Benzene-containing polycyclic derivative modulator, preparation method therefor and use thereof

Abstract

The present invention relates to a benzene-containing polycyclic derivative modulator, a preparation method therefor and the use thereof. In particular, the present invention relates to a compound as shown in general formula (I-1), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as a modulator in the preparation of a drug for treating diabetes, obesity, NASH, renal diseases and diseases associated therewith, wherein each substituent in general formula (I-1) is the same as that defined in the specification.

Description

Benzene-containing polycyclic derivative modifiers, their preparation methods and applications Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a benzene-containing polycyclic derivative regulator, its preparation method, and its application. Background Technology

[0002] Glucose-dependent insulinotropic polypeptide (GIP) is an incretin composed of 42 amino acids. It is primarily generated by the cleavage of GIP precursor protein by prohormone convertase 1 / 3 (PC1 / 3) in intestinal K cells. Its receptor, GIPR, is widely distributed in various tissues, including the pancreas, stomach, adipose tissue, lung, heart, bone, vascular endothelium, and parts of the brain. After binding to its receptor, GIP activates adenylate cyclase, increasing intracellular cAMP levels, activating downstream PKA and EPAC2, promoting insulin release, and desensitizing and inducing receptor endocytosis by recruiting β-arrestin. Downstream, the ERK pathway promotes cell proliferation. GIP exerts its physiological functions in multiple tissues, enhancing glucose-dependent insulin secretion to regulate postprandial blood glucose levels, maintaining glycemic homeostasis by regulating insulin and glucagon release, inhibiting food intake, promoting glucose uptake in white adipose tissue, increasing lipase activity, and promoting lipid synthesis and degradation, among other things. Natural GIP is rapidly cleaved in vivo by dipeptidyl peptidase 4 (DPP4). GIP was one of the first incretins discovered, but current research on another incretin—glucagon-like peptide-1 (GLP-1)—far surpasses that on GIP. In recent years, numerous preclinical and clinical studies have confirmed that GIPR is also a very promising target; inhibiting GIPR activity can reduce weight and has broad market prospects in the fields of obesity and metabolic diseases.

[0003] In preclinical animal models, multiple studies have demonstrated the effectiveness of inhibiting GIPR activity in treating obesity and metabolic diseases. GIPR knockout mice have a protective effect against obesity induced by a high-fat diet, the GIPR antagonist (Pro3) GIP can reduce the body weight of obese mice fed a high-fat diet, and the GIPR inhibitory antibody Gipg013 can also lead to weight loss in mice. In clinical studies, GIP antibody conjugated with the GLP-1 peptide AMG133 has also shown stronger weight-reducing efficacy than the GLP-1 peptide.

[0004] GIPR antagonists are a highly promising target, potentially used as monotherapy or in combination with other drugs (such as GLP-1R agonists). The most advanced clinical candidate for this target, AMG133, is a GIPR antibody drug that requires subcutaneous administration, leading to poor patient compliance. Currently, no small molecule GIPR antagonists have entered clinical trials. There is a significant clinical need to develop new small molecule GIPR antagonists. Lower-cost, better-compliant oral small molecule GIPR antagonists have the potential to treat various metabolic diseases and possess a broad market prospect. They are expected to provide more treatment options for patients with diabetes, obesity, and NASH in the future. Summary of the Invention

[0005] The object of this invention is to provide a compound of general formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8) or (I-9) or a pharmaceutically acceptable salt thereof:

[0006] in:

[0007] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0008] L1, L2, or L3 are each independently selected from the bond, -C(O)-, or -NR. 11 C(O)-、-C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)NR 11 -、-NR 11 C(O)(CR 22 R 33 ) n3 -、-NR 11 C(O)NR 22 -、-C(S)-、-NR 11 C(S)-、-C(S)NR 11 -、-(CR 22 R 33 ) n3 C(S)NR 11 -、-NR 11 C(S)NR 22 -、-(CR 22 R 33 ) n3 -、-NR 11 -、-(CR 22 R 33 ) n3 NR11 -、-NR 11 (CR 22 R 33 ) n3 -、-S(O) n4 -、-NR 11 S(O) n4 -、-S(O) n4 NR 11 -、-NR 11 C=NR 22 -、-NR 11 C = CR 22 R 33 -、-R 11 C = CR 22 -、-NR 11 C(O)C(O)-、-C(O)C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 -、-NR 11 (CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 115-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally substituted with one or more of the following substituents: halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0009] Alternatively, L1 and L2 may form heterocyclic groups with the atoms they are attached to;

[0010] Ring A, ring B, ring C, or ring D are each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, or alkynylcarboxyl groups.

[0011] Alternatively, ring C does not exist;

[0012] R 11 R 22 Or R 33Each of the following groups is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0013] R1, R2, R3, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 -C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 C(O)C(O)R 31 -CR aa =CR aa R bb 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl groups.

[0014] Alternatively, any two atoms connected to R1, R2, R3, and R4 may form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups.

[0015] Alternatively, when y is 2, 3, or 4, the two R2 atoms connected to them form a cycloalkyl, heterocyclic, or aryl group, wherein the cycloalkyl, heterocyclic, or aryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups.

[0016] R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0017] Or, R aa R bb It forms cycloalkyl or heterocyclic groups with the atoms attached to it;

[0018] x, y, z and t are each independently 0, 1, 2, 3 or 4;

[0019] n1 or n2 can be 0, 1, 2 or 3 independently;

[0020] n3 can be 0, 1, 2 or 3 independently;

[0021] n4 or m2 are each independently 0, 1 or 2;

[0022] m1 can be 0, 1, 2 or 3 independently;

[0023] (1) In the general formula (I-1), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, and R1 is selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, and propylene. R2 is selected from one, two, or three substituents in the group consisting of methyl or methoxy; R4 is selected from one, two, or three substituents in the group consisting of hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido; and R5 is selected from one, two, or three substituents in the group consisting of halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2, and ring B is pyridine, phenyl, or methyl methoxy. When, ring C is not in Indicates connection to L1. Indicates connection to L2;

[0024] (2) In the general formula (I-2), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, and R1 is selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or The methoxy group has 1, 2, or 3 substituents; R2 is selected from one or more substituents chosen from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, and acetamido; R4 is selected from 1, 2, or 3 substituents chosen from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2; and ring A is pyridine, pyrazole, phenyl, or... When, ring C is not in Indicates connection to L1. Indicates connection to L2;

[0025] (3) In general formula (I-3), X0, X1, X2, X3, and X4 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, and ring A is pyridine, pyrazole, phenyl, or When ring B is not pyridine, benzene ring, or...

[0026] (4) When in general formula (I-9), L1 is -NHC(O)-, L2 is -C(O)NH-, ring D is phenyl or pyridine, n1 is 2, and n2 is 0, ring B is not naphthyl and

[0027] In some embodiments of the invention, general formula (I-1) is further a compound represented by general formula (I-1A) or a pharmaceutically acceptable salt thereof, and general formula (I-2) is further a compound represented by general formula (I-2A) or a pharmaceutically acceptable salt thereof:

[0028] The conditions are:

[0029] (1) In the general formula (I-1A), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, and R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, then ring B is not pyridine, phenyl,

[0030] (2) In the general formula (I-2A), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, and R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, then ring A is not pyridine, pyrazole, phenyl, or

[0031] In certain embodiments of the invention, a compound of general formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), or (II-8) or a pharmaceutically acceptable salt thereof is provided:

[0032] in:

[0033] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0034] L1 or L2 are each independently selected from the bond, -C(O)-, and -NR. 11 C(O)-、-C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)NR 11 -、-NR 11 C(O)(CR 22 R 33 ) n3 -、-NR 11 C(O)NR 22 -、-C(S)-、-NR 11 C(S)-、-C(S)NR 11 -、-(CR 22 R 33 ) n3 C(S)NR 11 -、-NR 11 C(S)NR 22 -、-(CR 22 R 33 ) n3 -、-NR 11-, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 R 33 -, -R 11 C=CR 22 -, -NR 11 C(O)C(O)-, -C(O)C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)-, -C(O)(CR 22 R 33 ) n3 -, -NR 11 (CR 22 R 33 ) n3 C(O)-, -C(O)(CR 22 R 33 ) n3 NR 11 -, -C(O)NR 11 (CR 22 R 33 ) n3 -, -(CR 22 R 33 ) n3 NR 11 C(O)-, -(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -, -NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -, -(NR 11 )3-10 membered heteroaryl group-, -3-10 membered heteroaryl group(NR 11 ), -, -(NR 11)3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally substituted with one or more of the following substituents: halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0035] Alternatively, L1 and L2 may form heterocyclic groups with the atoms they are attached to;

[0036] Ring A, ring B, ring C, or ring D are each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, or alkynylcarboxyl groups.

[0037] Alternatively, ring C does not exist;

[0038] R 11 R 22 Or R 33Each of the following groups is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0039] R1, R2, R3, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 -C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 C(O)C(O)R 31 -CR aa =CR aa R bb 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl groups.

[0040] And at least one R4 is selected from a carboxyl group;

[0041] Alternatively, any two atoms connected to R1, R2, R3, and R4 may form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups.

[0042] Alternatively, when y is 2, 3, or 4, the two R2 atoms connected to them form a cycloalkyl, heterocyclic, or aryl group, wherein the cycloalkyl, heterocyclic, or aryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups.

[0043] R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0044] Or, R aa R bb It forms cycloalkyl or heterocyclic groups with the atoms attached to it;

[0045] x, y, and z are each independently 0, 1, 2, 3, or 4;

[0046] t is 1, 2, 3, or 4;

[0047] n1 or n2 are each independently 0, 1 or 2;

[0048] n3 can be 0, 1, 2 or 3 independently;

[0049] n4 or m2 are each independently 0, 1, or 2; and

[0050] m1 can be 0, 1, 2 or 3 independently;

[0051] The conditions are:

[0052] (1) In general formula (II-1), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2, and ring B is pyridine, phenyl, When, ring C is not in Indicates connection to L1. Indicates connection to L2;

[0053] (2) In general formula (II-2), X0, X1, X2, X3, and X4 are each independently selected from CH or N; X5, X6, X7, X8, and X9 are each independently selected from CH or N; L1 is -NHC(O)-; L2 is -C(O)NH-; L1 and L2 do not form heterocyclic groups with the atoms they are attached to; R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy; R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido; R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2; and ring A is pyridine, pyrazole, phenyl, or... When, ring C is not in Indicates connection to L1. Indicates connection to L2;

[0054] (3) In general formula (II-3), X0, X1, X2, X3, and X4 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, and ring A is pyridine, pyrazole, phenyl, or When ring B is not pyridine, phenyl,

[0055] In certain embodiments of the invention, general formula (II-1) is further a compound represented by general formula (II-1A) or a pharmaceutically acceptable salt thereof, general formula (II-2) is further a compound represented by general formula (II-2A) or a pharmaceutically acceptable salt thereof, and general formula (II-3) is further a compound represented by general formulas (II-1A) and (II-2A) or a pharmaceutically acceptable salt thereof.

[0056] The conditions are:

[0057] (1) In general formula (II-1A), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, and R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, then ring B is not pyridine, phenyl,

[0058] (2) In general formula (II-2A), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, and R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, then ring A is not pyridine, pyrazole, phenyl, or

[0059] In certain preferred embodiments of the present invention, for general formulas (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-2A), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), or (II-2A), ring A is selected from C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms.

[0060] In certain preferred embodiments of the present invention, for general formulas (I-1), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-1A), (II-1), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), or (II-1A), ring B is selected from C. 3-10 Cycloalkyl or 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms.

[0061] In certain preferred embodiments of the invention, general formula (I-1) is further a compound represented by general formulas (III-1), (III-3), (III-6), and (III-7) or a pharmaceutically acceptable salt thereof; general formula (I-2) is further a compound represented by general formulas (III-2), (III-4), and (III-5) or a pharmaceutically acceptable salt thereof; general formula (I-4) is further a compound represented by general formula (III-5) or a pharmaceutically acceptable salt thereof; general formula (II-1) is further a compound represented by general formulas (III-1), (III-3), (III-6), and (III-7) or a pharmaceutically acceptable salt thereof; general formula (II-2) is further a compound represented by general formulas (III-2), (III-4), and (III-5) or a pharmaceutically acceptable salt thereof; and general formula (II-4) is further a compound represented by general formula (III-5) or a pharmaceutically acceptable salt thereof.

[0062] In certain preferred embodiments of the invention, general formula (III-1) is further a compound represented by general formula (III-1A) or a pharmaceutically acceptable salt thereof:

[0063] In certain preferred embodiments of the invention, general formula (III-1) is further a compound represented by general formulas (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof; general formula (III-2) is further a compound represented by general formulas (IV-3), (IV-4), and (IV-7) or a pharmaceutically acceptable salt thereof; general formula (III-6) is further a compound represented by general formulas (IV-5) and (IV-6) or a pharmaceutically acceptable salt thereof; and general formula (III-7) is further a compound represented by general formulas (IV-8) or (IV-9) or a pharmaceutically acceptable salt thereof.

[0064] In certain preferred embodiments of the invention, general formula (IV-1) is further a compound represented by general formula (IV-1A) or a pharmaceutically acceptable salt thereof, general formula (IV-2) is further a compound represented by general formula (IV-2A) or a pharmaceutically acceptable salt thereof, general formula (IV-3) is further a compound represented by general formula (IV-3A) or a pharmaceutically acceptable salt thereof, general formula (IV-4) is further a compound represented by general formula (IV-4A) or a pharmaceutically acceptable salt thereof, general formula (IV-7) is further a compound represented by general formula (IV-7A) or a pharmaceutically acceptable salt thereof, general formula (IV-8) is further a compound represented by general formula (IV-8A) or a pharmaceutically acceptable salt thereof, and general formula (IV-9) is further a compound represented by general formula (IV-9A) or a pharmaceutically acceptable salt thereof.

[0065] In certain preferred embodiments of the present invention, for general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-1A), (IV-2A), (IV-3A), (IV-4A), (IV-5A), (IV-6A), (IV-7A), (IV-8A), or (IV-9A), wherein:

[0066] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0067] L1 or L2 are each independently selected from the following: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-.

[0068] R1, R2, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -NR 31 (CR aa R bb ) m1 R 32 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 BR 31 R 32 、-(CR aa R bb ) m1C(O)R 31 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, optionally prefixed with halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3One or more substituents in the alkyl group are substituted;

[0069] R 31 R 32 R aa Or R bb Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 3-Alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1- 3-alkyl groups;

[0070] x, y, and t are each independently 0, 1, 2, 3, or 4;

[0071] m1 can be 0, 1, 2, or 3;

[0072] m2 can be 0, 1, or 2.

[0073] In certain preferred embodiments of the present invention, for general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-1A), (IV-2A), (IV-3A), (IV-4A), (IV-5A), (IV-6A), (IV-7A), (IV-8A), or (IV-9A), wherein:

[0074] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0075] L1 or L2 are each independently selected from the following: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-.

[0076] R1, R2, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, C1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -NR 31 (CR aa R bb ) m1 R 32 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 BR 31 R 32 、-(CR aa R bb ) m1 C(O)R 31 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 or -(CR) aaR bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, optionally prefixed with halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted;

[0077] And at least one R4 is selected from a carboxyl group;

[0078] R 31 R 32 R aa Or R bb Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 3-Alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1- 3-alkyl groups;

[0079] x and y are each independently 0, 1, 2, 3 or 4;

[0080] t is selected from 1, 2, 3, or 4;

[0081] m1 can be 0, 1, 2, or 3;

[0082] m2 can be 0, 1, or 2.

[0083] In a further preferred embodiment of the present invention, for general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-1A), (IV-2A), (IV-3A), (IV-4A), (IV-5A), (IV-6A), (IV-7A), (IV-8A), or (IV-9A), wherein:

[0084] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0085] L1 or L2 are each independently selected from the following: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-.

[0086] R1 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, propynyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or -SF5;

[0087] R2 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0088] R4 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, methoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, -(CH=CH)COOH, -B(OH)2, -CH2COOH, -S(O)OH.

[0089] x, y, and t are each independently 0, 1, 2, or 3.

[0090] In a further preferred embodiment of the present invention, for general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-1A), (IV-2A), (IV-3A), (IV-4A), (IV-5A), (IV-6A), (IV-7A), (IV-8A), or (IV-9A), wherein:

[0091] X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N;

[0092] L1 or L2 are each independently selected from the following: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-.

[0093] R1 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, propynyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or -SF5;

[0094] R2 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0095] R4 is selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, methoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, carboxyl, -(CH=CH)COOH, -B(OH)2, -CH2COOH, -S(O)OH.

[0096] And at least one R4 is selected from a carboxyl group;

[0097] x and y are each independently 0, 1, 2 or 3;

[0098] t can be 1, 2, or 3.

[0099] In some embodiments of the present invention Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or -SCF3.

[0100] In certain preferred embodiments of the present invention Selected from It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0101] In certain preferred embodiments of the present invention Selected from Optionally substituted with one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl, wherein Indicates connection to L1. This indicates that it is connected to L2.

[0102] In some embodiments of the present invention Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or -SCF3.

[0103] In certain preferred embodiments of the present invention Selected from It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0104] In certain preferred embodiments of the present invention Selected from Optionally substituted with one or more substituents selected from hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl, wherein Indicates connection to L1. This indicates that it is connected to L2.

[0105] In some embodiments of the present invention, L1, L2, or L3 are each independently selected from bond, -C(O)-, -NR 11 C(O)-、-C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)NR 11 -、-NR 11 C(O)(CR 22 R 33 ) n3 -、-NR 11 C(O)NR 22 -、-C(S)-、-NR 11 C(S)-、-C(S)NR 11 -、-(CR 22 R 33 ) n3 C(S)NR 11 -、-NR 11 C(S)NR 22 -、-(CR 22 R 33 ) n3 -、-NR 11 -、-(CR 22 R 33 ) n3 NR 11 -、-NR 11 (CR 22 R 33 ) n3 -、-S(O) n4 -、-NR 11 S(O) n4 -、-S(O) n4 NR 11 -、-NR 11 C=NR 22 -、-NR 11 C = CR 22 R 33 -、-R 11 C = CR 22 -、-NR 11 C(O)C(O)-、-C(O)C(O)NR 11-、-(CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 -、-NR 11 (CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11(CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally converted by a halogen, amino, hydroxyl, oxo, cyano, nitro, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0106] In some embodiments of the invention, L1, L2 and the atoms attached to them form 3-12 membered heterocyclic groups, optionally surrounded by halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6- 12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0107] In some embodiments of the present invention, R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1- 6-hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally surrounded by hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 It is replaced by one or more substituents of a haloalkyl group.

[0108] In a preferred embodiment of the present invention, L1, L2, or L3 are each independently selected from bond, -C(O)-, -NR. 11 C(O)-、-C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)NR 11 -、-NR 11 C(O)(CR 22 R 33 ) n3 -、-NR 11 C(O)NR 22 -、-C(S)-、-NR 11 C(S)-、-C(S)NR 11 -、-(CR 22 R 33 ) n3 C(S)NR 11 -、-NR 11 C(S)NR 22 -、-(CR 22 R 33 ) n3 -、-NR 11 -、-(CR 22 R 33 ) n3 NR 11 -、-NR 11 (CR 22 R 33 ) n3 -、-S(O) n4 -、-NR 11 S(O) n4 -、-S(O) n4 NR 11 -、-NR11 C=NR 22 -、-NR 11 C = CR 22 R 33 -、-R 11 C = CR 22 -、-NR 11 C(O)C(O)-、-C(O)C(O)NR 11 -、-(CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 -、-NR 11 (CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-8 membered cycloalkylene group-,-3-8 membered cycloalkylene group (NR 11 C(O))-、-(NR 11 (CR 22 R 33 ) n33-8 cyclic alkylene group - or -3-8 cyclic alkylene group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic group, cycloalkyl group, or heteroaryl group is optionally converted by a halogen, hydroxyl group, oxo group, or C- group. 1-3 Alkyl, C 2-3 alkenyl, C 1-3 One or more substituents in a haloalkyl group are substituted.

[0109] In a preferred embodiment of the invention, L1, L2 and their adjacent atoms form a 5-12 membered heterocyclic group containing 1-6 N, O or S atoms, optionally coated with a halogen, hydroxyl group, oxo group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 1-3 One or more substituents in a haloalkyl group are substituted.

[0110] In a preferred embodiment of the present invention, R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 It is replaced by one or more substituents of a haloalkyl group.

[0111] In a preferred embodiment of the present invention, R 11 R 22 Or R 33 Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, wherein the amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, optionally by a hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 It is replaced by one or more substituents of a haloalkyl group.

[0112] In a preferred embodiment of the present invention, L1, L2, or L3 are each independently selected from the following bonds: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-, -NHC(O)CH2-, -CH2NHC(O)NH-,

[0113] In a preferred embodiment of the present invention, L1, L2 and the atoms connected to them form It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0114] In a preferred embodiment of the present invention, L1 or L2 is independently selected from -NHC(O)-, -C(O)NH-, -NHC(S)-, -C(S)NH-, -CH2C(O)NH-, -CH2NHC(O)-, or

[0115] In some embodiments of the present invention, R1, R2, R3, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 -C(O)NR 31 S(O) m1 R 32 、-(CR aa Rbb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH, -CR aa =CR aa R bb 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1- 6-hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0116] In some embodiments of the present invention, R3, R4 and the atoms connected to them form C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, optionally further bonded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0117] In some embodiments of the invention, when y is 2, 3, or 4, the two R2 atoms and their connected atoms form C. 3- 14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, optionally further bonded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3- 12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0118] In some embodiments of the present invention, R 31 R 32 R 33 R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents of aryl or 5-12 heteroaryl groups are used for substitution.

[0119] In some embodiments of the present invention, R aa R bb Forming C with the attached atoms 3-15 Cycloalkyl or containing 1-5 3-15 membered heterocyclic groups selected from N, O or S heteroatoms.

[0120] In a preferred embodiment of the present invention, R1, R2, R3, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-4 N, O or S atoms, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa Rbb ) m1 (NR 31 S(O) m2 R 32 -C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH, -CR aa =CR aa R bb 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0121] In a preferred embodiment of the present invention, R3, R4 and the atoms connected to them form C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-3 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0122] In a preferred embodiment of the invention, when y is 2, 3, or 4, the two R2 atoms and their connected atoms form C. 3- 10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-3 Alkyl, C 2-4alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution.

[0123] In a preferred embodiment of the present invention, R 31 R 32 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 It is replaced by one or more substituents of a haloalkyl group.

[0124] In a preferred embodiment of the present invention, R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl or cyano-substituted C 1-3 Alkyl, the amino, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally replaced by hydroxyl, halogen, cyano, amino, or C groups. 1-3 Alkyl, C 1-3 It is replaced by one or more substituents of a haloalkyl group.

[0125] In a preferred embodiment of the present invention, R aa R bb Forming C with the attached atoms 3-10 Cycloalkyl or containing 1-4 3-10 membered heterocyclic groups selected from N, O or S heteroatoms.

[0126] In a preferred embodiment of the present invention, R 31 R 32 Or R 33 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl, wherein the amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl group is optionally replaced by hydroxyl, fluorine, chlorine, bromine, cyano, amino, C 1-3 Alkyl, C 1- It is substituted by one or more substituents of a 3-haloalkyl group.

[0127] In a preferred embodiment of the present invention, R aa R bb Or R cc Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxy, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy.

[0128] In a preferred embodiment of the present invention, Raa R bb Forming C with the attached atoms 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O or S heteroatoms.

[0129] In a preferred embodiment of the present invention, R aa R bb It forms pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups with the attached atoms. It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0130] In a preferred embodiment of the present invention, R1, R2, R3, or R4 are each independently selected from hydrogen, fluorine, chlorine, bromine, amino, oxo, methylamino, dimethylamino, hydroxy, cyano, nitro, carboxyl, methyl, ethyl, isopropyl, tert-butyl, n-butyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, difluorovinyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, cyclopropoxy, hydroxymethyl, hydroxyethyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -SF5, -B(OH)2, -SCF3, -CH2COOH, -S(O)OH, -C(O)NH2.

[0131] In a preferred embodiment of the present invention, R3, R4 and the atoms connected to them form It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0132] In a preferred embodiment of the invention, when y is 2, 3 or 4, the two R2 atoms connected to them form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

[0133] In a preferred embodiment of the present invention, R1, R2, R3, or R4 are each independently selected from fluorine, carboxyl, methyl, isopropyl, methoxy, trifluoromethyl, -SF5, -B(OH)2,

[0134] In a preferred embodiment of the present invention, at least one R4 is selected from a carboxyl group.

[0135] In some embodiments of the present invention, ring A is selected from C. 3-14Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32 One or more substituents are substituted in the sample.

[0136] In a preferred embodiment of the present invention, ring A is selected from C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C.1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in an alkyl group are substituted.

[0137] In a preferred embodiment of the present invention, ring A is selected from C. 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1- One or more substituents in the 3 alkyl group are substituted.

[0138] In a preferred embodiment of the present invention, ring A is selected from C. 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 5-10Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1- One or more substituents in the 3 alkyl group are substituted.

[0139] In a preferred embodiment of the present invention, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and... The radical can be optionally covered by hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. One or more substituents are substituted in the sample.

[0140] In a preferred embodiment of the present invention, ring A is selected from... It may optionally be substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0141] In a preferred embodiment of the present invention, ring A is selected from...

[0142] In some embodiments of the present invention, ring B is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb )m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample.

[0143] In a preferred embodiment of the present invention, ring B is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl or 5-14 membered heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 A aryl group or a 5-14 membered heteroaryl group containing 1-4 N, O, S, P or B atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -(CR) aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample.

[0144] In a preferred embodiment of the present invention, ring B is selected from C. 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, S, P or B atoms, 5-10 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 4-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, 5-8 member monoheteroaryl containing 1-4 N, O, S, P or B atoms, 8-14 member fused heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 4-14 membered fused heterocyclic groups containing 1-3 N, O, S, P or B atoms, 5-10 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 4-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, a 5-8 membered mono-heteroaryl containing 1-4 N, O, S, P or B atoms, or an 8-14 membered fused heteroaryl containing 1-4 N, O, S, P or B atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3alkyl, carboxyl, -(CR) aa =CR bb ) m1 COOH, -(CR aa R bb )m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample.

[0145] In a preferred embodiment of the present invention, ring B is selected from C. 3-6 Monocycloalkyl, C 6-14 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 6-14 membered fused heterocyclic groups containing 1-4 N, O, S, P or B atoms, 5-8 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 6-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, 5-6 member monoheteroaryl containing 1-4 N, O, S, P or B atoms, 8-14 member fused heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-6 Monocycloalkyl, C 6-14 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 4-10Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 6-14 membered fused heterocyclic groups containing 1-4 N, O, S, P or B atoms, 5-8 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 6-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, a 5-6 membered mono-heteroaryl containing 1-4 N, O, S, P or B atoms, or an 8-14 membered fused heteroaryl containing 1-4 N, O, S, P or B atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -(CR) aa =CR bb COOH, -S(O) m2 R 32 -S(O)(=NR) cc )R 32 -BR 31 R 32 、-(NR 31 )C(O)R 32 -C(O)C(O)R 31 -C(O)NR 31 R 32 or -S(O) m2 NR 31 R 32 One or more substituents are substituted in the sample.

[0146] In a preferred embodiment of the present invention, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The following groups are optionally covered: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, methoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, oxo, carboxyl, -(CH=CH)COOH, -B(OH)2, -CH2COOH, -S(O)OH, -C(O)NH2. One or more substituents are substituted in the sample.

[0147] In a preferred embodiment of the present invention, ring B is selected from cyclohexyl, phenyl, ... Optional radicals include hydrogen, methyl, ethyl, isopropyl, methoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, oxo, carboxyl, -B(OH)2, or... One or more substituents are substituted in the sample.

[0148] In a preferred embodiment of the present invention, ring B is selected from cyclohexyl, phenyl, ...

[0149] In some embodiments of the present invention, ring C is selected from C. 3-14 Cycloalkyl groups, containing 1-5 3-14 membered heterocyclic groups selected from N, O, S, P, B, or Si atoms, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32One or more substituents are substituted in the sample.

[0150] In some embodiments of the present invention, ring C is absent.

[0151] In a preferred embodiment of the present invention, ring C is selected from C. 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, S, P, B or Si atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -S(CR) aa R bb ) m1 R 31 One or more substituents are substituted in the sample.

[0152] In a preferred embodiment of the present invention, ring C is selected from C. 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P, B or Si atoms, 4-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P, B or Si atoms, 4-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -S(CR) aa R bb )R 31 One or more substituents are substituted in the sample.

[0153] In a preferred embodiment of the present invention, ring C is selected from C. 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P, B or Si atoms, 6-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P, B or Si atoms, 6-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -SR 31 One or more substituents are substituted in the sample.

[0154] In a preferred embodiment of the present invention, cycloC is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and... It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, or -SCF3.

[0155] In a preferred embodiment of the present invention, ring C is selected from... It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

[0156] In some embodiments of the present invention, ring D is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa Rbb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32 One or more substituents are substituted in the sample.

[0157] In a preferred embodiment of the present invention, ring D is selected from C. 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-10 One or more substituents of cycloalkyl, -SF5 or -SCF3 are used for substitution.

[0158] In a preferred embodiment of the present invention, ring D is selected from C. 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-12 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 4-10Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-12 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-8 One or more of the following substituents are selected from cycloalkyl, -SF5, or -SCF3: substituted.

[0159] In a preferred embodiment of the present invention, ring D is selected from C. 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-11 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 fused cycloalkyl, C 5-9 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-11 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-6 One or more of the following substituents are selected from cycloalkyl, -SF5, or -SCF3: substituted.

[0160] In a preferred embodiment of the present invention, cycloD is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, pyridazine, etc. Optional radicals include hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, n-butyl, propynyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, -SF5, -SCF3. One or more substituents are substituted in the sample.

[0161] In a preferred embodiment of the present invention, ring D is selected from cyclobutyl, cyclohexyl, phenyl, Optional radicals include hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, propynyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, -SF5, or One or more substituents are substituted in the sample.

[0162] The present invention further provides a method for preparing a compound of the general formula as described above or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0163] in:

[0164] The definitions of rings B, C, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in general formula (II-1); L2 is -C(O)NH-;

[0165] General formulas (M-1A) and (M-1B) react under the action of a condensing agent and a base to give general formula (II-1).

[0166] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP.

[0167] In some preferred embodiments of the present invention, the alkali used in the preparation method is selected from DIEA, TEA, NMP, DBU or DABCO.

[0168] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI or HATU, and the alkali is selected from DIEA.

[0169] In some preferred embodiments of the present invention, the preparation method, when at least one R4 is selected from C(O)O-PG1, further includes a step of removing the protecting group PG1 under the action of acid or base.

[0170] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl; the base is selected from LiOH, NaOH, KOH, or Cs2CO3; and the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA.

[0171] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl or tert-butyl; the base is selected from LiOH; and the acid is selected from MSA or TFA.

[0172] The present invention further provides a method for preparing a compound of the general formula as described above or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0173] in:

[0174] The definitions of ring A, ring C, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in general formula (II-2); L2 is -C(O)NH-;

[0175] General formulas (M-1A) and (M-1C) react under the action of a condensing agent and a base to give general formula (II-2).

[0176] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP.

[0177] In some preferred embodiments of the present invention, the alkali used in the preparation method is selected from DIEA, TEA, NMP, DBU or DABCO.

[0178] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI or HATU, and the alkali is selected from DIEA.

[0179] In some preferred embodiments of the present invention, the preparation method, when at least one R4 is selected from C(O)O-PG1, further includes a step of removing the protecting group PG1 under the action of acid or base.

[0180] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl; the base is selected from LiOH, NaOH, KOH, or Cs2CO3; and the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA.

[0181] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl or tert-butyl; the base is selected from LiOH; and the acid is selected from MSA or TFA.

[0182] The present invention further provides a method for preparing a compound of the general formula as described above or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0183] in:

[0184] The definitions of ring A, ring B, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in general formula (II-3); L2 is -C(O)NH-;

[0185] General formulas (M-2A) and (M-2B) react under the action of a condensing agent and a base to give general formula (II-3).

[0186] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP.

[0187] In some preferred embodiments of the present invention, the alkali used in the preparation method is selected from DIEA, TEA, NMP, DBU or DABCO.

[0188] In some preferred embodiments of the present invention, the condensing agent in the preparation method is selected from EDCI or HATU, and the alkali is selected from DIEA.

[0189] In some preferred embodiments of the present invention, the preparation method, when at least one R4 is selected from C(O)O-PG1, further includes a step of removing the protecting group PG1 under the action of acid or base.

[0190] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl; the base is selected from LiOH, NaOH, KOH, or Cs2CO3; and the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA.

[0191] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl or tert-butyl; the base is selected from LiOH; and the acid is selected from MSA or TFA.

[0192] The present invention further provides a method for preparing a compound of the general formula as described above or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0193] in:

[0194] The definitions of ring A, ring B, R1, R2, R3, R4, L2, X5, X6, X7, X8, X9, x, y, z, and t are as described in general formula (II-3); L1 is -NHC(O)-;

[0195] General formulas (M-3A) and (M-3B) react with a carbonylating agent and a base to give general formula (II-3).

[0196] In some preferred embodiments of the present invention, the carbonylating agent in the preparation method is selected from CDI, triphosgene, diester carbonate or isocyanate.

[0197] In some preferred embodiments of the present invention, the alkali used in the preparation method is selected from DIEA, TEA, NMP, DBU, DABCO or NMM.

[0198] In certain preferred embodiments of the present invention, the carbonylating agent in the preparation method is selected from CDI or triphosgene; the base is selected from TEA, DBU or NMM;

[0199] In some preferred embodiments of the present invention, the preparation method, when at least one R4 is selected from C(O)O-PG1, further includes a step of removing the protecting group PG1 under the action of acid or base.

[0200] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl; the base is selected from LiOH, NaOH, KOH, or Cs2CO3; and the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA.

[0201] In certain preferred embodiments of the present invention, in the step of removing the protecting group PG1 under the action of acid or base, PG1 is selected from methyl or tert-butyl; the base is selected from LiOH; and the acid is selected from MSA or TFA.

[0202] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown general formula compounds, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0203] In some embodiments of the invention, the pharmaceutical composition, based on free base, comprises 0.1% to 95% by weight of the compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%.

[0204] In some embodiments of the invention, the pharmaceutical composition is selected from tablets, capsules, liquid formulations or injections, preferably also containing a filler, optionally a disintegrant, or further containing one or more of a flow aid or lubricant.

[0205] In some embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0206] In some embodiments of the invention, the unit dose of the pharmaceutical composition, calculated as free base, of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg.

[0207] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof may be administered by any convenient method, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal, or transdermal administration, and accordingly modified pharmaceutical compositions.

[0208] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof may be formulated into liquid or solid dosage forms, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0209] The present invention further relates to any of the compounds of the general formula shown or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to GIPR.

[0210] The present invention further relates to compounds of the general formula or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of treatments for diabetes, obesity, NASH, kidney disease and related conditions, more preferably type I diabetes, type II diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, renal tubular dysfunction, proximal tubular pro-inflammatory changes, chronic kidney disease, diabetic retinopathy, obesity, glomerulosclerosis, chronic renal failure, metabolic syndrome, obesity or NASH.

[0211] The present invention further relates to a method of preparing a medicament for treating GIPR-related and related diseases, using a compound of the general formula or a pharmaceutically acceptable salt thereof.

[0212] The present invention also relates to a method for treating, preventing, and / or treating diseases associated with GIPR, comprising administering to a patient a therapeutically effective dose of a compound of the general formula, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0213] The present invention also provides a method for treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including but not limited to conditions related to GIPR.

[0214] The present invention also relates to a method for treating GIPR-related diseases in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[0215] Detailed description of the invention

[0216] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0217] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0218] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0219] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0220] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 6, 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0221] wait;

[0222] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0223] wait.

[0224] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0225] wait.

[0226] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0227] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0228] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, boron, silicon, S(O). m Heteroatoms of P(O)n (where m is an integer from 0 to 2) or P(O)n (where n is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; even more preferably, it contains a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spirocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0229] Non-limiting examples of monocyclic heterocyclic groups include pyrrolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, acrylonitrile, 1,4-diazaheptanyl, pyranyl, etc., preferably pyrrolyl, morpholinyl, piperidinyl, acrylonitrile, 1,4-diazaheptanyl, and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0230] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, boron, silicon, and S(O). m Heteroatoms of type P(O)n (where m is an integer from 0 to 2) or P(O)n (where n is an integer from 0 to 2), with the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include: wait.

[0231] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, boron, silicon, and S(O). m The heteroatoms are either P(O)n (where m is an integer from 0 to 2) or P(O)n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, they are 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: wait.

[0232] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, boron, silicon, and S(O). m The heteroatom is either P(O)n (where m is an integer from 0 to 2) or P(O)n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: wait.

[0233] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0234] wait.

[0235] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0236] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0237] The ring connected to the parent structure is an aryl ring, and non-limiting examples include: wait.

[0238] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0239] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: wait.

[0240] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0241] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0242] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0243] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0244] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0245] "Alkenyl" refers to an alkenyl group, also known as an olefinic group, which is a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located anywhere within the alkenyl group. Alkenyl groups have a carbon density of 2 to 20 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 A straight-chain or branched unsaturated hydrocarbon group containing 1 carbon atom. Non-limiting examples of alkenyl groups include: The alkenyl group described therein may be further substituted with other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0246] "Alynyl" refers to (CH≡C-) that contains at least one carbon-carbon triple bond, which can be located anywhere within the alkynyl group, and at least one carbon-carbon double bond, which can be located anywhere within the alkenyl group. The alkynyl group has 2 to 20 carbon atoms. 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2- 3) A straight-chain or branched unsaturated hydrocarbon group containing one carbon atom. Non-limiting examples of alkynyl groups include: The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0247] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as described above. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, and butenyl carbonyl. Alkenyl carbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0248] "Hydroxy" refers to the -OH group.

[0249] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0250] "Amino" refers to -NH2.

[0251] “Cyano” refers to -CN.

[0252] "Nitro" refers to -NO2.

[0253] "Carbonyl" refers to -C(O)-.

[0254] "Carboxyl group" refers to -C(O)OH.

[0255] "THF" refers to tetrahydrofuran.

[0256] “EtOAc” refers to ethyl acetate.

[0257] “MeOH” refers to methanol.

[0258] "DMF" refers to N,N-dimethylformamide.

[0259] "TFA" refers to trifluoroacetic acid.

[0260] “MeCN” refers to Yi Qing.

[0261] “DMA” stands for N,N-dimethylacetamide.

[0262] “Et2O” refers to diethyl ether.

[0263] “DCE” refers to 1,2-dichloroethane.

[0264] "DIPEA" refers to N,N-diisopropylethylamine.

[0265] “NBS” refers to N-bromosuccinimide.

[0266] “NIS” refers to N-iodosuccinimide.

[0267] “DIEA” refers to N,N-diisopropylethylamine.

[0268] “EDCI” refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0269] “DIC” refers to N,N'-diisopropylcarbodiimide.

[0270] “DCC” refers to N,N'-dicyclohexylcarboimide.

[0271] “TBTU” refers to O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid.

[0272] “HATU” refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0273] “HBTU” refers to benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0274] “HCTU” refers to 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate.

[0275] “DEPBT” refers to 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one.

[0276] “PyBOP” refers to benzotriazol-1-yl-oxytripyrrolidinyl phosphate hexafluorophosphate.

[0277] “PyAOP” refers to hexafluorophosphate (7-azabenzotriazole-1-oxy)tripyrrolidinephosphide.

[0278] "TEA" refers to triethylamine.

[0279] “NMP” refers to N-methylpyrrolidone.

[0280] “DBU” refers to 1,8-diazahexacyclic[5,4,0]undecene-7.

[0281] “DABCO” refers to 1,4-diazabicyclo[2.2.2]octane.

[0282] “CDI” refers to N,N'-carbonyldiimidazole.

[0283] “NMM” refers to N-methylmorpholine.

[0284] “MSA” stands for melanin.

[0285] This indicates that the site is selected from either a single bond or a double bond.

[0286] “N / A” means not detected.

[0287] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0288] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0289] The compounds of this invention include all pharmaceutically acceptable isotopically labeled compounds, wherein one or more atoms of the compounds disclosed herein are replaced by atoms having the same atomic number but a different atomic mass or mass number than those commonly found. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, and examples of isotopes include tritium, etc.

[0290] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0291] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0292] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0293] "Pharmaceutical acceptable salt" or "medicinal salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0294] The compounds of this invention, such as those of formulas (I) to (IV-9A) or specific compounds, are intended to include one or more of the following: a free base of the compound or a pharmaceutically acceptable salt thereof, a stereoisomer, or a mixture of two or more stereoisomers. A stereoisomer is a compound that differs only in its spatial arrangement. Stereoisomers include all diastereomers and enantiomers of the compound. An enantiomer is a stereoisomer that is a mirror image of another. A diastereomer is a stereoisomer having two or more distinct chiral centers that are not mirror images of each other. Detailed Implementation

[0295] Example

[0296] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0297] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0298] HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6mm column).

[0299] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0300] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0301] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0302] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0303] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0304] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0305] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0306] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0307] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0308] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0309] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0310] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0311] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0312] The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0313] Synthetic intermediate 1

[0314] ((3-Fluoro-4-isopropylphenyl)carbamoyl)-D-proline

[0315] first step

[0316] 4-Bromo-3-fluoroaniline (10.00 g, 52.63 mmol), pinacol isopropenylborate (17.69 g, 105.26 mmol), potassium carbonate (21.82 g, 157.88 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.16 g, 1.58 mmol) were dissolved in 1,4-dioxane (100 mL) and water (10 mL). The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system THF / PE = 0-40%) to give 3-fluoro-4-(prop-1-en-2-yl)aniline (14.30 g, 55% purity), yield: 98.8%. MS m / z (ESI): 152 [M+H] +

[0317] Step 2

[0318] 3-Fluoro-4-(prop-1-en-2-yl)aniline (14.30 g, 55% purity, 52.02 mmol) and 5% wet palladium / carbon (6.32 g) were dissolved in methanol (150 mL), and formic acid (5 mL) was added. The mixture was purged three times with a hydrogen balloon and stirred at 20 °C for 16 hours. The mixture was filtered through diatomaceous earth, washed with methanol (50 mL), and concentrated. The residue was purified by silica gel column chromatography (elution system THF / PE = 0-30%) to give 3-fluoro-4-isopropylaniline (7.0 g, 45.75 mmol), yield: 87.8%. MS m / z (ESI): 154 [M+H] +

[0319] Step 3

[0320] Under ice-water bath cooling, 3-fluoro-4-(prop-1-en-2-yl)aniline (4.00 g, 26.11 mmol) was added to a carbonyl diimidazole (4.23 g, 26.11 mmol) solution in acetonitrile (70 mL). After 5 minutes, the mixture was heated to 20 °C and stirred for 2 hours. Subsequently, the reaction solution was removed under reduced pressure, and then dissolved in tetrahydrofuran (50 mL). N-methylmorpholine and D-proline were added sequentially. After stirring at 20 °C for 6 hours until the reaction was complete, the reaction was quenched with sodium bicarbonate (50 mL), extracted with diethyl ether (30 mL x 2), the aqueous phase was adjusted to pH 2–3 with 6N hydrochloric acid, and then extracted with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated to give 3-fluoro-4-isopropylaniline (6.20 g, 95% purity, 20.01 mmol), yield: 76.6%. MS m / z(ESI): 295 [M+H] +

[0321] Synthetic intermediate 2

[0322] (R)-N-(3-fluoro-4-isopropylphenyl)pyrrole-2-carboxamide

[0323] first step

[0324] 3-Fluoro-4-isopropylaniline (150 mg, 0.98 mmol), tert-butyloxycarbonyl-D-proline (211 mg, 0.98 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbamoyldiimide hydrochloride (188 mg, 0.98 mmol) were dissolved in dichloromethane (10 mL) and stirred at 20 °C for 6 hours. The reaction mixture was quenched with water (100 mL), extracted with dichloromethane (30 mL x 3), dried over the organic phase, and concentrated to give crude (R)-2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrole-1-carboxylic acid tert-butyl ester (351 mg). MS m / z (ESI): 351 [M+H] +

[0325] Step 2

[0326] To a solution of (R)-2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrole-1-carboxylic acid tert-butyl ester (350 mg) in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product (R)-N-(3-fluoro-4-isopropylphenyl)pyrrole-2-carboxamide (370 mg). MS m / z (ESI): 251 [M+H] +

[0327] Example 1

[0328] 4-[4-({[1-({[4-(propyl-2-yl)phenyl]amino}carbonyl)azacyclohepta-2-yl]carbonyl}amino)phenyl]benzoic acid

[0329] Step 1: 2-(4-aminophenyl)benzoic acid-2-methylpropyl-2-yl ester

[0330] 4-Bromoaniline (2.06 g, 12 mmol) and (4-(tert-butoxycarbonyl)phenyl)boronic acid (2.66 g, 12 mmol) were dissolved in 1'-4-Dioxane (50 mL) and Water (10 mL). Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (421 mg, 0.6 mmol) and potassium phosphate (6.36 g, 30 mmol) were added. The mixture was stirred at 90 °C for 5 hours. The mixture was evaporated to dryness, the reaction was quenched with saturated brine (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 100:0 to 50:50 elution) to give the target product (2.74 g, yield: 85%).

[0331] MS m / z(ESI): 270.1 [M+H] + .

[0332] Step 2: 2-({[4-(4-{[(2-methylprop-2-yl)oxy]carbonyl}phenyl)phenyl]amino}carbonyl)azacycloheptane-1-carboxylic acid-2-methylprop-2-yl ester)

[0333] 2-Methylpropyl-2-yl 4-(4-aminophenyl)benzoate (2.5 g, 9.29 mmol), 1-{[(2-methylpropyl-2-yl)oxy]carbonyl}azacycloheptane-2-carboxylic acid (2.7 g, 11.1 mmol), and N,N-diisopropylethylamine (2.99 g, 23.2 mmol, 3.82 mL) were dissolved in N,N-dimethylformamide (20 mL). Under nitrogen protection, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.59 g, 12 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was then extracted with 150 mL of saturated brine and ethyl acetate (50 mL × 3). The organic phases were combined, washed successively with 50 mL of saturated brine (50 mL × 4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 60:40) to give the target product (3.8 g, yield: 83%).

[0334] MS m / z (ESI): 495.3 [M+H] + .

[0335] Step 3: 4-{4-[(azacycloheptan-2-ylcarbonyl)amino]phenyl}benzoic acid

[0336] 2-({[4-(4-{[(2-methylprop-2-yl)oxy]carbonyl}phenyl)phenyl]amino}carbonyl)azacycloheptan-1-carboxylic acid-2-methylprop-2-yl ester (3.1 g, 6.3 mmol) was dissolved in dichloromethane (10 mL). Under ice-water bath cooling and nitrogen protection, dioxane hydrochloride (4 M, 30 mL) was added. The mixture was stirred at 0 °C for 3 hours. The reaction solution was evaporated to dryness, and the crude product (2.2 g) was used directly in the next step.

[0337] MS m / z(ESI): 339.2 [M+H] + .

[0338] Step 4: 4-[4-({[1-({[4-(prop-2-yl)phenyl]amino}carbonyl)azacyclohepta-2-yl]carbonyl}amino)phenyl]benzoic acid

[0339] 4-{4-[(azacyclohepta-2-ylcarbonyl)amino]phenyl}benzoic acid (0.5 g, 1.48 mmol) and N-methylmorpholine (448 mg, 4.4 mmol) were dissolved in tetrahydrofuran (20 mL). Under ice-water bath cooling and nitrogen protection, 4-isocyano-1-(propane-2-yl)benzene (238 mg, 1.48 mmol) was added. The mixture was stirred at 25 °C for 4 hours. The reaction was quenched with saturated brine (5 mL). The mixture was separated, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (HPLC) to obtain the final product (273 mg, yield: 37%).

[0340] MS m / z (ESI): 500.2 [M+H] + .

[0341] Step 5: 4-[4-({[(2R)-1-({[4-(prop-2-yl)phenyl]amino}carbonyl)azacyclohepta-2-yl]carbonyl}amino)phenyl]benzoic acid and 4-[4-({[(2S)-1-({[4-(prop-2-yl)phenyl]amino}carbonyl)azacyclohepta-2-yl]carbonyl}amino)phenyl]benzoic acid

[0342] The target product was obtained by chiral separation using SFC (supercritical fluid chromatography).

[0343] MS m / z (ESI): 500.2 [M+H] + .

[0344] Examples 2-47 refer to the synthesis method of Example 1.

[0345] Example 39

[0346] 4'-(4-(((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid

[0347] Step 1: N-((2-bromo-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)methyl)-3-fluoro-4-isopropylaniline

[0348] The synthesis of the starting material 2-bromo-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridine-4-carboxaldehyde is based on patent WO2023151636A1. 2-bromo-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridine-4-carboxaldehyde (2.4 g, 10 mmol) and 3-fluoro-4-isopropylaniline (1.53 g, 10 mmol) were dissolved in dichloromethane (50 mL), and sodium borohydride acetate (0.76 g, 20 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was cooled to 0 °C, quenched with saturated ammonium chloride solution (30 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether:ethyl acetate = 100:0 to 50:50) to give the target product (3.2 g, yield: 85%). MS m / z (ESI): 377.1 [M+H] + .

[0349] Step 2: Methyl 4'-(4-((((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid ester

[0350] N-((2-bromo-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)methyl)-3-fluoro-4-isopropylaniline (3.0 g, 8 mmol) and methyl 4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-[1,1'-biphenyl]-4-carboxylic acid ester (3.4 g, 10 mmol) were dissolved in 1',4-Dioxane (50 mL) and Water (10 mL). Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (280 mg, 0.4 mmol) and potassium phosphate (4.2 g, 20 mmol) were added. The mixture was stirred at 90 °C for 5 hours. The mixture was evaporated to dryness, the reaction was quenched with saturated brine (100 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (elution with petroleum ether: ethyl acetate = 100:0 to 50:50) to give the target product (3.2 g, yield: 78%). MS m / z (ESI): 509.3 [M+H] + .

[0351] Step 3: 4'-(4-(((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid

[0352] Methyl 4'-(4-((((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid ester (0.5 g, 1 mmol) was dissolved in THF (5 mL) and water (2 mL), and LiOH (72 mg, 3 mmol) was added. The mixture was stirred at 25 °C for 4 hours. The pH was adjusted to neutral with 1 N HCl solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography to obtain the product (356 mg, yield: 72%). MS m / z (ESI): 494.2 [M+H] + .

[0353] Step 4: (R)-4'-(4-(((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid and (S)-4'-(4-(((3-fluoro-4-isopropylphenyl)amino)methyl)-7-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)-[1,1'-biphenyl]-4-carboxylic acid

[0354] The target product was obtained by chiral separation using SFC (supercritical fluid chromatography). MS m / z (ESI): 494.2 [M+H] + .

[0355] Examples 40-58 follow the synthesis method of Example 39.

[0356] Example A

[0357] (R)-5-(4-(1-(2-(1H-pyrrolo-2-yl)acetyl)pyrrolidin-2-carboxamide)phenyl)-6-methylpyridinecarboxylic acid

[0358] first step

[0359] At room temperature, (tert-butoxycarbonyl)-D-proline (100 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.62 mmol) were dissolved in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of methyl 5-(4-aminophenyl)-6-methylpyridinecarboxylate (71 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for another 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phase was dried and purified by silica gel column chromatography to give methyl(R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamide)phenyl)-6-methylpyridinecarboxylate (120 mg), yield: 67.0%. MS m / z (ESI): 440.2 [M+H]+.

[0360] Step 2

[0361] 100 mg (0.23 mmol) of methyl(R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamide)phenyl)-6-methylpyridinecarboxylate was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (2 mL, 4 M) was added dropwise. The mixture was stirred at room temperature for 2 hours. The solution was concentrated to give crude methyl(R)-6-methyl-5-(4-(pyrrolidine-2-carboxamide)phenyl)pyridinecarboxylate (70 mg), yield: 89.7%. MS m / z (ESI): 340.1 [M+H]+.

[0362] Step 3

[0363] At room temperature, 2-(1H-pyrrolo-2-yl)acetic acid (500 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg, 1.9 mmol) were dissolved in acetonitrile (10 mL), and 4-dimethylaminopyridine (35 mg, 0.29 mmol) was added with stirring. The reaction was stirred at room temperature for 1 hour, and then methyl(R)-6-methyl-5-(4-(pyrrolo-2-carboxamide)phenyl)pyridinecarboxylate (184 mg, 1.5 mmol) was added. The reaction was stirred at room temperature for another 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to give methyl(R)-5-(4-(1-(2-(1H-pyrrolo-2-yl)acetyl)pyrrolidine-2-carboxamide)phenyl)-6-methylpyridinecarboxylate (352 mg), yield: 52.6%. MS m / z (ESI): 447.2 [M+H]+.

[0364] Step 4

[0365] At room temperature, methyl(R)-5-(4-(1-(2-(1H-pyrrolo-2-yl)acetyl)pyrrolidine-2-carboxamide)phenyl)-6-methylpyridinecarboxylic acid (200 mg, 0.45 mmol) was dissolved in tetrahydrofuran / water = 2 / 1 (5 mL), and lithium hydroxide (37 mg, 0.89 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate (2 x 10 mL), the organic phase was dried, and purified by silica gel column chromatography to give (R)-5-(4-(1-(2-(1H-pyrrolo-2-yl)acetyl)pyrrolidine-2-carboxamide)phenyl)-6-methylpyridinecarboxylic acid (70 mg), yield: 36.1%. MS m / z(ESI):433.1[M+H]+.1H NMR(400MHz,Methanol-d4)δ8.09(d,1H),7.89(d,1H),7.77–7.71(m,2H),7.45–7.36(m,2H),6.68(t t,1H),6.03(q,1H),5.99(dq,1H),4.59(dd,1H),3.80–3.54(m,4H),2.60(s,3H),2.36–1.95(m,4H).

[0366] Example B

[0367] (R)-8-(1-((3-isopropylbicyclo[1.1.1]pent-1-yl)carbamoyl)pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid

[0368] first step

[0369] At room temperature, methyl 5-amino-2-bromobenzoate (2 g, 8.69 mmol), 4-dimethylaminopyridine (106 mg, 0.87 mmol), and triethylamine (1.76 g, 17.4 mmol) were dissolved in dichloromethane (30 mL). Di-tert-butyl dicarbonate (4.17 g, 19.1 mmol) was added to this solution, and the reaction was stirred at room temperature for 2 hours. The reaction solution was washed with water, the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 2-bromo-5-((tert-butoxycarbonyl)amino)benzoate (2.07 g), in 72.12% yield. 1 HNMR(CHLOROFORM-d,400MHz)δ7.7-7.8(m,1H),7.6-7.7(m,1H),7.3-7.3(m,1H),3.9-4.0(m,3H),1.4-1.5(m,9H).

[0370] Step 2

[0371] At room temperature, methyl 2-bromo-5-((tert-butyloxycarbonyl)amino)benzoate (1.5 g, 4.54 mmol) and lithium chloride were dissolved in a mixed solvent of tetrahydrofuran (15 mL) and ethanol (15 mL). Sodium borohydride (344 mg, 9.1 mmol) was added in portions. The reaction mixture was stirred at room temperature for 20 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give tert-butyl (4-bromo-3-(hydroxymethyl)phenyl)carbamate (1 g), yield: 72.85%. MS m / z (ESI): 300.2, 302.2 [MH] - .

[0372] Step 3

[0373] At room temperature, tert-butyl (4-bromo-3-(hydroxymethyl)phenyl)carbamate (1 g, 3.31 mmol) and imidazole (451 mg, 6.62 mmol) were dissolved in N,N-dimethylformamide (10 mL). Tert-butyldimethylchlorosilane (649 mg, 4.30 mmol) was added under ice bath conditions, and the mixture was stirred for 10 minutes under ice bath conditions, followed by stirring at room temperature for 20 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]carbamate (1.25 g), yield 90.70%. 1 HNMR(CHLOROFORM-d,400MHz)δ7.2-7.4(m,2H),7.1-7.2(m,1H),6.2-6.4(m,1H),4.4-4.6(m,2H),1.4-1.4(m,9H),0.8-0.9(m,9H),0.0-0.0(m,6H).

[0374] Step 4

[0375] At room temperature, tert-butyl N-[4-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]carbamate (600 mg, 1.44 mmol), methyl 3-acetoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate pinacol diborate (461 mg, 1.44 mmol), methanesulfonic acid (tri-tert-butylphosphino) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (82 mg, 0.15 mol), and sodium bicarbonate (363 mg, 4.32 mmol) were suspended in a mixed solution of 1,4-dioxane (12 mL) and water (3 mmol), and the reaction was carried out under nitrogen protection and stirred at 75 °C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the organic solvent, and the residue was added with water, extracted with dichloromethane, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 4'-(tert-butyloxycarbonyl)amino)-2'-((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxy-[1,1'-biphenyl]-4-carboxylic acid (560 mg), yield 79.7%. 1 HNMR(CHLOROFORM-d,400MHz)δ7.6-7.7(m,2H),7.4-7.5(m,2H),7.1-7.2(m,2H),6.4-6.7(m,1H) ,5.9-6.2(m,1H),4.39(s,2H),3.9-3.9(m,3H),1.4-1.5(m,9H),0.8-1.0(m,9H),0.0-0.0(m,6H).

[0376] Step 5

[0377] Methyl 4'-(tert-butyloxycarbonyl)amino)-2'-((tert-butyldimethylsilyl)oxy)methyl)-2-hydroxy-[1,1'-biphenyl]-4-carboxylic acid (560 mg, 1.15 mmol) was dissolved in a tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 6 mL). The reaction was carried out under nitrogen protection and stirred at room temperature for 0.5 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated to give 1.6 g of a brown oily substance. The residue was used directly in the next reaction step.

[0378] Step 6

[0379] Methyl 4'-((tert-Butoxycarbonyl)amino)-2-hydroxy-2'-(hydroxymethyl)-[1,1'-biphenyl]-4-carboxylic acid (1.6 g, crude) and triphenoxyphosphorus (590 mg, 2.25 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarbonate (2.25 mmol, 0.44 mmol) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 20 minutes, then heated to room temperature and stirred for another 20 hours. The mixture was diluted with water, extracted with dichloromethane, dried and concentrated the organic phase, and the residue was purified by silica gel column chromatography (elution system A) to obtain methyl 8-((tert-Butoxycarbonyl)amino)-6H-benzo[c]chromene-3-carboxylic acid (380 mg). 1 HNMR(CHLOROFORM-d,400MHz)δ7.7-7.8(m,2H),7.5-7.7(m,2H),7.4-7.5(m,1H),7 .1-7.2(m,1H),6.5-6.6(m,1H),5.1-5.2(m,2H),3.9-4.0(m,3H),1.4-1.6(m,9H).

[0380] Step 7

[0381] 8-(tert-Butoxycarbonylamino)-6H-benzo[c]chromene-3-carboxylic acid methyl ester (380 mg, 1.07 mmol) was dissolved in dichloromethane (4 mL) at room temperature, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate aqueous solution, dried, and concentrated to give 8-amino-6H-benzo[c]chromene-3-carboxylic acid methyl ester (345 mg), yield: 98.02%. MS m / z (ESI): 256.2 [M+H] + .

[0382] Step 8

[0383] At room temperature, methyl 8-amino-6H-benzo[c]chromene-3-carboxylic acid (210 mg, 0.82 mmol), N-(tert-butoxycarbonyl)-D-proline (177 mg, 0.82 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg, 1.23 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-2-((3-(methoxycarbonyl)-6H-benzo[c]benzo-8-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg), yield: 95.36%. MS m / z(ESI): 353.1 [M+H-100] + .

[0384] Step 9

[0385] At room temperature, tert-butyl (R)-2-((3-(methoxycarbonyl)-6H-benzo[c]benzo-8-yl)carbamoyl)pyrrolidine-1-carboxylic acid (tert-butyl ester, 0.78 mmol) and lithium hydroxide (188 mg, 7.85 mmol) were dissolved in a mixed solvent of water (5 mL), tetrahydrofuran (5 mL), and methanol (5 mL). The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, and the organic phase was dried and concentrated to give (R)-8-(1-(tert-butyloxycarbonyl)pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid (330 mg), yield: 95.93%. MS m / z (ESI): 339.1 [M+H-100] + .

[0386] Step 10

[0387] (R)-8-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid (330 mg, 0.75 mmol) was dissolved in dichloromethane (4 mL) at room temperature, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give (R)-8-(pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid trifluoroacetate (330 mg), yield: 96.93%. MS m / z (ESI): 339.1 [M+H] + .

[0388] Step 11

[0389] Under ice bath conditions, a solution of 3-isopropylbicyclo[1.1.1]pentan-1-amine hydrochloride (30 mg, 0.19 mmol) and 4-methylmorpholine (40 μL) in acetonitrile was added to a 3 mL acetonitrile solution of N,N'-carbonyldiimidazole (32 mg, 0.2 mmol) in acetonitrile. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was redissolved in tetrahydrofuran (2 mL). Then, ((R)-8-(pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid trifluoroacetate (84 mg, 0.19 mmol) was added. A 2 mL solution of tetrahydrofuran containing 0.19 mmol) and 4-methylmorpholine (55 μL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under pressure, and the residue was redissolved in dichloromethane. The residue was washed with water, dried over the organic phase, concentrated, and purified by preparative HPLC (formic acid system) to obtain (R)-8-(1-((3-isopropylbicyclo[1.1.1]pent-1-yl)carbamoyl)pyrrolidine-2-carboxamido)-6H-benzo[c]chromene-3-carboxylic acid. (32 mg), yield: 35.23%. MS m / z (ESI): 490.2 [M+H] + . 1 HNMR(DMSO-d6,400MHz)δ12.4-13.2(m,1H),10.17(s,1H),7.9-8.0(m,1H),7.8-7.9(m,1H),7.5-7.7(m,3H),7.3-7.5(m,1H),6.7-6.9(m,1 H),5.1-5.2(m,2H),4.3-4.4(m,1H),3.4-3.5(m,1H),3.2-3.3(m,1H),2.0-2.2(m,1H),1.8-2.0(m,3H),1.71(s,6H),0.80(d,6H,J=6.8Hz)

[0390] Example C

[0391] (R)-4-(4-(2-((4-chloro-3-(prop-1-yn-1-yl)phenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-3-carboxamido)phenyl)bicyclo[2.2.2]octane-1-carboxylic acid

[0392] first step

[0393] Under a nitrogen atmosphere, 2.0 M butylmagnesium chloride (9.54 mL, 19.09 mmol) was dissolved in ultra-dry toluene (20 mL) and cooled to -15 °C. 1.6 M butyllithium (23.8 mL, 38.18 mmol) was slowly added and stirred at -15 °C for 30 minutes, resulting in a white suspension. A toluene (20 mL) solution of 2,5-dibromobicyclo[4.2.0]octyl-1,3,5-triene (5.0 g, 19.09 mmol) was slowly added to the reaction system and stirred at -15 °C for 1 hour. A toluene (20 mL) solution of di-tert-butyl dicarbonate (12.50 g, 57.26 mmol) was added to the reaction system, and the temperature was slowly raised to 20 °C and stirred for 1 hour. After the reaction was complete, sodium bicarbonate solution (100 mL) was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3), drying of the organic phase, and concentration to obtain crude product tert-butyl 5-bromobicyclo[4.2.0]octyl-1,3,5-triene-2-carboxylate (5.0 g). 1 H NMR (400MHz, CDCl3) δ7.59(dd,J=8.6,0.8Hz,1H),7.34(d,J=8.6Hz,1H),3.32(dd,J=5.2,3.4Hz,2H),3.19–3.11(m,3H),1.57(s,10H).

[0394] Step 2

[0395] To a solution of 5-bromobicyclo[4.2.0]octyl-1,3,5-trien-2-carboxylic acid tert-butyl ester (5.0 g) in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated. The residue was slurried in 5% ethyl acetate / petroleum ether for 30 minutes and filtered to give the product 5-bromobicyclo[4.2.0]octyl-1,3,5-trien-2-carboxylic acid (1.25 g, 5.51 mmol), with a two-step yield of 28.9%. MS m / z (ESI): 225.0 [MH] - .

[0396] Step 3

[0397] To a methanol (20 mL) solution of 1.95 g (8.59 mmol) of 5-bromobicyclo[4.2.0]octyl-1,3,5-trien-2-carboxylic acid tert-butyl ester, sulfoxide (2.04 g, 17.18 mmol) was added, and the mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was quenched with sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL x 3), dried over the organic phase, concentrated, and the residue was purified by silica gel column chromatography to give the product methyl 5-bromobicyclo[4.2.0]octyl-1,3,5-trien-2-carboxylic acid (1.85 g), yield 88.5%. MS m / z (ESI): 241.0 [M+H] + .

[0398] Step 2

[0399] 1,3-Dioxoisoindoline-2-yl-3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1.81 g, 4.85 mmol), methyl 5-bromobicyclo[4.2.0]oct-1,3,5-trien-2-carboxylate (0.90 g, 3.73 mmol), ethylene glycol dimethyl ether nickel chloride (328 mg, 1.49 mmol), 5-methoxypicolinimidine hydrochloride (280 mg, 1.49 mmol), tetrabutylammonium iodide (1.38 g, 3.73 mmol), and zinc powder (2.44 g, 37.33 mmol) were placed in a two-necked flask, purged with nitrogen three times, and then N,N-dimethylacetamide (20 mL) and trifluoroacetic acid (286 μL, 3.73 mmol) were added. The mixture was stirred rapidly at room temperature for 2 hours. After the reaction was complete, ammonium chloride aqueous solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL x 2), washing with sodium chloride solution, drying the organic phase, concentrating, and purifying the residue by silica gel column chromatography to obtain methyl 5-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylate (530 mg), yield: 39.3%. MS m / z (ESI): 344.4 [M+H] + .

[0400] Step 3

[0401] 530 mg (1.54 mmol) of methyl 5-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylate was dissolved in trifluoroacetic acid (5 mL) and dichloromethane (20 mL) at room temperature, and the reaction was continued with stirring at room temperature for 2 hours. The reaction solution was concentrated, the residue was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3 x 20 mL), and concentrated to obtain crude methyl 5-(3-aminobicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylate (375 mg). MS m / z (ESI): 244.4 [M+H] + .

[0402] Step 4

[0403] A solution of 5-(3-aminobicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylate (90 mg, 370 μmol), ((3-isopropylbicyclo[1.1.1]pentan-1-yl)carbamoyl)-D-proline (99 mg, 370 μmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg, 740 μmol), and N,N-diisopropylethylamine (191 mg, 1.48 mmol) in dichloromethane (5 mL) was stirred at room temperature for 6 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (3 x 20 mL), and concentrated to obtain crude (R)-5-(3-(1-((3-isopropylbicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylic acid methyl ester (180 mg). MS m / z (ESI): 492.4 [M+H] + .

[0404] Step 5

[0405] At room temperature, crude (R)-5-(3-(1-((3-isopropylbicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylic acid methyl ester (180 mg) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide (176 mg, 7.36 mmol) was added. The reaction was stirred at room temperature for 3 hours. The pH was adjusted to 3 with 6N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(3-(1-((3-isopropylbicyclo[1.1.1]pentan-1-yl)carbamoyl)pyrrolidine-2-carboxamido)bicyclo[1.1.1]pentan-1-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-carboxylic acid (56 mg), yield: 32.1%. MS m / z (ESI): 478.3 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.63(s,1H),8.42(s,1H),7.59(d,J=8.2Hz,1H),7.07(d,J=8.2Hz,1H),6.69(s,1H),4.10(dd,J=8.5,2.5Hz ,1H),3.32–3.25(m,3H),3.22–3.11(m,3H),2.25(s,6H),1.92(tt,J=10.0,5.5Hz,1H),1.86–1.64(m,10H),0.81(d,J=6.8Hz,6H).

[0406] Example D

[0407] (R)-N2-(4-(4-(3-hydroxyisoxazol-5-yl)bicyclo[2.2.2]octane-1-yl)phenyl)-N1-(3-isopropylbicyclo[1.1.1]pent-1-yl)pyrrolidine-1,2-dicarboxamide

[0408] first step

[0409] methyl 4-[4-(tert-butoxycarbonylamino)phenyl]bicyclo[2.2.2]octane-1-carboxylic acid (700 mg, 1.95 mmol) and lithium hydroxide monohydrate (817.19 mg, 19.47 mmol) were dissolved in a mixed solvent of water (10 mL), tetrahydrofuran (10 mL), and methanol (10 mL) at room temperature and stirred for 20 hours. The reaction mixture was adjusted to pH 3 with hydrochloric acid, extracted with dichloromethane, dried, filtered, and concentrated to give 4-[4-(tert-butoxycarbonylamino)phenyl]bicyclo[2.2.2]octane-1-carboxylic acid (650 mg), yield: 96.63%. MS m / z (ESI): 291.1 [M+H-56] + .

[0410] Step 2

[0411] At room temperature, 4-[4-(tert-butoxycarbonylamino)phenyl]bicyclo[2.2.2]octane-1-carboxylic acid (800 mg, 2.32 mmol) and N,N'-carbonyldiimidazole (488 mg, 3.01 mmol) were suspended in acetonitrile (30 mL) and stirred for 1 hour to form solution A. At the same time, an acetonitrile suspension of potassium monoethyl malonate (872 mg, 5.10 mmol), triethylamine (7.41 mmol, 1.03 mL), and magnesium chloride (573 mg, 6.02 mmol) was stirred at room temperature for 1 hour to form mixture B. Then, solution A was added dropwise to mixture B, and the mixture was stirred at 80 °C for 20 hours under nitrogen protection. Cool to room temperature, filter, evaporate the filtrate to dryness under reduced pressure, extract the residue with dichloromethane and water, dry the organic phase, filter and concentrate, and purify the residue by silica gel column chromatography (elution system A) to give ethyl 3-[4-[4-(tert-butoxycarbonylamino)phenyl]-1-bicyclo[2.2.2]octyl]-3-oxo-propionate (650 mg), yield: 67.54%. MS m / z (ESI): 416.2 [M+H] + .

[0412] Step 3

[0413] Under nitrogen protection, at -20°C, a mixed solution of ethyl 3-[4-[4-(tert-butoxycarbonylamino)phenyl]-1-bicyclo[2.2.2]octyl]-3-oxo-propionate (570 mg, 1.37 mmol) in ethanol (20 mL) and tetrahydrofuran (20 mL) was added to 10 mL of an aqueous solution of hydroxylamine hydrochloride (143 mg, 2.06 mmol) and sodium hydroxide (220 mg, 5.49 mmol). The mixture was stirred at -20°C for 2 hours, then heated to 60°C and stirred for 5 hours. After cooling to room temperature, the pH was adjusted to 3 with 1 M dilute hydrochloric acid. The insoluble matter was collected by filtration, washed with cold water, and dried to give N-[4-[4-(3-hydroxyisoxazol-5-yl)-1-bicyclo[2.2.2]octyl]phenyl]carbamate tert-butyl ester (480 mg), yield: 91.01%. MS m / z (ESI): 385.2 [M+H] + .

[0414] Step 4

[0415] At room temperature, tert-butyl N-[4-[4-(3-hydroxyisoxazol-5-yl)-1-bicyclo[2.2.2]octyl]phenyl]carbamate (200 mg, 0.52 mmol) was dissolved in dioxane hydrochloride solution (4 M, 10 mL). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate (2 mL) to give 5-[4-(4-aminophenyl)-1-bicyclo[2.2.2]octyl]isoxazol-3-ol (130 mg), yield: 87.89%. MS m / z (ESI): 285.2 [M+H] + .

[0416] Step 5

[0417] The following were added: (2R)-1-[(3-isopropyl-1-bicyclo[1.1.1]pentyl)carbamoyl]pyrrolidine-2-carboxylic acid (50 mg, 0.19 mmol), 5-[4-(4-aminophenyl)-1-bicyclo[2.2.2]octyl]isoxazole-3-ol hydrochloride (60 mg, 0.19 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (72 mg, 0.19 mmol). 38 mmol) was dissolved in DMF (4 mL), stirred at room temperature for 20 hours, filtered, and then analyzed by preparative HPLC (formic acid system) to obtain (2R)-N2-[4-[4-(3-hydroxyisoxazol-5-yl)-1-bicyclo[2.2.2]octyl]phenyl]-N1-(3-isopropyl-1-bicyclo[1.1.1]pentyl)pyrrolidine-1,2-dicarboxamide (21 mg), yield: 21.00%. MS m / z (ESI): 533.4 [M+H] + . 1H NMR(DMSO-d6,400MHz)δ9.86(s,1H),7.50(d,2H,J=8.8Hz),7.25(d,1H,J=8.6Hz),6.77(s,1H),4.7-5.1(m,1H),4.2-4.4(m,1H ),3.7-4.0(m,1H),3.4-3.4(m,1H),3.2-3.3(m,1H),2.0-2.1(m,1H),1.8-1.9(m,15H),1.6-1.7(m,7H),0.79(d,6H,J=6.8Hz).

[0418] Example E

[0419] (R)-2-methoxy-4-(4-(2-methyl-1-(spiro[3.3]heptane-2-amido)pyrrolidine-2-carboxamido)piperidin-1-yl)benzoic acid

[0420] first step

[0421] At room temperature, spiro[3.3]hept-2-amine hydrochloride (377.24 mg, 2.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (707.22 mg, 4.65 mmol, 693.35 μL) were dissolved in acetonitrile (10 mL), and N,N'-carbonyldiimidazole (451.96 mg, 2.79 mmol) was added with stirring. The reaction was stirred at room temperature for 3 hours. The solvent was removed, tetrahydrofuran (10 mL) was added, and then (R)-2-methylpyrrolidine-2-carboxylic acid (300 mg, 2.32 mmol) was added. The reaction was stirred at room temperature for 13 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to obtain (R)-2-methyl-1-(spiro[3.3]heptane-2-ylcarbamoyl)proline-2-carboxylic acid (600 mg). Yield: 96.99%. MS m / z (ESI): 267.1 [M+H].

[0422] Step 2

[0423] Under nitrogen protection, (R)-2-methyl-1-(spiro[3.3]heptane-2-ylcarbamoyl)proline-2-carboxylic acid (180 mg, 675.84 μmol) and tert-butyl-4-aminopiperidine-1-carboxylic acid ester (135.36 mg, 675.84 μmol) were dissolved in ethyl acetate (6 mL), followed by N,N-diisopropylethylamine (262.04 mg, 2.03 mmol, 353.16 μL) and 1-butylphosphine anhydride (973.91 mg, 1.35 mmol, 50% purity). The reaction was stirred at room temperature for 3 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl(R)-4-(2-methyl-1-(spirocyclic[3.3]heptane-2-ylaminocarboxyl)pyrrolidine-2-carboxamido)piperidine-1-carboxylic acid ester (240 mg), yield: 79.16%. MS m / z (ESI): 449.3 [M+H] + .

[0424] Step 3

[0425] Under nitrogen protection, tert-butyl(R)-4-(2-methyl-1-(spiro[3.3]heptane-2-ylaminocarboxyl)pyrrolidine-2-carboxamido)piperidine-1-carboxylic acid ester (200 mg, 445.83 μmol) was dissolved in dichloromethane (6 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed, and saturated sodium bicarbonate aqueous solution (15 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (2 x 30 mL), dried, and concentrated to give (R)-2-methyl-N2-(piperidine-4-yl)-N1-(spiro[3.3]heptane-2-yl)pyrrolidine-1,2-dicarboxamide (150 mg), yield: 95.55%. MS m / z (ESI): 349.2 [M+H] + .

[0426] Step 4

[0427] At room temperature, (R)-2-methyl-N2-(piperidin-4-yl)-N1-(spiro[3.3]heptane-2-yl)pyrrolidine-1,2-dicarboxamide (120 mg, 344.35 μmol), tert-butyl 4-bromo-2-methoxybenzoate (148.32 mg, 516.53 μmol) were dissolved in 1,4-dioxane (10 mL), followed by the addition of cesium carbonate (336.59 mg, 1.03 mmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphineoxanthracene))(2'-amino-1 1'-Biphenyl-2-yl)palladium(II) (32.69 mg, 34.44 μmol) was reacted at 100 °C for 16 hours with stirring. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl(R)-2-methoxy-4-(4-(2-methyl-1-(spirocyclic[3.3]hept-2-ylcarbamoyl)pyrrolidine-2-carboxamido)piperidin-1-yl)benzoate (150 mg), yield: 78.53%. MS m / z (ESI): 555.3 [M+H] + .

[0428] Step 5

[0429] At room temperature, tert-butyl(R)-2-methoxy-4-(4-(2-methyl-1-(spiro[3.3]hept-2-ylcarbamoyl)pyrrolidine-2-carboxamido)piperidin-1-yl)benzoate (130 mg, 234.35 μmol) was dissolved in dichloromethane (6 mL), followed by the addition of trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain the residue, which was purified by preparative HPLC (formic acid system) to give methyl 8-(2-fluoro-4-((R)-2-((3-fluoro-4-isopropylphenyl)aminourea)-pyrrolidine-1-carboxamido)phenyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid ester (100.4 mg, yield: 85.92%). MS m / z (ESI): 499.3 [M+H] +1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),7.62(d,J=8.8Hz,1H),7.51(d,J=8.0Hz,1H),6.52(dd,J=9 .0,2.3Hz,1H),6.47(d,J=2.3Hz,1H),6.06(d,J=7.7Hz,1H),3.90(q,J=8.2Hz,1H),3.81(s,6H),3 .38(dt,J=7.2,1.9Hz,1H),3.29–3.23(m,1H),3.01(ddd,J=14.2,8.8,3.6Hz,2H),2.21–2.06(m, 3H),1.94(t,J=7.3Hz,2H),1.89–1.80(m,4H),1.79–1.59(m,7H),1.54–1.43(m,2H),1.39(s,3H).

[0430] Example 59

[0431] (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)azacycloheptane-2-carboxamide)phenyl)-6-methyl-2-pyridinic acid

[0432] first step

[0433] Under nitrogen protection, 1-a (896 mg, 4.09 mmol), tert-butyl 5-bromo-6-methylpyridinecarboxylate (1.12 g, 4.11 mmol), palladium dichloride (287 mg, 0.409 mmol), and tripotassium phosphate (2.61 g, 12.3 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), and the mixture was heated to 90 °C and stirred for 16 hours. After cooling to room temperature, a saturated ammonium chloride solution (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (2 x 100 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate 1-b (755 mg), yield: 64.8%. MS m / z (ESI): 284.2 [M+H] + .

[0434] Step 2

[0435] 1-b (284 mg, 1 mmol), (R)-1-(tert-butoxycarbonyl)azacycloheptane-2-carboxylic acid (291.6 mg, 4.11 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.3 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (2 x 30 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-2-((4-(6-(tert-butoxycarbonyl)-2-methylpyridin-3-yl)phenyl)carboxamide)azacycloheptane-1-carboxylic acid tert-butyl ester 1-c (350 mg), yield: 68.8%. MS m / z (ESI): 510.3 [M+H] + .

[0436] Step 3

[0437] At room temperature, 1-c (350 mg, 0.687 mmol) was dissolved in 1,4-dioxane (5 mL), and 1,4-dioxane hydrochloride solution (4 M, 3.5 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued to be stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, and purified by silica gel column chromatography (elution system A) to give (R)-5-(4-(azacycloheptan-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester 1-d (280 mg), yield: 91.6%. MS m / z (ESI): 410.2 [M+H] + .

[0438] Step 4

[0439] At room temperature, 3-fluoro-4-isopropylaniline (56.1 mg, 0.366 mmol) and triethylamine (37 mg, 0.366 mmol) were dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (350 mg, 0.687 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour, and the reaction solution was concentrated. The residue was dissolved in acetonitrile (2 mL) and added dropwise to acetonitrile (5 mL) containing 1-d (150 mg, 0.366 mmol) and triethylamine (185 mg, 1.83 mmol). The reaction was stirred at room temperature for another hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography (elution system A) to give (R)-5-(4-(1-((3-fluoro-4-isopropylaniline)carbamoyl)azacycloheptane-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester 1-e (280 mg), yield: 91.6%. MS m / z (ESI): 589.3 [M+H]+ .

[0440] Step 5

[0441] At room temperature, methanesulfonic acid (80 mg, 0.83 mmol) was added to a 1-e (150 mg, 0.166 mmol) solution in hexafluoroisopropanol (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was suspended in acetonitrile (1 mL) and water (2 mL). The filtered solid was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(1-((3-fluoro-4-isopropylaniline)carbamoyl)azacycloheptane-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid (36 mg), yield: 40.8%. MS m / z (ESI): 533.2 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ10.13(s,1H),8.47(s,1H),7.92(d,1H),7.78-7.68(m,3H),7.48-7.33(m,3H),7.26(dd,1H),7.17(t,1H),4.76(dd,1H),3.9 6(d,1H),3.07(p,1H),2.50(s,3H),2.34(dt,1H),1.95-1.68(m,1H), 1.85-1.66(m,3H),1.51-1.39(d,1H),1.38-1.21(m,3H),1.18(d,6H).

[0442] Example 60

[0443] 5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)azacycloheptane-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid

[0444] Following the synthetic method of Example 59, the target product 5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)azacycloheptane-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid was synthesized. MS m / z (ESI): 533.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.47(s,1H),7.92(d,1H),7.78-7.68(m,3H),7.48-7.33(m,3H),7.26(dd,1H),7.17(t,1H),4.76(dd,1H) ,3.96(d,1H),3.07(p,1H),2.50(s,3H),2.34(dt,1H),1.95-1.68(m,1H ),1.85-1.66(m,3H),1.51-1.39(d,1H),1.38-1.21(m,3H),1.18(d,6H).

[0445] Example 61

[0446] (R)-6-methyl-5-(4-(1-((3-(pentafluorothio)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid

[0447] Following the synthesis method of Example 59, the target product (R)-6-methyl-5-(4-(1-((3-(sulfur pentafluoride)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid was synthesized.

[0448] MS m / z(ESI): 571.1 [M+H] + . 1 H NMR(400 MHz, DMSO-d6)δ10.19(s,1H),8.75(s,1H),8.22(t,1H),7.93(d,1H),7.81(d,1H),7.75(dd,3H),7.51-7.35(m ,4H),4.50(dd,1H),3.74-3.65(m,1H),3.62-3.53(m,1H),2.50(s,3H),2.28-2.19(m,1H),2.06-1.88(m,3H).

[0449] Example 62

[0450] (R)-6-methyl-5-(4-(1-((4-(pentafluorothio)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-2-pyridinecarboxylic acid

[0451] first step

[0452] Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)aniline (1.9 g, 8.69 mmol), methyl 5-bromo-6-methylpyridinecarboxylate (2.0 g, 8.69 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (318 mg, 0.435 mmol) and potassium carbonate (3.0 g, 21.7 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and the mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 100 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (1.45 g), yield: 68.8%. MS m / z (ESI): 243.1 [M+H] + .

[0453] Step 2

[0454] Under nitrogen protection, methyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (1.0 g, 4.13 mmol), N-(tert-butoxycarbonyl)-D-proline (888 mg, 4.13 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g, 5.37 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-5-(4-(1-(tert-butoxycarbonyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (1.6 g), yield: 65.0%. MS m / z (ESI): 440.2 [M+H] + .

[0455] Step 3

[0456] At room temperature, methyl (R)-5-(4-(1-(tert-butoxycarbonyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (1.6 g, 3.64 mmol) was dissolved in 1,4-dioxane (10 mL), and 1,4-dioxane hydrochloride solution (4 M, 4.5 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued to be stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol. Then, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and purified by silica gel column chromatography (elution system A) to give methyl (R)-6-methyl-5-(4-(tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylate (1.24 g), yield: 97.1%. MS m / z (ESI): 340.2 [M+H] + .

[0457] Step 4

[0458] At room temperature, 4-(pentafluorothio)aniline (226 mg, 1.03 mmol) and triethylamine (104 mg, 1.03 mmol) were dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (200 mg, 1.24 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour, and the reaction solution was concentrated. The residue was dissolved in acetonitrile (2 mL) and added dropwise to acetonitrile (5 mL) containing (R)-6-methyl-5-(4-(tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylate (350 mg, 1.03 mmol) and triethylamine (313 mg, 3.09 mmol). The reaction was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography (elution system A) to give (R)-6-methyl-5-(4-(1-((4-(pentafluoride)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid methyl ester (260 mg), yield: 43.1%. MS m / z (ESI): 585.2 [M+H] + .

[0459] Step 5

[0460] At room temperature, methyl (R)-6-methyl-5-(4-(1-((4-(pentafluoride)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid (260 mg, 0.445 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution of lithium hydroxide (150 mg, 0.166 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to about 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-6-methyl-5-(4-(1-((4-(pentafluoride)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid (110 mg), yield: 43.4%. MS m / z(ESI): 571.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.81(s,1H),7.93(d,1H),7.78-7.70(m,7H),7.45-7.33(m,2H), 4.50(dd,1H),3.74-3.65(m,1H),3.62-3.53(m,1H),2.50(s,3H),2.28-2.19(m,1H),2.06-1.88(m,3H).

[0461] Example 63

[0462] (R)-5-(4-(1-((4-(bicyclo[1.1.1]octane-1-yl)-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid

[0463] first step

[0464] Under nitrogen protection, methyl (R)-5-(4-(1-((4-bromo-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (300 mg, 0.54 mmol), N-phthalimide-bicyclo[1.1.1]octane-1-carboxylate (208 mg, 0.81 mmol), and (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)- 2,2'-Bipyridine-κN1,κN1′] nickel dibromide (52.6 mg, 0.108 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (274 mg, 1.08 mmol) and sodium bicarbonate (90.8 mg, 1.08 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred in a photoreactometer (violet light 390 nm-395 nm) for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give (R)-5-(4-(1-((4-(bicyclo[1.1.1]octane-1-yl)-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (55 mg), yield: 18.8%. MS m / z (ESI): 543.2 [M+H]+.

[0465] Step 2

[0466] At room temperature, methyl (R)-5-(4-(1-((4-(bicyclo[1.1.1]octane-1-yl)-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (55 mg, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL), and an aqueous solution of lithium hydroxide (7.2 mg, 0.3 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was... Dissolved in water (5 mL), the pH was adjusted to approximately 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(1-((4-(bicyclo[1.1.1]octane-1-yl)-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid (24.5 mg), yield: 45.7%. MS m / z(ESI):529.2[M+H]+.1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.46(s,1H),7.92(d,1H),7.78-7.71(m,3H),7.47-7.35(m,2H),7.24(dd,1H),7.01( t,1H),4.47(dd,1H),3.70-3.62(m,1H),3.58-3.48(m,1H),2.50(s,3H),2.25-2.17(m,1H),2.08(s,6H),2.03-1.90(m,3H).

[0467] Example 64

[0468] (R)-5-(4-(1-((3-fluoro-4-(1-propynyl)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid

[0469] first step

[0470] At room temperature, 4-bromo-3-fluoroaniline (300 mg, 1.47 mmol) and triethylamine (149 mg, 1.47 mmol) were dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (262 mg, 1.62 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour, and the reaction solution was concentrated. The residue was dissolved in acetonitrile (3 mL) and added dropwise to a solution of 3-2-d (500 mg, 1.47 mmol) and triethylamine (446 mg, 4.41 mmol) in acetonitrile (5 mL). The reaction was stirred at room temperature for another hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to obtain (R)-5-(4-(1-((4-bromo-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid methyl ester (600 mg), yield: 66%. MS m / z (ESI): 537.1 [M+H]+.

[0471] Step 2

[0472] Under nitrogen protection, (R)-5-(4-(1-((4-bromo-3-fluorophenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylate (100 mg, 0.18 mmol), tributylpropynyl tinane (89 mg, 0.27 mmol), and bis(triphenylphosphine)palladium dichloride (12.6 mg, 0.409 mmol) were dissolved in 1,4-dioxane (30 mL) and water (8 mL), and the mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride solution (20 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 30 mL), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give (R)-5-(4-(1-((3-fluoro-4-(1-propyne)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid methyl ester (65 mg), yield: 70.2%. MS m / z (ESI): 497.2 [M+H]+.

[0473] Step 3

[0474] At room temperature, methyl (R)-5-(4-(1-((3-fluoro-4-(1-propynyl)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid (65 mg, 0.126 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution of lithium hydroxide (15 mg, 0.631 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to about 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(1-((3-fluoro-4-(1-propynyl)phenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)pyridine-2-carboxylic acid (23 mg), yield: 36.4%. MS m / z(ESI):483.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.65(s,1H),7.92(d,1H),7.78-7.70(m,3H),7.60-7.53(m,1H),7.43-7.36(m,2H),7.32-7 .27(m,2H),4.49(dd,1H),3.70-3.62(m,1H),3.58-3.50(m,1H),2.50(s,3H),2.28-2.17(m,1H),2.05(s,3H),2.06-1.89(m,3H).

[0475] Example 65

[0476] 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carbamate)phenyl)-6-methylpyridine-2-carboxylic acid

[0477] first step

[0478] To a solution of N,N'-carbodiimidazole (233 mg, 1.44 mmol) in acetonitrile (10 mL), 3-fluoro-4-isopropylaniline (200 mg, 1.31 mmol) was added. The reaction was stirred at 20 °C for 1 hour, and the acetonitrile was removed by concentration under reduced pressure. The solution was dissolved in tetrahydrofuran (10 mL), followed by the sequential addition of N-methylmorpholine (264 mg, 2.61 mmol) and pyrazolidine-1-carboxylic acid benzyl ester (296 mg, 1.44 mmol). The reaction was stirred at 20 °C for 6 hours until complete. The reaction mixture was quenched with sodium bicarbonate (50 mL), washed with diethyl ether (20 mL x 2), and the pH was adjusted to 3 with 2N hydrochloric acid. Extraction was performed with ethyl acetate (50 mL x 3), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give 2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carboxylic acid benzyl ester (320 mg), yield: 63.6%. MS m / z (ESI): 386.2 [M+H] +

[0479] Step 2

[0480] 2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carboxylate benzyl ester (320 mg, 0.83 mmol) and wet palladium on carbon (252 mg) were dissolved in tetrahydrofuran (10 mL). The reaction was carried out by purging with hydrogen three times and stirring at 20 °C for 16 hours under 15 psi pressure. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane / methanol, dried, and concentrated to obtain the crude product N-(3-fluoro-4-isopropylphenyl)pyrazolidine-1-carboxamide (300 mg). MS m / z (ESI): 252.2 [M+H] + .

[0481] Step 3

[0482] At room temperature, tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (294 mg, 1.03 mmol) was added to a 10 mL solution of N,N'-carbodiimidazole (201 mg, 1.24 mmol) in acetonitrile. The reaction was stirred at 20 °C for 1 hour, and the acetonitrile was removed by concentration under reduced pressure. The solution was dissolved in tetrahydrofuran (10 mL), followed by the sequential addition of N-methylmorpholine (209 mg, 2.07 mmol) and N-(3-fluoro-4-isopropylphenyl)pyrazolidine-1-carboxamide (260 mg, 1.03 mmol). The reaction was stirred at 20 °C for 6 hours until complete. After concentration, the reaction solution was purified by silica gel column chromatography to obtain 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (500 mg, 70% purity, 0.62 mmol), yield: 60.2%. MS m / z (ESI): 562.4 [M+H] + .

[0483] Step 4

[0484] At room temperature, tert-butyl 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid (500 mg, 70% purity, 0.62 mmol) in hexafluoroisopropanol (10 mL) was reacted with methanesulfonic acid (428 mg, 4.45 mmol) and stirred at room temperature for 1 hour. The addition of tert-butyl methyl ether (50 mL) precipitated a solid. The residue obtained by filtration was purified by preparative HPLC to give 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrazolidine-1-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid (100 mg, 0.18 mmol), yield: 20.6%. MS m / z (ESI): 506.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.45(s,1H),9.42(s,1H),7.92(d,J=7.9Hz,1H),7.83–7.77(m,2H),7.75(d,J=7.9Hz,1H) ,7.56(dd,J=13.6,2.1Hz,1H),7.43(dd,J=8.5,2.1Hz,1H),7.38–7.32(m,2H),7.20(t,J=8.7Hz,1H),4.16(br s,4H),2.97-3.07(m,1H),2.51(br s,3H),1.97(quin,J=7.35Hz,2H),1.18(d,J=6.88Hz,6H).

[0485] Example 66

[0486] (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)piperidin-2-carboxamide)phenyl)-6-methylpyridinic acid

[0487] first step

[0488] At room temperature, (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, 2.18 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (541 mg, 2.83 mmol) were dissolved in dichloromethane (10 mL), and 4-dimethylaminopyridine (53 mg, 0.43 mmol) was added with stirring. The reaction was stirred at room temperature for 1 hour, and then 4-aminophenylboronic acid pinacol ester (525 mg, 2.4 mmol) was added. The reaction was stirred at room temperature for another 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to give tert-butyl(R)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)carbamoyl)piperidine-1-carboxylic acid ester (352 mg), yield: 37.5%. MS m / z (ESI): 431.2 [M+H]+.

[0489] Step 2

[0490] Under nitrogen protection, tert-butyl(R)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)carbamoyl)piperidine-1-carboxylic acid ester (119 mg, 0.277 mmol), 5-bromo-6-methylpyridinecarboxylic acid (50 mg, 0.23 mmol), sodium carbonate (96 mg, 0.92 mmol), and bis(triphenylphosphine)-palladium dichloride (16 mg, 0.012 mmol) were dissolved in 1,4-dioxane:water = 5:1 (10 mL), and the reaction was heated to 90 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give (R)-5-(4-(1-(tert-butoxycarbonyl)piperidin-2-carboxamide)phenyl)-6-methylpyridinic acid (82 mg), yield: 67.2%. MS m / z (ESI): 440.1 [M+H]+.

[0491] Step 3

[0492] (R)-5-(4-(1-(tert-butoxycarbonyl)piperidin-2-carboxamide)phenyl)-6-methylpyridine acid (100 mg, 0.227 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (2 mL, 4 M) was added dropwise. The mixture was stirred at room temperature for 2 hours. The solution was concentrated to give crude (R)-6-methyl-5-(4-(piperidin-2-carboxamide)phenyl)pyridinecarboxylic acid (75 mg), yield: 98.7%. MS m / z (ESI): 340.1 [M+H]+.

[0493] Step 4

[0494] At room temperature, 3-fluoro-4-isopropylaniline (342 mg, 0.974 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N'-carbonyldiimidazole (105 mg, 0.649 mmol) was added with stirring. The reaction was stirred at room temperature for 1 hour, and (R)-6-methyl-5-(4-(piperidin-2-carboxamide)phenyl)pyridinecarboxylic acid (100 mg, 0.649 mmol) was added. The reaction was stirred at room temperature for another 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to give (R)-5-(4-(1-(((3-fluoro-4-isopropylphenyl)carbamoyl)piperidin-2-carboxamide)phenyl)-6-methylpyridine acid (122 mg), yield: 36.2%. MS m / z(ESI):519.1[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.09(d,1H),7.75(d,1H),7.67(d,2H),7.29(d,2H),7.17(t,1H),6.99(d,1H),6.55(s,1H),5.07 (d,1H),3.69(d,1H),3.28(t,1H),3.19(p,1H),2.57(s,3H),2.35(d,1 H),1.96(t,1H),1.80(s,2H),1.66(dd,2H),1.25(s,3H),1.23(s,3H).

[0495] Example 67

[0496] (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid

[0497] first step

[0498] To a solution of 5-bromo-6-methylpyridine-2-carboxylic acid (5.00 g, 23.14 mmol) in pyridine (100 mL) and tert-butanol (50 mL), p-toluenesulfonyl chloride (13.24 g, 69.43 mmol) was added, and the mixture was stirred at 20 °C for 4 hours. The reaction mixture was quenched with water (200 mL), extracted with 2N hydrochloric acid (100 mL), and methyl tert-butyl ether (150 mL x 3). The mixture was washed with 1N sodium hydroxide solution, dried over the organic phase, and concentrated to obtain crude tert-butyl 5-bromo-6-methylpyridine-2-carboxylic acid (6.50 g). MS m / z (ESI): 272 [M+H] +

[0499] Step 2

[0500] Crude tert-butyl 5-bromo-6-methylpyridine-2-carboxylate (6.50 g), pinacol ester of aminophenylboronic acid (5.23 g, 23.33 mmol), potassium carbonate (6.60 g, 47.77 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (873 mg, 1.19 mmol) were dissolved in 1,4-dioxane (100 mL) and water (10 mL). The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over the organic phase, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (7.20 g, 90% purity), yield: 95.4%. MS m / z(ESI): 285 [M+H] +

[0501] Step 3

[0502] A solution of tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (284 mg, 1.00 mmol) and N,N'-carbodiimidazole (162 mg, 1.00 mmol) in acetonitrile (10 mL) was stirred at 20 °C for 1 hour and concentrated under reduced pressure. A solution of crude (R)-N-(3-fluoro-4-isopropylphenyl)pyrrole-2-carboxamide (370 mg) and N-methylmorpholine (500 mg, 5.00 mmol) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at 20 °C for 6 hours. The reaction solution was quenched with water (10 mL), and the pH was adjusted to 5 with 2N hydrochloric acid (3 mL). Extraction was performed with ethyl acetate (20 mL x 3). The organic phase was dried and concentrated to obtain crude (550 mg) of (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-1-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester. MS m / z (ESI): 561 [M+H] +

[0503] Step 4

[0504] Crude tert-butyl 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-1-carbamate)phenyl)-6-methylpyridine-2-carboxylic acid (tert-butyl ester) (550 mg) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL), and the reaction was stirred at 20 °C for 4 hours until complete. The crude product was concentrated under reduced pressure and purified by preparative HPLC (formic acid system) to give (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-1-carbamate)phenyl)-6-methylpyridine-2-carboxylic acid (147 mg), yield: 30.4%. MS m / z (ESI): 505 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.03(br s,1H),10.12(s,1H),8.46(s,1H),7.91(d,J=7.88Hz,1H),7.75(d,J=7.88Hz,1H),7. 65(d,J=8.63Hz,2H),7.51-7.58(m,1H),7.32(d,J=8.63Hz,2H),7.22-7.30(m,2H),4. 46(dd,J=8.19,3.69Hz,1H),3.62-3.74(m,1H),3.51-3.60(m,1H),3.10(spt,J=6.92H z,1H),2.51(s,3H),2.14-2.25(m,1H),1.88-2.09(m,3H),1.18(d,J=6.88Hz,6H)ppm.

[0505] Example 68

[0506] 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid

[0507] Following the synthesis method of Example 67, the target product 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid was synthesized.

[0508] MS m / z (ESI): 505.2 [M+H] + . 1H NMR (400MHz, DMSO) δ10.13(s,1H),8.47(s,1H),7.91(d,J=7.9Hz,1H),7.75(d,J=7.9Hz,1H),7.69–7.61(m,2H),7.58–7.50(m,1H),7.33( d,J=2.0Hz,1H),7.33–7.17(m,3H),4.45(dd,J=8.3,3.8Hz,1H),3.73–3.63(m,1H),3.55(q,J=7.8Hz,1H),3.09(p,J=6.8Hz,1H),2.49(br s,3H),2.19(dt,J=11.9,7.9Hz,1H),2.09–1.88(m,3H),1.18(d,J=6.9Hz,6H).

[0509] Example 69

[0510] (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)tetrahydropyrrole-1,2-dicarboxamide

[0511] first step

[0512] 4-Bromobenzonitrile (1.0 g, 5.49 mmol), hydroxylamine hydrochloride (515 mg, 7.42 mmol), and potassium carbonate (759 mg, 5.49 mmol) were dissolved in ethanol (20 mL), and the mixture was heated to 80 °C and stirred for 6 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by recrystallization from toluene to give 4-bromo-N'-hydroxybenzomidine (950 mg), yield: 80.4%. MS m / z (ESI): 215.0 [M+H]+.

[0513] Step 2

[0514] 4-Bromo-N'-hydroxybenzomididine (950 mg, 4.42 mmol), N,N'-carbonyldiimidazole (860 mg, 5.3 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (740 mg, 4.86 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 5 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 50 mL), the organic phase was dried, and the solution was concentrated to give 3-(4-bromophenyl)-1,2,4-oxadiazol-5-(4H)-one (750 mg), yield: 63.4%. MS m / z (ESI): 241.0 [M+H]+.

[0515] Step 3

[0516] Under nitrogen protection, 3-(4-bromophenyl)-1,2,4-oxadiazol-5-(4H)-one (41 mg, 0.169 mmol), (R)-N1-(3-fluoro-4-isopropylphenyl)N2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)tetrahydropyrrole-1,2-dicarboxamide (70 mg, 0.14 mmol), (1,1”-bis(diphenylphosphino)ferrocene)palladium dichloride (10.3 mg, 0.014 mmol), and potassium carbonate (57 mg, 0.424 mmol) were dissolved in... The mixture was heated to 90°C and stirred for 3 hours in 1,4-dioxane (4 mL) and water (1 mL). After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)tetrahydropyrrole-1,2-dicarboxamide (10 mg), yield: 13.4%.

[0517] MS m / z(ESI):530.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),10.15(s,1H),8.41(s,1H),7.90-7.82(m,4H),7.77-7.70(m,4H),7.41(dd,1H),7.25(dd,1H),7 .16(t,1H),4.48(dd,1H),3.73-3.60(m,1H),3.60-3.45(m,1H),3.12-3.02(m,1H),2.26-2.14(m,1H),2.12-1.88(m,3H),1.18(d,6H).

[0518] Example 70

[0519] (R)-5-(4-(1-(2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid

[0520] first step

[0521] To a solution of 3-fluoro-4-isopropylaniline (400 mg, 2.61 mmol) and triethylamine (793 mg, 7.83 mmol) in dichloromethane (20 mL), oxaloyl chloride monoethyl ester (713 mg, 5.22 mmol) was added, and the reaction was stirred at 20 °C for 2 hours. The reaction mixture was quenched with sodium bicarbonate solution (100 mL), extracted with dichloromethane (30 mL x 3), dried over the organic phase, concentrated, and the residue was purified by silica gel column chromatography to give ethyl 2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoethyl acetate (400 mg, 78% purity, 1.23 mmol), yield: 47.2%. MS m / z (ESI): 254.1 [M+H] +

[0522] Step 2

[0523] Ethyl 2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetic acid (400 mg, 1.23 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL). Lithium hydroxide (189 mg, 7.90 mmol) was added, and the reaction was stirred at 20 °C for 4 hours until complete. The mixture was neutralized with 2N hydrochloric acid and the pH was adjusted to 3-4. Extraction was performed with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated under reduced pressure to give the crude product 2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetic acid (250 mg). MS m / z (ESI): 226.2 [M+H] + .

[0524] Step 3

[0525] 2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetic acid (248 mg, 1.10 mmol), (R)-6-methyl-5-(4-(pyrrolidine-2-carboxamido)phenyl)pyridine-2-carboxylic acid tert-butyl ester (419 mg, 1.10 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (415 mg, 1.10 mmol) and N,N-diisopropylethylamine (426 mg, 3.30 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 20 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography to obtain (R)-5-(4-(1-(2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (500 mg, 0.85 mmol), yield: 77.3%. MS m / z (ESI): 589.4 [M+H] + .

[0526] Step 4

[0527] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of (R)-5-(4-(1-(2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (200 mg, 87% purity, 0.31 mmol) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 1 hour. The residue obtained by concentration of the reaction solution was purified by preparative HPLC to (R)-5-(4-(1-(2-((3-fluoro-4-isopropylphenyl)amino)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid (27.0 mg, 0.05 mmol), yield: 5.92%. MS m / z (ESI): 533.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.76(d,J=19.7Hz,1H),10.31(d,J=24.2Hz,1H),7.92(t,J=7.5Hz,1H),7.80–7.7 0(m,2H),7.70–7.64(m,1H),7.64–7.50(m,1H),7.50–7.33(m,3H),7.26(dt,J=29.0,8.6Hz,1H),5.16( dd,J=8.3,4.4Hz,0.5H),4.59(dd,J=8.5,3.7Hz,0.5H),3.95(ddd,J=17.8,11.5,6.4Hz,1H),3.62(hep t,J=6.3Hz,1H),3.09(dp,J=21.0,6.9Hz,1H),2.43–2.23(m,1H),2.12–1.81(m,3H),1.23–1.12(m,7H).

[0528] Example 71

[0529] 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid

[0530] first step

[0531] 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (250 mg, 1.10 mmol) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (10 mL), and the reaction was stirred at 20 °C for 1 hour until complete. The crude product, 2-azabicyclo[2.1.1]hexane-1-carboxylic acid (270 mg), was obtained by concentration under reduced pressure. MS m / z (ESI): 128 [M+H]+ .

[0532] Step 2

[0533] A solution of 3-fluoro-4-isopropylaniline (168 mg, 1.10 mmol) and N,N'-carbodiimidazole (214 mg, 1.32 mmol) in acetonitrile (10 mL) was stirred at 20 °C for 1 hour and concentrated under reduced pressure. Crude 2-azabicyclo[2.1.1]hexane-1-carboxylic acid (270 mg) and a solution of N-methylmorpholine (445 mg, 4.40 mmol) in tetrahydrofuran (10 mL) were added, and the mixture was stirred at 20 °C for 6 hours. After the reaction was complete, water (10 mL) was added to quench the reaction mixture, and the pH was adjusted to 5 with 2N hydrochloric acid (3 mL). The mixture was extracted with ethyl acetate (20 mL x 3), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (150 mg), yield 40.2%. MS m / z (ESI): 307 [M+H] +

[0534] Step 3

[0535] 2-((3-fluoro-4-isopropylphenyl)methylamino)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (150 mg, 0.44 mmol), tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (185 mg, 0.65 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg, 0.65 mmol) were dissolved in dichloromethane (5 mL) and stirred at 20 °C for 6 hours. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL x 3), the organic phase was dried, and concentrated to obtain crude 5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (500 mg). MS m / z (ESI): 573 [M+H] + .

[0536] Step 4

[0537] Crude tert-butyl 5-(4-(2-((3-fluoro-4-isopropylphenyl)aminocarbamoyl)-2-azabicyclo[2.1.1]hexane-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid (tert-butyl ester) (500 mg) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL), and the reaction was stirred at 20 °C for 4 hours until complete. The crude product was concentrated under reduced pressure and purified by preparative HPLC (formic acid system) to obtain 5-(4-(2-((3-fluoro-4-isopropylphenyl)aminocarbamoyl)-2-azabicyclo[2.1.1]hexane-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid (63 mg), yield 27.3%. MS m / z (ESI): 517 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.61(s,1H),8.92(s,1H),7.93(d,J=7.88Hz,1H),7.81(d,J=8.63Hz,2H),7.76 (d,J=7.88Hz,1H),7.35-7.40(m,3H),7.10-7.23(m,2H),3.48-3.62(m,2H),2.94-3.17(m,1H),2.81(br s,1H),2.52(s,3H),2.06-2.17(m,2H),1.70(br d,J=3.00Hz,2H),1.16(d,J=6.88Hz,6H)ppm.

[0538] Example 72

[0539] (R)-5-(4-(1-(2-(4-isopropylphenyl)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid

[0540] first step

[0541] At room temperature, tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (800 mg, 2.81 mmol), tert-butyloxycarbonyl-D-proline (666 mg, 3.09 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (593 mg, 3.09 mmol) were dissolved in dichloromethane (20 mL) and stirred at 20 °C for 6 hours. After concentration, the reaction solution was purified by silica gel column chromatography to give (R)-5-(4-(1-(tert-butyloxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylate (1.20 g, 2.27 mmol), yield: 80.6%. MS m / z (ESI): 482.4 [M+H] + .

[0542] Step 2

[0543] To a solution of (R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (1.20 g, 2.27 mmol) in dichloromethane (20 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product (R)-6-methyl-5-(4-(pyrrolidine-2-carboxamido)phenyl)pyridine-2-carboxylic acid tert-butyl ester (1.50 g). MS m / z (ESI): 382.4 [M+H] +

[0544] Step 3

[0545] Ethyl 4-isopropylbenzoylcarbamate (1.0 g, 4.54 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL). Lithium hydroxide (1.08 g, 45.40 mmol) was added, and the reaction was stirred at 20 °C for 4 hours until complete. The mixture was neutralized with 2N hydrochloric acid and the pH was adjusted to 3-4. Extraction was performed with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated under reduced pressure to give the crude product 4-isopropylbenzoylcarbamate (850 mg). MS m / z (ESI): 193.1 [M+H] +

[0546] Step 4

[0547] 4-Isopropylbenzoylcarboxylic acid (96 mg, 0.50 mmol), (R)-6-methyl-5-(4-(pyrrolidine-2-carboxamido)phenyl)pyridine-2-carboxylic acid tert-butyl ester (190 mg, 0.50 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (188 mg, 0.50 mmol) and N,N-diisopropylethylamine (192 mg, 1.50 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 20 °C for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography to obtain (R)-5-(4-(1-(2-(4-isopropylphenyl)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (200 mg, 87% purity, 0.31 mmol), yield: 62.9%. MS m / z (ESI): 556.4 [M+H] +

[0548] Step 5

[0549] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of (R)-5-(4-(1-(2-(4-isopropylphenyl)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (200 mg, 87% purity, 0.31 mmol) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 1 hour. The residue obtained by concentration of the reaction solution was purified by preparative HPLC to (R)-5-(4-(1-(2-(4-isopropylphenyl)-2-oxoacetyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid (59.5 mg, 0.12 mmol), yield: 38.0%. MS m / z (ESI): 500.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.46(s,0.7H),10.15(s,0.3H),8.03–7.25(m,10H),4.70–4.57(m,1H),3.75–3.4 0(m,2H),3.09–2.86(m,1H),2.52(s,3H),2.38–2.29(m,1H),1.98(s,3H),1.21(dd,J=29.7,6.9Hz,6H).

[0550] Example 73

[0551] (R)-(5-(4-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamate)phenyl)pyridin-2-yl)carbamate

[0552] Following the synthesis method of Example 59, the target product (R)-(5-(4-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamate)phenyl)pyridin-2-yl)carbamate was synthesized.

[0553] MS m / z(ESI): 519.58[M+H]+. 1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.11(s,1H),8.57(d,1H),8.41(s,1H),8.06(dd,1H),7.90(d,1H),7.76–7.62(m,4H),7.41(dd,1H),7.25 (dd,1H),7.16(t,1H),4.47(dd,1H),3.70(s,3H),3.64(dd,1H),3.56–3 .48(m,1H),3.07(p,1H),2.20(ddd,1H),2.10–1.88(m,3H),1.17(d,6H).

[0554] Example 74

[0555] (R)-N2-(4-(1,3-dioxoisoindol-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide

[0556] first step

[0557] Under nitrogen protection, (R)-1-tert-butyl-2-[(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)carbamoyl]pyrrolidine-1,2-dicarboxylate (1.00 g, 2.40 mmol), 5-bromoisoindoline-1,3-dione (543 mg, 2.40 mmol), potassium carbonate (664 mg, 4.80 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (167 mg, 0.240 mmol) were dissolved in a mixture of dioxane (20 mL) and water (4 mL). The mixture was heated to 90 °C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 97:3) to give compound (R)-1-tert-butyl-2-[(4-(1,3-dioxoisoindoline-5-yl)phenyl)carbamoyl]pyrrolidine-1,2-dicarboxylate (324 mg, 0.744 mmol), yield: 31.0%. MS m / z (ESI): 436.1 [M+H]+.

[0558] Step 2

[0559] At room temperature, dichloromethane (10 mL) and an ethyl acetate solution of hydrogen chloride (4 M, 3 mL) were added sequentially to (R)-1-tert-butyl-2-[(4-(1,3-dioxoisoindoline-5-yl)phenyl)carbamoyl]pyrrolidine-1,2-dicarboxylate (324 mg, 0.744 mmol), and the mixture was stirred for 3 hours. The reaction mixture was poured into a saturated sodium carbonate aqueous solution (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried, and concentrated to give (R)-N-[4-(1,3-dioxoisoindoline-5-yl)phenyl]pyrrolidine-2-carboxamide (176 mg, 0.525 mmol). The product was used directly in the next reaction without purification. MS m / z (ESI): 336.1 [M+H]+.

[0560] Step 3

[0561] Under nitrogen protection, a solution of 3-fluoro-4-isopropylaniline (120.6 mg, 0.787 mmol) and triethylamine (212 mg, 2.10 mmol) in tetrahydrofuran (3.5 mL) was added to a solution of triphosgene (77.9 mg, 0.262 mmol) in tetrahydrofuran (3.5 mL), and the mixture was stirred at 0 °C for 1 hour. Then, (R)-N-[4-(1,3-dioxoisoindoline-5-yl)phenyl]pyrrolidine-2-carboxamide (176 mg, 0.525 mmol) and triethylamine (212 mg, 2.10 mmol) were added sequentially to the above reaction solution, and the mixture was stirred at room temperature for 1 hour. Direct purification by preparative liquid chromatography yielded compound (R)-N2-(4-(1,3-dioxoisoindol-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (21 mg, 0.041 mmol), yield: 7.8%. MS m / z (ESI): 515.2 [M+H]+. 1 H NMR(400MHz,MeOD)δ8.04(dd,J=4.0,2.6Hz,2H),7.87(d,J=8.2Hz,1H),7.77( d,J=8.7Hz,2H),7.70(d,J=8.7Hz,2H),7.27(d,J=13.6,1H),7.19–7.15(m,2H ),4.61(dd,J=8.2,3.5Hz,1H),3.78-3.73(m,1H),3.64-3.58(m,1H),3.16(he pt,J=6.8Hz,1H),2.40–2.27(m,1H),2.24–2.05(m,3H),1.24(d,J=6.9Hz,6H).

[0562] Example 75

[0563] 5-(4-((1S,3R,4R)-2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-3-carbamoyl)phenyl)-6-methylpyridinecarboxylic acid

[0564] first step

[0565] Under nitrogen protection, (1S,3R,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 g, 4.14 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.18 g, 6.22 mmol) and 4-dimethylaminopyridine (101 mg, 0.82 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 1 hour. Then, 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)aniline (0.91 g, 4.14 mmol) was added and stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give tert-butyl(1S,3R,4R)-3-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g), yield: 82.0%. MS m / z (ESI): 443.2 [M+H] + .

[0566] Step 2

[0567] Under nitrogen protection, tert-butyl(1S,3R,4R)-3-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.4 g, 3.16 mmol), 5-bromo-6-methylpyridinecarboxylic acid (676.24 mg, 3.16 mmol), bis(triphenylphosphine)palladium(II) dichloride (221.52 mg, 0.316 mmol) and sodium carbonate (1.3 g, 12.64 mmol) were added. l) was dissolved in 1,4-dioxane (25 mL) and water (5 mL), and heated to 90 °C with stirring for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (2 x 100 mL) were added to the reaction solution for extraction. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 5-(4-((1S,3R,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxamido)phenyl)-6-methylpyridinic acid (0.96 g), yield: 65.0%. MS m / z (ESI): 452.1 [M+H] + .

[0568] Step 3

[0569] At room temperature, 0.96 g (2.05 mmol) of 5-(4-((1S,3R,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxamido)phenyl)-6-methylpyridinecarboxylic acid was dissolved in 10 mL of dichloromethane, and 3 mL of 4 M ethyl acetate hydrochloride solution was slowly added dropwise with stirring. After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, and the product was purified by silica gel column chromatography (elution system A) to give 708.7 mg of 5-(4-((1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxamido)phenyl)-6-methylpyridinecarboxylic acid, yield: 98.5%. MS m / z (ESI): 352.1 [M+H] + .

[0570] Step 4

[0571] At room temperature, 3-fluoro-4-isopropylaniline (100.0 mg, 0.65 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N'-carbonyldiimidazole (126.9 mg, 0.78 mmol) was added with stirring. The reaction was stirred at room temperature for 1 hour, and then a solution of 5-(4-((1S,3R,4R)-2-azabicyclo[2.2.1]heptane-3-carboxamido)phenyl)-6-methylpyridinecarboxylic acid (275.1 mg, 0.78 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. The reaction was stirred at room temperature for another 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 5-(4-((1S,3R,4R)-2-((3-fluoro-4-isopropylphenyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-3-carbamate)phenyl)-6-methylpyridinecarboxylic acid (110 mg), yield: 32.1%. MS m / z (ESI): 531.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.09(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.6 8(d,J=8.2Hz,2H),7.37–7.31(m,1H),7.29(s,1H),7.18(t,J=8.4Hz,1H),7.03(d,J=8.1Hz,1 H),6.43(s,1H),4.20(s,1H),4.10(s,1H),3.18(s,2H),2.56(s,3H),2.06(d,J=10.6Hz,1H), 1.90(d,J=9.5Hz,2H), 1.80(d,J=12.3Hz,1H), 1.62(d,J=10.3Hz,2H), 1.24(d,J=7.0Hz,6H).

[0572] Example 76

[0573] 5-[2-[(2R)-1-[(3-fluoro-4-isopropyl-phenyl)carbamoyl]pyrrolidine-2-yl]-3H-benzimidazol-5-yl]-6-methylpyridine-2-carboxylic acid

[0574] first step

[0575] (tert-Butoxycarbonyl)-D-proline (5 g, 23.23 mmol) was dissolved in tetrahydrofuran (50 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10.52 g, 27.88 mmol) and N,N-diisopropylethylamine (4.50 g, 34.84 mmol, 6.07 mL) were added. After reacting at room temperature for 30 minutes, 4-bromophenyl-1,2-diamine (4.34 g, 23.23 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction was quenched with water, extracted with ethyl acetate, washed with 1N hydrochloric acid, washed with saturated brine, and concentrated to dryness to give (2R)-2-[(2-amino-4-bromophenyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (7.3 g, 19.00 mmol), yield: 81.78%. MS m / z(ESI): 383.2 / 385.4 [M+H] + .

[0576] Step 2

[0577] (2R)-2-[(2-amino-4-bromophenyl)carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (7.3 g, 19.00 mmol) was dissolved in glacial acetic acid (70 mL). The reaction system was heated to 40 °C and reacted for 16 hours. The solvent, glacial acetic acid, was then removed by concentration. The solution was diluted with ethyl acetate, washed with 50 mL of water and 50 mL of saturated brine, concentrated, and the residue was purified by silica gel column chromatography to give (2R)-2-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.6 g, 12.56 mmol), yield: 66.11%. MS m / z (ESI): 365.9 / 368.1 [M+H] + .

[0578] Step 3

[0579] (2R)-2-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.6 g, 12.56 mmol), pinacol diboronate (4.79 g, 18.84 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (911.83 mg, 1.26 mmol), and potassium acetate (2.46 g, 25.12 mmol) were placed in a reaction flask, and dioxane (50 mL) was added. The mixture was purged with nitrogen three times, and the reaction system was carried out at 80 °C for 16 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue purified by silica gel column chromatography (elution system A) to give (2R)-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (3.2 g, 7.74 mmol), yield: 61.64%. MS m / z (ESI): 414.2 [M+H] + .

[0580] Step 4

[0581] (2R)-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (5.3 g, 12.82 mmol), 5-bromo-6-methylpyridinecarboxylic acid (2.77 g, 12.82 mmol), bis(triphenylphosphine)palladium(II) chloride (900.05 mg, 1.28 mmol), and sodium carbonate (5.44 g, 51.29 mmol) were placed in a reaction flask, and dioxane (50 mL) and water (10 mL) were added. The mixture was purged with nitrogen three times, and the reaction system was carried out at 100 °C for 16 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue purified by silica gel column chromatography (elution system A) to give 5-[2-[(2R)-1-tert-butoxycarbonylpyrrolidine-2-yl]-3H-benzimidazol-5-yl]-6-methylpyridine-2-carboxylic acid (3.5 g, 8.28 mmol), yield: 64.61%. MS m / z (ESI): 422.8 [M+H] + .

[0582] Step 5

[0583] 5-[2-[(2R)-1-tert-butoxycarbonylpyrrolidine-2-yl]-3H-benzimidazol-5-yl]-6-methylpyridin-2-carboxylic acid (3.5 g, 8.28 mmol) was dissolved in ethyl acetate (50 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 50 mL) was added. The reaction was carried out at room temperature for 1 hour. A large amount of solid precipitated out. The solid was filtered, washed with methyl tert-butyl ether, and dried to give 6-methyl-5-[2-[(2R)-pyrrolidine-2-yl]-3H-benzimidazol-5-yl]pyridin-2-carboxylic acid (2.0 g, 5.57 mmol), yield: 67.28%. MS m / z (ESI): 323.2 [M+H] +

[0584] Step 6

[0585] Dissolve 3-fluoro-4-isopropylaniline (64.04 mg, 418.04 μmol) and N,N'-carbonyldiimidazole (60.18 mg, 418.04 μmol) in dichloromethane (2 mL). After reacting the system at room temperature for 1 hour, add 6-methyl-5-[2-[(2R)-pyrrolidine-2-yl]-3H-benzimidazol-5-yl]pyridine-2-carboxylic acid (0.15 g, 418.04 μmol, CL) and continue the reaction at this temperature for 2 hours. The reaction solution was quenched with water, extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with water (10 mL), dried, concentrated, and the residue was purified by preparative liquid chromatography to give 5-[2-[(2R)-1-[(3-fluoro-4-isopropyl-phenyl)carbamoyl]pyrrolidine-2-yl]-3H-benzimidazol-5-yl]-6-methylpyridine-2-carboxylic acid (25.8 mg, 51.44 μmol), yield: 12.3%. MS m / z (ESI): 501.8 [M+H] + .1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.50(s,1H),7.94(d,1H),7.79(d,1H),7.58(s,2H),7.42(dd,1H),7.30-7.09( m,3H),5.25(dd,1H),3.79(s,1H),3.60-3.54(m,1H),3.05(q,1H),2.36-2.28(m,1H),2.18-2.01(m,3H),1.17(d,6H).

[0586] Example 77

[0587] (R)-3-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)phenyl)bicyclo[1.1.1]octane-1-carboxylic acid

[0588] first step

[0589] At room temperature, 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.0 g, 5.88 mmol), N-hydroxyphthalimide (1.15 g, 7.06 mmol), and 4-dimethylaminopyridine (72 mg, 0.588 mmol) were dissolved in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through a silica gel pad (50 g), washed with dichloromethane (100 mL), and the filtrate was concentrated to give N-phthalimide-bicyclo[1.1.1]octane-1-carboxylic acid-3-carboxylic acid methyl ester (1.5 g), yield: 81.1%. MS m / z (ESI): 316.1 [M+H]+.

[0590] Step 2

[0591] Under nitrogen protection, N-phthalimide-bicyclo[1.1.1]octane-1-carboxylic acid-3-carboxylic acid methyl ester (950 mg, 3 mmol), N-tert-butoxycarbonyl-4-bromoaniline (545 mg, 2 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (97.6 mg, 0.2 mmol), 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.02 g, 4 mmol) and sodium bicarbonate (337 mg, 4 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 16 hours under a photoluminescence apparatus (violet light 390 nm-395 nm). Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl ((N-tert-butoxycarbonyl)amino)phenyl-bicyclo[1.1.1]octane-1-carboxylic acid (55 mg), yield: 18.8%. MS m / z (ESI): 318.2 [M+H]+.

[0592] Step 3

[0593] Methyl ((N-tert-butoxycarbonyl)amino)phenyl-bicyclo[1.1.1]octane-1-carboxylate) (90 mg, 0.284 mmol) was dissolved in methanol (2 mL) at room temperature, and 1,4-dioxane hydrochloride solution (4 M, 0.7 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was dissolved in methanol. The pH was then adjusted to 8 with saturated sodium bicarbonate solution, and purified by silica gel column chromatography (elution system A) to give methyl 3-(4-aminophenyl)bicyclo[1.1.1]octane-1-carboxylate (38.5 mg), yield: 62.5%. MS m / z (ESI): 218.1 [M+H]+.

[0594] Step 4

[0595] Under nitrogen protection, methyl 3-(4-aminophenyl)bicyclo[1.1.1]octane-1-carboxylate (38.5 mg, 0.177 mmol), intermediate 4-8-b (52.5 mg, 0.177 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40.7 mg, 0.213 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-3-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)phenyl)bicyclo[1.1.1]octane-1-carboxylate (35 mg), yield: 40.0%. MS m / z(ESI): 494.2[M+H]+.

[0596] Step 5

[0597] At room temperature, methyl (R)-3-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)phenyl)bicyclo[1.1.1]octane-1-carboxylate (35 mg, 0.071 mmol) was dissolved in tetrahydrofuran (3 mL), and an aqueous solution of lithium hydroxide (8.5 mg, 0.355 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was then concentrated, and the residue... The substance was dissolved in water (5 mL), the pH was adjusted to about 3 with citric acid aqueous solution, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-3-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)phenyl)bicyclo[1.1.1]octane-1-carboxylic acid methyl ester (12.5 mg), yield: 36.8%. MS m / z(ESI):480.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),9.98(d,1H),8.39(d,1H),7.59-7.50(m,2H),7.40(dt,1H),7.23(dd,2H),7.19-7.11(m,3H),4. 43(dd,1H),3.67-3.58(m,1H),3.54-3.45(m,1H),3.10-3.02(m,1H),2.18(s,6H),2.17-2.10(m,1H),2.05-1.85(m,3H),1.17(d,6H).

[0598] Example 78

[0599] (R)-4-(3-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carboxamide)bicyclo[1.1.1]octane-1-yl)benzoic acid

[0600] first step

[0601] At room temperature, 1-({[(2-methylprop-2-yl)oxy]carbonyl}amino)bicyclo[1.1.1]pentane-3-carboxylic acid (1.0 g, 4.4 mmol), N-hydroxyphthalimide (862 mg, 5.28 mmol), and 4-dimethylaminopyridine (53.8 mg, 0.44 mmol) were dissolved in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through a silica gel pad (50 g), washed with dichloromethane / ethyl acetate (100 mL / 10 mL), and the filtrate was concentrated to give N-phthalimide-3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]octane-1-carboxylic acid ester (1.1 g), yield: 67.1%. MS m / z (ESI): 373.1 [M+H] + .-

[0602] Step 2

[0603] Under nitrogen protection, N-phthalimide-3-((tert-butyloxycarbonyl)amino)bicyclo[1.1.1]octane-1-carboxylic acid ester (1.0 g, 2.69 mmol), methyl 4-bromobenzoate (404 mg, 1.88 mmol), (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-κN1,κN1′]nickel dibromide (261.5 mg, 0.537 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (1.36 g, 5.37 mmol) and sodium bicarbonate (451 mg, 5.37 mmol) were dissolved in N,N-dimethylacetamide (5 mL) and stirred at room temperature for 16 hours under a photoluminescence apparatus (UV light 390 nm-395 nm). Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 4-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]octane-1-benzoate (230 mg), yield: 27%. MS m / z (ESI): 318.2 [M+H] + .

[0604] Step 3

[0605] 4-(3-((tert-Butoxycarbonyl)amino)bicyclo[1.1.1]octane-1-benzoate methyl ester (230 mg, 0.725 mmol) was dissolved in methanol (3 mL) at room temperature, and 1,4-dioxane hydrochloride solution (4 M, 1.8 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued to be stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was dissolved in methanol, and then the pH was adjusted to 8 with saturated sodium bicarbonate solution. The product was then purified by silica gel column chromatography (elution system A) to obtain 4-(3-aminobicyclo[1.1.1]octane-1-yl)benzoate methyl ester (180 mg), yield: 83.2%. MS m / z (ESI): 218.1 [M+H] + .

[0606] Step 4

[0607] Under nitrogen protection, methyl 4-(3-aminobicyclo[1.1.1]octane-1-yl)benzoate (101 mg, 0.34 mmol), intermediate ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (100 mg, 0.34 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.2 mg, 0.407 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-4-(3-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)phenyl)bicyclo[1.1.1]octane-1-yl)benzoate (95 mg), yield: 56.6%. MS m / z (ESI): 494.2 [M+H] + .

[0608] Step 5

[0609] At room temperature, methyl (R)-4-(3-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)phenyl)bicyclo[1.1.1]octane-1-yl)benzoate (95 mg, 0.192 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution of lithium hydroxide (23 mg, 0.96 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour, and the reaction solution was concentrated. The residue was dissolved in water (5 mL), and the pH was adjusted to approximately 3 with citric acid aqueous solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated. The residue was purified by preparative HPLC (formic acid system) to obtain (R)-4-(3-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)tetrahydropyrrole-2-carbamoyl)bicyclo[1.1.1]octane-1-yl)benzoic acid (45 mg), yield: 48.8%. MS m / z (ESI): 480.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.31(s,1H),7.92-7.84(m,2H),7.43(dd,2H),7.38-7.31(m,2H),7.17(t,1H),4.24(dd, 1H),3.63-3.55(m,1H),3.50-3.38(m,1H),3.13-3.02(m,1H),2.18(s,6H),2.10-2.00(m,1H),1.97-1.78(m,3H),1.18(d,6H).

[0610] Example 79

[0611] (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(N-methylaminesulfonyl)-[1,1'-biphenyl]-4-yl)tetrahydropyrrole-1,2-dicarboxamide

[0612] Following the synthesis method of Example 59, the target product (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(N-methylaminesulfonyl)-[1,1'-biphenyl]-4-yl)tetrahydropyrrole-1,2-dicarboxamide was synthesized.

[0613] MS m / z (ESI): 539.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.42(s,1H),7.92-7.85(m,2H),7.85- 7.79(m,2H),7.78-7.69(m,4H),7.50-7.45(m,1H),7.41(dd,1H),7.24(dd,1 H),7.16(t,1H),4.48(dd,1H),3.70-3.60(m,1H),3.57-3.47(m,1H),3.12-3 .00(m,1H),2.43(d,3H),2.25-2.15(m,1H),2.10-1.89(m,3H),1.17(d,6H).

[0614] Example 80

[0615] (R)-N2-(4-(1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)tetrahydropyrrole-1,2-dicarboxamide

[0616] first step

[0617] At room temperature, 3-fluoro-4-isopropylaniline (2.0 g, 13.06 mmol) and triethylamine (1.3 g, 13.06 mmol) were dissolved in acetonitrile (20 mL). N,N'-carbonyldiimidazole (2.3 g, 14.36 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour. The reaction solution was concentrated, and the residue was dissolved in acetonitrile (20 mL). This residue was then added dropwise to a solution of D-proline (1.5 g, 13.06 mmol) and triethylamine (4.0 g, 39.18 mmol) in acetonitrile (30 mL). The reaction was continued with stirring at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phase was dried, and the extract was purified by silica gel column chromatography (elution system A) to give ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (3.5 g), yield: 86.5%. MS m / z(ESI): 295.2[M+H]+.

[0618] Step 2

[0619] ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (500 mg, 1.7 mmol), pinacol 4-aminophenylboronic acid (409 mg, 1.87 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (391 mg, 2.04 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-N1-(3-fluoro-4-isopropylphenyl)N2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)tetrahydropyrrole-1,2-dicarboxamide (720 mg), yield: 78.7%. MS m / z(ESI): 496.3[M+H]+.

[0620] Step 3

[0621] Under nitrogen protection, (R)-N1-(3-fluoro-4-isopropylphenyl)N2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)tetrahydropyrrole-1,2-dicarboxamide (80 mg, 0.161 mmol), 5-bromo-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (52 mg, 0.21 mmol), (1,1”-bis(diphenylphosphino)ferrocene)palladium dichloride (11.8 mg, 0.016 mmol), and potassium carbonate (67 mg, 0.483 mmol) were added. Dissolved in 1,4-dioxane (4 mL) and water (1 mL), the mixture was heated to 90 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 20 mL), the organic phase was dried, concentrated, and the residue was purified by preparative HPLC (formic acid system) to give (R)-N2-(4-(1,1-dioxide-2,3-dihydrobenzo[d]isothiazolyl-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)tetrahydropyrrole-1,2-dicarboxamide (25 mg), yield: 28.9%. MS m / z(ESI):537.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.35(s,1H),7.81-7.72(m,4H),7.72-7.61(m,4H),7.34(dd,1H),7.18(dd,1H),7.09(t,1H ),4.45-4.32(m,3H),3.65-3.52(m,1H),3.50-3.40(m,1H),3.05-2.90(m,1H),2.20-2.08(m,1H),2.00-1.80(m,3H),1.10(d,6H).

[0622] Example 81

[0623] (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)-2,5-dihydro-1H-pyrrolo-2-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid

[0624] Following the synthesis method of Example 59, the target product (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)-2,5-dihydro-1H-pyrrole-2-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid was synthesized.

[0625] MS m / z (ESI): 503.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.49(s,1H),7.93(d,1H),7.79-7.70(m,3H),7.48-7.38(m,3H),7.26(dd,1H),7.18(t,1H),6. 18-6.12(m,1H),5.98-5.92(m,1H),5.24-5.13(m,1H),4.44(dt,1H),4.36-4.28(m,1H),3.12-3.02(m,1H),2.50(s,3H),1.18(d,6H).

[0626] Example 82

[0627] 5-(4-((2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid

[0628] first step

[0629] Under nitrogen protection, 1-tert-butyl-2-methyl(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid ester (300 mg, 1.225 mmol), tetrabutylammonium iodide (5.4 g, 14.68 mmol), potassium iodide (1.6 g, 9.78 mmol), and silver trifluoromethanethiol (230 mg, 0.725 mmol) were dissolved in toluene (15 mL), and the mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain (2R,4R)-1-tert-butyl-2-methyl-4-(trifluoromethylthio)tetrahydropyrrolidine-1,2-dicarboxylic acid ester (160 mg), yield: 39.6%. MS m / z (ESI): 330.1 [M+H]+.

[0630] Step 2

[0631] (2R,4R)-1-tert-butyl-2-methyl-4-(trifluoromethylthio)tetrahydropyrrolidine-1,2-dicarboxylate (160 mg, 0.486 mmol) was dissolved in 1,4-dioxane (5 mL) at room temperature, and 1,4-dioxane hydrochloride solution (4 M, 1.2 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction was continued to be stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was dissolved in methanol, and then the pH was adjusted to 8 with saturated sodium bicarbonate solution. The product was purified by silica gel column chromatography to obtain (2R,4R)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylate (100 mg), yield: 90.1%. MS m / z (ESI): 230.1 [M+H]+.

[0632] Step 3

[0633] At room temperature, 3-fluoro-4-isopropylaniline (66.8 mg, 0.436 mmol) and triethylamine (44 mg, 0.436 mmol) were dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (77.7 mg, 0.48 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour, and the reaction solution was concentrated. The residue was dissolved in acetonitrile (2 mL) and added dropwise to (2R,4R)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylate (100 mg, 0.436 mmol) and triethylamine (132 mg, 1.308 mmol) in acetonitrile (5 mL). The reaction was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to obtain (2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylate (120 mg), yield: 67.4%. MS m / z (ESI): 409.1 [M+H]+.

[0634] Step 4

[0635] At room temperature, (2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylic acid (120 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), and an aqueous solution of lithium hydroxide (34.8 mg, 1.45 mmol) (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to approximately 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated to obtain (2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylic acid (90 mg), yield: 78.9%. MS m / z (ESI): 395.1 [M+H]+.

[0636] Step 5

[0637] (2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carboxylic acid (90 mg, 0.16 mmol), tert-butyl-5-(4-aminophenyl)-6-methylpyridinecarboxylate (45.5 mg, 0.16 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (36.7 mg, 0.19 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography to give 5-(4-(2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester 2-5-f (60 mg), yield: 57.1%. MS m / z (ESI): 661.2 [M+H]+.

[0638] Step 6

[0639] At room temperature, methanesulfonic acid (17.5 mg, 0.18 mmol) was added to a hexafluoroisopropanol solution (2 mL) of 2-5-f (60 mg, 0.09 mmol). The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was suspended in acetonitrile (1 mL) and water (2 mL). The filtered solid was purified by preparative HPLC (formic acid system) to obtain 5-(4-(2R,4R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid 2-5 (21.5 mg), yield: 39.8%. MS m / z(ESI):605.2[M+H]+.1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.63(s,1H),7.93(d,1H),7.79-7.70(m,3H),7.45-7.36(m,3H),7.27-7.15(m,2H),4.57( t,1H),4.23-4.12(m,2H),3.71-3.60(m,1H),3.12-3.02(m,1H),2.84-2.75(m,1H),2.50(s,3H),2.06-1.95(m,1H),1.18(d,6H).

[0640] Example 83

[0641] 5-(4-((2R,4S)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrole-2-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid

[0642] Following the synthesis method of Example 82, the target product 5-(4-(2R,4S)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)-4-(trifluoromethylthio)tetrahydropyrrolidine-2-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid was synthesized.

[0643] MS m / z (ESI): 605.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.62(s,1H),7.93(d,1H),7.79-7.70(m,3H),7.45-7.36(m,3H),7.27-7.15(m,2H),4.64(d d,1H),4.23-4.12(m,2H),3.71-3.60(m,1H),3.12-3.02(m,1H),2.84-2.75(m,1H),2.50(s,3H),2.06-1.95(m,1H),1.17(d,6H).

[0644] Example 84

[0645] (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid

[0646] first step

[0647] Under a nitrogen atmosphere at -78°C, lithium diisopropylamino (18.17 mL, 18.17 mmol) was added to a tetrahydrofuran (100 mL) solution of tert-butyl 4-bromo-2-fluorobenzoate (5.0 g, 18.17 mmol) and stirred for 30 minutes. Ethylene oxide (6.06 mL, 18.17 mmol) was then added, and the mixture was stirred at -78°C for another 30 minutes, followed by a slow increase to 20°C over 4 hours. The reaction mixture was quenched with sodium bicarbonate solution (100 mL), extracted with ethyl acetate (30 mL x 3), dried over dryness, concentrated, and the residue purified by silica gel column chromatography to give tert-butyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate (2.00 g, 6.35 mmol), yield: 35.0%. MS m / z (ESI): 299.0 [M+H] +

[0648] Step 2

[0649] Under a nitrogen atmosphere, tert-butyl 4-bromo-2,3-dihydrobenzofuran-7-carboxylate (1.00 g, 3.34 mmol), pinacol 4-aminophenylboronic acid (732 mg, 3.34 mmol), potassium carbonate (1.39 g, 10.03 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (245 mg, 0.33 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). The nitrogen atmosphere was purged three times, and the reaction system was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over the organic phase, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl 4-(4-aminophenyl)-2,3-dihydrobenzofuran-7-carboxylate (0.82 g, 2.55 mmol), yield: 76.4%. MS m / z (ESI): 312.2 [M+H] +

[0650] Step 3

[0651] 4-(4-aminophenyl)-2,3-dihydrobenzofuran-7-carboxylate tert-butyl ester (200 mg, 0.64 mmol), ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (189 mg, 0.64 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg, 0.71 mmol) were dissolved in dichloromethane (10 mL) and stirred at 20 °C for 6 hours. The reaction solution was concentrated and purified by silica gel column chromatography to give (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylate tert-butyl ester (150 mg, 47% purity, 0.076 mmol), yield: 11.9%. MS m / z (ESI): 588.3 [M+H] + .

[0652] Step 4

[0653] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid tert-butyl ester (150 mg, 47% purity, 0.12 mmol) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 1 hour. The residue obtained by concentration of the reaction solution was purified by preparative HPLC to (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-7-carboxylic acid (37.7 mg, 0.07 mmol), yield: 59.3%. MS m / z (ESI): 532.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.16(s,1H),8.41(s,1H),7.76–7.69(m,2H),7.65(d,J=8.2Hz,1H),7.54–7.48(m,2 H),7.41(dd,J=13.7,2.1Hz,1H),7.24(dd,J=8.5,2.1Hz,1H),7.16(t,J=8.7Hz,1H),6.96(d,J=8.2Hz,1H) ,4.60(t,J=8.7Hz,2H),4.47(dd,J=8.3,3.7Hz,1H),3.70–3.60(m,1H),3.52(q,J=7.3Hz,1H),3.28(t,J= 8.7Hz,2H),3.06(p,J=6.9Hz,1H),2.20(dq,J=11.4,7.9Hz,1H),2.10–1.83(m,3H),1.17(d,J=6.9Hz,6H).

[0654] Example 85

[0655] (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(6-(2,2,2-trifluoroacetamide)pyridin-3-yl)phenyl)pyrrolidine-1,2-dicarboxamide)

[0656] first step

[0657] At room temperature, dichloromethane (30 mL) and an ethyl acetate solution of hydrogen chloride (4 M, 10 mL) were added sequentially to the intermediate (R)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (2.00 g, 4.80 mmol), and the mixture was stirred for 1 hour. The pH of the reaction solution was adjusted to 7–8 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (50 mL × 4). The organic phases were combined, dried, and concentrated to give (R)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)pyrrolidine-2-carboxamide (1.07 g, 3.38 mmol). The product was used directly in the next reaction without purification. MS m / z (ESI): 317.2 [M+H] + .

[0658] Step 2

[0659] Under nitrogen protection, a solution of 3-fluoro-4-isopropylaniline (741 mg, 4.84 mmol) and triethylamine (1.31 g, 12.9 mmol) in tetrahydrofuran (20 mL) was added to a solution of triphosgene (478 mg, 1.61 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at 0 °C for 1 hour. Then, (R)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyrrolidine-2-carboxamide (1.02 g, 3.23 mmol) and triethylamine (1.31 g, 12.9 mmol) were added to the above reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20–67:33) to give compound (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyrrolidine-1,2-dicarboxamide (1.04 g, 2.10 mmol), yield: 65.1%. MS m / z (ESI): 496.3 [M+H] + .

[0660] Step 3

[0661] Under nitrogen protection, (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyrrolidine-1,2-dicarboxamide (400 mg, 0.807 mmol), 2-amino-5-bromopyridine (154 mg, 0.888 mmol), sodium carbonate (171 mg, 1.61 mmol), and bis(triphenylphosphine)palladium dichloride (57 mg, 0.081 mmol) were dissolved in a mixture of dioxane (8 mL) and water (1.6 mL), and the mixture was heated to 80 °C and stirred for 16 hours. The reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 97:3) to give compound (R)-N2-(4-(6-aminopyridin-3-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (184 mg, 0.399 mmol), yield: 49.4%. MS m / z (ESI): 462.2 [M+H] + .

[0662] Step 4

[0663] At room temperature, a solution of (R)-N2-(4-(6-aminopyridin-3-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (164 mg, 0.335 mmol) and diisopropylethylamine (91.9 mg, 0.711 mmol) in tetrahydrofuran (5 mL) was added to trifluoroacetic anhydride (61.6 mg, 0.497 mmol), and the mixture was stirred for 2 hours. The reaction solution was purified by preparative liquid chromatography to give compound (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(6-(2,2,2-trifluoroacetamido)pyridin-3-yl)phenyl)pyrrolidine-1,2-dicarboxamide (21 mg, 0.110 mmol), yield: 31.1%. MS m / z (ESI): 558.1 [M+H] + . 1 HNMR(400MHz,MeOD)δ8.66(s,1H),8.15–8.08(m,2H),7.74(d,J=8.7Hz,2H),7.64(d,J=8.7Hz,2H),7.27(d,J=13.6Hz,1H),7.18-7.14(m,2H),4. 60(dd,J=8.2,3.5Hz,1H),3.80–3.69(m,1H),3.65-3.57(m,1H),3.23–3 .09(m,1H),2.41–2.27(m,1H),2.25–2.01(m,3H),1.24(d,J=6.9Hz,6H).

[0664] Example 86

[0665] (R)-2-(4'-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamoyl)-[1,1'-biphenyl]-4-yl)-2-oxoacetic acid

[0666] first step

[0667] Under nitrogen protection, (R)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.40 mmol), 2-(4-bromophenyl)-2-oxoacetic acid (550 mg, 2.40 mmol), sodium carbonate (1.02 g, 9.60 mmol), and bis(triphenylphosphine)-palladium dichloride (168 mg, 0.24 mmol) were dissolved in a mixture of dioxane (15 mL) and water (3 mL), and the mixture was heated to 95 °C and stirred overnight. The reaction solution was cooled to room temperature, concentrated, and water (50 mL) and ethyl acetate (50 mL) were added. The mixture was separated, and the aqueous phase was washed with ethyl acetate (30 mL × 2). The aqueous phase was adjusted to pH approximately 4 with dilute hydrochloric acid (1M), and then extracted with a mixed solvent of dichloromethane and methanol (20:1, 50 mL × 3). The organic phases were combined, dried, and concentrated to give (R)-2-(4'-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-yl)-2-oxoacetic acid (780 mg), yield: 74.1%. The product was used directly in the next reaction without purification. MS m / z (ESI): 339.1 [M + H-Boc] + .

[0668] Step 2

[0669] (R)-2-(4'-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-yl)-2-oxoacetic acid (780 mg, 1.78 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (2 M, 20 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated to give (R)-2-oxo-2-(4'-(pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-yl)acetic acid dihydrochloride (650 mg), yield: 88.8%. The product was used directly in the next reaction without purification. MS m / z (ESI): 339.1 [M+H] + .

[0670] Step 3

[0671] Triphosgene (36 mg, 0.122 mmol) was dissolved in tetrahydrofuran (2 mL). A tetrahydrofuran solution containing 3-fluoro-4-isopropylaniline (56 mg, 0.365 mmol) and triethylamine (98 mg, 0.972 mmol) was added dropwise under an ice-water bath, and the mixture was stirred for 1 hour. A tetrahydrofuran solution containing (R)-2-oxo-2-(4'-(pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-yl)acetate dihydrochloride (100 mg, 0.243 mmol) and triethylamine (98 mg, 0.972 mmol) was added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative liquid chromatography to give (R)-2-(4'-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-[1,1'-biphenyl]-4-yl)-2-oxoacetic acid (24 mg), yield: 19.1%. MS m / z (ESI): 518.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.41(s,1H),7.95(dd,4H),7.77(s,4H),7.41(d,1H),7.24(d,1H),7.16(t,1H),4.52 –4.44(m,1H),3.69–3.61(m,1H),3.54–3.51(m,1H),3.09–3.02(m,1H),2.24–2.15(m,1H),2.06–1.89(m,3H),1.17(d,6H).

[0672] Example 87

[0673] (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)pyrrolidine-1,2-dicarboxamide

[0674] first step

[0675] Under nitrogen protection, (R)-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.40 mmol), 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (568 mg, 2.64 mmol), sodium carbonate (1.02 g, 9.60 mmol), and bis(triphenylphosphine)palladium dichloride (168 mg, 0.24 mmol) were dissolved in a mixture of dioxane (15 mL) and water (3 mL), and the mixture was heated to 95 °C and stirred overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and ethyl acetate (50 mL), filtered, and the filtrate was separated. The aqueous phase was washed with ethyl acetate (30 mL) and then extracted with a mixture of dichloromethane and methanol (10:1, 50 mL × 2). The organic phases were combined, dried, and concentrated to give crude (R)-2-((4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg), yield: 23.5%. The product was used directly in the next reaction without further purification. MS m / z (ESI): 325.0 [M+H-Boc] + .

[0676] Step 2

[0677] (R)-2-((4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.565 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (2 M, 10 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated to give crude (R)-N-(4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)pyrrolidine-2-carboxamide dihydrochloride (200 mg), yield: 89.0%. The product was used directly in the next reaction without purification. MS m / z (ESI): 325.0 [M+H] + .

[0678] Step 3

[0679] Triphosgene (37 mg, 0.126 mmol) was dissolved in tetrahydrofuran (2 mL). A tetrahydrofuran solution of 3-fluoro-4-isopropylaniline (58 mg, 0.377 mmol) and triethylamine (102 mg, 1.00 mmol) in 2 mL was added dropwise under an ice-water bath, and the mixture was stirred for 1 hour under an ice-water bath. A tetrahydrofuran solution of (R)-N-(4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)pyrrolidine-2-carboxamide dihydrochloride (100 mg, 0.252 mmol) and triethylamine (102 mg, 1.00 mmol) in 2 mL was added dropwise under an ice-water bath, and the mixture was stirred for 1 hour at room temperature. The reaction solution was purified by preparative liquid chromatography to give (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)phenyl)pyrrolidine-1,2-dicarboxamide (18 mg), yield: 14.2%. MS m / z (ESI): 504.1 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.28(s,1H),7.79(s,1H),7.72(d,2H),7.58(d,2H),7.27(d,1H),7.20–7.12(m,2H),4.64–4.57 (m,1H),3.79–3.70(m,1H),3.65–3.57(m,1H),3.20–3.09(m,1H),2.39–2.26(m,1H),2.22–2.04(m,3H),1.24(d,6H).

[0680] Example 88

[0681] 5-(4-(7-((3-fluoro-4-isopropylphenyl)carbamoyl)-7-azabicyclo[2.2.1]heptane-1-carbamoyl)phenyl)-6-methylpyridine-2-carboxylic acid

[0682] Following the synthetic method of Example 59, the target product 5-(4-(7-((3-fluoro-4-isopropylphenyl)carbamoyl)-7-azabicyclo[2.2.1]heptane-1-carbamate)phenyl)-6-methylpyridine-2-carboxylic acid was synthesized. MS m / z (ESI): 531.2 [M+H] + . 1HNMR (400MHz, DMSO) δ9.54(s,1H),9.13(s,1H),7.93(d,J=7.9Hz,1H),7.87–7.79(m,2H),7.76(d,J=7.9Hz,1H),7.42–7.32(m,3H),7.18(d,J=7.4H z,2H),4.64(t,J=4.6Hz,1H),3.06(p,J=6.9Hz,1H),2.17(t,J=10.8Hz,2H ),1.96–1.73(m,4H),1.61(td,J=10.5,3.9Hz,2H),1.17(d,J=6.9Hz,6H).

[0683] Example 89

[0684] 4'-((R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid

[0685] first step

[0686] Under nitrogen protection, tert-butyl carbamate (500 mg, 1.55 mmol), methyl 4-bromobenzoate (399.17 mg, 1.86 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (113.18 mg, 0.15 mmol), and potassium phosphate (985.04 mg, 4.64 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), and the mixture was heated to 90 °C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and water (15 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 30 mL), the organic phase was dried, and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution system A) to give methyl 4'-((tert-butoxycarbonyl)amino)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (450 mg), yield: 86.5%. MS m / z (ESI): 276.1 [M-(t-Bu)+H] + .

[0687] Step 2

[0688] Methyl 4'-((tert-Butoxycarbonyl)amino)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (250 mg, 0.74 mmol) was dissolved in dichloromethane (3.0 mL) under ice bath conditions. Trifluoroacetic acid (1.0 mL, 12.87 mmol) was slowly added dropwise with stirring, and the mixture was brought to room temperature and stirred for 16 hours. The pH of the reaction mixture was adjusted to approximately 8 by adding saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (2 x 30 mL), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 4'-amino-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (140 mg), yield: 80.6%. MS m / z (ESI): 232.3 [M+H] + .

[0689] Step 3

[0690] Under nitrogen protection, methyl 4'-amino-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (70 mg, 0.30 mmol), ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (88.12 mg, 0.30 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (68.88 mg, 0.36 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 4'-((R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (120 mg), yield: 68.2%. MS m / z (ESI): 508.4 [M+H] + .

[0691] Step 4

[0692] At room temperature, methyl 4'-((R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (120 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (19.55 mg, 0.82 mmol) was added with stirring, and the reaction was stirred at room temperature for 6 hours. The reaction solution was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain 4'-((R)-1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (23 mg), yield: 21.8%. MS m / z (ESI): 494.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.28(s,1H),7.86(d,2H,J=8.5Hz),7.80(d,1H,J=7.8Hz),7.52 (d,2H,J=8.4Hz),7.40(dd,1H,J=1.9,13.6Hz),7.21(dd,1H,J=2.0,8.5Hz),7.13(t,1H,J=8.7Hz),6.2 4(m,1H),4.30(dd,1H,J=3.1,8.1Hz),3.87(m,1H),3.58(dt,1H,J=4.5,8.2Hz),3.4-3.5(m,1H),3.07( q,1H,J=6.9Hz),2.43(m,2H),2.0-2.2(m,2H),1.8-2.0(m,5H),1.6-1.7(m,1H),1.18(d,6H,J=6.9Hz).

[0693] Example 90

[0694] (2R)-N1-(3-fluoro-4-isopropyl-phenyl)-N2-[4-[4-(methoxycarbamoyl)phenyl]phenyl]pyrrolidine-1,2-dicarboxamide

[0695] first step

[0696] At room temperature, (2R)-N1-(3-fluoro-4-isopropyl-phenyl)-N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]pyrrolidine-1,2-dicarboxamide (50 mg, 100.93 μmol), 4-bromo-N-methoxybenzamide (23.22 mg, 100.93 μmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (7.39 mg, 10.09 μmol), and potassium carbonate (27.90 mg, 201.86 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) under nitrogen protection and heated and stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was poured into water, extracted with EA (2 x 10 mL), the organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by preparative HPLC (formic acid system) to obtain (2R)-N1-(3-fluoro-4-isopropyl-phenyl)-N2-[4-[4-(methoxycarbamoyl)phenyl]phenyl]pyrrolidine-1,2-dicarboxamide (15 mg), yield: 28.4%. MS m / z (ESI): 519.5 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.76(s,1H),10.14(s,1H),8.40(s,1H),7.82(d,J=8.5Hz,2H),7.79– 7.66(m,6H),7.41(dd,J=13.7,2.1Hz,1H),7.24(dd,J=8.5,2.1Hz,1H),7.16(t,J=8.6Hz,1H ),4.47(dd,J=8.3,3.7Hz,1H),3.72(s,3H),3.64(t,J=7.5Hz,1H),3.52(q,J=7.6Hz,1H),3. 06(p,J=6.9Hz,1H),2.20(dq,J=11.6,8.0Hz,1H),2.08–1.89(m,3H),1.17(d,J=6.9Hz,6H).

[0697] Example 91

[0698] (R)-N2-(4-(3,3-difluoro-2-oxoindololin-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide

[0699] first step

[0700] Under nitrogen protection, the starting materials 5-bromoindolin-2-one (4.84 g, 22.8 mmol), pinacol 4-aminophenylboronic acid (5.00 g, 22.8 mmol), potassium carbonate (3.83 g, 45.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.67 g, 2.28 mmol) were dissolved in a mixture of dioxane (66 mL) and water (33 mL). The mixture was heated to 100 °C and stirred for 15 hours. The reaction solution was cooled, concentrated, and the residue was purified by reversed-phase column chromatography (acetonitrile:water = 25:75–100:0) to give compound 5-(4-aminophenyl)indolin-2-one (2.50 g, 11.2 mmol), yield: 48.9%. MS m / z (ESI): 225.1 [M+H] + .

[0701] Step 2

[0702] At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (313 mg, 1.63 mmol) was added to a tetrahydrofuran (8 mL) solution of (2R)-1-[(3-fluoro-4-isopropyl-phenyl)carbamoyl]pyrrolidine-2-carboxylic acid (400 mg, 1.36 mmol) and stirred for 0.5 h. Then, 5-(4-aminophenyl)indol-2-one (425 mg, 1.63 mmol) and diisopropylethylamine (351 mg, 2.72 mmol) were added sequentially to the reaction solution, and stirring was continued at room temperature for 20 h. The reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 98:2–95:5) to give compound (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(2-oxoindoline-5-yl)phenyl)pyrrolidine-1,2-dicarboxamide (439 mg, 0.877 mmol), yield: 64.5%. MS m / z (ESI): 501.2 [M+H] + .

[0703] Step 3

[0704] (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(2-oxoindoline-5-yl)phenyl)pyrrolidine-1,2-dicarboxamide (367 mg, 0.733 mmol) and selenium dioxide (203 mg, 1.83 mmol) were added to dimethyl sulfoxide (9 mL), and the mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was poured into water (70 mL), filtered, and the filter cake was washed with water (20 mL). The filter cake was dried to give crude (R)-N2-(4-(2,3-dioxoindoline-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (361 mg, 0.702 mmol), yield: 95.7%. MS m / z (ESI): 515.2 [M+H] + .

[0705] Step 4

[0706] Under nitrogen protection, diethylaminosulfur trifluoride (748 mg, 4.64 mmol) was added to a solution of (R)-N2-(4-(2,3-dioxoindoline-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (341 mg, 0.663 mmol) in dichloromethane (13 mL) at room temperature, and stirred at room temperature for 1.5 hours. The solution was quenched at 0°C with methanol (2 mL), poured into a saturated sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (20 mL × 2). The organic phases were combined, concentrated, and the residue was dissolved in N,N-dimethylformamide (5 mL). The solution was purified by preparative liquid chromatography to give compound (R)-N2-(4-(3,3-difluoro-2-oxoindoline-5-yl)phenyl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (11.7 mg, 0.022 mmol), yield: 3.3%. MS m / z (ESI): 537.1 [M+H] + . 1 H NMR (400MHz, MeOD) δ10.06(s,1H),8.32(s,1H),7.82(d,J=1.4Hz,1H),7.77(d,J=8.8 Hz,1H),7.73–7.67(m,2H),7.62–7.57(m,2H),7.31–7.24(m,1H),7.19–7.15(m,2H), 7.06(d,J=8.2Hz,1H),4.59(dd,J=8.2,3.6Hz,1H),3.79-3.72(m,1H),3.65–3.56(m, 1H),3.20–3.12(m,1H),2.40–2.30(m,1H),2.24–2.09(m,3H),1.24(d,J=6.9Hz,6H).

[0707] Example 92

[0708] (R)-1-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)piperidine-4-carboxylic acid

[0709] first step

[0710] At room temperature, methyl 4-piperidinecarboxylate (1.43 g, 9.99 mmol) and 4-fluoronitrobenzene (1.55 g, 10.99 mmol) were dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (3.45 g, 24.97 mmol) was added with stirring, and the mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (30 mL) was added to the reaction solution. Ethyl acetate (2 x 50 mL) was added for extraction. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give methyl 1-(4-nitrophenyl)piperidine-4-carboxylic acid (2.5 g), yield: 76.1%. MS m / z (ESI): 265.1 [M+H] + .

[0711] Step 2

[0712] 1-(4-nitrophenyl)piperidine-4-carboxylic acid methyl ester (550 mg, 1.67 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. 10% palladium on carbon (266.93 mg, 2.51 mmol) was added with stirring, followed by hydrogen purging. The reaction was stirred at room temperature for 12 hours. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate (2 x 30 mL), dried over the organic phase, concentrated, and the residue purified by silica gel column chromatography (elution system A) to obtain 1-(4-aminophenyl)piperidine-4-carboxylic acid methyl ester (400 mg), yield: 97.6%. MS m / z (ESI): 235.2 [M+H] + .

[0713] Step 3

[0714] Under nitrogen protection, methyl 1-(4-aminophenyl)piperidin-4-carboxylate (70 mg, 0.29 mmol), ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (84.07 mg, 0.29 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (65.71 mg, 0.34 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-4-(4-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclohexane-1-carboxylate (120 mg), yield: 77.5%. MS m / z (ESI): 511.4 [M+H] + .

[0715] Step 4

[0716] Methyl (R)-4-(4-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)cyclohexane-1-carboxylic acid (110 mg, 0.20 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL) at room temperature. Lithium hydroxide (19.01 mg, 0.80 mmol) was added with stirring, and the reaction was carried out at room temperature for 6 hours. The reaction solution was concentrated, and the residue was dissolved in water (5 mL). The pH was adjusted to 3 with citric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried and concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-1-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)piperidine-4-carboxylic acid (40 mg), yield: 41.5%. MS m / z(ESI): 494.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.23(br s,1H),9.73(s,1H),8.36(s,1H),7.43(d,2H,J=9.2Hz),7.39(dd,1H,J=2.0,8.4Hz),7.23( dd,1H,J=2.0,8.4Hz),7.15(t,1H,J=8.6Hz),6.87(d,2H,J=9.0Hz),4.41(dd,1H,J=3.6,8.2 Hz),3.66-3.58(m,1H),3.65-3.44(m,3H),3.06(q,1H,J=6.8Hz),2.71-2.62(m,2H),2.40-2 .30(m,1H),2.20-2.09(m,1H),2.06-1.84(m,5H),1.70-1.57(m,2H),1.17(d,6H,J=7.0Hz).

[0717] Example 93

[0718] (R)-5-(6-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid

[0719] first step

[0720] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridine-2-amine (1.10 g, 5.00 mmol), N-tert-butoxycarbonyl-D-proline (1.18 g, 5.50 mmol), and N-methylimidazolium (821 mg, 10.00 mmol) were dissolved in acetonitrile (20 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.68 g, 6.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography to give (R)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.76 g), yield: 84.4%. MS m / z (ESI): 335.9 [M+H-82] + .

[0721] Step 2

[0722] Under nitrogen protection, (R)-2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.40 mmol), 5-bromo-1,3-thiazolyl-2-carboxylic acid (498 mg, 2.40 mmol), sodium carbonate (1.02 g, 9.60 mmol), and bis(triphenylphosphine)palladium dichloride (168 mg, 0.24 mmol) were dissolved in a mixture of dioxane (15 mL) and water (3 mL), and the mixture was heated to 95 °C and stirred overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL) and ethyl acetate (50 mL). The mixture was separated, and the aqueous phase was washed with ethyl acetate (50 mL × 2). The aqueous phase was adjusted to pH approximately 5 with dilute hydrochloric acid (1M), and then extracted with a mixed solvent of dichloromethane and methanol (10:1, 50 mL × 3). The organic phases were combined, dried, and concentrated to give crude (R)-5-(6-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid (540 mg), yield: 53.8%. The product was used directly in the next reaction without purification. MS m / z (ESI): 419.1 [M+H] + .

[0723] Step 3

[0724] (R)-5-(6-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid (540 mg, 1.29 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (2 M, 12 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated to give crude (R)-5-(6-(pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid dihydrochloride (440 mg), yield: 86.8%. The product was used directly in the next reaction without purification. MS m / z (ESI): 319.1 [M+H] + .

[0725] Step 4

[0726] Triphosgene (38 mg, 0.128 mmol) was dissolved in tetrahydrofuran (2 mL). A solution of 3-fluoro-4-isopropylaniline (59 mg, 0.384 mmol) and triethylamine (104 mg, 1.02 mmol) in tetrahydrofuran (2 mL) was added dropwise under an ice-water bath, and the mixture was stirred for 1 hour under an ice-water bath. A solution of (R)-5-(6-(pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid dihydrochloride (100 mg, 0.256 mmol) and triethylamine (104 mg, 1.02 mmol) in tetrahydrofuran (2 mL) was added dropwise under an ice-water bath, and the mixture was brought to room temperature and stirred for 1 hour. The reaction solution was purified by preparative liquid chromatography to give (R)-5-(6-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)pyridin-3-yl)thiazolyl-2-carboxylic acid (3.0 mg), yield: 2.3%. MS m / z (ESI): 498.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.66(d,1H),8.32–8.18(m,2H),8.11(dd,1H),7.27(d,1H),7.20–7.14(m,2H),4.67(d,1H ),3.79–3.72(m,1H),3.65–3.57(m,1H),3.21–3.09(m,1H),2.39–2.26(m,1H),2.21–2.06(m,3H),1.24(d,6H).

[0727] Example 94

[0728] (R)-(4'-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamide)-[1,1'-biphenyl]-4-yl)boronic acid

[0729] first step

[0730] At room temperature, ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (500 mg, 1.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (482 mg, 2.5 mmol) were dissolved in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 1 hour, and then 4-aminophenylboronic acid pinacol ester (409 mg, 1.9 mmol) was added. The reaction mixture was stirred at room temperature for another 5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to give (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)pyrrolidine-1,2-dicarboxamide (380 mg), yield: 45.1%. MS m / z(ESI): 496.2[M+H]+.

[0731] Step 2

[0732] Under nitrogen protection, (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)pyrrolidine-1,2-dicarboxamide (100 mg, 0.201 mmol), 1,4-dibromobenzene (56 mg, 0.24 mmol), sodium carbonate (64 mg, 0.604 mmol), and bis(triphenylphosphine)palladium dichloride (7 mg, 0.01 mmol) were dissolved in 1,4-dioxane:water = 5:1 (10 mL), and the reaction was heated to 90 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give (R)-N2-(4'-bromo-[1,1'-biphenyl]-4-yl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (64 mg), yield: 60.9%. MS m / z (ESI): 524.1 [M+H]+.

[0733] Step 3

[0734] Under nitrogen protection, (R)-N2-(4'-bromo-[1,1'-biphenyl]-4-yl)-N1-(3-fluoro-4-isopropylphenyl)pyrrolidine-1,2-dicarboxamide (50 mg, 0.096 mmol), pinacol diboronate (36.5 mg, 0.14 mmol), potassium acetate (28 mg, 0.29 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8 mg, 0.01 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and water (5 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (2 x 10 mL). The organic phase was washed with saturated brine (2 x 5 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-1,2-dicarboxamide (32 mg), yield: 58.1%. MS m / z (ESI): 572.1 [M+H]+.

[0735] Step 4

[0736] At room temperature, (R)-N1-(3-fluoro-4-isopropylphenyl)-N2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)pyrrolidine-1,2-dicarboxamide (50 mg, 0.087 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (2 mL), and sodium periodate (224 mg, 1.05 mmol) was added with stirring. The reaction was stirred at room temperature for half an hour, and hydrochloric acid (0.26 mL, 1 M) was added. The reaction was continued to be stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phase was dried and purified by silica gel column chromatography to obtain ((R)-(4'-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamide)-[1,1'-biphenyl]-4-yl)boronic acid (22 mg), yield: 51.1%. MS m / z (ESI): 490.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.41(s,1H),8.06(s,2H),7.85(d,2H),7.71(d,2H),7.63(dd,4H),7.41(dd,1H),7.24( dd,1H),7.16(t,1H),4.47(dd,1H),3.64(d,1H),3.51(q,1H),3.12–3.01(m,1H),2.25–2.13(m,1H),1.95(q,3H),1.17(d,6H).

[0737] Example 95

[0738] (R)-4-(2,2-difluoro-7-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)benzo[d][1,3]dioxacyclopenten-4-yl)benzoic acid

[0739] first step

[0740] 2,2-Difluoro-1,3-benzodioxo-4-amine (4 g, 23.11 mmol) was dissolved in acetonitrile (5 mL) and added to a 100 mL single-necked flask. N-bromosuccinimide (4.11 g, 23.11 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 hours. The solvent was removed by vacuum concentration, diluted with ethyl acetate, washed with water and saturated brine, the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give 7-bromo-2,2-difluoro-1,3-benzodioxo-4-amine (5.1 g, 20.24 mmol, yield: 87.58%). MS m / z (ESI): 293.1 / 295.2 [M+H]+.

[0741] Step 2

[0742] 7-Bromo-2,2-difluoro-1,3-benzodioxo-4-amine (1 g, 3.97 mmol), (2R)-1-[(3-fluoro-4-isopropyl-phenyl)carbamoyl]pyrrolidine-2-carboxylic acid (1.17 g, 3.97 mmol), and N,N-diisopropylethylamine (1.54 g, 11.90 mmol, 2.07 mL) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.25 g, 5.95 mmol) were added. The reaction system was reacted at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give (2R)-N2-(7-bromo-2,2-difluoro-1,3-benzodioxo-4-yl)-N1-(3-fluoro-4-isopropyl-phenyl)pyrrolidine-1,2-dicarboxamide (1.3 g, 2.46 mmol), yield: 62.01%. MS m / z (ESI): 528.8 [M+H]+

[0743] Step 3

[0744] ((2R)-N2-(7-bromo-2,2-difluoro-1,3-benzodioxo-4-yl)-N1-(3-fluoro-4-isopropyl-phenyl)pyrrolidine-1,2-dicarboxamide (200 mg, 378.56 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoic acid (93.91 mg, 378.56 μmol), bis(triphenylphosphine)palladium(II) chloride (13.27 mg, 18.93 μmol), and sodium carbonate (160.51 mg, 1.51 mmol) were placed in a reaction flask, and dioxane (5 mL) and water were added. (1 mL), nitrogen purged three times, the reaction system was reacted at 100 °C for 16 hours. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-4-(2,2-difluoro-7-(1-(3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)benzo[d][1,3]dioxane-4-yl)benzoic acid (20 mg, 35.12 μmol), yield: 7.49%. MS m / z(ESI):569.8[M+H]+.1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.50(s,1H),8.10-8.02(m,2H),7.84-7.77(m,2H),7.73(d,1H),7.53(d,1H),7.42(dd,1H),7.25(dd, 1H),7.17(t,1H),4.64(dd,1H),7.70-3.63(m,1H),3.55-3.49(m,1H), 3.12-3.02(m,1H),2.28-2.18(m,1H),2.06-1.91(m,3H),1.18(d,6H).

[0745] Example 96

[0746] (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)isoindoline-1-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid

[0747] first step

[0748] (R)-2-(tert-Butoxycarbonyl)isoindoline-1-carboxylic acid (90 mg, 0.34 mmol), tert-butyl 5-(4-aminophenyl)-6-methylpyridin-2-carboxylate (97 mg, 0.34 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-1-((4-(6-(tert-Butoxycarbonyl)-2-methylpyridin-3-yl)phenyl)carboxamide)isoindoline-2-pyridincarboxylate tert-butyl ester (80 mg), yield: 44.2%. MS m / z (ESI): 530.3 [M+H] + .

[0749] Step 2

[0750] At room temperature, (R)-1-((4-(6-(tert-butoxycarbonyl)-2-methylpyridin-3-yl)phenyl)carboxamide)isoindoline-2-pyridinecarboxylic acid tert-butyl ester (20 mg, 0.038 mmol) was dissolved in 1,4-dioxane (0.5 mL), followed by the addition of 1,4-dioxane hydrochloride solution (4 M, 0.5 mL). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was pumped dry and used directly in the next step. MS m / z (ESI): 430.2 [M+H] + .

[0751] Step 3

[0752] At room temperature, 3-fluoro-4-isopropylaniline (7 mg, 0.046 mmol) was dissolved in acetonitrile (1 mL), and N,N'-carbonyldiimidazole (8.2 mg, 0.05 mmol) was added with stirring. The mixture was stirred at room temperature for half an hour, and the reaction solution was concentrated. The residue was dissolved in acetonitrile (1 mL). This solution was added dropwise to (R)-5-(4-(isoindoline-1-carboxamide)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl hydrochloride (20 mg, 0.043 mmol) and N-methylmorpholine (17 mg, 0.17 mmol) in acetonitrile (1 mL). The reaction was continued with stirring at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phase was dried and purified by silica gel column chromatography (elution system A) to obtain (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)isoindoline-1-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid tert-butyl ester (20 mg), yield: 78.4%. MS m / z (ESI): 609.2 [M+H] + .

[0753] Step 4

[0754] At room temperature, tert-butyl (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)isoindoline-1-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid (tert-butyl ester) (20 mg, 0.033 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 3 hours, concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(2-((3-fluoro-4-isopropylphenyl)carbamoyl)isoindoline-1-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid (12 mg), yield: 63.6%. MS m / z (ESI): 553.2 [M+H] + . 1H NMR(400MHz,MeOD)δ8.05(d,J=7.9Hz,1H),7.84(d,J=7.8Hz,1H),7.75(d,J=8 .6Hz,2H),7.51(d,J=7.4Hz,1H),7.46–7.34(m,5H),7.31(dd,J=13.1,1.8Hz, 1H),7.25–7.15(m,2H),5.76(d,J=2.7Hz,1H),5.10(dd,J=13.3,2.9Hz,1H),4 .92(d,J=13.2Hz,1H),3.20–3.13(m,1H),2.57(s,3H),1.24(d,J=6.9Hz,6H).

[0755] Example 97

[0756] (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)(methyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridinecarboxylic acid

[0757] first step

[0758] At room temperature, 4-bromo-3-fluoro-N-methylaniline (1000 mg, 4.90 mmol), pinacol isopropenylborate (990 mg, 5.88 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (200 mg, 0.25 mmol), and potassium carbonate (1.35 g, 9.80 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL). The mixture was heated to 90 °C and stirred for 5 hours under nitrogen protection. The solvent was removed by vacuum concentration. The residue was extracted with water and ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography to give 3-fluoro-4-isopropenyl-N-methylaniline (700 mg), yield: 86.5%. MS m / z (ESI): 166.2 [M+H]+.

[0759] Step 2

[0760] 3-Fluoro-4-isopropenyl-N-methylaniline (700 mg, 4.24 mmol) was dissolved in methanol (8 mL) at room temperature, and wetted palladium on carbon (10%, 100 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen balloon. The solution was filtered, concentrated, and the residue was purified by silica gel column chromatography to give 3-fluoro-4-isopropyl-N-methylaniline (470 mg, yield: 66.3%). MS m / z (ESI): 168.2 [M+H]+.

[0761] Step 3

[0762] N-Boc-D-proline (380 mg, 1.77 mmol), tert-butyl 5-(4-aminophenyl)-6-methylpyridinecarboxylate (500 mg, 1.77 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (406 mg, 2.12 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography to give (R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridinecarboxylate (675 mg), yield: 79.4%. MS m / z (ESI): 482.3 [M+H]+.

[0763] Step 4

[0764] At room temperature, (R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridinecarboxylate tert-butyl ester (200 mg, 0.42 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 1,4-dioxane hydrochloride solution (4 M, 2 mL). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was pumped dry and used directly in the next step. MS m / z (ESI): 326.2 [M+H]+.

[0765] Step 5

[0766] Under ice bath conditions, a solution of triphosgene (30 mg, 0.1 mmol) in dichloromethane (1 mL) was added to a 2 mL solution of 3-fluoro-4-isopropyl-N-methylaniline (50 mg, 0.3 mmol) in dichloromethane. The mixture was stirred under ice bath conditions for 10 minutes. Then, this solution was added dropwise to a 4 mL solution of (R)-6-methyl-5-(4-(pyrrolidine-2-carbamoyl)phenyl)pyridinecarboxylate (110 mg, 0.3 mol) and N-methylmorpholine (90 mg, 0.9 mmol) in dichloromethane. The mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (2 x 10 mL). The organic phase was dried, concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)(methyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)-6-methylpyridinecarboxylic acid, yield: 3.2%. MS m / z (ESI): 519.4 [M+H]+; 1H NMR (400MHz, MeOD) δ8.07(d,J=7.9Hz,1H),7.87(d,J=7.8Hz,1H),7.75(d,J= 8.4Hz,2H),7.39(d,J=8.3Hz,2H),7.30(t,J=8.4Hz,1H),7.12(ddd,J=14.0, 11.2,2.3Hz,2H),4.49(t,J=7.3Hz,1H),3.18(s,5H),2.92–2.83(m,1H),2.5 9(s,3H),2.33–2.23(m,1H),1.94–1.71(m,3H),1.25(dd,J=7.0,1.4Hz,6H).

[0767] Example 98

[0768] (R)-5-(4-(1-((3-fluoro-4-3-fluoro-4-isopropylphenyl)carbamoyl)indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid

[0769] first step

[0770] (R)-indoline-2-carboxylic acid (150 mg, 0.92 mmol), tert-butyl 5-(4-aminophenyl)-6-methylpyridine-2-carboxylate (262 mg, 0.92 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (211 mg, 1.1 mmol) were dissolved in dichloromethane (6 mL) and stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phase was dried, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-5-(4-(indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylate tert-butyl ester (160 mg). Yield: 40.5%. MS m / z (ESI): 430.2 [M+H] + .

[0771] Step 2

[0772] Under ice bath conditions, a solution of triphosgene (19 mg, 0.064 mmol) in dichloromethane (0.5 mL) was added to a solution of 3-fluoro-4-isopropylaniline (32 mg, 0.21 mmol) in dichloromethane (1 mL). The mixture was stirred under ice bath conditions for 10 minutes. Then, this solution was added dropwise to a solution of (R)-5-(4-(indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylate tert-butyl ester (160 mg) (80 mg, 0.19 mol) and N-methylmorpholine (57 mg, 0.56 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 16 hours. Add saturated ammonium chloride solution (10 mL) to the reaction mixture, extract with dichloromethane (2 x 10 mL), dry the organic phase, concentrate, and precipitate the residue by silica gel column chromatography (elution system A): (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid tert-butyl ester (50 mg), yield: 44.1%. MS m / z (ESI): 609.4 [M+H] + .

[0773] Step 3

[0774] At room temperature, tert-butyl (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid (50 mg, 0.082 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 3 hours, concentrated, and the residue was purified by preparative HPLC (formic acid system) to obtain (R)-5-(4-(1-((3-fluoro-4-3-fluoro-4-isopropylphenyl)carbamoyl)indoline-2-carboxamide)phenyl)-6-methyl-2-pyridinecarboxylic acid (21 mg), 46.3%, MS m / z (ESI): 553.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.38(s,1H),8.97(s,1H),7.91(d,J=7.9Hz,1H),7.79–7.64(m,4H),7.46–7.29(m,3H),7.28–7.12(m,4H),6.94(t,J=7. 4Hz,1H),5.31(d,J=10.8Hz,1H),3.63(dd,J=16.8,10.8Hz,1H),3.25–3.19(m,1H),3.08(q,J=7.0Hz,1H),2.49(s,3H),1.18(d,J=6.9Hz,6H).

[0775] Example 99

[0776] (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamoyl)-2,3-dihydrobenzofuran-7-yl)benzoic acid

[0777] first step

[0778] At 0 °C, N-bromosuccinimide (1.32 g, 7.40 mmol) was added to a solution of 2,3-dihydrobenzofuran-4-amine (1.00 g, 7.40 mmol) in dichloromethane (20 mL), and the mixture was stirred for 2 hours. After concentration, the residue was purified by silica gel column chromatography to give the product 7-bromo-2,3-dihydrobenzofuran-4-amine (1.00 g, 4.53 mmol), yield: 61.2%. MS m / z (ESI): 214.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.15(dd,J=8.4,0.9Hz,1H),6.16(d,J=8.5Hz,1H),4.60(t,J=8.7Hz,2H),3.96(s,2H),3.03(t,J=8.7Hz,2H).

[0779] Step 2

[0780] Under a nitrogen atmosphere, 7-bromo-2,3-dihydrobenzofuran-4-amine (1.00 g, 4.53 mmol), 4-tert-butoxycarbonylphenylboronic acid (1.04 g, 4.67 mmol), potassium carbonate (1.29 g, 9.34 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (342 mg, 0.47 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL). The nitrogen atmosphere was purged three times, and the reaction system was stirred at 90 °C for 16 hours. The reaction was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over the organic phase, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl 4-(4-amino-2,3-dihydrobenzofuran-7-yl)benzoate (802 mg, 2.58 mmol), yield: 55.1%. MS m / z (ESI): 312.2 [M+H] +

[0781] Step 3

[0782] At 0°C, phosphorus oxychloride (591 mg, 3.81 mmol) was added to a solution of tert-butyl 4-(4-amino-2,3-dihydrobenzofuran-7-yl)benzoate (200 mg, 0.64 mmol), ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (189 mg, 0.64 mmol) and pyridine (406 mg, 5.14 mmol) in N,N-dimethylacetamide (5 mL). After stirring for 5 minutes, the reaction was raised to 20°C and stirred for 2 hours. Quenching with sodium bicarbonate solution (20 mL), extraction with ethyl acetate (20 mL x 3), drying the organic phase, concentrating, and purifying the residue by silica gel column chromatography to give (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)-2,3-dihydrobenzofuran-7-yl)tert-butyl benzoate (100 mg, 60% purity, 0.10 mmol), yield: 15.9%. MS m / z (ESI): 588.3 [M+H] + .

[0783] Step 4

[0784] At room temperature, trifluoroacetic acid (5 mL) was added to a solution of (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamoyl)-2,3-dihydrobenzofuran-7-yl)benzoate (100 mg, 60% purity, 0.10 mmol) in dichloromethane (5 mL), and the reaction was stirred at room temperature for 1 hour. The residue obtained by concentration of the reaction solution was purified by preparative HPLC to (R)-4-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carbamoyl)-2,3-dihydrobenzofuran-7-yl)benzoic acid (20.4 mg, 0.038 mmol), yield: 37.2%. MS m / z (ESI): 532.2 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.44(s,1H),8.24(s,1H),7.90–7.83(m,2H),7.44–7.36(m,2H),7.33 (dd,J=13.6,2.1Hz,1H),7.18(dd,J=8.5,2.2Hz,1H),7.14–7.04(m,2H),6.71(d,J=8.2Hz, 1H),4.57–4.42(m,2H),4.28(dd,J=8.5,3.2Hz,1H),3.55–3.40(m,1H),3.35(dt,J=9.1,7 .2Hz,1H),3.07–2.88(m,3H),2.03–1.90(m,1H),1.90–1.66(m,3H),1.11(d,J=6.9Hz,6H).

[0785] Example 100

[0786] (R)-5-(5-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrole-2-carboxamido)bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid

[0787] first step

[0788] Dibromobicyclo[4.2.0]octyl-1(6),2,4-triene (520 mg, 1.99 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine-2-carboxylate (303 mg, 0.99 mmol), potassium carbonate (411 mg, 2.98 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73 mg, 0.99 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was purged with nitrogen three times and stirred at 90 °C for 6 hours. The reaction was cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to give tert-butyl 5-(5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)pyridine-2-carboxylate (150 mg), yield: 40.0%. MS m / z (ESI): 360.1 [M+H] +

[0789] Step 2

[0790] 5-(5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid tert-butyl ester (150 mg, 0.42 mmol), tris(dibenzylacetone)dipalladium (47 mg, 0.04 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (48 mg, 0.08 mmol), benzophenone imine (113 mg, 0.62 mmol), and cesium carbonate (407 mg, 1.25 mmol) were dissolved in ultradry 1,4-dioxane (5 mL) and toluene (5 mL). The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and washed with dichloromethane (20 mL). Hydroxylamine hydrochloride (145 mg, 2.08 mol) was added to the filtrate, and the mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL x 3), dried, concentrated, and the residue was purified by silica gel column chromatography to obtain tert-butyl 5-(5-aminobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)pyridine-2-carboxylate (100 mg), yield: 81.0%. MS m / z (ESI): 297.2 [M+H] +

[0791] Step 3

[0792] At 0°C, phosphorus oxychloride (414 mg, 2.70 mmol) was added to a solution of ((3-fluoro-4-isopropylphenyl)carbamoyl)-D-proline (99 mg, 0.34 mmol), 5-(5-aminobicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid tert-butyl ester (100 mg, 0.34 mmol) and pyridine (160 mg, 2.02 mmol) in N,N-dimethylacetamide (5 mL). After stirring for 5 minutes, the reaction was raised to 20°C and stirred for 2 hours. Quenching with sodium bicarbonate solution (20 mL), extraction with ethyl acetate (20 mL x 3), drying the organic phase, concentrating, and purifying the residue by silica gel column chromatography to obtain (R)-5-(5-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-2-carboxamido)bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid tert-butyl ester (152 mg), yield: 74.8%. MS m / z (ESI): 573.3 [M+H] +

[0793] Step 4

[0794] (R)-5-(5-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-2-carboxamido)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid tert-butyl ester (550 mg, 0.26 mmol) was dissolved in trifluoroacetic acid (3 mL) and dichloromethane (3 mL), and the reaction was stirred at 20 °C for 4 hours until complete. The crude product was concentrated under reduced pressure and purified by preparative HPLC to obtain (R)-5-(5-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolo-2-carboxamido)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)pyridine-2-carboxylic acid (34 mg), yield: 24.5%. MS m / z (ESI): 517.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.12(br s,1H),10.08(s,1H),8.97-9.01(m,1H),8.40(s,1H),8.20(dd,J=8.25,2.25Hz, 1H),8.08(d,J=8.25Hz,1H),7.66(d,J=8.63Hz,1H),7.47(d,J=8.76Hz,1H),7.4 1(dd,J=13.70,1.94Hz,1H),7.24(dd,J=8.50,1.88Hz,1H),7.16(t,J=8.63Hz,1 H),4.52(dd,J=8.19,3.56Hz,1H),3.59-3.68(m,1H),3.47-3.55(m,1H),3.34(br d,J=4.00Hz,2H),3.22-3.30(m,2H),3.07(dt,J=13.79,6.93Hz,1H),2.13-2.25(m,1H),1.87-2.08(m,3H),1.18(d,J=7.00Hz,6H)

[0795] Example 101

[0796] 5-(4-(2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetamide)phenyl)-6-methylpyridinecarboxylic acid

[0797] first step

[0798] At 0 °C, 1-chloro-2-isocyanoethane (1 g, 6.53 mmol) and 3-fluoro-4-isopropylaniline (686 mg, 6.53 mmol) were dissolved in dichloromethane (20 mL), and the reaction was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 30 mL). The organic phase was dried and purified by silica gel column chromatography to give 1-(2-chloroethyl)-3-(3-fluoro-4-isopropylphenyl)urea (1.2 g), yield: 71.4%. MS m / z (ESI): 259.1 [M+H]+.

[0799] Step 2

[0800] 1-(2-chloroethyl)-3-(3-fluoro-4-isopropylphenyl)urea (1.68 g, 6.53 mmol) was dissolved in tetrahydrofuran (30 mL) at 0 °C, and sodium hydrogen (0.78 g, 19.59 mmol) was added. The mixture was stirred at room temperature for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give 1-(3-fluoro-4-isopropylphenyl)imidazolidine-2-one (1.2 g), yield: 82.7%. MS m / z (ESI): 223.1 [M+H]+.

[0801] Step 3

[0802] At 0 °C, 1-(3-fluoro-4-isopropylphenyl)imidazolidine-2-one (1 g, 4.5 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydrogen (0.32 g, 13.51 mmol) was added. The mixture was stirred at room temperature for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried, and concentrated. The residue was purified by silica gel column chromatography to give methyl 2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetate (0.9 g), yield: 69.2%. MS m / z (ESI): 295.1 [M+H]+.

[0803] Step 4

[0804] 500 mg (1.7 mmol) of methyl 2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetate was dissolved in a 2 / 1 (2 mL) solution of tetrahydrofuran / water. Lithium hydroxide (143 mg, 3.4 mmol) was added with stirring, and the reaction was continued for 2 hours at room temperature. The reaction solution was adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate (2 x 10 mL), dried, and purified by silica gel column chromatography to give 400 mg of 2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetic acid, yield: 84.0%. MS m / z (ESI): 281.2 [M+H]+.

[0805] Step 5

[0806] At room temperature, 2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetic acid (100 mg, 0.36 mmol) and methyl 5-(4-aminophenyl)-6-methylpyridinecarboxylate (82 mg, 0.36 mmol) were dissolved in dichloromethane (2 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.54 mmol) was added with stirring, and the reaction was continued with stirring at room temperature for 6 hours. The reaction mixture was then extracted with water (5 mL) and ethyl acetate (2 x 10 mL). The organic phase was dried and purified by silica gel column chromatography to give methyl 5-(4-(2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetamide)-6-methylpyridinecarboxylate (70 mg), yield: 38.9%. MS m / z(ESI): 505.2[M+H]+.

[0807] Step 6

[0808] At room temperature, methyl 5-(4-(2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetamide)phenyl)-6-methylpyridinecarboxylate (100 mg, 0.20 mmol) was dissolved in tetrahydrofuran / water = 2 / 1 (2 mL), and lithium hydroxide (17 mg, 0.4 mmol) was added with stirring. The reaction was continued with stirring at room temperature for 2 hours. The reaction solution was adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate (2 x 10 mL), dried, and purified by silica gel column chromatography to give 5-(4-(2-(3-(3-fluoro-4-isopropylphenyl)-2-oxoimidazolidine-1-yl)acetamide)phenyl)-6-methylpyridinecarboxylic acid (40 mg), yield: 40.8%. MS m / z(ESI):491.2[M+H]+.1H NMR(400MHz,Methanol-d4)δ8.07(d,1H),7.86(d,1H),7.74(d,2H),7.47(dd,1H),7.42–7.37(m,2H), 7.29–7.18(m,2H),4.16(s,2H),3.94(dd,2H),3.70(dd,2H),3.17(dt,1H),2.58(s,3H),1.25(d,6H).

[0809] Example 102

[0810] (R)-2,2-Difluoro-7-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)benzo[d][1,3]dioxane-4-carboxylic acid

[0811] first step

[0812] 4-Bromo-2,2-difluoro-1,3-benzodioxo (1 g, 4.22 mmol) and N-isopropylpropyl-2-amine (426.97 mg, 4.22 mmol) were dissolved in tetrahydrofuran (10 mL) and added to a 50 mL single-necked flask. The mixture was cooled to -100 °C with liquid nitrogen, and n-butyllithium (2.5 M, 1.69 mL) was added dropwise. The mixture was stirred at -100 °C for 2 hours. The reaction mixture was poured into dry ice and allowed to rise naturally to room temperature while stirring for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed successively with water (30 mL) and saturated sodium chloride solution (30 mL). The mixture was dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-bromo-2,2-difluoro-1,3-benzodione-4-carboxylic acid (680 mg, 2.4 mmol), yield: 57.1%. MS m / z(ESI):280.7 / 282.9 / [M+H]+

[0813] Step 2

[0814] 7-Bromo-2,2-difluoro-1,3-benzodione-4-carboxylic acid (680 mg, 2.4 mmol), (2R)-2-[[4-(3,3,4,4-tetramethyl-1,2,5-bromooxypentane-1-yl)phenyl]carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (1.17 g, 2.42 mmol), bis(triphenylphosphine)palladium(II) chloride (16.8 mg, 240 μmol), and sodium carbonate (763.2 mg, 7.2 mmol) were placed in a reaction flask, and dioxane (5 mL) and water (1 mL) were added. The mixture was purged with nitrogen three times, and the reaction system was carried out at 100 °C for 16 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 7-[4-[(1-tert-butoxycarbonylpyrrolidine-2-carbonyl)amino]phenyl]-2,2-difluoro-1,3-benzodioxo-4-carboxylic acid (800 mg, 162 μmol), yield: 67.47%. MS m / z (ESI): 490.9 [M+H]+.

[0815] Step 3

[0816] 7-[4-[(1-tert-butoxycarbonylpyrrolidine-2-carbonyl)amino]phenyl]-2,2-difluoro-1,3-benzodioxo-4-carboxylic acid (800 mg, 162 μmol)] was dissolved in ethyl acetate (10 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 10 mL) was added. The reaction was carried out at room temperature for 1 hour. A large amount of solid precipitated out. The solid was filtered, washed with methyl tert-butyl ether, and dried to give 2,2-difluoro-7-[4-(pyrrolidine-2-carbonylamino)phenyl]-1,3-benzodioxane-4-carboxylic acid (0.58 g, 1.36 mmol), yield: 83.31%. MS m / z (ESI): 391.3 [M+H]+

[0817] Step 4

[0818] 3-Fluoro-4-isopropylaniline (35.89 mg, 234.30 μmol) and N,N'-carbonyldiimidazole (37.99 mg, 234.30 μmol) were dissolved in dichloromethane (2 mL). After reacting the system at room temperature for 1 hour, 2,2-difluoro-7-[4-(pyrrolidine-2-carbonylamino)phenyl]-1,3-benzodioxane-4-carboxylic acid (0.1 g, 234.30 μmol) was added, and the reaction was continued at this temperature for 2 hours. The reaction solution was quenched with water, extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with water (10 mL), dried, concentrated, and the residue was purified by preparative liquid chromatography to give (R)-2,2-difluoro-7-(4-(1-((3-fluoro-4-isopropylphenyl)carbamoyl)pyrrolidine-2-carboxamido)phenyl)benzo[d][1,3]dioxane-4-carboxylic acid (25.1 mg, 43.9 μmol), yield: 18.7%. MS m / z(ESI):570.1[M+H]+.1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.45(s,1H),7.81(d,2H),7.76(d,2H),7.70(d,1H),7.58(d,1H),7.42(dd,1H),7.25( dd,1H),7.16(t,1H),4.49(dd,1H),3.69-3.63(m,1H),3.54(t,1H),3.05(p,1H),2.28-2.16(m,1H),1.99(m,3H)1.17(d,6H).

[0819] Example 103

[0820] (R)-5-(4-(1-((3-fluoro-4-isopropylphenyl)thiocarbamoyl)pyrrolo-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid

[0821] first step

[0822] 5-(4-aminophenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (800 mg, 2.81 mmol), tert-butoxycarbonyl-D-proline (666 mg, 3.09 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (593 mg, 3.09 mmol) were dissolved in acetonitrile (20 mL) and stirred at 20 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give (R)-5-(4-(1-(tert-butoxycarbonyl)pyrrolo-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (1.10 g), yield 80.6%. MS m / z (ESI): 482 [M+H] + .

[0823] Step 2

[0824] To a solution of (R)-5-(4-(1-(tert-butyloxycarbonyl)pyrrolo-2-carboxamido)phenyl)-6-methylpyridine-2-carboxylic acid tert-butyl ester (1.10 g, 2.29 mmol) in dichloromethane (20 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude product (R)-6-methyl-5-(4-(pyrrolo-2-c...

Claims

1. A compound of general formula (I-1), (I-2), (I-3) or (I-4), or a pharmaceutically acceptable salt thereof: in: X0, X1, X2, X3, X4, X5, X6, X7, X8, or X9 are each independently selected from CH or N; L1, L2, or L3 is independently selected from a bond, -C(O)-, -NR 11 C(O)-, -C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)NR 11 -, -NR 11 C(O)(CR 22 R 33 ) n3 -, -NR 11 C(O)NR 22 -, -C(S)-, -NR 11 C(S)-, -C(S)NR 11 -, -(CR 22 R 33 ) n3 C(S)NR 11 -, -NR 11 C(S)NR 22 -, -(CR 22 R 33 ) n3 -, -NR 11 -, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 R 33 -, -R 11 C=CR 22 -, -NR 11 C(O)C(O)-, -C(O)C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)-, -C(O)(CR 22 R 33 ) n3 -, -NR 11 (CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally substituted with one or more of the following substituents: halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. Alternatively, L1 and L2 may form heterocyclic groups with the atoms they are attached to; Ring A, ring B, ring C, or ring D are each independently selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, alkenylcarboxyl, or alkynylcarboxyl groups. Alternatively, ring C does not exist; R 11 R 22 Or R 33 Each of the following groups is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R1, R2, R3, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 -C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH、 -(CR aa R bb ) m1 C(O)C(O)R 31 -CR aa =CR aa R bb 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or carboxyl groups. Alternatively, any two atoms connected to R1, R2, R3, and R4 may form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. Alternatively, when y is 2, 3, or 4, the two R2 atoms connected to them form a cycloalkyl, heterocyclic, or aryl group, wherein the cycloalkyl, heterocyclic, or aryl group is optionally substituted by one or more substituents selected from hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or carboxyl groups. R 31 R 32 R 33 R aa R bb Or R cc Each of the following is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, optionally substituted by one or more substituents selected from halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; Or, R aa R bb It forms cycloalkyl or heterocyclic groups with the atoms attached to it; x, y, z and t are each independently 0, 1, 2, 3 or 4; n1 or n2 can be 0, 1, 2 or 3 independently; n3 can be 0, 1, 2 or 3 independently; n4 or m2 are each independently 0, 1 or 2; m1 can be 0, 1, 2 or 3 independently; The conditions are: (1) In the general formula (I-1), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, L3 is a bond, and R1 is selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, and propylene. R2 is selected from one, two, or three substituents in the group consisting of methyl or methoxy; R4 is selected from one, two, or three substituents in the group consisting of hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido; and R5 is selected from one, two, or three substituents in the group consisting of halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2, and ring B is pyridine, phenyl, or methyl methoxy. When, ring C is not in This indicates that it is connected to L1. Indicates connection to L2; (2) In the general formula (I-2), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, and R1 is selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or The methoxy group has 1, 2, or 3 substituents; R2 is selected from one or more substituents chosen from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, and acetamido; R4 is selected from 1, 2, or 3 substituents chosen from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2; and ring A is pyridine, pyrazole, phenyl, or... When, ring C is not in This indicates that it is connected to L1. Indicates connection to L2; (3) In general formula (I-3), X0, X1, X2, X3, and X4 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L3 is a bond, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, and ring A is pyridine, pyrazole, phenyl, or When ring B is not pyridine, phenyl, 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is further represented by general formula (II-1), (II-2), (II-3), or (II-4): in: n1 or n2 are each independently 0, 1 or 2; The definitions of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, L1, L2, ring A, ring B, ring C, ring D, R1, R2, R3, R4, x, y, and z are as described in claim 1; And at least one R4 is selected from a carboxyl group; t is 1, 2, 3, or 4; The conditions are: (1) In general formula (II-1), X0, X1, X2, X3, and X4 are each independently selected from CH or N, X5, X6, X7, X8, and X9 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2, and ring B is pyridine, phenyl, When, ring C is not in This indicates that it is connected to L1. Indicates connection to L2; (2) In general formula (II-2), X0, X1, X2, X3, and X4 are each independently selected from CH or N; X5, X6, X7, X8, and X9 are each independently selected from CH or N; L1 is -NHC(O)-; L2 is -C(O)NH-; L1 and L2 do not form heterocyclic groups with the atoms they are attached to; R1 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy; R2 is selected from one or more substituents selected from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido; R4 is selected from 1, 2, or 3 substituents selected from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, ethylamino, carboxyl, cyano, -S(O)2NH2, -S(O)2CH3, or -C(O)NH2; and ring A is pyridine, pyrazole, phenyl, or... When, ring C is not in This indicates that it is connected to L1. Indicates connection to L2; (3) In general formula (II-3), X0, X1, X2, X3, and X4 are each independently selected from CH or N, L1 is -NHC(O)-, L2 is -C(O)NH-, n1 is 2, n2 is 0, L1 and L2 do not form heterocyclic groups with the atoms they are attached to, R1 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, tert-butyl, 3-6 membered cycloalkyl, trifluoromethyl, propenyl, or methoxy, R2 is selected from one or more substituents from hydrogen, fluorine, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, cyano, or acetamido, R4 is selected from 1, 2, or 3 substituents from halogen, methyl, isopropyl, hydroxy, trifluoromethyl, methoxy, carboxyl, cyano, or -C(O)NH2, and ring A is pyridine, pyrazole, phenyl, or When ring B is not pyridine, phenyl, 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is further represented by general formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), or (III-7): in: Selected from single or double bonds; The definitions of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, L1, L2, ring A, ring B, ring C, R1, R2, R4, x, y, and t are as described in claim 1.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are further represented by general formulas (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), or (IV-9): in: The definitions of X0, X1, X2, X3, X4, X5, X6, X7, X8, X9, L1, L2, R1, R2, R4, x, y, and t are as described in claim 1; Preferably, the compound further comprises the general formula (IV-1A), (IV-2A), (IV-3A), (IV-4A), (IV-5A), (IV-6A), (IV-7A), (IV-8A), or (IV-9A):

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that, L1 or L2 is independently selected from a bond, -C(O)-, -NR 11 C(O)-, -C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)NR 11 -, -NR 11 C(O)(CR 22 R 33 ) n3 -, -NR 11 C(O)NR 22 -, -C(S)-, -NR 11 C(S)-, -C(S)NR 11 -, -(CR 22 R 33 ) n3 C(S)NR 11 -, -NR 11 C(S)NR 22 -, -(CR 22 R 33 ) n3 -, -NR 11 -, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally converted by a halogen, amino, hydroxyl, oxo, cyano, nitro, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Alternatively, L1, L2, and the atoms attached to them form 3-12 membered heterocyclic groups, optionally surrounded by halogen, amino, hydroxyl, oxo, cyano, nitro, or C groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6-alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally surrounded by hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 The alkyl halogroup is substituted by one or more substituents; Preferably, each of L1 and L2 is independently selected from a bond, -C(O)-, -NR 11 C(O)-, -C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)NR 11 -, -NR 11 C(O)(CR 22 R 33 ) n3 -, -NR 11 C(O)NR 22 -, -C(S)-, -NR 11 C(S)-, -C(S)NR 11 -, -(CR 22 R 33 ) n3 C(S)NR 11 -, -NR 11 C(S)NR 22 -, -(CR 22 R 33 ) n3 -, -NR 11 -, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 R​​​​​​​​​​​​​​​​​​​​​​​​​​​​ n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-8 membered cycloalkylene group-,-3-8 membered cycloalkylene group (NR 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 3-8 cyclic alkylene group - or -3-8 cyclic alkylene group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic group, cycloalkyl group, or heteroaryl group is optionally converted by a halogen, hydroxyl group, oxo group, or C- group. 1-3 Alkyl, C 2-3 alkenyl, C 1-3 One or more substituents in the haloalkyl group are substituted; Alternatively, L1, L2, and the atoms attached to them form a 5-12 membered heterocyclic group containing 1-6 N, O, or S atoms, optionally coated with a halogen, hydroxyl group, oxo group, or C group. 1-3 Alkyl, C 2-3 alkenyl, C 1-3 One or more substituents in the haloalkyl group are substituted; R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; More preferably, R 11 R 22 Or R 33 Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, wherein the amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, optionally by a hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; More preferably, L1 or L2 is independently selected from the following: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-, -NHC(O)CH2-, -CH2NHC(O)NH-, Alternatively, L1, L2 and the atoms connected to them form Optionally substituted with one or more of the following: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. More preferably, L1 or L2 is independently selected from -NHC(O)-, -C(O)NH-, -NHC(S)-, -C(S)NH-, -CH2C(O)NH-, -CH2NHC(O)- or 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, L3 is selected from a bond, -C(O)-, -NR 11 C(O)-, -C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)NR 11 -, -NR 11 C(O)(CR 22 R 33 ) n3 -, -NR 11 C(O)NR 22 -, -C(S)-, -NR 11 C(S)-, -C(S)NR 11 -, -(CR 22 R 33 ) n3 C(S)NR 11 -, -NR 11 C(S)NR 22 -, -(CR 22 R 33 ) n3 -, -NR 11 -, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 R 33 -, -R 11 C=CR 22 -, -NR 11 C(O)C(O)-, -C(O)C(O)NR 11 -, -(CR 22 R<​​​​​​​​​​​​​​​​C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-10 cycloalkylene group-, -3-10 cycloalkylene group (NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )3-10 cycloalkylene group -, -3-10 cycloalkylene group (NR 11 (CR 22 R 33 ) n3 )-、-(NR 11 C(O))4-10 heterocyclic group-,-4-10 heterocyclic group(NR) 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 )4-10-membered heterocyclic group- or -4-10-membered heterocyclic group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic, cycloalkyl, or heteroaryl group is optionally converted by a halogen, amino, hydroxyl, oxo, cyano, nitro, or C group. 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6-alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally surrounded by hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 The alkyl halogroup is substituted by one or more substituents; Preferably, L3 is selected from a bond, -C(O)-, -NR 11 C(O)-, -C(O)NR 11 -, -(CR 22 R 33 ) n3 C(O)NR 11 -, -NR 11 C(O)(CR 22 R 33 ) n3 -, -NR 11 C(O)NR 22 -, -C(S)-, -NR 11 C(S)-, -C(S)NR 11 -, -(CR 22 R 33 ) n3 C(S)NR 11 -, -NR 11 C(S)NR 22 -, -(CR 22 R 33 ) n3 -, -NR 11 -, -(CR 22 R 33 ) n3 NR 11 -, -NR 11 (CR 22 R 33 ) n3 -, -S(O) n4 -, -NR 11 S(O) n4 -, -S(O) n4 NR 11 -, -NR 11 C=NR 22 -, -NR 11 C=CR 22 R 33 -, -R 11 C=CR 22 -, -NR 11 C(O)C(O)-, -C(O)C(O)NR 11 -, -(CR[[ID=9,3]] 22 R 33 ) n3 C(O)-, -C(O)(CR 22 R 33 ) n3 -, -NR 11 (CR 22 R 33 ) n3 C(O)-、-C(O)(CR 22 R 33 ) n3 NR 11 -、-C(O)NR 11 (CR 22 R 33 ) n3 -、-(CR 22 R 33 ) n3 NR 11 C(O)-、-(CR 22 R 33 ) n3 NR 11 C(O)NR 22 -、-NR 11 C(O)NR 22 (CR 22 R 33 ) n3 -、-(NR 11 )3-10-membered heterocyclic group-, -3-10-membered heterocyclic group (NR 11 )-、-(NR 11 )3-8 cycloalkylene group -, -3-8 cycloalkylene group (NR 11 )-、-(NR 11 5-10-membered heteroaryl-, -5-10-membered heteroaryl (NR) 11 )-、-O-、-(NR 11 C(O))3-8 membered cycloalkylene group-,-3-8 membered cycloalkylene group (NR 11 C(O))-、-(NR 11 (CR 22 R 33 ) n3 3-8 cyclic alkylene group - or -3-8 cyclic alkylene group (NR) 11 (CR 22 R 33 ) n3 The heterocyclic group, cycloalkyl group, or heteroaryl group is optionally converted by a halogen, hydroxyl group, oxo group, or C- group. 1-3 Alkyl, C 2-3 alkenyl, C 1-3 One or more substituents in the haloalkyl group are substituted; R 11 R 22 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl or containing 1-3 5-10 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; More preferably, R 11 R 22 Or R 33 Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, wherein the amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, epoxyethyl, epoxypropyl, or epoxybutyl, optionally by a hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; More preferably, L3 is selected from the following bonds: -C(O)-, -NHC(O)-, -C(O)NH-, -NH-, -C(S)-, -NHC(S)-, -C(S)NH-, -NHC(O)NH-, -NHS(O)2-, -CH2-, -NHCH2-, -CH2NH-, -C(O)C(O)-, -CH2C(O)-, -C(O)CH2-, -C(O)N(CH3)-, -N(CH3)C(O)-, -CH2C(O)NH-, -O-, -NHCH2C(O)-, -CH2C(O)NH-, -C(O)NHCH2-, -CH2NHC(O)-, -NHC(O)CH2-, -CH2NHC(O)NH-.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that, R1, R2, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 、-C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH、-CR aa =CR aa R bb 、 -(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Alternatively, when y is 2, 3, or 4, the two R2 atoms and their connected atoms form C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, optionally further bonded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; R 31 R 32 R 33 R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Or, R aa R bb Forming C with the attached atoms 3-15 Cycloalkyl or containing 1-5 3-15 membered heterocyclic groups selected from N, O or S heteroatoms; Preferably, R1, R2, or R4 are each independently selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-4 N, O or S atoms, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 )S(O) m2 R 32 、-C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH、 -CR aa =CR aa R bb 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. Alternatively, when y is 2, 3, or 4, the two R2 atoms and their connected atoms form C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-3 Alkyl, C 2- 4-Alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1- 3-alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. R 31 R 32 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, the amino groups, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally replaced by hydroxyl, halogen, cyano, amino, or C groups. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; Or, R aa R bb Forming C with the attached atoms 3-10 Cycloalkyl groups or containing 1-4 3-10 membered heterocyclic groups selected from N, O or S heteroatoms; More preferably, R 31 R 32 Or R 33 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl, wherein the amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl group is optionally replaced by hydroxyl, fluorine, chlorine, bromine, cyano, amino, C 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; R aa R bb Or R cc Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy. Or, R aa R bb Forming C with the attached atoms 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O or S heteroatoms; More preferably, R aa R bb It forms pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups with the attached atoms. Optionally substituted with one or more of the following: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. More preferably, R1, R2, or R4 are each independently selected from hydrogen, fluorine, chlorine, bromine, amino, oxo, methylamino, dimethylamino, hydroxy, cyano, nitro, carboxyl, methyl, ethyl, isopropyl, tert-butyl, n-butyl, fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, difluoromethyl, difluoroethyl, difluorovinyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, cyclopropoxy, hydroxymethyl, hydroxyethyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -SF5, -B(OH)2, -SCF3, -CH2COOH, -S(O)OH, -C(O)NH2, Alternatively, when y is 2, 3 or 4, the two R2 atoms connected to them form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl groups; More preferably, R1, R2, or R4 are each independently selected from hydrogen, fluorine, carboxyl, methyl, isopropyl, methoxy, trifluoromethyl, -SF5, -B(OH)2, 8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl, 5-12 heteroaryl, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 S(O) m2 R 32 、-C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH、-CR aa =CR aa R bb 、 -(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally further converted by halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Alternatively, R3, R4, and the atoms they are bonded to form C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3- 14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, optionally further bonded by hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; R 31 R 32 R 33 R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-12 heteroaryl groups, optionally halogenated, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 One or more substituents in the aryl or 5-12 heteroaryl groups are used for substitution; Or, R aa R bb Forming C with the attached atoms 3-15 Cycloalkyl or containing 1-5 3-15 membered heterocyclic groups selected from N, O or S heteroatoms; Preferably, R3 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3- 10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 aryl, 5-10 heteroaryl groups containing 1-4 N, O or S atoms, carboxyl, -O(CR) aa R bb ) m1 R 31 -NR 31 (CR aa R bb ) m1 R 32 -S(CR) aa R bb ) m1 R 31 -OCR 31 R 32 R 33 、-(CR aa R bb ) m1 C(O)R 31 N = S = OR 31 R 32 、N(R 31 ) = S = OR 32 -、-(CH2) m1 C(O)NR 31 R 32 -(CH2) m1 P(O)R 31 R 32 -(CH2) m1 P(O)2R 31 R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)NR 31 R 32 、-(CR aa R bb ) m1 (NR 31 )S(O) m2 R 32 、-C(O)NR 31 S(O) m1 R 32 、-(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa =CR bb ) m1 COOH、 -CR aa =CR aa R bb 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(=NR 31 )R 32 The amino, hydroxyl, thiol, and C groups mentioned above 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1- 3-alkoxy group, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-4 N, O, or S atoms, C 6-10 Aryl or containing 1-4 5-10 heteroaryl groups selected from N, O, or S atoms, optionally coated with halogen, amino, hydroxyl, oxo, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. Alternatively, R3, R4, and the atoms they are bonded to form C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally coated with hydrogen, halogen, amino, hydroxyl, oxo, cyano, nitro, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 The aryl group or one or more substituents selected from 1-3 5-10 heteroaryl groups chosen from N, O or S atoms are used for substitution. R 31 R 32 Or R 33 Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 The aryl group or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, wherein the amino group, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or containing 1-3 5-8 heteroaryl groups selected from N, O, or S atoms, optionally surrounded by hydroxyl, halogen, cyano, amino, or C atoms. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; R aa R bb Or R cc Each is independently selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, the amino groups, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 Alkyl groups, optionally replaced by hydroxyl, halogen, cyano, amino, or C groups. 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; Or, R aa R bb Forming C with the attached atoms 3-10 Cycloalkyl groups or containing 1-4 3-10 membered heterocyclic groups selected from N, O or S heteroatoms; More preferably, R 31 R 32 Or R 33 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl, wherein the amino, methylamino, dimethylamino, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminomethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or oxazolyl group is optionally replaced by hydroxyl, fluorine, chlorine, bromine, cyano, amino, C 1-3 Alkyl, C 1-3 The alkyl halogroup is substituted by one or more substituents; R aa R bb Or R cc Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, methylamino, dimethylamino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, aminomethyl, methoxy, ethoxy, or propoxy. Or, R aa R bb Forming C with the attached atoms 3-6 Cycloalkyl or containing 1-4 4-6 membered heterocyclic groups selected from N, O or S heteroatoms; More preferably, R aa R bb It forms pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups with the attached atoms. Optionally substituted with one or more of the following: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. More preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, amino, oxo, methylamino, dimethylamino, hydroxy, cyano, nitro, carboxyl, methyl, ethyl, isopropyl, tert-butyl, n-butyl, fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, difluoromethyl, difluoroethyl, difluorovinyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, cyclopropoxy, hydroxymethyl, hydroxyethyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -SF5, -B(OH)2, -SCF3, -CH2COOH, -S(O)OH, -C(O)NH2, Alternatively, R3, R4 and the atoms they are bonded to form It may optionally be substituted with one or more of the following substituents: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, Ring A is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32 One or more substituents are substituted in the sample; Preferably, ring A is selected from C. 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-10 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; More preferably, ring A is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; More preferably, ring A is selected from C. 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl or cyano-substituted C 1-3 One or more substituents in the alkyl group are substituted; More preferably, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... The radical can be optionally covered by hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. One or more substituents are substituted in the sample; More preferably, ring A is selected from... Optionally substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl; More preferably, ring A is selected from 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, Ring B is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample; Preferably, ring B is selected from C. 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6- 14 Aryl or 5-14 membered heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 A aryl group or a 5-14 membered heteroaryl group containing 1-4 N, O, S, P or B atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -(CR) aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R 32 、-(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample; More preferably, ring B is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 4-14 membered fused heterocyclic groups containing 1-4 N, O, S, P or B atoms, 5-10 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 4-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, 5-8 member monoheteroaryl containing 1-4 N, O, S, P or B atoms, 8-14 member fused heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5- 10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S, P or B atoms, 4-14 membered fused heterocyclic groups containing 1-3 N, O, S, P or B atoms, 5-10 membered spirocyclic groups containing 1-4 N, O, S, P or B atoms, 4-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P or B atoms, C 6-14 Aryl, a 5-8 membered mono-heteroaryl containing 1-4 N, O, S, P or B atoms, or an 8-14 membered fused heteroaryl containing 1-4 N, O, S, P or B atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1- 3-Hydroalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -(CR) aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 S(O) m2 NR 31 R 32 、-(CR aa R bb ) m1 S(O) m2 R3, -(CR aa R bb ) m1 S(O)(=NR cc )R 32 、-(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 、-(CR aa R bb ) m1 BR 31 R 32 or -(CR) aa R bb ) m1 C(O)NR 31 R 32 One or more substituents are substituted in the sample; More preferably, ring B is selected from C. 3-6 Monocycloalkyl, C 6-14 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-4 N, O, S, P, or B atoms, 6-14 membered fused heterocyclic groups containing 1-4 N, O, S, P, or B atoms, 5-9 membered spirocyclic groups containing 1-4 N, O, S, P, or B atoms, 6-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P, or B atoms, C 6-14 Aryl, 5-6 member monoheteroaryl containing 1-4 N, O, S, P or B atoms, 8-14 member fused heteroaryl containing 1-4 N, O, S, P or B atoms, wherein the C 3-6 Monocycloalkyl, C 6-14 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-4 N, O, S, P, or B atoms, 6-14 membered fused heterocyclic groups containing 1-4 N, O, S, P, or B atoms, 5-9 membered spirocyclic groups containing 1-4 N, O, S, P, or B atoms, 6-10 membered bridged heterocyclic groups containing 1-4 N, O, S, P, or B atoms, C 6-14 Aryl, a 5-6 membered mono-heteroaryl containing 1-4 N, O, S, P or B atoms, or an 8-14 membered fused heteroaryl containing 1-4 N, O, S, P or B atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, carboxyl, -(CR) aa =CR bb COOH, -S(O) m2 R 32 -S(O)(=NR) cc )R 32 -BR 31 R 32 、-(NR 31 )C(O)R 32 -C(O)C(O)R 31 -C(O)NR 31 R 32 or -S(O) m2 NR 31 R 32 One or more substituents are substituted in the sample; More preferably, ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The following groups are optionally covered: hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, oxo, carboxyl, -(CH=CH)COOH, -B(OH)2, -CH2COOH, -S(O)OH, -C(O)NH2. One or more substituents are substituted in the sample; More preferably, ring B is selected from cyclohexyl, phenyl, Optional radicals include hydrogen, methyl, ethyl, isopropyl, methoxy, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, oxo, carboxyl, -B(OH)2, or... One or more substituents are substituted in the sample; More preferably, ring B is selected from cyclohexyl, phenyl, 11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, Ring C is selected from C 3-14 Cycloalkyl groups, containing 1-5 3-14 membered heterocyclic groups selected from N, O, S, P, B, or Si atoms, C 6- 14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32 One or more substituents are substituted in the sample; Preferably, ring C is selected from C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-5 N, O, S or Si atoms, C 6-12 Aryl or 5-12 heteroaryl containing 1-4 N, O or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -S(CR) aa R bb ) m1 R 31 One or more substituents are substituted in the sample; More preferably, ring C is selected from C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S or Si atoms, 4-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S or Si atoms, 4-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-10 membered spirocyclic groups containing 1-3 N, O or S atoms, 4-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -S(CR) aa R bb )R 31 One or more substituents are substituted in the sample; More preferably, ring C is selected from C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S or Si atoms, 6-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-8 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-4 N, O, S or Si atoms, 6-12 membered fused heterocyclic groups containing 1-5 N, O or S atoms, 5-8 membered spirocyclic groups containing 1-3 N, O or S atoms, 6-10 membered bridged heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 2-3 Haloalkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl or -SR 31 One or more substituents are substituted in the sample; More preferably, ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Optionally substituted with one or more of the following: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or -SCF3; More preferably, ring C is selected from... Optionally substituted with one or more of the following: hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoroethyl. Alternatively, ring C does not exist.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, Ring D is selected from C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 The aryl group or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P, or B atoms, wherein the C 3-14 Cycloalkyl groups, 3-14 membered heterocyclic groups containing 1-5 atoms selected from N, O, S, P or B, C 6-14 Aryl or containing 1-5 5-14 heteroaryl groups selected from N, O, S, P or B atoms, optionally surrounded by hydrogen, halogen, amino, hydroxyl, mercapto, oxo, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, carboxyl, -S(CR) aa R bb ) m1 R 31 、-(CR aa =CR bb ) m1 COOH, -(CR aa R bb ) m1 (NR 31 )C(O)R 32 、-(CR aa R bb ) m1 C(O)C(O)R 31 or -(CR) aa R bb ) m1 BR 31 R 32 One or more substituents are substituted in the sample; Preferably, ring D is selected from C. 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 heteroaryl groups containing 1-3 N, O, or S atoms, wherein the C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 A aryl group or a 5-12 heteroaryl group containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, or C. 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl group, C 3-10 One or more substituents from cycloalkyl, -SF5, or -SCF3 are used for substitution; More preferably, ring D is selected from C. 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-12 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-12 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-8 Monocycloalkyl, C 4-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 4-10 Bridged cycloalkyl groups, 3-8 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-12 membered spirocyclic groups containing 1-3 N, O, or S atoms, 4-12 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-8 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-12 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally surrounded by hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 One or more substituents from cycloalkyl, -SF5, or -SCF3 are used for substitution; More preferably, ring D is selected from C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-11 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 member monoheteroaryl containing 1-3 N, O or S atoms, or 8-10 member fused heteroaryl containing 1-3 N, O or S atoms, wherein the C 3-6 Monocycloalkyl, C 6-10 Polycyclic alkyl, C 5-9 Spirocycloalkyl, C 6-10 Bridged cycloalkyl groups, 3-6 membered monoheterocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered fused heterocyclic groups containing 1-3 N, O, or S atoms, 5-11 membered spirocyclic groups containing 1-3 N, O, or S atoms, 6-11 membered bridged heterocyclic groups containing 1-3 N, O, or S atoms, C 6-10 Aryl, 5-6 membered mono-heteroaryl containing 1-3 N, O, or S atoms, or 8-10 membered fused heteroaryl containing 1-3 N, O, or S atoms, optionally prefixed with hydrogen, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3- One or more substituents selected from 6-cycloalkyl, -SF5, or -SCF3; More preferably, ring D is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, pyridazine, etc. Optional radicals include hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, n-butyl, cyclopropyl, propynyl, methoxy, ethoxy, fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, -SF5, -SCF3. One or more substituents are substituted in the sample; More preferably, ring D is selected from cyclobutyl, cyclohexyl, phenyl, Optional radicals include hydrogen, oxo, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, propynyl, fluoromethyl, fluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, -SF5, or One or more substituents are substituted in the sample.

13. The following compounds, or their pharmaceutically acceptable salts, have the following specific structures:

14. A method for preparing the compounds as described in claims 1-13 or pharmaceutically acceptable salts thereof, characterized in that, It includes the following steps: in: The definitions of ring B, ring C, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in claim 1; L2 is -C(O)NH-; General formulas (M-1A) and (M-1B) react under the action of a condensing agent and a base to give general formula (II-1); Preferably, the condensing agent is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP; more preferably, EDCI or HATU. Preferably, the alkali is selected from DIEA, TEA, NMP, DBU, or DABCO; more preferably, DIEA; When at least one R4 is selected from C(O)O-PG1, the process also includes the step of removing the protecting group PG1 under the action of acid or base. Preferably, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl, more preferably methyl or tert-butyl; Preferably, the alkali is selected from LiOH, NaOH, KOH or Cs2CO3, and more preferably LiOH; Preferably, the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA, more preferably MSA or TFA; Alternatively, it may include the following steps: in: The definitions of ring A, ring C, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in claim 1; L2 is -C(O)NH-; General formulas (M-1A) and (M-1C) react under the action of a condensing agent and a base to give general formula (II-2); Preferably, the condensing agent is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP; more preferably, EDCI or HATU. Preferably, the alkali is selected from DIEA, TEA, NMP, DBU, or DABCO; more preferably, DIEA; When at least one R4 is selected from C(O)O-PG1, the process also includes the step of removing the protecting group PG1 under the action of acid or base. Preferably, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl, more preferably methyl or tert-butyl; Preferably, the alkali is selected from LiOH, NaOH, KOH or Cs2CO3, and more preferably LiOH; Preferably, the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA, more preferably MSA or TFA; Alternatively, it may include the following steps: in: The definitions of ring A, ring B, R1, R2, R3, R4, L1, X5, X6, X7, X8, X9, x, y, z, and t are as described in claim 1; L2 is -C(O)NH-; General formulas (M-2A) and (M-2B) react under the action of a condensing agent and a base to give general formula (II-3); Preferably, the condensing agent is selected from EDCI, DIC, DCC, TBTU, HATU, HBTU, HCTU, EPBT, PyBOP, or PyAOP; more preferably, EDCI or HATU. Preferably, the alkali is selected from DIEA, TEA, NMP, DBU, or DABCO; more preferably, DIEA; When at least one R4 is selected from C(O)O-PG1, the process also includes the step of removing the protecting group PG1 under the action of acid or base. Preferably, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl, more preferably methyl or tert-butyl; Preferably, the alkali is selected from LiOH, NaOH, KOH or Cs2CO3, and more preferably LiOH; Preferably, the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA, or TFA, more preferably MSA or TFA; Alternatively, it may include the following steps: in: The definitions of ring A, ring B, R1, R2, R3, R4, L2, X5, X6, X7, X8, X9, x, y, z, and t are as described in claim 1; L1 is -NHC(O)-; General formulas (M-3A) and (M-3B) react in the presence of a carbonylating agent and a base to give general formula (II-3); Preferably, the carbonylating agent is selected from CDI, triphosgene, diester carbonate, or isocyanate; more preferably, CDI or triphosgene. Preferably, the alkali is selected from DIEA, TEA, NMP, DBU, DABCO, or NMM; more preferably, TEA, DBU, or NMM. When at least one R4 is selected from C(O)O-PG1, the process also includes the step of removing the protecting group PG1 under the action of acid or base. Preferably, PG1 is selected from methyl, ethyl, isopropyl, tert-butyl, or benzyl, more preferably methyl or tert-butyl; Preferably, the alkali is selected from LiOH, NaOH, KOH or Cs2CO3, and more preferably LiOH; Preferably, the acid is selected from hydrochloric acid, formic acid, acetic acid, MSA or TFA, more preferably MSA or TFA.

15. A pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown in claims 1 to 13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

16. The use of any compound shown in claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 15 in the preparation of a medicament for treating GIPR-related diseases, preferably, GIPR-related diseases are selected from diabetes, obesity, NASH, kidney disease and related conditions, more preferably type I diabetes, type II diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, renal tubular dysfunction, proximal tubular pro-inflammatory changes, chronic kidney disease, diabetic retinopathy, obesity, glomerulosclerosis, chronic renal failure, metabolic syndrome, obesity or NASH.

Images