 mmol) were added in sequence. The temperature was raised to 80°C, and the reaction was allowed to proceed overnight. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 23 g of the product with a yield of 73.2%. Ms: 375.2 (M+H + ).

[0608] Step 2: Synthesis of the intermediate (S)-3-(3-(2,2-dimethoxyethyl)urea)-2-(4-fluoro-3,5-dimethylphenyl)-7-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (118-2)

[0609] Intermediate 118-1 (2 g, 5.35 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (1.38 g, 6.42 mmol), and potassium tert-butoxide (0.9 g, 8.03 mmol) were added to DMAc (10 mL) in sequence, stirred at room temperature, and monitored by TLC. After the reaction, the reaction solution was cooled to room temperature, added dropwise to water, filtered, and purified by solid column chromatography to obtain 1.1 g of the product in a yield of 40.7%. Ms: 506.1 (M+H + ).

[0610] Step 3: Synthesis of intermediate (S)-2-(4-fluoro-3,5-dimethylphenyl)-7-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (118-3)

[0611] Intermediate 118-2 (1.1 g, 2.17 mmol) was dissolved in tetrahydrofuran (22 mL), and methanesulfonic acid (0.21 g, 2.17 mmol) was added dropwise. The mixture was stirred at 60°C and monitored by TLC. Water (110 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic layer was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification by column chromatography, 0.92 g of the product was obtained with a yield of 96.1%. Ms: 442.1 (M+H + ).

[0612] Step 4: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-(methyl-d3)-1H-imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-7-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (118-4)

[0613] Intermediate 118-3 (0.92 g, 2 mmol), 4-fluoro-5-iodo-1-deuteromethyl-1H-indazole (1.1 g, 4 mmol), ligand (0.28 g, 2 mmol), cuprous iodide (0.38 g, 2 mmol), potassium carbonate (0.82 g, 6 mmol), and molecular sieves (0.92 g) were added to NMP (10 mL) in sequence, protected by N2(g), and reacted at 130°C for 12 hours. The mixture was diluted with ethyl acetate (50 mL), washed once with water (10 mL) and once with saturated brine (60 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 735 mg of the product in a yield of 63.7%. Ms: 593.1 (M+H + ).

[0614] Step 5: Synthesis of intermediate (S)-1-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (118-5)

[0615] Intermediate 118-4 (680 mg, 1.15 mmol) was added to a solution of dichloromethane (7 ml) and hydrogen chloride in 1,4-dioxane (4 M, 3 mL) and reacted at room temperature for 2 hours. The pH was adjusted to >7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 505 mg of the product with a yield of 89%. Ms: 493.1 (M+H + ).

[0616] Step 6: Synthesis of compound 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-(methyl-d3)-1H-indolazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxazol-5(4H)-one (118)

[0617] Intermediate 1-9 (40 mg, 0.1 mmol), intermediate 118-6 (50 mg, 0.1 mmol), HATU (46 mg, 0.12 mmol), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL), and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 50 mg of the product in a yield of 56.8%. Ms: 886.2 (M+H + ).

[0618] Referring to the synthesis methods of the above examples, the remaining target compounds in Table 1 were prepared using appropriate reagents under appropriate conditions:

[0619] Table 1. Compounds synthesized in the present invention and characterization data

[0620] Example 13. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 214)

[0621] Step 1: Synthesis of the intermediate (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (214-1)

[0622] Procedure: Intermediate Int 1-3 (0.92 g, 2.1 mmol), intermediate ref-2 (0.84 g, 4.2 mmol), and potassium tert-butoxide (0.71 g, 6.3 mmol) were added to N,N-dimethylacetamide (15 mL) in sequence and reacted at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed once with water (25 mL) and once with saturated brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.1 g of the product in a yield of 92.1%. Ms: 570.2 / 572.2 (M+H + ).

[0623] Step 2: Synthesis of intermediate (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (214-2)

[0624] Procedure: Intermediate 214-1 (1.1 g, 1.9 mmol) and methanesulfonic acid (0.37 g, 3.8 mmol) were added to tetrahydrofuran (55 mL) in sequence and reacted at 60°C for 2 hours. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed once with saturated sodium bicarbonate aqueous solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.84 g of the product in a yield of 86.0%. Ms: 506.1 / 508.1 (M+H + ).

[0625] Step 3: Synthesis of the intermediate (S)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (214-3)

[0626] Procedure: Intermediate 214-2 (290 mg, 0.57 mmol), (R)-(+)-3-butyn-2-ol (200 mg, 2.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (80 mg, 0.11 mmol), cuprous iodide (22 mg, 0.11 mmol), and triethylamine (580 mg, 5.7 mmol) were added to dimethyl sulfoxide (6 mL) in sequence. The atmosphere was replaced with nitrogen three times and the mixture was reacted at 85°C for 4 hours. The mixture was cooled to room temperature and filtered. The filter cake was slurried with ethyl acetate (20 mL × 2). The filtrates were combined, washed with water (20 mL × 2), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 205 mg of the product in a yield of 72.2%. Ms: 496.2 (M+H + ).

[0627] Step 4: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (214-4)

[0628] Procedure: Intermediate 214-3 (205 mg, 0.41 mmol), intermediate 1-N-methyl-4-fluoro-5-iodoindazole (137 mg, 0.50 mmol), (1S,2S)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (59 mg, 0.41 mmol), cuprous iodide (79 mg, 0.41 mmol), and potassium carbonate (86 mg, 0.62 mmol) were added sequentially to N,N-dimethylacetamide (6 mL). The atmosphere was replaced with nitrogen three times, and the mixture was reacted at 120°C for 4 hours. The mixture was cooled to room temperature and filtered. The filter cake was slurried with ethyl acetate (20 mL × 2). The filtrates were combined, washed with water (20 mL × 2), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 160 mg of the product in a yield of 60.1%. Ms: 644.2 (M+H + ).

[0629] Step 5: Synthesis of intermediate 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (214-5)

[0630] Procedure: Add intermediate 214-4 (160 mg, 0.25 mmol) to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL) and react at room temperature for 2 hours. Adjust the pH to >7 with saturated sodium bicarbonate aqueous solution and extract with ethyl acetate (20 mL x 2). Combine the organic layers, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 120 mg of the product in a yield of 88.8%. Ms: 544.2 (M+H + ).

[0631] Step 6: Synthesis of compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 214)

[0632] Procedure: Intermediate 214-5 (100 mg, 0.18 mmol), Intermediate 1-9 (91 mg, 0.22 mmol), HATU (105 mg, 0.28 mmol), and N,N-diisopropylethylamine (48 mg, 0.37 mmol) were added to N,N-dimethylacetamide (2 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL), and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 90 mg of the product in a yield of 52.2%. Ms: 937.2 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.29(s,1H),7.64(d,J=8.8Hz,1H),7.53(s,1H),7.51–7.45(m,1H),7.40(d ,J=8.1Hz,2H),7.30–7.23(m,2H),7.12(d,J=3.1Hz,1H),6.99(s,1H),6.95(s,1H),5.63–5.55(m,1H),4.70–4.59( m,1H),4.44–4.34(m,1H),4.11(s,3H),3.76–3.65(m,2H),3.09–2.97(m,2H),2.96–2.85(m,1H),2.29(s,3H),1.8 2–1.58(m,3H),1.54–1.36(m,4H),1.30–1.21(m,6H),1.17(d,J=6.5Hz,6H),1.09–0.98(m,1H),0.88–0.79(m,4H).

[0633] Example 14. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3-(3-hydroxy-3-methylbut-1-enyl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazepine-5(4H)-one (Compound 203)

[0634] Step 1: Synthesis of Intermediate (S)-2-(4-fluoro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 203-2)

[0635] Intermediate Int 7 (0.3 g, 0.61 mmol), 2-methylbut-3-yn-2-ol (307.53 mg, 3.66 mmol), triethylamine (246.64 mg, 2.44 mmol), cuprous iodide (23.21 mg, 121.86 umol), and bistriphenylphosphine palladium dichloride (85.54 mg, 121.86 umol) were dissolved in DMSO (10 mL) at room temperature and stirred at 85°C under nitrogen for 12 h. TLC confirmed the complete reaction. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford Intermediate 203-2 (0.22 g, 415 umol) as a pale yellow solid in a 68% yield. M / S: 496.2 (M+H + ).

[0636] Step 2: Synthesis of the intermediate ((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 203-3)

[0637] Intermediate 203-2 (120 mg, 201.79 μmol), 4-fluoro-5-iodo-1-methyl-1H-indazole (114.41 mg, 403.59 μmol), cuprous iodide (15.37 mg, 80.72 μmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (28.70 mg, 201.79 μmol), and potassium carbonate (41.83 mg, 302.69 μmol) were stirred in anhydrous N,N-dimethylacetamide (5 mL) under nitrogen at 120°C for 4 h. TLC confirmed the complete reaction. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with 10 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 203-3 (40.0 mg, 62.14 μmol). Yield: 25%. M / S: 644.3 (M+H + ).

[0638] Step 3: Synthesis of Intermediate 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (Intermediate 203-4)

[0639] Intermediate 203-3 (40.0 mg, 62.14 μmol) was dissolved in ethyl acetate (2 mL) and dioxane hydrochloride (2 mL) was added. The reaction was stirred at room temperature for 2 h. TLC confirmed the complete reaction. The reaction solution was concentrated under reduced pressure to afford Intermediate 203-4 (25.0 mg, 45.99 μmol) as a pale yellow solid in a 74% yield. M / S: 544.2 (M+H+).

[0640] Step 4: Synthesis of compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3-(3-hydroxy-3-methylbut-1-enyl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazepine-5(4H)-one (203)

[0641] Intermediate 203-4 (20.0 mg, 36.79 umol), Intermediate 1-9 (Example 2) (23.31 mg, 56.66 umol), and DIEA (9.51 mg, 73.59 umol) were dissolved in DMF (1.0 mL) at room temperature. HATU (20.99 mg, 55.19 umol) was added and the mixture was stirred at room temperature for 2 h. TLC confirmed the complete reaction of the starting materials. The reaction solution was diluted with 5.0 mL of water and extracted with ethyl acetate (5.0 mL × 3). The organic phase was washed with 5.0 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 203 (10.0 mg, 10.67 umol) as a light yellow solid in a yield of 29%. M / S: 937.4 (M+H + ).

[0642] Example 15. Synthesis of Compound 3-[(1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3-(R)-3-hydroxybut-1-en-1-yl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazepine-5(4H)-one (204)

[0643] Compound 204 was synthesized using a method similar to that of 203, using (R)-but-3-yn-2-ol instead of 2-methylbut-3-yn-2-ol, with a yield of 28%. M / S: 923.4 (M+H + ).

[0644] Example 16. Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (206)

[0645] The intermediate was dissolved in DMAc (1.0 mL) with compound 204 (20.0 mg, 21.67 μmol) and potassium carbonate (29.95 mg, 216.69 μmol) at room temperature and stirred at 120°C for 24 h. TLC confirmed the complete reaction. The reaction solution was diluted with 5.0 mL of water and extracted with ethyl acetate (5.0 mL x 3). The organic phase was washed with 5.0 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford the product 206 (10.0 mg, 11.38 μmol) as a pale yellow solid in a 52% yield. M / S: 879.3 (M+H + ).

[0646] Example 17. Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (210):

[0647] Step 1: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (210-1):

[0648] Intermediate Int 1 (6.7 g, 10.2 mmol), tributyl vinyl tin (7.5 g, 20.5 mml), Pd(dppf)Cl2 (1.5 g, 2.1 mmol), and DIPEA (2.7 g, 20.5 mmol) were dissolved in dioxane (67 mL) under N2 protection and reacted at 90°C for 12 h. The reaction was monitored by TLC and cooled to room temperature. Water (150 mL) was added to quench the reaction. EA (100 mL) was added, the mixture was filtered through celite pad, and the filter cake was rinsed with EA (50 mL x 2). The layers were separated and extracted with EA (50 mL x 2). The EA was combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The product was concentrated and purified by column chromatography to give 5.9 g of a white solid (210-1) with a yield of 95.3%, M / S: 602 (M+H + ).

[0649] Step 2: Synthesis of intermediate (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (210-2):

[0650] Intermediate 210-1 (5.9 g, 9.8 mmol) was dissolved in DCM (18 mL), and HCl-Dioxane (27 mL, 4 N) was added dropwise under ice bath. The reaction was allowed to warm naturally for 3 h and monitored by TLC. The reaction was quenched by adding water (50 mL). The pH was adjusted to 8-9 with saturated NaHCO3 solution, and the mixture was extracted with DCM (100 mL × 3). The DCM solution was combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.7 g of a white solid (210-2). The yield was 95.5%, M / S: 502 (M+H + ).

[0651] Step 3: Synthesis of compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (210):

[0652] Intermediate 210-2 (4.7 g, 9.4 mmol), intermediate 1-9 (5 g, 12.2 mmol), and HATU (7.1 g, 18.7 mmol) were dissolved in DMA (15 mL), and DIPEA (2.4 g, 18.7 mmol) was added dropwise. The reaction was allowed to react at room temperature for 8 h and monitored by TLC. The reaction was quenched by adding water (50 mL), extracted with EA (50 mL × 3), and the EA was combined. The product was washed with water (50 mL × 3) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 6 g of a white solid (210). The yield was 71.5%, M / S: 895 (M+H + ).

[0653] 1HNMR(400MHz,DMSO-d6)δ11.76(s,1H),8.30(s,1H),7.63(d,J=8.9Hz,1H),7.57–7.47(m,2H),7.43(dd ,J=16.7,8.2Hz,2H),7.38–7.30(m,1H),7.27(d,J=8.6Hz,1H),7.15–6.93(m,2H),6.87(dd,J=17.6,11. 3Hz,1H),5.84(d,J=17.6Hz,1H),5.54(dd,J=48.7,9.1Hz,2H),4.40(d,J=12.8Hz,1H),4.11(s,3H),3.7 8–3.58(m,3H),3.28–2.68(m,5H),2.28(d,J=12.3Hz,3H),1.83–1.40(m,9H),1.27(s,3H),1.11(s,6H).

[0654] Example 18. Synthesis of Compound 3-((1S,2S)-1-(2-((S)-2-(3-(3,3-dimethylbut-1-en-1-yl)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (213)

[0655] Step 1: Synthesis of the intermediate (S)-2-(3-(3,3-dimethylbut-1-yn-1-yl)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (213-1)

[0656] Int 1 (653 mg, 1 mmol), tert-butylacetylene (164 mg, 2 mmol), CuI (190 mg, 1 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol), and triethylamine (202 mg, 2 mmol) were added to DMSO (7 mL) in sequence and stirred at 90°C for 4 h. After cooling to room temperature, column chromatography was performed to obtain intermediate compound 213-1 (282 mg, 0.43 mmol) in a yield of 43%. M / S: 656.3 (M+H + ).

[0657] Step 2: Synthesis of intermediate (S)-1-(2-(3-(3,3-dimethylbut-1-yn-1-yl)-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (213-2)

[0658] Intermediate 213-1 (282 mg, 0.43 mmol) was dissolved in DCM (3 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL) was added. The mixture was reacted at room temperature for 2 hours. The pH was adjusted to >7 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (211 mg, 0.38 mmol) in a yield of 88.8%. Ms: 556.2 (M+H + ).

[0659] Step 3: Synthesis of intermediate 3-((1S,2S)-1-(2-((S)-2-(3-(3,3-dimethylbut-1-yn-1-yl)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (213-3)

[0660] Compound 1-9 (Example 2) (49 mg, 0.1 mmol), 213-2 (55 mg, 0.1 mmol), HATU (76 mg, 0.2 mmol) and DIPEA (26 mg, 0.2 mmol) were added to DMAc (0.5 mL) and reacted at room temperature for 8 h. The reaction was monitored by TLC. Water (5 mL) was added to quench the reaction and the mixture was extracted with EA (5 mL × 3). The EA was combined and the mixture was washed with water (5 mL × 3) and saturated brine (5 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 213-3 (68 mg, 0.072 mml) in a yield of 71.5%, M / S: 949.1 (M+H + ).

[0661] Step 4: Synthesis of compound 3-((1S,2S)-1-(2-((S)-2-(3-(3,3-dimethylbut-1-yn-1-yl)-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (213)

[0662] 213-3 (68 mg, 0.072 mmol) was added to methanol (1 mL), and Lindlar catalyst (3.4 mg, 5%) was added. The mixture was stirred under hydrogen and monitored by TLC. After the reaction was completed, the mixture was filtered and purified by column chromatography to obtain compound 213 (34 mg, 0.036 mmol). Yield: 50%, M / S: 951.1 (M+H + ).

[0663] Example 19 Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (215)

[0664] Step 1: Synthesis of intermediate 3-bromo-4-fluoro-5-methylaniline (215-1)

[0665] Procedure: 3,5-Dibromo-4-fluoroaniline (10.8 g, 40.0 mmol), potassium methyltrifluoroborate (9.8 g, 80.0 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (2.9 g, 4.0 mmol), and potassium phosphate (25.4 g, 120.0 mmol) were added sequentially to toluene / water (10:1, 150 mL). The atmosphere was replaced with nitrogen three times. The oil bath was heated to 100°C and reacted overnight. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (50 mL). The filtrates were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 4.1 g of the product in a yield of 50.0%. Ms: 204.0 / 206.0 (M+H + ).

[0666] Step 2: Synthesis of intermediate (3-bromo-4-fluoro-5-methylphenyl)hydrazine (215-2)

[0667] Procedure: Dissolve intermediate 215-1 (4.1 g, 20.1 mmol) in 6N hydrochloric acid (40 mL), cool to 0°C, add dropwise a solution of sodium nitrite (2.1 g, 30.1 mmol) in water (4 mL), react at 0°C for 0.5 h, add dropwise a solution of stannous chloride (7.6 g, 40.1 mmol) in concentrated hydrochloric acid (10 mL), warm to room temperature for 3 h, filter, and slurry the filter cake with methyl tert-butyl ether (50 mL), filter, and dry the filter cake to obtain 2.2 g of the product hydrochloride, yield: 50.0%. Ms: 219.0 / 221.0 (M+H + ).

[0668] Step 3: Synthesis of intermediate (S)-3-amino-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (215-3)

[0669] Procedure: Intermediate 215-2 hydrochloride (1.6 g, 6.3 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.3 mmol), and N,N-diisopropylethylamine (1.6 g, 12.6 mmol) were added to ethanol (20 mL) in sequence. The mixture was reacted at 80°C overnight, concentrated under reduced pressure, and purified by column chromatography to obtain 0.92 g of the product in a yield of 33.4%. Ms: 439.1 / 441.1 (M+H + ).

[0670] Step 4: Synthesis of intermediate (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (215-4)

[0671] Procedure: Intermediate 215-3 (0.92 g, 2.1 mmol), intermediate ref-2 (0.84 g, 4.2 mmol), and potassium tert-butoxide (0.71 g, 6.3 mmol) were added to N,N-dimethylacetamide (15 mL) in sequence and reacted at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed once with water (25 mL), and once with saturated brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.1 g of the product in a yield of 92.1%. Ms: 570.2 / 572.2 (M+H + ).

[0672] Step 5: Synthesis of intermediate (S)-2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (215-5)

[0673] Procedure: Intermediate 215-4 (1.1 g, 1.9 mmol) and methanesulfonic acid (0.37 g, 3.8 mmol) were added to tetrahydrofuran (55 mL) in sequence and reacted at 60°C for 2 hours. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed once with saturated sodium bicarbonate aqueous solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.84 g of the product in a yield of 86.0%. Ms: 506.1 / 508.1 (M+H + ).

[0674] Step 6: Synthesis of the intermediate (S)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (215-6)

[0675] Procedure: Intermediate 215-5 (290 mg, 0.57 mmol), (R)-(+)-3-butyn-2-ol (200 mg, 2.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (80 mg, 0.11 mmol), cuprous iodide (22 mg, 0.11 mmol), and triethylamine (580 mg, 5.7 mmol) were added to dimethyl sulfoxide (6 mL) in sequence. The atmosphere was replaced with nitrogen three times and the mixture was reacted at 85°C for 4 hours. The mixture was cooled to room temperature and filtered. The filter cake was slurried with ethyl acetate (20 mL × 2). The filtrates were combined, washed with water (20 mL × 2), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 205 mg of the product in a yield of 72.2%. Ms: 496.2 (M+H + ).

[0676] Step 7: Synthesis of intermediate (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (215-7)

[0677] Procedure: Intermediate 215-6 (205 mg, 0.41 mmol), Intermediate 1-4 (137 mg, 0.50 mmol), (1S,2S)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (59 mg, 0.41 mmol), cuprous iodide (79 mg, 0.41 mmol), and potassium carbonate (86 mg, 0.62 mmol) were added to N,N-dimethylacetamide (6 mL) in sequence. The atmosphere was replaced with nitrogen three times and the mixture was reacted at 120°C for 4 hours. The mixture was cooled to room temperature and filtered. The filter cake was slurried with ethyl acetate (20 mL × 2). The filtrates were combined, washed with water (20 mL × 2), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 160 mg of the product in a yield of 60.1%. Ms: 644.2 (M+H + ).

[0678] Step 8: Synthesis of intermediate 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (215-8)

[0679] Procedure: Add intermediate 215-7 (160 mg, 0.25 mmol) to a solution of hydrogen chloride in 1,4-dioxane (4 M, 5 mL) and react at room temperature for 2 hours. Adjust the pH to >7 with saturated sodium bicarbonate aqueous solution and extract with ethyl acetate (20 mL x 2). Combine the organic layers, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 120 mg of the product in a yield of 88.8%. Ms: 544.2 (M+H + ).

[0680] Step 9: Synthesis of intermediate 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxybut-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (215-9)

[0681] Procedure: Intermediate 215-8 (100 mg, 0.18 mmol), Intermediate 1-9 (91 mg, 0.22 mmol), HATU (105 mg, 0.28 mmol), and N,N-diisopropylethylamine (48 mg, 0.37 mmol) were added to N,N-dimethylacetamide (2 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL) and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 90 mg of the product in a yield of 52.2%. Ms: 937.2 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.29(s,1H),7.64(d,J=8.8Hz,1H),7.53(s,1H),7.51–7.46(m,1H ),7.44–7.33(m,2H),7.32–7.21(m,2H),7.12(d,J=3.2Hz,1H),7.04–6.92(m,2H),5.66–5.52(m,2H),4. 71–4.57(m,1H),4.47–4.33(m,1H),4.17–4.03(m,4H),3.74–3.66(m,3H),3.10–2.97(m,1H),2.96–2.83 (m,1H),2.37–2.20(m,4H),1.76–1.48(m,5H),1.46–1.35(m,5H),1.34–1.21(m,5H),1.20–1.14(m,6H).

[0682] Step 10: Synthesis of compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (215)

[0683] Procedure: Intermediate 215-9 (35 mg, 0.04 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at 120°C for 24 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was washed with water (5 mL x 2) and saturated brine (5 mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 15 mg of the product in a yield of 45.0%. Ms: 893.0 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.29(d,J=5.3Hz,1H),7.64(d,J=8.8Hz,1H),7.53(s, 1H),7.50–7.33(m,3H),7.31–7.21(m,2H),7.12(d,J=3.1Hz,1H),7.02(s,1H),6.95(s,1H), 5.74–5.60(m,1H),4.59(s,1H),4.17–3.99(m,4H),3.78–3.62(m,2H),3.10–2.96(m,1H),2. 96–2.85(m,1H),2.34–2.22(m,4H),1.84–1.37(m,7H),1.36–1.21(m,7H),1.20–1.14(m,6H).

[0684] Example 20. Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (232)

[0685] Step 1: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-4-methyl-3-((2,2,2-trichloroethoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Int2-3)

[0686] At room temperature, intermediate Int 2-2 (8 g, 15.9 mmol) was dissolved in THF (160 mL). Pyridine (2.5 g, 79.1 mmol) was added. After nitrogen replacement, 2,2,2-trichloroethyl chloroformate (1.6 g, 7.44 mmol) was slowly added dropwise in an ice bath. The mixture was stirred at room temperature overnight, and then saturated aqueous sodium hydroxide was added to adjust the pH to 12 and stirred for half an hour. TLC confirmed the complete reaction of the starting material. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 9.5 g of the product as a light yellow solid in an 88% yield. M / S: 677 (M+H + ).

[0687] Step 2: Synthesis of the intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(2,2-dimethoxypropyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (232-2)

[0688] Intermediate Int 2-3 (9.5 g, 14 mmol), Intermediate B (7.5 g, 28 mmol), and pyridine (33.2 g, 419 mmol) were dissolved in DMF (100 mL) and stirred at 90°C for 3 h. TLC confirmed the complete reaction. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 10 g of a yellow solid compound in a 91% yield. M / S: 796 (M+H + ).

[0689] Step 3: Synthesis of intermediate (S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (232-3)

[0690] Intermediate 232-2 (10 g, 12.8 mmol) and methanesulfonic acid (12.3 g, 128 mmol) were dissolved in THF (200 mL) at room temperature and stirred at 60°C for 1 h. TLC confirmed the complete reaction. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 8.6 g of the product as a light yellow solid in a 90% yield. M / S: 732 (M+H + ).

[0691] Step 4: Synthesis of intermediate (S)-3-(2-(3,5-dibromo-4-fluorophenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-4-methyl-1,3-dihydro-2H-imidazol-2-one (232-4)

[0692] Compound 232-3 (8.6 g, 11.7 mmol) was placed in a 250 mL single-necked bottle at room temperature. 1,4-dioxane hydrochloride solution (50 mL, 4 N) was added and stirred at room temperature for 1 h. Aqueous potassium carbonate solution was added to adjust the pH to 11, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.9 g of a yellow solid product with a yield of 94%. M / S: 632 (M+H + ).

[0693] Step 5: Synthesis of intermediate ((1S,2S)-1-(2-((S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (232-5)

[0694] At room temperature, 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (160 mg, 0.46 mmol) was dissolved in DMF (20 mL). HATU (250 mg, 0.68 mmol) and DIPEA (175 mg, 1.4 mmol) were added. The mixture was stirred for 20 minutes before the addition of Intermediate 232-4 (290 mg, 0.46 mmol). The mixture was stirred for 2 hours at room temperature. TLC confirmed the complete reaction of the starting material. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford 300 mg of the product as a pale yellow solid in a 68% yield. M / S: 966 (M+H + ).

[0695] Step 6: Synthesis of the intermediate (1S,2S)-1-(2-((S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1-methyl-2-oxo-2,3-dihydro-1-imidazol-1-yl)-4-methyl-4,5,6,6,7-tetrahydro-2-dihydro-4,4,3-pyridine-5-carbonyl-5-pyranyl)ethyl ester (232-6)

[0696] Intermediate 232-5 (300 mg, 0.31 mmol) was dissolved in anhydrous ethanol (30 mL), and hydrochloric acid gas was introduced at 10°C with stirring for 6 h. TLC monitored the complete reaction of the starting material. The reaction solution was adjusted to pH ≈ 7 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (50 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 290 mg of the crude product, with a yield of 79%. M / S: 1012 (M+H + ).

[0697] Step 7: Synthesis of intermediate (1S,2S)-1-(2-((S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboxylic acid hydrazide (232-7)

[0698] Intermediate 232-6 (290 mg, 0.29 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrochloride (200 mg, 2.9 mmol) and saturated sodium bicarbonate solution (2 mL) were added under ice-cooling conditions and the mixture was stirred at room temperature for 2 h. TLC confirmed the complete reaction. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford 170 mg of the product as a pale yellow solid in a 65% yield. M / S: 998 (M+H+).

[0699] Step 8: Synthesis of intermediate 3-((1S,2S)-1-(2-(S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (232-8)

[0700] Intermediate 232-7 (170 mg, 0.19 mmol) was dissolved in toluene (10 mL), and ethyl glyoxylate (52 mg, 0.5 mmol) was added. The mixture was stirred at 100°C for 1 h. TLC was used to monitor the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 100 mg of a light yellow solid product in a yield of 51%. M / S: 1036 (M+H + ).

[0701] Step 9: Synthesis of Compound 3 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazole-5-( ...4-fluoro-1-methyl-1H-indazole-5-(5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-fluoro-1-methyl-1H-indazole-5-(5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-fluoro-1-methyl-1H-indazole-5-(5-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(4-fluoro-1-methyl-1H-indazole-5-(5-(5-(S)-2,2-

[0702] Intermediate 232-8 (170 mg, 0.19 mmol), tributyl vinyl tin (190 mg, 0.6 mmol), DIPEA (78 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) were dissolved in 1,4-dioxane (3 mL). After nitrogen substitution three times, the mixture was stirred at 90°C overnight. TLC monitored the complete reaction of the starting materials. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 50 mg of the product as a light yellow solid in a yield of 28%. M / S: 932 (M+H + ).

[0703] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.14(d,J=2.0Hz,1H),7.65(d,J=9.2Hz,1H),7. 56(d,J=6.1Hz,1H),7.50(d,J=7.2Hz,1H),7.41(s,1H),7.20(s,1H),6.99–6.72(m,4H ),5.88(d,J=17.6Hz,2H),5.52(d,J=11.2Hz,2H),4.12(s,3H),3.74–3.65(m,2H),3.0 1(d,J=12.8Hz,2H),2.67(d,J=1.6Hz,1H),2.00(d,J=7.6Hz,1H),1.80–1.06(m,26H).

[0704] Example 21. Synthesis of Compound 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (322)

[0705] Step 1: Synthesis of the intermediate 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-((R)-3-hydroxy-1-yn-1-yl)-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (322-1)

[0706] Procedure: Intermediate 215-8 (100 mg, 0.18 mmol), Intermediate 41-4 (88 mg, 0.22 mmol), HATU (105 mg, 0.28 mmol), and N,N-diisopropylethylamine (48 mg, 0.37 mmol) were added to N,N-dimethylacetamide (2 mL) in sequence and reacted at room temperature for 4 hours. The mixture was diluted with ethyl acetate (15 mL), washed once with water (10 mL), and once with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 90 mg of the product in a yield of 53.0%. Ms: 923.2 (M+H + ).

[0707] Step 2: Synthesis of compound 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (322)

[0708] Procedure: Intermediate 322-1 (50 mg, 0.05 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added to N,N-dimethylacetamide (1 mL) in sequence and reacted at 120°C for 24 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was washed with water (5 mL x 2) and saturated brine (5 mL) once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 20 mg of the product in a yield of 42.0%. Ms: 879.3 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.30(s,1H),8.16(d,J=7.2Hz,1H),7.64(d,J=8.7Hz, 1H),7.50–7.40(m,1H),7.38–7.25(m,4H),7.15–6.99(m,1H),6.72(d,J=7.3Hz,1H),6.43(s, 1H),5.74–5.60(m,1H),4.59(s,1H),4.17–3.99(m,4H),3.78–3.62(m,2H),2.99–2.86(m,1H ),2.83–2.65(m,1H),2.27(s,3H),1.77–1.41(m,7H),1.38–1.10(m,10H),0.89–0.77(m,2H).

[0709] Example 22. Synthesis of Compound 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (302)

[0710] Procedure: Compound 1-9 (41 mg, 0.1 mmol) and Int 3 (51 mg, 0.1 mmol) were dissolved in DMAc (0.5 mL), and HATU (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added respectively. The reaction mixture was stirred at room temperature for 5 h. 5 mL of water was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the target compound (42 mg, yield 47%). Ms: 907.1 (M+H + )

[0711] 1H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.14(d,J=2.0Hz,1H),7.65(d,J=9.2Hz,1H),7. 56(d,J=6.1Hz,1H),7.50(d,J=7.2Hz,1H),7.41(s,1H),7.20(s,1H),6.99–6.72(m,4H ),5.88(d,J=17.6Hz,2H),5.52(d,J=11.2Hz,2H),4.12(s,3H),3.74–3.65(m,2H),3.0 1(d,J=12.8Hz,2H),2.67(d,J=1.6Hz,1H),2.00(d,J=7.6Hz,1H),1.80–1.06(m,26H).

[0712] Using a similar method to that of Examples 13 to 22 above, with appropriate reactants and under appropriate conditions, the compounds shown in Table 2 below can be obtained.

[0713] Table 2. Compounds synthesized in the present invention and characterization data

[0714] Example 23, Compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carbonitrile (Compound 419)

[0715] 3-[(2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carboxylic acid)-1H-indol-1-yl)-2-methylcyclopropyl]-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid, ethyl ester (Compound 430)

[0716] Compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid (Compound 429)

[0717] Synthesis of Compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide (Compound 432)

[0718] Step 1: Synthesis of Intermediate (2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (Intermediate M-1)

[0719] At room temperature, Int 6 (1.6 g, 4.55 mmol) was dissolved in DMF (20 mL), and HATU (2.59 g, 6.82 mmol) and DIPEA (1.76 g, 13.65 mmol) were added. After stirring for 20 min, Int 4 (2.23 g, 4.55 mmol) was added and the reaction was stirred at room temperature for 2 h. TLC monitoring showed that the reaction of the starting material was complete. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the light yellow solid product intermediate M-1 (3.0 g, 3.65 mmol) in a yield of 80.2%. M / S: 824 (M+H + ).

[0720] Step 2: Synthesis of intermediate (2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboximidate (Intermediate M-2)

[0721] Intermediate M-1 (3.0 g, 3.65 mmol) was dissolved in anhydrous ethanol (30 mL). Hydrochloric acid gas was introduced at 10°C and stirred for 6 h. TLC monitored the reaction to confirm the complete reaction. The reaction solution was adjusted to pH ≈ 7 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (50 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude intermediate M-2 (2.5 g, 2.88 mmol). The yield was 78.9%. M / S: 870 (M+H + ).

[0722] Step 3: Synthesis of intermediate (2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboxylic acid hydrazide (Intermediate M-3)

[0723] Intermediate M-2 (2.5 g, 2.88 mmol) was dissolved in ethanol (30 mL). Hydrazine hydrochloride (1.8 g, 28.8 mmol) and saturated sodium bicarbonate solution (2 mL) were added under ice-cooling conditions and the reaction was stirred at room temperature for 2 h. TLC monitored the reaction completion. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford Intermediate M-3 (1.5 g, 1.75 mmol) as a pale yellow solid in a 60.9% yield. M / S: 856 (M+H+).

[0724] Step 4: Synthesis of compound 3-[(2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carboxylic acid)-1H-indol-1-yl)-2-methylcyclopropyl]-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid ethyl ester (Compound 430)

[0725] Intermediate M-3 (700 mg, 0.82 mmol) was dissolved in toluene (10 mL), and sodium ethoxide (111 mg, 1.63 mmol) and diethyl ketomalonate (1.1 g, 0.21 mmol) were added. The mixture was stirred at 60°C for 8 h. TLC monitored the complete reaction of the starting materials. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain a light yellow solid product, compound 430 (500 mg, 0.52 mmol), in a yield of 63%. M / S: 966 (M+H + ).

[0726] 1HNMR (400MHz, DMSO-d6) δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,1H),7.36( d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03(s,1H),6.95 (s,2H),4.28(d,J=7.2Hz,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J =16.4Hz,1H),2.26(d,J=2.2Hz,6H),2.02(s,1H),1.69–1.38(m,10H),1.31–1.21(m,9H),1.19(m,5H).

[0727] Step 5: Synthesis of compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid (Compound 429)

[0728] Compound 430 (300 mg, 0.31 mmol) was dissolved in tetrahydrofuran (6 mL) at room temperature, and potassium trimethylsilanol (199 mg, 1.55 mmol) was added. The reaction was stirred at room temperature for 1 h. TLC monitoring confirmed the complete reaction of the starting material. The reaction solution was adjusted to pH ≈ 3 with hydrochloric acid (2N) solution and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain a light yellow solid product, compound 429 (250 mg, 0.27 mmol), in a yield of 87%. M / S: 938 (M+H + ).

[0729] 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,2H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 6H), 2.02 (s, 1H), 1.69–1.38 (m, 7H), 1.31–1.21 (m, 9H), 1.19 (m, 5H).

[0730] Step 6: Synthesis of compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide (Compound 432)

[0731] Compound 429 (200 mg, 0.21 mmol) was dissolved in DMF (4 mL) at room temperature, and HATU (200 mg, 0.32 mmol) and DIEA (82 mg, 0.63 mmol) were added. The mixture was stirred for 20 min, followed by the addition of ammonium chloride (34 mg, 0.63 mmol) and the reaction was stirred at room temperature for 2 h. TLC confirmed the complete reaction. The reaction solution was diluted with 20 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound 432 (160 mg, 0.17 mmol) as a pale yellow solid in an 80.9% yield. M / S: 937 (M+H + ).

[0732] 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,2H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,2H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 6H), 2.02 (s, 1H), 1.69–1.38 (m, 7H), 1.31–1.21 (m, 9H), 1.19 (m, 5H).

[0733] Step 7: Synthesis of compound 3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carbonitrile (Compound 419)

[0734] Compound 432 (60 mg, 0.06 mmol) and pyridine (19 mg, 0.24 mmol) were added sequentially to dichloromethane (2 mL). Trifluoroacetic anhydride (38 mg, 0.18 mmol) was then added at 0°C. The reaction was stirred at 0°C for 1 h. TLC monitored the complete reaction. The reaction solution was diluted with 10 mL of water and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford compound 419 (30 mg, 0.03 mmol) as a pale yellow solid in a 54.4% yield. M / S: 919 (M+H+).

[0735] 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,1H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 6H), 2.02 (s, 1H), 1.69–1.38 (m, 7H), 1.31–1.21 (m, 9H), 1.19 (m, 5H).

[0736] Example 24. Compound 6-((dimethylamino)methyl)-3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (Compound 433)

[0737] Synthesis of 3-((2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carbaldehyde (Compound 434)

[0738] Step 1: Synthesis of (3-((2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carbaldehyde (Compound 434)

[0739] Compound 430 (100 mg, 0.10 mmol) was dissolved in dichloromethane (20 mL). After nitrogen substitution three times, DIBAL-H (1.5 N, 0.08 mL, 0.12 mmol) was slowly added dropwise at -70°C. After the addition was complete, the reaction was stirred at -70°C for 1 h. TLC confirmed the complete reaction of the starting material. The reaction solution was quenched with saturated sodium hydroxide (0.2 mL) at 0°C and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product 434 (60 mg, 0.06 mmol) as a pale yellow solid in a yield of 65.1%. M / S: 922 (M+H + ).

[0740] Step 2: Synthesis of compound 6-((dimethylamino)methyl)-3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (Compound 433)

[0741] Compound 434 (60 mg, 0.06 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). After nitrogen substitution three times, a solution of dimethylamine in tetrahydrofuran (2N, 0.2 mL, 0.36 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (25 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. TLC monitored the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the product (compound 433) (30 mg, 0.03 mmol) as a pale yellow solid. The yield was 52.6%. M / S: 952 (M+H + ).

[0742] 1 HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,1H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 8H), 2.02 (s, 1H), 1.69–1.38 (m, 13H), 1.31–1.21 (m, 9H), 1.19 (m, 5H).

[0743] Example 25. Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (401)

[0744] Intermediate M-3 (70 mg, 0.08 mmol) was dissolved in toluene (10 mL), and ethyl glyoxylate (26 mg, 0.25 mmol) was added. The mixture was stirred at 100°C for 1 h. TLC monitored the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 40 mg of a light yellow solid product in a yield of 51%. M / S: 894 (M+H + ).

[0745] 1 HNMR (400MHz, DMSO-d6) δ13.20(d,J=2.0Hz,1H), δ8.31(d,J=0.8Hz,1H),7.70(s,1H),7.64(d,J=8.8Hz,1 H),7.58–7.44(m,2H),7.38(d,J=8.4Hz,1H),7.26(dd,J=8.8,1.6Hz,1H),7.19(d,J=6.4Hz,2H),7.08(d,J =3.2Hz,1H),7.03(s,1H),6.96(s,1H).4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92 (d,J=16.4Hz,1H),2.26(d,J=2.4Hz,6H),2.02(s,1H),1.69–1.38(m,7H),1.31–1.21(m,9H),1.19(m,5H).

[0746] Example 26. Synthesis of Compound 3-(1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazine-5(4H)-one (405):

[0747] Step 1: Synthesis of intermediate (S)-1-(2-(3-bromo-4-fluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (405-1):

[0748] Intermediate Int 1 (1.5 g, 2.3 mmol) was dissolved in DCM (5 mL), and HCl-Dioxane (7.5 mL, 4 N) was added dropwise under ice bath. The reaction was allowed to warm naturally for 3 h and monitored by TLC. The reaction was quenched by adding water (20 mL). The pH was adjusted to 8-9 with saturated NaHCO 3 solution, and the mixture was extracted with DCM (50 mL × 3). The DCM solution was combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.2 g of a white solid (405-1). The yield was 94.5%, M / S: 554 (M+H + ).

[0749] Step 2: Synthesis of intermediate (1S,2S)-1-(2-((S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropane-1-carbonitrile (405-2):

[0750] Intermediate 405-1 (1.2 g, 2.16 mmol), Intermediate 1-9 (1.16 g, 2.82 mmol), and HATU (1.65 g, 4.33 mmol) were dissolved in DMA (5 mL), and DIPEA (0.56 g, 4.33 mmol) was added dropwise. The reaction was allowed to react at room temperature for 8 h. The reaction was monitored by TLC. Water (20 mL) was added to quench the reaction, and the mixture was extracted with EA (30 mL × 3). The EA was combined, washed with water (30 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 1.67 g of a white solid (405-2) in a yield of 86.8%, M / S: 888 (M+H + ).

[0751] Step 3: Synthesis of intermediate (1S,2S)-1-((2Z,5E)-1-(S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-oxoocta-2,5,7-trien-2-yl)amino)-2-methylcyclopropane-1-carboxylic acid hydrazide (405-3):

[0752] Intermediate 405-2 (1.67 g, 1.88 mmol) was dissolved in EtOH (25 mL) and HCl was passed through for 6 h. The reaction mixture was monitored by TLC. The reaction solution was concentrated to dryness, washed with DCM three times, and clarified by adding MeOH (25 mL). The pH was adjusted to 8-9 with DIPEA. Hydrazine hydrochloride (3.87 g, 56.4 mmol) was added. The pH was measured to be >8. The reaction was allowed to react at room temperature for 4 h. The reaction was monitored by TLC. Water (50 mL) was added to quench the reaction. The mixture was extracted with DCM (50 mL × 3). The combined DCM was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. 1.12 g of a white solid (405-3) was obtained by column chromatography. The yield was 64.7%, M / S: 920 (M+H + ).

[0753] Step 4: Synthesis of intermediate 3-((1S,2S)-1-(2-(S)-2-(3-bromo-4-fluoro-5-methylphenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazine-5(4H)-one (405-4):

[0754] Intermediate 405-3 (200 mg, 0.22 mmol), ethyl glyoxylate (110 mg, 1.1 mmol), and glacial acetic acid (53 mg, 0.88) were dissolved in EtOH (5 mL) under N2 protection. The reaction was allowed to proceed at 90°C for 4 h and monitored by TLC. The reaction was quenched by adding water (20 mL), extracted with DCM (20 mL × 3), combined with DCM, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 150 mg of a white solid. The solid was dissolved in THF (3 mL), and MsOH (150 mg, 1.56 mmol) was added. The mixture was stirred at 60°C for 30 min and monitored by Lc-Ms. The reaction was quenched by adding water (20 mL), adjusted to pH 6-7 with NaHCO3, extracted with DCM (20 mL × 3), combined with DCM, and washed with saturated brine (20 mL × 2). 2) Wash, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography to obtain 130 mg of a white solid (405-4), with a yield of 62.4%, M / S: 958 (M+H + )

[0755] Step 5: Synthesis of compound 3-(1S,2S)-1-5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3-methyl-5-vinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazine-5(4H)-one (405):

[0756] Intermediate 405-4 (130 g, 0.136 mmol), tributyl vinyl tin (86 mg, 0.272 mml), Pd(dppf)Cl2 (19 mg, 0.027 mmol), and DIPEA (35 mg, 0.272 mmol) were dissolved in dioxane (5 mL) under N2 protection and reacted at 90°C for 8 h. The reaction was monitored by TLC and cooled to room temperature. Water (10 mL) was added to quench the reaction. EA (10 mL) was added, the mixture was filtered through celite pad, and the filter cake was rinsed with EA (10 mL x 2). The layers were separated and extracted with EA (10 mL x 2). The EA was combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The product was concentrated and purified by column chromatography to give 90 mg of a white solid (405) in a yield of 73.3%, M / S: 906 (M+H + ).

[0757] 1HNMR (400MHz, DMSO-d6) δ14.12(s,1H),8.29(d,J=0.9Hz,1H),7.70(s,1H),7.63(d,J=8.9Hz,1H),7.49(dd,J=6.3,2.7Hz,1H),7.47–7.40(m,1H),7. 38(d,J=8.5Hz,1H),7.33(dd,J=6.4,2.6Hz,1H),7.26(dd,J=8.7,1.7Hz,1 H),7.12(d,J=3.2Hz,1H),7.03(d,J=5.0Hz,2H),6.92–6.82(m,1H),5.84(d ,J=17.6Hz,1H),5.63(q,J=6.5Hz,1H),5.51–5.45(m,1H),4.51–4.35(m,1 H),4.10(s,3H),3.70(d,J=9.6Hz,3H),3.06–2.89(m,2H),2.30(d,J=2.1Hz ,3H),2.00(dd,J=8.0,5.5Hz,1H),1.83(dt,J=14.5,7.5Hz,1H),1.65(d,J =10.8Hz,3H),1.46(dd,J=6.7,3.7Hz,4H),1.27–1.22(m,6H),1.17(s,3H).

[0758] Example 27, Step 1: Synthesis of Compound 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-6-methyl-1,2,4-triazin-5(4H)-one (413)

[0759] Intermediate M-3 (70 mg, 0.08 mmol) was dissolved in toluene (10 mL), and ethyl pyruvate (29 mg, 0.25 mmol) was added. The mixture was stirred at 100°C for 1 h. TLC was used to monitor the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 40 mg of a light yellow solid product in a 50% yield. M / S: 908 (M+H + ).

[0760] 1 HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,1H) ,7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.8Hz,2H),7.08(d,J=3.2Hz,1H),7.0 3(s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J= 16.4Hz,1H),2.26-2.18(m,9H),2.02(s,1H),1.69–1.38(m,7H),1.31–1.21(m,9H),1.19(m,5H).

[0761] Example 28. Synthesis of Compound 2-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)pyrimidin-4(3H)-one (420)

[0762] Step 1: Synthesis of the intermediate (1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboximide (420-1)

[0763] Intermediate 430-2 (2 g, 2.3 mmol) was dissolved in a 10 N amine methanol solution (20 mL) and stirred at room temperature for 2 h. TLC confirmed the complete reaction. The reaction solution was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford 1 g of the product as a pale yellow solid in a 52% yield. M / S: 841 (M+H+).

[0764] Step 2: Synthesis of compound 2-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)pyrimidin-4(3H)-one (420)

[0765] Intermediate 420-1 (100 mg, 0.12 mmol) was dissolved in toluene (2 mL), and sodium ethoxide (9 mg, 0.24 mmol) and ethyl (E)-3-ethoxyacrylate (52 mg, 0.36 mmol) were added. The mixture was stirred at 100°C for 3 h. TLC monitored the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 30 mg of a light yellow solid product in a yield of 28%. M / S: 893 (M+H + ).

[0766] 1 HNMR(400MHz,DMSO-d6)δ13.20(d,J=2.0Hz,1H),δ8.31(d,J=0.8Hz,1H),8.00(d,J=6.4Hz,1H),7.64(dd,J =8.8,1.0Hz,1H),7.55–7.41(m,3H),7.25(dd,J=8.4,1.6Hz,2H),7.19(d,J=6.4Hz,2H),7.08(d,J=3.2Hz,1 H),7.01(s,1H),6.98(d,J=5.2Hz,1H).,4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.9 2(d,J=16.4Hz,1H),2.26(d,J=2.4Hz,6H),2.02(s,1H),1.69–1.38(m,7H),1.31–1.21(m,9H),1.19(m,5H).

[0767] Example 29. Synthesis of Compound 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-triazin-5(4H)-one (426)

[0768] Step 1: Synthesis of the intermediate 1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropane-1-carbonitrile (426-1)

[0769] Intermediate Int.5 (2 g, 5.91 mmol) was dissolved in DMF (20 mL), and DIEA (1.53 g, 11.82 mmol) and HATU (3.37 g, 8.87 mmol) were added. After stirring at room temperature for 20 min, intermediate Int4 (3.18 g, 6.50 mmol) was added and stirred at room temperature for 2 h. TLC monitoring confirmed the completion of the reaction of the starting materials. After post-treatment, water (50 mL) was added and extracted with EA (50 ml × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and then column chromatography was performed to obtain 3.8 g of a light yellow solid with a yield of 79.4%. M / S: 810 (M+H + ).

[0770] Step 2: Synthesis of intermediate 1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropane-1-carboxylate (426-2)

[0771] Intermediate 426-1 (3.8 g, 4.69 mmol) was dissolved in anhydrous ethanol (40 mL) and reacted with hydrochloric acid gas at 10°C for 6 h. The reaction was completed by TLC monitoring. After post-treatment, sodium bicarbonate aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with EA (50 ml × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 3.2 g of crude product. Yield: 84%. M / S: 856 (M+H + ).

[0772] Step 3: Synthesis of intermediate 1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropane-1-carboxylic acid hydrazide (426-3)

[0773] Intermediate 426-2 (1.0 g, 1.17 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrochloride (0.4 g, 5.85 mmol) and a saturated sodium bicarbonate solution were added. The mixture was stirred at room temperature for 2 h. TLC confirmed the completion of the reaction. After post-treatment, water (20 mL) was added and extracted with EA (30 ml x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and then purified by column chromatography to obtain 500 mg of a light yellow solid, in a yield of 50.4%. M / S: 842 (M+H+).

[0774] Step 4: Synthesis of 3-(1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-triazin-5(4H)-one (426)

[0775] Intermediate 426-3 (60 mg, 0.07 mmol) was dissolved in DMA (1 mL), potassium carbonate (39 mg, 0.28 mmol) and ethyl glyoxylate (22 mg, 0.21 mmol) were added, and the mixture was stirred at 120°C for 12 h. TLC confirmed the completion of the reaction. After post-treatment, water (10 mL) was added and extracted with EA (10 ml × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and then subjected to column chromatography to obtain 25 mg of a white solid with a yield of 40.0%. M / S: 880 (M+H+ ).

[0776] 1 H NMR (400MHz, DMSO-d6) δ11.78(s,1H),8.31(s,1H),7.66(d,J=8.9Hz,1H),7.53(s,1H),7.47(d,J= 7.9Hz,1H),7.39(d,J=8.5Hz,1H),7.26(d,J=8.5Hz,1H),7.16(d,J=6.2Hz,2H),7.09(s,1H),6.97 (s,2H),4.12(d,J=10.7Hz,3H),3.73(d,J=8.4Hz,2H),3.16(s,1H),3.02(d,J=12.1Hz,1H),2.86( d,J=14.9Hz,1H),2.28(s,3H),1.66(d,J=12.2Hz,7H),1.45(d,J=6.7Hz,2H),1.28–1.17(m,14H).

[0777] Example 30. Synthesis of Compound 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid (428)

[0778] Step 1: Synthesis of intermediate 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid ethyl ester (428-1)

[0779] Intermediate 427-3 (168 mg, 0.2 mmol) was dissolved in toluene (3 mL), and sodium ethoxide (68 mg, 1.0 mmol) and diethyl ketomalonate (172 mg, 1.0 mmol) were added. The mixture was stirred at 60°C for 8 h. TLC confirmed the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 10 mL of water, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 90 mg of the product in a yield of 47.3%. M / S: 952 (M+H + ).

[0780] Step 2: Synthesis of 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylic acid (428)

[0781] Intermediate 428-1 (57 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, and potassium trimethylsilanol (38 mg, 0.3 mmol) was added. The reaction was stirred at room temperature for 1 h. TLC confirmed the complete reaction. The reaction solution was adjusted to pH ≈ 3 with hydrochloric acid (2N) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 50 mg of the product in a yield of 90.2%. M / S: 924 (M+H + ).

[0782] 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,2H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 6H), 2.02 (s, 1H), 1.69–1.38 (m, 7H), 1.31–1.21 (m, 7H), 1.19 (m, 5H).

[0783] Example 31. Synthesis of Compound 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide (437)

[0784] At room temperature, intermediate 428 (28 mg, 0.03 mmol) was dissolved in DMF (1 mL). HATU (17 mg, 0.05 mmol) and DIEA (19 mg, 0.15 mmol) were added. The mixture was stirred for 20 min, followed by the addition of ammonium chloride (8 mg, 0.15 mmol). The mixture was stirred for 2 h at room temperature. TLC confirmed the complete reaction of the starting material. The reaction solution was diluted with 4 mL of water and extracted with ethyl acetate (3 mL × 3). The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The product was concentrated under reduced pressure and purified by column chromatography to afford 20 mg of the product in a yield of 72.2%. M / S: 923 (M+H + ).

[0785] 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,2H), 7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03( s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16. 4Hz, 1H), 2.26 (d, J = 2.2Hz, 6H), 2.02 (s, 1H), 1.69–1.38 (m, 7H), 1.31–1.21 (m, 7H), 1.19 (m, 5H).

[0786] Example 32. Synthesis of Compound 6-((dimethylamino)methyl)-3-((2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-triazin-5(4H)-one (442)

[0787] Step 1: Synthesis of 3-((2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-6-(hydroxymethyl)-1,2,4-triazin-5(4H)-one (442-1)

[0788] Intermediate 430 (100 mg, 0.10 mmol) was dissolved in dichloromethane (20 mL). After nitrogen substitution three times, DIBAL-H (1.5 N, 0.08 mL, 0.12 mmol) was slowly added dropwise at -70°C. After complete addition, the reaction was stirred at -70°C for 1 h. TLC confirmed the complete reaction of the starting material. The reaction solution was quenched with saturated sodium hydroxide (0.2 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 60 mg of the product as a light yellow solid in a yield of 65.1%. M / S: 924 (M+H + ).

[0789] Step 2: Synthesis of 3-((2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-6-(fluoromethyl)-1,2,4-triazin-5(4H)-one (442)

[0790] Intermediate 442-1 (60 mg, 0.06 mmol) was dissolved in anhydrous dichloromethane (30 mL). After nitrogen replacement three times, bis(2-methoxyethyl)aminosulfur trifluoride (18 mg, 0.08 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction was stirred at room temperature for 1 h. The reaction solution was cooled to 0°C and quenched with methanol. The reaction solution was diluted with 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 30 mg of a light yellow solid product in a yield of 52.6%. M / S: 926 (M+H + ).

[0791] 1HNMR(400MHz, DMSO-d6)δ13.20(d,J=2.0Hz,1H),δ8.31(d,J=0.8Hz,1H),7.70(s,1H),7.64(d,J=8.8Hz,1H),7. 58–7.44(m,1H),7.38(d,J=8.4Hz,1H),7.26(dd,J=8.8,1.6Hz,1H),7.19(d,J=6.4Hz,2H),7.08(d,J=3.2Hz,1H) ,7.03(s,1H),6.96(s,1H).4.11(s,3H),4.09(d,J=2.4Hz,2H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H) ,2.92(d,J=16.4Hz,1H),2.26(d,J=2.4Hz,6H),2.02(s,1H),1.69–1.38(m,7H),1.31–1.21(m,9H),1.19(m,5H).

[0792] Example 33. Synthesis of Compound 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-triazin-5(4H)-one (447)

[0793] Step 1: Synthesis of Intermediate 1-(2-(S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropane-1-carbonitrile (Intermediate 447-2)

[0794] At room temperature, Intermediate Int 5 (700 mg, 1.13 mmol), Int.2-5 (347 mg, 1.03 mmol), and DIPEA (0.265 g, 2.06 mmol) were dissolved in DMF (10 mL). HATU (586 mg, 1.54 mmol) was added and the mixture was stirred at room temperature for 2 h. TLC confirmed the complete reaction of the starting materials. The reaction solution was diluted with 10 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with 50 mL of saturated brine, dried over sodium sulfate, and filtered. The concentrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain Intermediate 447-2 (0.9 g, 0.95 mmol) as a light yellow solid in a 93% yield. M / S: 938.2 (M+H + ).

[0795] Step 2: Synthesis of 1-(2-(S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropane-1-carboximidyl ester (Intermediate 447-3)

[0796] Intermediate 447-2 (0.9 g, 0.95 mmol) was dissolved in anhydrous ethanol (10 mL). Hydrochloric acid gas was introduced at 10°C and stirred for 6 h. TLC confirmed the complete reaction. The reaction mixture was directly concentrated to dryness to obtain crude intermediate 447-3 (0.8 g, 0.81 mmol). Yield: 84%. M / S: 984.2 (M+H + ).

[0797] Step 3: Synthesis of Intermediate 1-(2-(S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropane-1-carboxylic acid hydrazide (Intermediate 447-4)

[0798] Intermediate 447-3 (0.7 g, 0.71 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrochloride (0.8 g, 10.65 mmol) and TEA (1.44 g, 14.20 mmol) were added under ice-cooling conditions and stirred at room temperature for 2 h. TLC confirmed the complete reaction. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to afford Intermediate 447-4 (0.5 g, 0.5 mmol) as a pale yellow solid in a 72% yield. M / S: 970.2 (M+H+).

[0799] Step 4: Synthesis of compound 3-(1-(2-(S)-2-(3,5-dibromo-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-triazin-5(4H)-one (447-5)

[0800] Intermediate 4 (500 mg, 0.51 mmol) was dissolved in ethanol (10 mL), and acetic acid (92 mg, 1.54 mmol) and ethyl 2-oxoacetate (136 mg, 0.66 mmol) were added. The mixture was stirred at 90°C for 3 h. TLC monitored the complete reaction of the starting material. The mixture was cooled to room temperature, diluted with 10 mL of water, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain a light yellow solid product, compound 447-5 (300 mg, 0.29 mmol), in a yield of 57%. M / S: 1008.2 (M+H + ).

[0801] Step 5: Synthesis of compound 3-(1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-divinylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)cyclopropyl)-1,2,4-triazin-5(4H)-one (447)

[0802] Compound 447-5 (80 mg, 79.23 μmol), tributyl(vinyl)stannane (125.62 mg, 396.15 μmol), DIEA (20.48 mg, 158.46 μmol), and tetrakistriphenylphosphine palladium (27.81 mg, 39.15 μmol) were dissolved in 1,4-dioxane (2.0 mL) at room temperature and stirred at 80°C under nitrogen for 12 h. TLC confirmed the complete reaction. The reaction solution was stirred with potassium fluoride solution (2.0 mL) for 1 h and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by HPLC to give compound 447 (19 mg, 21.02 μmol) as a white solid in a 26% yield. M / S: 904.4 (M+H + ). 1HNMR(400MHz,DMSO-d6)δ8.31(s,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.48(d,J=7.6Hz,2H) ,7.36(d,J=8.4Hz,1H),7.25(d,J=8.8Hz,1H),7.18(d,J=6.6Hz,2H),7.08(d,J=3.2Hz,1H),7.03 (s,1H),6.95(s,2H),4.11(s,3H),3.70(d,J=8.8Hz,2H),3.17(s,1H),3.03(s,1H),2.92(d,J=16 .4Hz,1H),2.26(d,J=2.2Hz,6H),2.02(s,1H),1.69–1.38(m,7H),1.31–1.21(m,9H),1.19(m,5H).

[0803] The compounds in Table 3 and Table 4 below can be synthesized by referring to the synthesis methods of the above examples using corresponding reagents under appropriate conditions.

[0804] Table 3. Compounds synthesized by the present invention and characterization data

[0805] Table 4. Compounds synthesized by the present invention and characterization data

[0806] Example 34, Compound Calcium Salt Preparation Method 1:

[0807] Sodium hydroxide (93 mg, 1.2 eq) and water (1.23 g, 0.7 W) were added to a glass reaction bottle and stirred to dissolve. 95% ethanol (8.8 ml, 5 V) and compound 302 (1.75 g) were added in sequence and stirred to dissolve. Calcium acetate aqueous solution (calcium acetate (213 mg, 0.68 eq) was added and dissolved in water (1.05 g, 0.6 W)) was added. Water (1 ml, 0.57 V) and a small amount of seed crystals were added. Water (9.5 ml, 5.4 V) was slowly added. The mixture was stirred at room temperature for 4-6 hours, filtered, and dried under reduced pressure at 45 ° C to obtain 1.70 g of the calcium salt of compound 302.

[0808] The preparation process of calcium salts of compounds R, 210, 401, etc. is the same as that of calcium salt 302.

[0809] Example 35, Compound Calcium Salt Preparation Method 2:

[0810] Compound 430 (1.75 g) and 95% ethanol (15 ml, 8.6 V) were added to a glass reaction bottle and stirred to dissolve. Calcium acetate aqueous solution (calcium acetate (195 mg, 0.68 eq) was dissolved in water (1.05 g, 0.6 W)) was added, and water (22 ml, 12.6 V) was slowly added. The mixture was stirred at room temperature for 16-20 hours, filtered, and dried under reduced pressure at 45°C to obtain 1.54 g of the calcium salt of compound 430.

[0811] The beneficial effects of the compounds of the present invention are demonstrated below through specific test examples.

[0812] Test Example 1: GLP-1R agonist activity detection (intracellular cAMP concentration detection)

[0813] HEK 293 cells stably expressing GLP-1R were used to detect the agonist activity of the test compounds on GLP-1R. Frozen cells were rapidly thawed in a 37°C water bath and resuspended in HBSS buffer (Invitrogen, #14025). Cells were collected by centrifugation at 1,000 rpm for 5 minutes and resuspended in assay buffer. Cells were counted using a Vi-cell cell counter (Beckman) and the cell density was adjusted to 1×10 5Cells / mL. 10 μL of the cell suspension was seeded into a white 384-well cell plate (PerkinElmer, #6007290) per well. The test compound (starting working concentration 10 μM, 4-fold dilution, 10 concentration gradients, duplicate wells) was added and incubated at 37°C, 5% CO2 for 30 minutes. The intracellular cAMP concentration was measured using a cAMP assay kit (Cisbio, #62AM4PEJ) and an EnVision multi-function microplate reader (PerkinElmer). The agonist activity of the test compound was calculated as follows: Relative activity (%) = [(cAMP concentration 受试化合物 – cAMP concentration 阴性对照 ) / (cAMP concentration 阳性对照 – cAMP concentration 阴性对照 )]*100%. The concentration of the test compound that produces 50% agonist activity is the half-maximal effect concentration (EC) 50 .

[0814] The result data are shown in Table 5.

[0815] Experimental Example 2: β-arrestin recruitment experiment

[0816] The effects of test compounds on β-arrestin 2 recruitment were assessed using GLP1R / β-arrestin / CHO reporter cells (COBIOER, #CBP71420). Reporter cell lines were seeded in complete medium (COBIOER, #CBP71420M) in 96-well cell culture plates (LABSELECT, #11515) at a density of 20,000 cells per well. After overnight incubation, the complete medium was replaced with Opti-MEM (Thermo Fisher, #31985062). Test compounds were added (starting at a 10 μM working concentration, diluted fourfold, in duplicate, in a 9-well concentration series) in a total volume of 100 μL and incubated at 37°C, 5% CO₂ for 30 minutes. Following incubation, 25 μL of Nano-Glo detection reagent (Promega, N2012) was added to each well. The plates were shaken at 300 rpm for 3 minutes at room temperature, and chemiluminescence was measured using a multi-function microplate reader (FLUOstar Omega). The calculation formula for the effect of the test compound on β-arrestin 2 recruitment is as follows: Relative activity (%) = [(luminescence value 受试化合物 – Luminous value 阴性对照 ) / (luminous value 阳性对照 – Luminous value 阴 性对照 )]*100%. The concentration of the test compound that produces 50% recruitment activity is the half-maximal effect concentration (EC) 50 .

[0817] The result data are shown in Table 5.

[0818] Test Example 3: GLP-1R downstream transcriptional activity detection method

[0819] The effects of test compounds on human GLP-1R downstream transcriptional activity were detected using the HEK 293 GLP-1R / Cre-Luc luciferase reporter cell line (COBIOER, #CBP71117). The reporter cell line was seeded into a 96-well cell culture plate (LABSELECT, #11515) at 20,000 cells per well in complete medium (DMEM / HIGH GLUCOSE + 10% FBS + 1% P / S + 400 μg / mL G418, including DMEM / HIGH GLUCOSE (HyClone, SH30243.01), FBS (Biological Industries, 04-001-1ACS), P / S (Gibco, 15140-122), and G418 (Gibco, 10131-035). After overnight incubation, the complete medium was replaced with Opti-MEM medium (Thermo Fisher, #31985062). Test compounds were added (starting at a working concentration of 100 nM, diluted fourfold, with a nine-dose concentration gradient in duplicate) and incubated at 37°C, 5% CO₂ for 6 hours in a total volume of 100 μL. After incubation, 100 μL of Bright-Glo detection reagent (Promega, E2620) was added to each well. The cells were shaken at 300 rpm for 3 minutes at room temperature, and chemiluminescence was measured using a multi-function microplate reader (FLUOstar Omega). The effect of the test compound on transcriptional activity was calculated as follows: Relative activity (%) = [(luminescence value of the test compound - luminescence value of the negative control) / (luminescence value of the positive control - luminescence value of the negative control)] * 100%.

[0820] The result data are shown in Table 5.

[0821] Table 5. Experimental results of GLP-1R stimulation, β-arrestin 2 recruitment, and GLP-1R downstream transcriptional activity

[0822] The data show that some compounds of the present invention have comparable or better GLP-1R agonist activity and selectivity than the reference compound.

[0823] Test Example 4: Liver microsome stability test

[0824] (1) Pipette 100 μL of 2 mg / mL liver microsome working solution (add 50 μL of 0.8 mg / mL liver microsome working solution for positive cells) into a 96-well plate, add 196 μL of 6 mM MgCl2 solution working solution (add 98 μL of MgCl2 solution working solution for positive cells), then add 4 μL of the analyte working solution (add 2 μL of working solution for positive cells), mix well to obtain a mixed solution of the incubation system, and repeat in duplicate;

[0825] (2) Pre-incubate the system in a 37°C water bath in a constant temperature oscillator for 5 minutes;

[0826] (3) Control group (without NADPH): Take 120 μL of the incubation system mixed solution and add 40 μL of PB. Repeat in duplicate. Vortex for 30 seconds to mix. Place in a 37°C water bath in a constant temperature oscillator for incubation. Start the timer and remove 20 μL of the reaction solution from the system at 0, 30, and 60 minutes respectively to a 96-deep-well plate. Add 275 μL of stop solution.

[0827] (4) Sample group (containing NADPH): Take 120 μL of the incubation system mixed solution, add 40 μL of 4 mM NADPH solution, and repeat in duplicate. Vortex to mix thoroughly, place in a 37°C water bath constant temperature oscillator for incubation, and start the timer. At 0, 5, 15, 30, 45, and 60 min, remove 20 μL of the reaction solution from the system and transfer it to a 96-well deep-well plate, and add 275 μL of stop solution.

[0828] (5) Positive group (containing NADPH): Take 120 μL of the incubation system mixed solution, add 40 μL of 4 mM NADPH solution, and repeat in duplicate. Vortex to mix thoroughly, place in a 37°C water bath constant temperature oscillator for incubation, and start the timer. At 0 and 60 min, remove 20 μL of the reaction solution from the system and transfer it to a 96-deep-well plate, and add 275 μL of stop solution.

[0829] (6) All samples were vortexed for 2 min and centrifuged at 3800 rpm for 15 min at 4°C;

[0830] (7) Take 140 μL of the supernatant, add 70 μL of ultrapure water, vortex mix, and inject into LC / MS / MS for analysis.

[0831] The half-life (t 1 / 2 ) and clearance (CL) C t =C0*e -kt t 1 / 2 =ln2 / k=0.693 / k CL=V d *k V d =1 / protein content in liver microsomes CL int (liver)=CL int(mic) × liver weight to body weight ratio × liver microsomal protein concentration per gram of liver

[0832] The experimental results are shown in Table 6:

[0833] Table 6. Results of liver microsome stability experiments

[0834] The compounds of the present invention have better liver microsomal stability than the reference compounds

[0835] Test Example 5: Pharmacokinetic Experiment

[0836] Six healthy adult male SD rats, ICR mice, or cynomolgus monkeys were dosed intravenously and orally, with three animals per dosing regimen. Intravenous administration allowed for food and water, while oral administration fasted overnight (>12 hours) without water. Food was resumed 4 hours after dosing. At various time points after dosing, venous blood was collected and anticoagulated using EDTA-K2 (blood samples were placed in an ice bath after collection). Plasma was separated by centrifugation at 6000g for 5 minutes at 4°C and stored at -70°C until analysis. Plasma compound concentrations were determined by LC-MS / MS.

[0837] The plasma concentration data of the compound at all time points were used to calculate the main pharmacokinetic parameters using the Winnolin 8.3 non-compartmental model.

[0838] Area under the concentration-time curve (AUC) all Value: calculated using the trapezoidal method; AUC inf =AUC all +C t / ke,C t is the plasma drug concentration at the last measurable time point, ke is the elimination rate constant;

[0839] Elimination half-life t 1 / 2 =0.693 / ke;

[0840] Clearance CL = D / AUC inf (D is the dosage);

[0841] Steady-state volume of distribution V ss =CL x MRT, mean residence time MRT = AUMC / AUC;

[0842] Absolute bioavailability F = (AUC i.g. x D i.v. ) / (AUC i.v. x D i.g. )×100%

[0843] Table 7. Pharmacokinetic data in rats

[0844] The reference compound R is LY3502970, with the structure

[0845] Table 8. Pharmacokinetic data in cynomolgus monkeys

[0846] The above results indicate that the compound of the present invention has good pharmacokinetics.

[0847] Test Example 6: Solubility Test

[0848] 30 μL of 10 mM stock solutions of test compounds and control drugs were added to the corresponding positions of the corresponding 96-well plates in the specified order. 970 μL of FaSSGF, FaSSIF, or PBS pH 7.4 was added to the corresponding vials in the sample plate. Experiments were performed in duplicate. A stir bar was placed in each vial and capped with a Teflon / silicone stopper. The sample plate was then placed in an Eppendorf Thermomixer Comfort and shaken at 1100 rpm at 25°C for 2 hours. After 2 hours, the stoppers were removed, the stir bars were removed using a magnet, and the samples were transferred from the sample plate to a filter plate. A vacuum pump was used to generate negative pressure and filter the samples. 5 μL of the filtrate was transferred to a new sample plate, followed by the addition of 5 μL of DMSO and 490 μL of acetonitrile-water (V:V = 1:1). 200 μL of the diluent was transferred to a new 96-well plate for LC-MS / MS analysis. The dilution factor may be adjusted depending on the solubility of the analyte or the strength of its LC / MS response. The sample plate is placed in the autosampler's sample tray and the sample is evaluated by LC / MS analysis. All calculations are performed in Microsoft Excel.

[0849] The analysis and quantification of the sample filtrate were completed by qualitative and quantitative analysis of the standard peaks with known concentrations using liquid chromatography-mass spectrometry.

[0850] Table 9. Solubility data

[0851] It can be seen from Table 9 that the compounds of the present invention have excellent solubility and even better drug properties.

[0852] In summary, the present invention provides a new class of small molecule compounds that can be used as GLP-1 receptor agonists for the preparation of medicaments for preventing and / or treating diseases such as diabetes, obesity, fatty liver disease, and polycystic ovary syndrome. Compared with LY3502970, the compounds of the present invention have superior drugability, as demonstrated by improved pharmacokinetic (PK) properties, improved oral bioavailability, lower toxicity, improved permeability, and improved efficacy. Therefore, the compounds of the present invention have broad application prospects.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, Ring A is selected from aryl, heteroaryl, fused cycloalkyl, and heterofused cycloalkyl; The E ring is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; The C ring is selected from substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; Ring D is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Z1 is selected from N, CH; f is a substituent R Z1 The number of is selected from integers from 0 to 6; R Z1 Each independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, halogen; or two adjacent R Z1 Connected to form a 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl; or two non-adjacent R Z1 Connection formation m is 1, 2, or 3; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; Z2 is selected from NR z2 、CHR z2 ; R z2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; X is selected from O, S; i is selected from 0 or 1; W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N; Y1 and Y2 are each independently selected from C=O, C=S, N or CR 14 ; R 14 Each is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, halogen, hydroxy, carboxyl, substituted or unsubstituted 3-10 membered cycloalkyl; The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2; h is an integer selected from 0 to 3; g is the number of substituents R, selected from an integer of 0-3; R is independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, and halogen; Ring B is selected from null, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: deuterium, halogen, hydroxyl, cyano, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C(O)R1', -NR2'R3'; The substituents of the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are selected from the following groups: substituted or unsubstituted C1-C8 alkyl, halogen, cyano, hydroxyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C1-C8 ester, substituted or unsubstituted C1-C8 amide, amino, carboxyl, substituted or unsubstituted C1-C8 aldehyde, substituted or unsubstituted C1-C8 amine, =O; or the substituents on the same carbon atom in the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups form =O or =S; R1', R2', and R3' are independently selected from hydrogen, C1-C8 alkyl; The compound is not:

2. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The compound is shown in formula I-1: in, Ring A is selected from aryl, heteroaryl, fused cycloalkyl, and heterofused cycloalkyl; The E ring is selected from substituted or unsubstituted 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocycloalkyl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen; The C ring is selected from substituted or unsubstituted 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocycloalkyl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen; Ring D is selected from aryl and heteroaryl; Z1 is selected from N, CH; f is an integer selected from 0 to 6; R Z1 Each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen; or two adjacent R Z1 Connected to form a 3-8 membered saturated cycloalkyl, a 3-8 membered saturated heterocycloalkyl; or two non-adjacent R Z1 Connection formation m is 1, 2, or 3; Z2 is selected from NR z2 、CHR z2 ; R z2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents are each independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocycloalkyl; X is selected from O, S; Selected from or when for When Y1 is selected from C=O, C=S; when for When Y1 is selected from N or CR 14 ; R 14 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen, and hydroxy; g is an integer selected from 0 to 3; R is independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogen; Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituents are each independently selected from C1-C8 alkyl, deuterated C1-C8 alkyl, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, and halogen; The compound is not:

3. The compound according to claim 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula II-1: in, A is R1 is selected from hydrogen, C1-C5 alkyl, halogen; R2 is selected from hydrogen, C1-C5 alkyl, halogen; R3 is selected from hydrogen, C1-C5 alkyl, halogen; R4 is selected from hydrogen, C1-C5 alkyl, halogen; R5 is selected from hydrogen, C1-C5 alkyl, halogen; R6 is selected from hydrogen, C1-C5 alkyl, halogen; R7 is selected from hydrogen, C1-C5 alkyl, halogen; R8 is selected from hydrogen, C1-C5 alkyl, halogen; R9 is selected from hydrogen, C1-C5 alkyl, halogen; R 10 Selected from hydrogen, C1-C5 alkyl, halogen; Alternatively, R5 and R6 are linked to form a 3-6 membered saturated cycloalkyl group; Alternatively, R5 and R9 are connected to form m1 is 1, 2, or 3; Alternatively, R5 and R7 are connected to form m2 is 1, 2 or 3; R 11 Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C5 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Selected from or when for When Y1 is C=O or C=S; when for When Y1 is N or CR 14 ; R 14 Selected from hydrogen, C1-C5 alkyl, halogen, hydroxyl; R 15 Selected from hydrogen, C1-C5 alkyl, halogen; R 16 Selected from C1~C5 alkyl, deuterated C1~C5 alkyl.

4. The compound according to claim 3, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula III-1: in, A is R1 is selected from hydrogen, C1-C3 alkyl, halogen; R2 is selected from hydrogen, C1-C3 alkyl, halogen; R3 is selected from hydrogen, C1-C3 alkyl, halogen; R4 is selected from hydrogen, C1-C3 alkyl, halogen; R5 is selected from hydrogen, C1-C3 alkyl, halogen; R6 is selected from hydrogen, C1-C3 alkyl, halogen; R7 is selected from hydrogen, C1-C3 alkyl, halogen; R9 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Selected from or when for When Y1 is C=O or C=S; when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

5. The compound according to claim 3, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula III-1-1, Formula III-2-1, Formula III-3-1, Formula III-4-1, Formula III-5-1, Formula III-6-1, Formula III-7-1, Formula III-8-1, Formula III-9-1 or Formula III-10-1: in, A is R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

6. The compound according to claim 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structures of the compounds are shown in Formula III-11-1, Formula III-12-1, and Formula III-13-1: in, A is R9 is selected from hydrogen, C1-C3 alkyl, halogen; R 10 is selected from hydrogen, C1-C3 alkyl, and halogen; Or, R9 and R 10 Connected to form a 3-6 membered saturated cycloalkyl group; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 Selected from hydrogen, C1-C5 alkyl, halogen; R 16 Selected from C1~C5 alkyl, deuterated C1~C5 alkyl.

7. The compound according to claim 3, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula IV-1 or Formula IV'-1: in, A is R1 is selected from hydrogen, C1-C3 alkyl, halogen; R2 is selected from hydrogen, C1-C3 alkyl, halogen; R3 is selected from hydrogen, C1-C3 alkyl, halogen; R4 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Selected from or when for When Y1 is C=O or C=S; when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

8. The compound according to claim 7, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula IV-1-1, Formula IV-2-1, Formula IV-3-1, Formula IV-4-1, Formula IV-5-1, Formula IV-6-1, Formula IV-7-1 or Formula IV-8-1: in, A is R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

9. The compound according to claim 3, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula V-1: in, A is R1 is selected from hydrogen, C1-C3 alkyl, halogen; R2 is selected from hydrogen, C1-C3 alkyl, halogen; R3 is selected from hydrogen, C1-C3 alkyl, halogen; R4 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Selected from or when for When Y1 is C=O or C=S; when for When Y1 is N or CR 14 ; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

10. The compound according to claim 9, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula V-1-1, Formula V-2-1, Formula V-3-1 or Formula V-4-1: in, A is R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; R 14 is selected from hydrogen, C1-C3 alkyl, halogen, and hydroxyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1~C3 alkyl, deuterated C1~C3 alkyl.

11. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula I-2, Formula I-3, Formula I-4 or Formula I-5: in, A is R5 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy; h is 0 or 1; R 15 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; in, A is R5 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; Y2 is selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1-C3 alkyl, deuterated C1-C3 alkyl; in, A is R5 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N; Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl; The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2; R 15 is selected from hydrogen, C1-C3 alkyl, and halogen; R 16 Selected from C1-C3 alkyl, deuterated C1-C3 alkyl; in, A is R5 is selected from hydrogen, C1-C3 alkyl, halogen; R 11 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 12 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; R 13 Selected from hydrogen, C1-C3 alkyl, halogen, 3-6 membered saturated cycloalkyl; X is selected from O, S; W1 and W2 are each independently selected from N or C; W3 is selected from CH or N; and at least one of W1, W2, and W3 is N; Y1 and Y2 are each independently selected from N or CR 14 ; R 14 Selected from hydrogen, C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, carboxyl, halogen, hydroxy, 3-6 membered saturated cycloalkyl; The dashed lines between W1, W2, W3, Y1, and Y2 are either absent or bonded depending on the selection of W1, W2, W3, Y1, and Y2; R 15 Selected from hydrogen, C1-C3 alkyl, and halogen.

12. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The compound is shown in formula I-6: in, R 12 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R1, R5, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

13. The compound according to claim 12, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula II-6: in, R 12 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

14. The compound according to claim 13, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula III-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

15. The compound according to claim 14, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula IV-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R1, R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

16. The compound according to claim 15, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The structure of the compound is shown in formula Va-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

17. The compound according to claim 15, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula Vb-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; X1 is selected from N or C; X2 is selected from N or CH2; and there is only one N in X1 and X2; the dotted line between X1 and X2 is either absent or a bond depending on the selection of X1 and X2; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; The substituents of the alkyl, alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

18. The compound according to any one of claims 12 to 17, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3'; The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; R1', R2', and R3' are independently selected from hydrogen, C1-C6 alkyl; The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl and indolyl are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen and hydroxyl.

19. The compound according to any one of claims 12 to 17, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: for 20. The compound according to any one of claims 12 to 17, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: for 21. The compound according to any one of claims 12 to 17, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula VIa-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3'; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl, and indolyl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

22. The compound according to claim 21, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula VIa-6-1: in, R 13 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and halogen.

23. The compound according to any one of claims 12 to 17, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula VIb-6: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and halogen; and R 11 and R 13 At least one of them is selected from substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl; The substituents of the alkenyl and alkynyl groups are selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted indolyl, -C(O)R1', -NR2'R3'; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; The substituents of the cycloalkyl, tetrahydropyranyl, piperidinyl, pyridinyl, phenyl, pyrazolyl, pyrrolyl, indazolyl, and indolyl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; The substituent of the alkoxy group is selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, -C(O)R1'; The substituent of the alkyl group is selected from the following groups: halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

24. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The compound is shown in formula I-7: in, R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 、R 17 、R 18 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; R1, R5, R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; V1, V2, V3 are independently selected from N or C; V4 is selected from N or CH; the dotted line connecting V1, V2, V3, V4 is either absent or a bond depending on the selection of V1, V2, V3, V4; n is 0 or 1; U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R 23 are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

25. The compound according to claim 24, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula II-A-7 or Formula II-B-7: in, R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide; R 141 、R 142 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and halogen; R 15 、R 16 、R 17 、R 18 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; R1, R 19 、R 20 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and halogen; n is 0 or 1; U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R 23 are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

26. The compound according to claim 25, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula III-A-7 or Formula III-B-7: in, R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide; R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen; n is 0 or 1; U1 is selected from N or CH; U2, U3, U4 are independently selected from N, C, O; R 21 、R 22 、R 23 are independently selected from none, hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; the dotted line connecting U1, U2, U3, U4 is according to U1, U2, U3, U4, R 21 、R 22 、R 23 The options are None or Key; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, -C(O)R1', -NR2'R3'; The substituents of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl; R1', R2', and R3' are each independently selected from hydrogen and C1-C6 alkyl.

27. The compound according to any one of claims 24 to 26, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Selected from R 21 、R 22 、R 23 are independently selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, and O=; The substituents of the alkyl, alkoxy, aldehyde, amino, ester and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy; The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, and hydroxyl.

28. The compound according to claim 27, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: Selected from R 22 Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

29. The compound according to claim 27, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula IV-7: in, R 11 、R 12 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide; R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen; R 22 Selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester, and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy; The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, hydroxyl; Preferably, R 22 Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

30. The compound according to claim 29, its pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The structure of the compound is shown in Formula V-7: in, R 11 、R 13 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halogen, cyano, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide; R1 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, halogen; R 22 Selected from hydrogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, halogen, substituted or unsubstituted 3-10 membered cycloalkyl, cyano, amino, carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 aldehyde, substituted or unsubstituted C1-C6 amine, O=; The substituents of the alkyl, alkenyl, alkynyl, alkoxy, aldehyde, amino, ester, and amide groups are selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, and C1-C6 alkoxy; The substituents of the cycloalkyl group are selected from the following groups: C1-C6 alkyl, halogenated C1-C6 alkyl, halogen, hydroxyl; Preferably, R 22 Selected from hydrogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, methyl substituted by 1-3 fluorine groups, halogen, 3-6 membered cycloalkyl, cyano, amino, carboxyl, C3 ester, C1 amide, formaldehyde, C3 amine, O=.

31. The compound according to claim 30, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The structure of the compound is shown in Formula V-7-1: in, R 11 、R 13 are independently selected from C1 to C6 alkyl; R 22 Selected from hydrogen, R is selected from C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

32. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, characterized in that: The compound is one of the compounds with the following structures:

33. Use of the compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a GLP-1 receptor agonist.

34. Use of the compound according to any one of claims 1 to 32, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating diseases associated with GLP-1 receptors.

35. The use according to claim 34, characterized in that: The diseases related to GLP-1 receptor are diabetes, obesity, fatty liver, and polycystic ovary syndrome; Preferably, the diabetes is type 2 diabetes.

36. A drug, characterized in that: The invention relates to a preparation prepared by using the compound according to any one of claims 1 to 32, its pharmaceutically acceptable salt or its stereoisomer as an active ingredient, and adding pharmaceutically acceptable excipients or auxiliary ingredients.

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