Glp-1 receptor agonist, and preparation method therefor and use thereof

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

A GLP-1 receptor agonist and its preparation method and application

[0001] This application claims priority to:

[0002] CN202410405950.6, application date April 3, 2024; CN202411388926.2, application date September 30, 2024; CN202411923665.X, application date December 24, 2024; CN202510107397.2, application date January 22, 2025. Technical Field

[0003] The present invention relates to the technical field of chemical medicine, and in particular to a GLP-1 receptor agonist, a preparation method thereof, and an application thereof. Background Art

[0004] Glucagon-like peptide-1 (GLP-1) is a hormone produced primarily by intestinal L cells and belongs to the incretin class. The GLP-1 receptor was first discovered in 1987 through radioligand binding experiments with GLP-1 in rat pancreatic islet cell cultures and was soon localized to various tissues, including the brain. GLP-1 receptors are expressed in a variety of tissues, including the pancreas, lungs, heart, kidneys, stomach, intestines, pituitary gland, vagus nerve, and multiple regions of the central nervous system.

[0005] GLP-1 receptor agonists activate the GLP-1 receptor, enhancing insulin secretion in a glucose-dependent manner, inhibiting glucagon secretion, and delaying gastric emptying. This central appetite suppression reduces food intake, thereby achieving effects such as lowering blood sugar (Ralph A. DeFronzo et al, 2013; Yiming Mu et al, Dalong Zhu et al, 2020) and weight loss (Yingying Wang et al, 2020). GLP-1 analogs, such as liraglutide and exenatide, have been developed as effective therapeutic agents for the treatment of diabetes and obesity. GLP-1 receptor activation can reduce the size of cerebral infarction by enhancing cell survival signaling pathways, reducing ischemia-reperfusion injury, promoting brain repair, and inhibiting inflammation and oxidative stress (Zhang L et al, 2021; He W et al, 2020; Basalay MV et al, 2019; Grieco M et al, 2019).

[0006] Studies have shown that GLP-1 receptor agonists are a new class of antidiabetic drugs and an important part of the treatment of patients with type 2 diabetes (Maselli DB et al, 2021; Nauck MA et al, 2021; Brown E et al, 2018).

[0007] In addition, a large number of studies have shown that in non-diabetic populations, GLP-1 receptor agonists also show the ability to treat cardiovascular disease, chronic kidney disease, obesity and overweight, dyslipidemia and hypertension, non-alcoholic fatty liver disease, polycystic ovary syndrome, etc. (Dan Xu et al, 2022).

[0008] GLP-1 receptor agonists not only have a glucose-lowering effect but also have cardiovascular and cerebrovascular protective effects, such as those affecting stroke, cognitive impairment, Parkinson's disease, and Alzheimer's disease (Tianyuan Guan et al, 2019). Several large-scale clinical trials have also demonstrated that GLP-1 receptor agonists can reduce the risk of cardiovascular events (Hirsch IB et al, 2019; Wen S et al, 2021).

[0009] In addition, since GLP-1 receptors are widely distributed in the body and can act on multiple organs and tissues, semaglutide and tilpotide are being expanded into multiple indications, including non-alcoholic fatty liver disease, MACE, HFpEF, kidney disease, Alzheimer's disease, etc., all of which are treatment areas with large unmet clinical needs.

[0010] Currently, researchers have conducted a number of studies in the hope of finding therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications include WO2018056453A1, WO2018109607, WO2019239319, WO2019239371, WO2020103815, WO2020207474, WO2020263695, WO2021154796, WO2021112538, WO2021096304, WO2021096284, WO2021081207, WO2021018023, WO2021254470, WO2021249492, and WO20 ... 7979, WO2022017338A1, WO2022031994, WO2022040600, WO2022068772, and WO2022116693 disclose numerous small molecule compounds that are used as GLP-1 receptor agonists for preventing or treating diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease, or dementia. However, there is still an urgent need for more and better GLP-1 receptor agonists in clinical practice. Summary of the Invention

[0011] The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a GLP-1 receptor agonist. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by stimulating the GLP-1 receptor. The present invention further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0012] Specifically:

[0013] In one aspect, the present invention relates to a compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0014] in:

[0015] L1 is -C(=O)-, -S(=O)2- or -CR 10 R 11 -;

[0016] L2 is -NR 12-, -C(=O)NR 13 -、-NR 14 C(=O)NR 15 -or-CR 16 R 17 -;

[0017] L3 is a key or -CR 18 R 19 -;

[0018] L4 is a key or -CR 20 R 21 -;

[0019] X1 is CH, NH, O or S;

[0020] X2 is C or N;

[0021] Y1 and Y2 are each independently CH or N;

[0022] Y3 and Y4 are each independently C or N;

[0023] R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace;

[0024] R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0025] R 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace;

[0026] R 2aD, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0027] R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0028] or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl;

[0029] R 3 is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace;

[0030] R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0031] R4 for

[0032] R 5 and R 6 Each independently is H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent;

[0033] or R 5 and R 6 Together with the carbon atoms to which they are attached, they can form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 1-3 substituted by an alkylamino substituent;

[0034] R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 and R 25 Each independently represents H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino or nitro, provided that R22 、R 23 、R 24 and R 25 At least one of them is not hydrogen;

[0035] or R 22 and R 23 、R 24 and R 25 、R 23 and R 24 independently and optionally together with the carbon atom to which they are attached may form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1- 3 alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 substituted by an alkylamino substituent;

[0036] R 9 H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 substituted by a cycloalkyl substituent;

[0037] R 12 、R 13 、R 14 and R 15 Each independently is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro;

[0038] Wherein, formula (I) is not the following compound:

[0039] In some embodiments,

[0040] In some embodiments, R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace;

[0041] R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0042] R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace;

[0043] R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0044] R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0045] or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl;

[0046] R 3 is a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace;

[0047] R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

[0048] In some embodiments, R 1 Phenyl, The phenyl group, Can be optionally replaced by 1, 2 or 3 R 1a replace;

[0049] R 1a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0050] R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R 2a replace;

[0051] R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c , methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the ... 2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0052] R 2b and R 2c each independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0053] or R 2b and R 2c Together with the phosphorus atoms to which they are attached, they can form

[0054] R 3 is oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, The oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, Can be optionally replaced by 1, 2 or 3 R 3a replace;

[0055] R 3a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, ethyl , n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

[0056] In some embodiments, R 5 and R 6Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent;

[0057] or R 5 and R 6 Together with the carbon atom to which they are attached, they may form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino;

[0058] R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 and R 25Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, Ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro, provided that R 22 、R 23 、R 24 and R 25 At least one of them is not hydrogen;

[0059] or R 22 and R 23 、R 24 and R 25 、R 23 and R 24 independently and optionally together with the carbon atom to which they are attached can form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino;

[0060] R 9is H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, Methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently and optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0061] R 12 、R 13 、R 14 and R 15 Each is independently H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0062] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

[0063] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0064] In one aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

[0065] In some embodiments, the disease mediated by the GLP-1 receptor agonist of the present invention is diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease or dementia.

[0066] In some embodiments, the diabetes described in the present invention is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of adults.

[0067] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0068] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0069] Definitions and General Terms

[0070] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0071] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference.

[0072] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0073] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.The substituents may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (=O) O-alkyl, -alkylene-S (=O) 2 -alkyl, -alkylene-S (=O) 2 -amino, -S (=O) 2 -alkyl, -S (=O) 2 -amino, -S (=O) 2 OH, -O-alkylene-C (=O) O-alkyl, -O-alkylene-S (=O) 2 -alkyl, -O-alkylene -S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, - N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C (=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and the like.

[0074] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t- -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0075] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in still other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0076] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0077] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0078] The term "heteroatom" means one or more of O, S, N, P and Si, including C, N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl); or in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0079] The term "halogen" refers to F, Cl, Br or I.

[0080] The term "deuterium" refers to heavy hydrogen, D.

[0081] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0082] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups; examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, etc., and the alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0083] The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 Alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, etc., and the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0084] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a nitrogen atom. In some embodiments, the alkylamino group is C 1-4 Alkylamino groups; examples thereof include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups. The alkylamino groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0085] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, a cycloalkyl group contains 3-10 carbon atoms; in another embodiment, a cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, a cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0086] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, never including aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0087] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0088] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0089] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,3 ... oxadiazole, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic rings, but are in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0090] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0091] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0092] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. Examples include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0093] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0094] As described herein, a ring system formed by a linker attached to a ring (e.g., Formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0095] As described herein, the group "-O-(CR m R n ) p -" has two connection sites that can be connected to the rest of the molecule, and the connection methods of the two connection sites can be interchanged. For example, formula f represents the group -O-(CR m R n ) p - can be linked to the rest of the molecule via the E-terminus or the E'-terminus. For example, EO-(CR m R n ) p -E' or E'-O-(CR m R n ) p -E.

[0096] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0097] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0098] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0099] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described herein, or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits similar activity in vivo or in vitro as the compound of formula (I). The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0100] The definitions and conventions of stereochemistry used herein are generally those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, or (+), (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0101] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of bonding electrons.

[0102] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0103] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0104] The "solvate" of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0105] "Esters" herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.

[0106] The "nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (e.g., dichloromethane), by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0107] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form. Other prodrug forms include phosphates, such as these phosphate compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0108] Unless otherwise indicated herein or the context clearly indicates a contrary meaning, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural.

[0109] The term "GLP-1 receptor agonist" as used herein refers to a substance that can agonize the activity of the GLP-1 receptor.

[0110] General synthesis process

[0111] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0112] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified. The following reaction schemes and examples are provided to further illustrate the present invention.

[0113] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0114] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Myrel Chemical Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. and used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Ocean Chemical Factory.

[0115] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, and methanol were of analytical grade.

[0116] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0117] The silica gel column was purchased from Tianjin Bona Aijieer Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0118] 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 solvents (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0119] Low-resolution mass spectrometry (MS) data were collected using an Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL / min). Mobile phase: 0%-95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0120] Compounds were purified using Cheetah Pro medium-pressure rapid purification preparative chromatography (Tianjin Bona Aijieer Technology Co., Ltd.) with UV detection at 210 nm / 254 nm.

[0121] The following abbreviations are used throughout this disclosure:

[0122] PE petroleum ether EA / EtOAc ethyl acetate

[0123] mg milligram mmol millimole

[0124] mL ml g g

[0125] M mol / L rpm revolutions / min

[0126] μM μmol / L h hour

[0127] DCMDichloromethaneMeOHMethanol

[0128] min CDCl3 deuterated chloroform

[0129] DMSO-d6 deuterated dimethyl sulfoxide nM nanomolar / liter

[0130] HEPES 4-hydroxyethylpiperazineethanesulfonic acid BSA bovine serum albumin

[0131] IBMX 3-Isobutyl-1-methylxanthine HBSS Hank's Balanced Salt Solution

[0132] nL nanoliter DIPEAN, N-diisopropylethylamine

[0133] THF Tetrahydrofuran CDI N,N'-Carbonyldiimidazole

[0134] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0135] HATU 2-(7-Azabenzotriazole)-N,N,N',N'-LiHMDS Lithium bis-(trimethylsilyl)amide or hexamethyl

[0136] Lithium tetramethyluronium hexafluorophosphate disilazide

[0137] HOAT 1-Hydroxy-7-azabenzotriazole NMP N-methylpyrrolidone

[0138] The following schemes describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, each of X1, X2, Y1, Y2, Y3, Y4, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 22 、R 23, L3 and L4 have the same meanings as those described in the present invention. Boc is a commonly used protecting group tert-butyloxycarbonyl.

[0139] Reaction Scheme 1

[0140] The compound represented by formula (15) can be prepared by reaction scheme 1: the compound represented by formula (1) is oxidized to obtain the compound represented by formula (2). The compound represented by formula (2) is reacted with the compound represented by formula (3) to obtain the compound represented by formula (4). The compound represented by formula (4) is subjected to Boc protection reaction to obtain the compound represented by formula (5). The compound represented by formula (5) is subjected to intramolecular cyclization reaction to obtain the compound represented by formula (6). The compound represented by formula (6) and the compound represented by formula (7) are subjected to cyclization reaction to obtain the compound represented by formula (8). The compound represented by formula (8) is reacted with phenyl chloroformate and 2,2-dimethoxyethane-1-amine in sequence to obtain the compound represented by formula (9). The compound represented by formula (9) is subjected to intramolecular cyclization reaction to obtain the compound represented by formula (10). The compound represented by formula (10) is reacted with the compound represented by formula (11) to obtain the compound represented by formula (12). The compound represented by formula (12) is subjected to removal of the N-Boc protecting group to obtain the compound represented by formula (13). The compound represented by formula (13) and the compound represented by formula (14) react to obtain the compound represented by formula (15). The compound represented by formula (14) is synthesized with reference to the preparation methods of patents CN109790161A and CN116390926A. DETAILED DESCRIPTION

[0141] The present invention is described below with reference to specific examples. It should be noted that these examples are merely illustrative and do not limit the present invention in any way.

[0142] Example 1 Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 1)

[0143] Step 1: Synthesis of ethyl 1-formylcyclopropane-1-carboxylate

[0144] To the reaction flask, ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (10 g, 69.36 mmol) and dichloromethane (200 mL) were added in batches. Dess-Martin periodinane (44.2 g, 104.04 mmol) was added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 2 hours. Under an ice bath, saturated sodium thiosulfate solution was added to quench the mixture. Saturated sodium bicarbonate was then added to adjust the pH to a weakly alkaline state. The mixture was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-5:1) to obtain the title compound.

[0145] Step 2: Synthesis of ethyl ((S)-1-(((1-cyanopropan-2-yl)amino)methyl)cyclopropane-1-carboxylate

[0146] To a reaction flask, (S)-3-aminobutyronitrile hydrochloride (2g, 16.59mmol), methanol (30mL), and diisopropylethylamine (2.14g, 16.59mmol) were added sequentially. The reaction mixture was stirred for 20 minutes. Acetic acid (896mg, 14.93mmol) and ethyl 1-formylcyclopropane-1-carboxylate (3.1g, 21.73mmol) were then added. Stirring was continued for 2 hours. Sodium triacetoxyborohydride (5.25g, 24.88mmol) was added and stirring was continued at room temperature for 6 hours. The reaction mixture was stopped, diluted with water, and extracted with ethyl acetate (30mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used directly in the next step.

[0147] Step 3: Synthesis of (S)-ethyl 1-(((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)methyl)cyclopropane-1-carboxylate

[0148] To the reaction flask, ethyl ((S)-1-(((1-cyanopropan-2-yl)amino)methyl)cyclopropane-1-carboxylate obtained in the previous step, dichloroethane (30 mL), and di-tert-butyl dicarbonate (4.36 g, 20.0 mmol) were added sequentially. The reaction was allowed to react at room temperature overnight. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-5:1) to obtain the title compound.

[0149] Step 4: Synthesis of tert-butyl (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylate

[0150] To the reaction flask, add (S)-ethyl 1-(((tert-butoxycarbonyl)(1-cyanopropyl-2-yl)amino)methyl)cyclopropane-1-carboxylate (1.05 g, 3.38 mmol), tetrahydrofuran (10 mL), and a 1M solution of potassium tert-butoxide in THF (5 mL, 5.0 mmol). After the addition, stir at room temperature for 1 hour. Quench with saturated ammonium chloride solution and extract with ethyl acetate (15 mL x 3). The combined organic phases are washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used directly in the next step.

[0151] Step 5: Synthesis of tert-butyl (S)-3'-amino-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0152] (4-Fluoro-3,5-dimethylphenyl)hydrazine (560 mg, 3.63 mmol), (6S)-7-cyano-6-methyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (480 mg, 1.82 mmol), and toluene (10 mL) were added to a reaction flask. Under nitrogen protection, a dioxane hydrochloride solution (0.45 mL) was added, the temperature was raised to 80°C, and the reaction was carried out for 1.5 hours. After cooling to room temperature, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the title compound.

[0153] LC-MS(ESI):[M+H] + =401.4.

[0154] Step 6: Synthesis of tert-butyl (S)-3'-(3-(2,2-dimethoxyethyl)urea)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0155] To a reaction flask, tert-butyl (S)-3'-amino-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate (660 mg, 1.65 mmol), DIPEA (1064 mg, 8.24 mmol), and tetrahydrofuran (10 mL) were added. Phenyl chloroformate (774 mg, 4.95 mmol) was added dropwise with stirring. After reacting at room temperature for 1 hour, 2,2-dimethoxyethane-1-amine (693 mg, 6.59 mmol) was added to the system. Stirring was continued for 1 hour to stop the reaction. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1-2:1) to obtain the title compound.

[0156] LC-MS(ESI):[M+H] + =532.4.

[0157] Step 7: Synthesis of tert-butyl (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0158] (S)-tert-Butyl 3'-(3-(2,2-dimethoxyethyl)urea)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate (540 mg, 1.02 mmol), trifluoromethanesulfonic acid (137 mg, 0.91 mmol), and tetrahydrofuran (6 mL) were added to a reaction flask. The temperature was raised to react for 1 hour. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (PE:EA (v / v) = 10:1-2:1) to obtain the title compound.

[0159] LC-MS(ESI):[M+H] + =468.4.

[0160] Step 8: Synthesis of tert-butyl (S)-3'-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0161] (S)-2'-(4-Fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (400 mg, 0.86 mmol), 5-bromo-4-fluoro-1-methyl-1H-indole (254 mg, 1.11 mmol), cuprous iodide (135.7 mg, 0.43 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (60.8 mg, 0.43 mmol) and NMP (15 mL) were added to the reaction flask. Under nitrogen protection, the temperature was raised to 130°C and the reaction was carried out for 2 hours. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the target compound was obtained by column chromatography.

[0162] LC-MS(ESI):[M+H] + =616.5.

[0163] Step 9: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0164] (S)-tert-Butyl 3'-(3-(4-fluoro-1-methyl-1H-indol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate (600 mg, 0.97 mmol) and dioxane hydrochloride (4 mL) were added to a reaction flask, reacted at room temperature for 1 hour, and concentrated to obtain the title compound.

[0165] LC-MS(ESI):[M+H] + =516.4.

[0166] Step 10: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0167] (S)-1-(4-fluoro-1-methyl-1H-indol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (46.4 mg, 0.09 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (35 mg, 0.0.9 mmol), HATU (48.5 mg, 0.13 mmol), and DMF (4 mL) were added to a reaction flask, and DIPEA (54.9 mg, 0.43 mmol) was added with stirring. The reaction was allowed to react at room temperature overnight, and saturated brine (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound was separated and purified by silica gel column chromatography (PE:EA (v / v) = 1:1-1:3) to obtain the title compound.

[0168] LC-MS(ESI):[M+H] + =909.5;

[0169] 1H NMR (400MHz, CDCl3) δ11.28–11.22(m,1H),8.07–7.93(m,1H),7.53–7.37(m,3H),7.23–7.09(m,2H),7.06–6.90(m,2 H),6.66–6.36(m,2H),6.25–5.90(m,1H),5.81–5.24(m,1H),4.98–4.87(m,1H),4.05–3.98(m,3H),3.84–3.53(m,3H ),3.00–2.91(m,1H),2.21–2.19(m,3H),2.17–2.14(m,3H),1.73–1.69(m,1H),1.64–1.57(m,2H),1.53–1.50(m,1H) ,1.28–1.25(m,3H),1.22–1.21(m,3H),1.18–1.17(m,3H),1.17–1.13(m,6H),1.13–0.99(m,2H),0.82–0.78(m,2H).

[0170] Example 2 Synthesis of 3-((1S,2S)-1-(2-(S)-3'-(3-(1-methyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 2)

[0171] Step 1: Synthesis of 1-(1-cyanocyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0172] 1-(Cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (400 mg, 1.07 mmol) and 1,3,2-dioxathiane 2,2-dioxide (399 mg, 3.21 mmol) were added to anhydrous tetrahydrofuran (5 mL), and the atmosphere was replaced with nitrogen three times. 1 M lithium bistrimethylsilylamide (4.3 mL) was slowly added dropwise with stirring at 0°C. After the addition was complete, the reaction was continued at 0°C for 3 hours, and 1N dilute hydrochloric acid was added dropwise to quench the reaction. Water (30 mL) was added to dilute the reaction, and the mixture was extracted with ethyl acetate (15 mL×3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1-3:1) to obtain the title compound.

[0173] LC-MS(ESI):[M+H] + =400.2.

[0174] Step 2: Synthesis of N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0175] To a solution of 1-(1-cyanocyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (500 mg, 1.25 mmol) in DMSO (8 mL) were added sodium bicarbonate (526 mg, 6.26 mmol) and hydroxylamine hydrochloride (435 mg, 6.26 mmol). The mixture was reacted at 60°C for 16 hours, diluted with water (30 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give a crude product. The crude product, CDI (397 mg, 2.45 mmol) and DBU (466 mg, 3.06 mmol) were added to DMSO (5 mL). The reaction was allowed to react at room temperature for 2 hours, then diluted with water (30 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1-0:1) to obtain the title compound.

[0176] LC-MS(ESI):[M+H] + =459.3.

[0177] Step 3: Synthesis of 1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0178] The compound N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (210 mg, 0.46 mmol) and potassium hydroxide (514 mg, 9.16 mmol) were added to DMF (5 mL), reacted at 125 ° C for 16 hours, and 1N dilute hydrochloric acid was added dropwise to adjust the pH to acidic. The mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and then subjected to preparative HPLC to obtain the title compound.

[0179] LC-MS(ESI):[M+H] + =370.2.

[0180] Step 4: Synthesis of 3-((1S,2S)-1-(2-(S)-3'-(3-(1-methyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0181] (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, 0.06 mmol), 1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)- 1H-Indole-2-carboxylic acid (22 mg, 0.06 mmol), EDCI (28 mg, 0.15 mmol), HOAT (12 mg, 0.09 mmol) and DMF (1 mL) were added to a single-necked flask, and DIPEA (23 mg, 0.17 mmol) was added with stirring. The reaction was allowed to react at room temperature overnight, and water (20 mL) was added to dilute the mixture. The mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the title compound.

[0182] LC-MS(ESI):[M+H] + =867.6;

[0183] 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.32(s,1H),7.61–7.37(m,4H),7.28–7.21(m,2H), 7.18–7.07(m,3H),6.68(s,1H),4.90(p,J=6.2Hz,1H),4.15–4.10(m,3H),4.05–3.90(m,3 H),3.80–3.63(m,1H),3.56–3.44(m,2H),2.96–2.80(m,1H),2.28–2.20(m,6H),1.91–1.6 5(m,3H),1.55–1.36(m,3H),1.35–1.22(m,5H),1.19(d,J=6.3Hz,2H),0.91–0.84(m,2H).

[0184] Example 3 Synthesis of 3-((1S,2S)-1-(2-((S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 3)

[0185] Step 1: Synthesis of ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0186] To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (2.0 g, 7.46 mmol) in dioxane / H2O (46 mL / 12 mL) were added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.57 g, 7.46 mmol), Pd(dppf)Cl2·CH2Cl2 (0.61 g, 0.75 mmol), and K2CO3 (3.09 g, 22.38 mmol). The mixture was stirred at 80°C under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature, filtered, diluted with DCM (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 9:1-3:1) to obtain the title compound.

[0187] LC-MS(ESI):[M+H]+ =272.3.

[0188] Step 2: Synthesis of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0189] To a solution of ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (1.91 g, 7.04 mmol) in MeOH / THF (15 mL / 45 mL) was added 10% w / w Pd / C (200 mg), and the mixture was stirred at room temperature under H2 atmosphere overnight. The reaction was filtered, concentrated, slurried with MeOH, and filtered to give the title compound.

[0190] LC-MS(ESI):[M+H] + =274.1.

[0191] Step 3: Synthesis of ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0192] To a solution of ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (1.87 g, 6.84 mmol) in DMF (60 mL) was added NaH (60% in oil) (0.41 g, 10.26 mmol) at 0°C, and the mixture was stirred at 0°C for 0.5 h. 2-Chloroacetonitrile (1.03 g, 13.68 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with H2O (50 mL) at 0°C, and the suspension was filtered and dried to give the title compound.

[0193] LC-MS(ESI):[M+H] + =313.3.

[0194] Step 4: Synthesis of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0195] To a solution of ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (1.8 g, 5.76 mmol) in H2O / THF (16 mL / 28 mL) was added LiOH·H2O (360 mg, 86.4 mmol) at 0°C. The mixture was stirred at room temperature for 3 hours. The THF was removed in vacuo and the pH was adjusted to about 4-5 with 1N HCl solution. The suspension was filtered to give the title compound.

[0196] Step 5: Synthesis of 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0197] To a mixed solution of 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (1.51 g, 5.31 mmol) in DMF (70 mL) and HATU (3.03 g, 7.97 mmol) at 0°C was added DIPEA (2.6 mL, 15.93 mmol). The mixture was stirred at 0°C for 1 hour, followed by the addition of N-methylaniline (0.9 mL, 7.97 mmol). The mixture was stirred at room temperature overnight, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1 to 1:1) to obtain the title compound.

[0198] LC-MS(ESI):[M+H] + =374.3.

[0199] Step 6: Synthesis of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0200] Under N2 atmosphere at 0°C, to a solution of 1-(cyanomethyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (0.55 g, 1.47 mmol) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (0.51 g, 3.68 mmol) in THF (10 mL) was added dropwise LiHMDS (1.0 mol / L solution in THF, 5.9 mL, 5.89 mmol). The mixture was stirred at 0°C for 2 hours, quenched by addition of HCOOH (10 mL), concentrated in vacuo, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to give the title compound.

[0201] LC-MS(ESI):[M+H] + =414.2.

[0202] Step 7: Synthesis of N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide

[0203] A solution of 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-N-methyl-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (475 mg, 1.15 mmol), NH2OH·HCl (399 mg, 5.74 mmol) and K2CO3 (873 mg, 6.32 mmol) in EtOH (10 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated and then diluted with H2O (50 mL). The suspension was filtered and dried under vacuum. The solid was dissolved in DMSO (5 mL), followed by the addition of carbonyldiimidazole (373 mg, 2.3 mmol) and 1,8-diazabicycloundec-7-ene (437 mg, 2.87 mmol). The mixture was stirred at 80 ° C. for 1 hour, concentrated in vacuo, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to obtain the title compound.

[0204] LC-MS(ESI):[M+H] + =473.3.

[0205] Step 8: Synthesis of 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0206] A solution of N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxamide (215 mg, 0.45 mmol) and KOH (894 mg, 15.9 mmol) in diethanol methyl ether (10 mL) was stirred at 125°C overnight. The reaction solution was adjusted to pH = 3 with 5N HCl solution. The reaction solution was filtered, the solid was washed with H2O (5 mL), and dried under reduced pressure to give the title compound.

[0207] LC-MS(ESI):[M+H] + =384.2.

[0208] Step 9: Synthesis of 3-((1S,2S)-1-(2-((S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0209] (S)-1-(4-fluoro-1-methyl-1H-indol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.1 mmol), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran To a reaction flask were added 1H-indole-2-carboxylic acid (37 mg, 0.1 mmol), HOAT (19.8 mg, 0.15 mmol), EDCI·HCl (47 mg, 0.24 mmol), and DMF (2 mL). DIPEA (37.6 mg, 0.29 mmol) was added with stirring, and the mixture was reacted at room temperature overnight. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 60%-900%?) to obtain the title compound.

[0210] LC-MS(ESI):[M+H] + =881.5;

[0211] 1H NMR (400MHz, DMSO-d6) δ11.73(s,1H),8.33(s,1H),7.66(d,J=8.8Hz,1H),7.60(d,J=11.2Hz,1H) ,7.51(d,J=8.1Hz,1H),7.41(d,J=8.7Hz,1H),7.28(d,J=8.6Hz,1H),7.15(s,2H),7.09(s,1H),6 .98(d,J=29.2Hz,1H),5.75–5.26(m,1H),4.13(s,3H),3.98(d,J=11.0Hz,2H),3.47(s,4H),2.92 –2.71(m,1H),2.26(s,6H),1.75(d,J=10.5Hz,8H),1.38(s,4H),1.25(s,4H),1.22–1.11(m,2H).

[0212] Example 4 Synthesis of 3-((1S,2S)-1-(2-(S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 4)

[0213] Step 1: Synthesis of 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole

[0214] 5-Bromo-4-fluoro-1H-indazole (350 mg, 1.63 mmol), cyclopropylboronic acid (280 mg, 3.26 mmol), copper acetate (296 mg, 1.63 mmol), 2,2'-bipyridine (156 mg, 1.63 mmol), sodium carbonate (345 mg, 3.26 mmol) and dichloroethane (10 mL) were added to a reaction flask. The temperature was raised to 70°C and the reaction was allowed to react for 2 hours. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0215] LC-MS(ESI):[M+H] + =255.1.

[0216] Step 2: Synthesis of tert-butyl (S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0217] (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol), 5-bromo-1-cyclopropyl-4-fluoro-1H-indole (71 mg, 0.28 mmol), cuprous iodide (32 mg, 0.17 mmol), (1S,2S) -(+)-N,N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.17 mmol), potassium carbonate (89 mg, 0.64 mmol) and NMP (3 mL) were added to the reaction flask under nitrogen protection. After heating to 130 ° C and reacting for 2 hours, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0218] LC-MS(ESI):[M+H] + =642.4.

[0219] Step 3: Synthesis of (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0220] (S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) and dioxane hydrochloride (1 mL) were added to a reaction flask and reacted at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, extracted with ethyl acetate (15 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound.

[0221] LC-MS(ESI):[M+H] + =542.4.

[0222] Step 4: Synthesis of 3-((1S,2S)-1-(2-(S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0223] (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.09 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4- To the reaction flask were added 1H-indole-2-carboxylic acid (57 mg, 0.14 mmol), EDCI (44 mg, 0.23 mmol), HOAT (19 mg, 0.14 mmol) and DMF (2 mL). DIPEA (36 mg, 0.28 mmol) was added with stirring, and the mixture was reacted at room temperature overnight. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the title compound.

[0224] 1H NMR (400MHz, DMSO-d6) δ11.73(s,1H),8.29(s,1H),7.72–7.58(m,2H),7.57–7.48(m,1H),7.40(d,J=9. 0Hz,1H),7.27(d,J=8.6Hz,1H),7.12(d,J=26.1Hz,3H),6.97(d,J=31.6Hz,1H),6.83–6.67(m,1H),4.95 –4.85(m,1H),4.27–3.93(m,1H),3.91–3.83(m,1H),3.80–3.66(m,3H),3.14–2.97(m,1H),2.28–2.20( m,6H),1.79–1.48(m,5H),1.44–1.35(m,2H),1.29–1.24(m,12H),1.23–1.19(m,6H),0.91–0.81(m,2H).

[0225] Example 5 Synthesis of 3-((1S,2S)-1-(2-(S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 5)

[0226] (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.09 mmol), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyridin-2-yl)-1-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.09 mmol) and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyridin-2-yl)-1-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.09 mmol) were added. To the reaction flask were added 1H-indole-2-carboxylic acid (35 mg, 0.09 mmol), EDCI (44 mg, 0.23 mmol), HOAT (19 mg, 0.14 mmol) and DMF (2 mL). DIPEA (36 mg, 0.28 mmol) was added under stirring, and the mixture was reacted at room temperature overnight. Water (30 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the target compound.

[0227] 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.27(s,1H),7.67(d,J=8.8Hz,1H),7.59–7.56(m,1H),7.54– 7.46(m,1H),7.39(d,J=7.8Hz,1H),7.26(d,J=7.8Hz,1H),7.13–7.06(m,3H),7.00–6.91(m,1H),6.7 9–6.67(m,1H),5.33–5.30(m,1H),4.21–3.66(m,5H),3.51–3.37(m,2H),2.87–2.83(m,1H),2.24(s, 6H),2.07–1.90(m,1H),1.79–1.47(m,7H),1.41–1.22(m,6H),1.20–1.06(m,6H),0.85–0.81(m,1H).

[0228] Example 6 Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 6)

[0229] Step 1: Synthesis of 5-bromo-4-fluoro-1-(methyl-d3)-1H-indazole

[0230] Under ice bath, sodium hydride (60% dispersion in mineral oil) (48 mg, 1.21 mmol) was added portionwise to a solution of 5-bromo-4-fluoro-1H-indazole (200 mg, 0.93 mmol) in anhydrous DMF. The reaction was allowed to proceed for 1 hour after the addition was complete. Deuterated iodomethane (175 mg, 1.21 mmol) was slowly added, and the temperature was raised to room temperature for 4 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the title compound.

[0231] 1 H NMR (400MHz, DMSO-d6) δ 8.24 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 8.8, 6.4 Hz, 1H), 7.41 (dd, J = 8.8, 1.0 Hz, 1H).

[0232] Step 2: Synthesis of tert-butyl (S)-3'-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0233] (S)-2'-(4-Fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol), 5-bromo-4-fluoro-1-(methyl-d3)-1H-indole (60 mg, 0.26 mmol), cuprous iodide (32 mg, 0.17 mmol), (1S, 2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.17 mmol), potassium carbonate (89 mg, 0.64 mmol) and NMP (3 mL) were added to a bottle, protected by nitrogen, heated to 130 ° C and reacted for 2 hours, diluted with water (20 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0234] LC-MS(ESI):[M+H] + =619.4.

[0235] Step 3: Synthesis of (S)-1-(1-4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0236] (S)-3'-(3-(1-4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (78 mg, 0.13 mmol) and dioxane hydrochloride (1 mL) were added to a reaction flask and reacted at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, extracted with ethyl acetate (15 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound.

[0237] LC-MS(ESI):[M+H] + =519.4.

[0238] Step 4: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0239] (S)-1-(1-4-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (30 mg, 0.06 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2 ,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (36 mg, 0.9 mmol), EDCI (28 mg, 0.14 mmol), HOAT (12 mg, 0.09 mmol) and DMF (2 mL) were added to a single reaction bottle, and DIPEA (22 mg, 0.17 mmol) was added under stirring. The reaction was allowed to proceed at room temperature overnight, and water (20 mL) was added for dilution. The mixture was extracted with ethyl acetate (15 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the target compound.

[0240] 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.33(s,1H),7.70–7.60(m,2H),7.51(t,J=7.8Hz,1H),7 .44–7.38(m,1H),7.31–7.25(m,1H),7.24–7.07(m,3H),7.03–6.92(m,1H),6.85–6.64(m,1H),4 .93–4.85(m,1H),4.27–3.94(m,1H),3.89–3.65(m,3H),3.14–2.99(m,1H),2.29–2.21(m,6H),1 .80–1.49(m,5H),1.45–1.30(m,2H),1.29–1.26(m,10H),1.23–1.16(m,4H),0.92–0.82(m,2H).

[0241] Example 7 Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-2-(((S)-oxetane-2-yl)methyl)-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 7)

[0242] Step 1: Synthesis of (S)-5-bromo-4-fluoro-2-(oxetan-2-ylmethyl)-2H-indazole

[0243] 5-Bromo-4-fluoro-1H-indazole (200 mg, 0.93 mmol), oxetan-2-ylmethyl (S)-4-methylbenzenesulfonate (180 mg, 0.74 mmol), cesium carbonate (606 mg, 1.86 mmol) and acetonitrile (4 mL) were added to a reaction flask, heated to 80°C and reacted for 3 hours. Water (20 mL) was added to dilute the mixture, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0244] LC-MS(ESI):[M+H] + =285.0.

[0245] Step 2: Synthesis of tert-butyl (S)-3'-(3-(4-fluoro-2-(((S)-oxetane-2-yl)methyl)-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0246] (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol), (S)-5-bromo-4-fluoro-2-(oxetan-2-ylmethyl)-2H-indazole (39 mg, 0.13 mmol), cuprous iodide (16 mg, 0.09 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (12 mg, 0.09 mmol), potassium carbonate (44 mg, 0.32 mmol) and NMP (2 mL) were added to a bottle, protected by nitrogen, heated to 130 ° C and reacted for 2 hours. Water (20 mL) was added to dilute, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0247] LC-MS(ESI):[M+H] + =672.4.

[0248] Step 3: Synthesis of 1-(4-fluoro-2-(((S)-oxetan-2-yl)methyl)-2H-indazol-5-yl)-3-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0249] (S)-3'-(3-(4-fluoro-2-(((S)-oxetane-2-yl)methyl)-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol), 2,6-dimethylpyridine Pyridine (23 mg, 0.22 mmol) and dichloromethane (1 mL) were added to the reaction flask, and a solution of TMSOTf (41 mg, 0.19 mmol) dissolved in dichloromethane was slowly added dropwise at room temperature. After the addition was complete, the reaction was continued for 10 hours. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound, which was used directly in the next step without purification.

[0250] LC-MS(ESI):[M+H] + =572.3.

[0251] Step 4: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-2-(((S)-oxetan-2-yl)methyl)-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0252] 1-(4-fluoro-2-(((S)-oxetane-2-yl)methyl)-2H-indazol-5-yl)-3-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 0.07 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dimethylphenyl)- To the reaction flask were added (43 mg, 0.1 mmol) of (1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (43 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOAT (14 mg, 0.15 mmol) and DMF (2 mL). DIPEA (27 mg, 0.21 mmol) was added with stirring, and the mixture was reacted at room temperature overnight. Water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the title compound.

[0253] 1H NMR (400MHz, DMSO-d6) δ11.71(s,1H),8.72(s,1H),7.61–7.59(m,1H),7.39–7.37(m,2H),7.30–7.26(m,2H),7.13–7.06(m, 3H),6.98–6.91(m,1H),6.79–6.64(m,1H),5.34–5.31(m,1H),5.18–5.11(m,1H),4.79–4.72(m,2H),4.50(dd,J=13.6,7.4Hz ,1H),4.33–4.26(m,1H),4.18–3.99(m,1H),3.76–3.70(m,3H),3.09–2.97(m,1H),2.74–2.66(m,1H),2.48–2.37(m,1H),2.2 4(s,6H),2.03–1.96(m,1H),1.81–1.47(m,7H),1.36–1.30(m,3H),1.27–1.23(m,7H),1.14–1.10(m,4H),0.93–0.75(m,1H).

[0254] Example 8 Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 8)

[0255] Step 1: Synthesis of (S)-5-bromo-4-fluoro-1-(oxetan-2-ylmethyl)-1H-indazole

[0256] 5-Bromo-4-fluoro-1H-indazole (200 mg, 0.93 mmol), (S)-4-methylbenzenesulfonic acid oxetan-2-ylmethyl ester (180 mg, 0.74 mmol), cesium carbonate (606 mg, 1.86 mmol), and acetonitrile (4 mL) were added to the reaction, the temperature was raised to 80°C, and the reaction was carried out for 3 hours. Water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0257] LC-MS(ESI):[M+H] + =285.0.

[0258] Step 2: Synthesis of tert-butyl (S)-3'-(3-(4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0259] (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol), (S)-5-bromo-4-fluoro-1-(oxetan-2-ylmethyl)-1H-indazole (39 mg, 0.13 mmol), cuprous iodide (16 mg, 0.09 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (12 mg, 0.09 mmol), potassium carbonate (44 mg, 0.32 mmol) and NMP (2 mL) were added to the reaction flask. Under nitrogen protection, the temperature was raised to 130°C and the reaction was reacted for 2 hours. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, the title compound was obtained by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1).

[0260] LC-MS(ESI):[M+H] + =672.4.

[0261] Step 3: Synthesis of 1-(4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-indazol-5-yl)-3-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0262] (S)-3'-(3-(4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (61 mg, 0.09 mmol), 2,6-dimethylpyridine Pyridine (29 mg, 0.27 mmol) and dichloromethane (1 mL) were added to the reaction flask, and a solution of TMSOTf (50 mg, 0.23 mmol) dissolved in dichloromethane was slowly added dropwise at room temperature. After the addition was complete, the reaction was continued for 10 hours. Saturated sodium bicarbonate solution was added to adjust the pH to alkaline, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound, which was used directly in the next step without purification.

[0263] LC-MS(ESI):[M+H] + =572.4.

[0264] Step 4: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0265] 1-(4-Fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-indazol-5-yl)-3-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (40 mg, 0.07 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dimethylphenyl)- To the reaction flask were added (43 mg, 0.1 mmol) of (1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (43 mg, 0.1 mmol), EDCI (33 mg, 0.17 mmol), HOAT (14 mg, 0.15 mmol) and DMF (2 mL). DIPEA (27 mg, 0.21 mmol) was added with stirring, and the mixture was reacted at room temperature overnight. Water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the title compound.

[0266] 1H NMR (400MHz, DMSO-d6) δ11.71(s,1H),8.37(s,1H),7.72(d,J=8.7Hz,1H),7.60–7.56(m,1H),7.50–7.40(m,1H),7.40–7.32(m,1 H),7.27–7.23(m,1H),7.13–7.08(m,3H),6.98–6.93(m,1H),6.78–6.65(m,1H),5.34–5.31(m,1H),5.12–5.05(m,1H),4.81–4.62 (m,2H),4.45–4.41(m,1H),4.22–4.05(m,2H),3.76–3.71(m,3H),3.06–3.01(m,1H),2.69–2.65(m,1H),2.46–2.37(m,1H),2.28 –2.24(m,6H),2.02–1.98(m,1H),1.80–1.44(m,7H),1.41–1.28(m,3H),1.29–1.21(m,7H),1.18–1.12(m,4H),0.88–0.82(m,1H).

[0267] Example 9 Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-(3-fluorooxetane-3-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 9)

[0268] Step 1: Synthesis of 5-bromo-4-fluoro-1-((3-fluorooxetan-3-yl)methyl)-1H-indazole

[0269] 5-Bromo-4-fluoro-1H-indazole (150 mg, 0.7 mmol), (3-fluorooxetane-3-yl)methyl 4-methylbenzenesulfonate (145 mg, 0.56 mmol), cesium carbonate (454 mg, 1.4 mmol) and acetonitrile (3 mL) were added to a reaction flask, heated to 80°C and reacted for 2 hours. Water (20 mL) was added to dilute the mixture, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the target compound.

[0270] LC-MS(ESI):[M+H] + =303.0;

[0271] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=1.0Hz,1H),7.52(dd,J=8.9,6.2Hz,1H),7.17(dt,J=8.9,1.2Hz,1H),4.94–4.76(m,6H).

[0272] Step 2: Synthesis of (S)-1-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0273] (S)-2'-(4-Fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (68 mg, 0.15 mmol) and dioxane hydrochloride (1 mL) were added to a reaction flask, reacted at room temperature for 1 hour, and concentrated under reduced pressure to obtain the title compound.

[0274] Step 3: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0275] (S)-1-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (50 mg, 0.14 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic Acid (73 mg, 0.18 mmol), EDCI (65 mg, 0.34 mmol), HOAT (28 mg, 0.2 mmol) and DMF (2 mL) were added to a reaction flask, and DIPEA (352 mg, 2.72 mmol) was added with stirring. The reaction was allowed to react at room temperature overnight, diluted with water (20 mL), extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1-0:1) to obtain the title compound.

[0276] Step 4: Synthesis of 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-(3-fluorooxetan-3-yl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0277] 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.04 mmol), 5-bromo-4-fluoro-1-((3-fluorooxetane)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (30 mg, 0.04 mmol), -3-yl)methyl)-1H-indazole (18 mg, 0.06 mmol), cuprous iodide (6 mg, 0.03 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (4.5 mg, 0.03 mmol), potassium carbonate (16 mg, 0.12 mmol) and NMP (2 mL) were added to the reaction flask, protected by nitrogen, and heated to 130 ° C for 2 hours. Water (20 mL) was added to dilute, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and then subjected to preparative HPLC to obtain the target compound.

[0278] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H), δ8.41(s,1H),7.68(d,J=9.1Hz,1H),7.55–7.51(m,1H),7.42–7.37(m, 2H),7.18–6.96(m,5H),6.72–6.52(m,1H),5.33–5.31(m,1H),5.15–5.09(m,2H),4.86(dd,J=21.4,8.2Hz,2H ),4.65(dd,J=20.3,8.2Hz,2H),4.14–4.05(m,1H),3.75–3.70(s,3H),3.05–2.97(m,1H),2.23(s,6H),2.03– 1.97(m,1H),1.76–1.51(m,7H),1.35–1.30(m,3H),1.31–1.21(m,7H),1.18–1.15(m,4H),0.92–0.84(m,1H).

[0279] Example 10: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 10)

[0280] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (50 mg, 0.12 mmol), (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H -Imidazol-2-one (75 mg, 0.15 mmol), HOAT (25 mg, 0.18 mmol), EDCI·HCl (58 mg, 0.3 mmol) and DMF (2 mL) were added to the reaction flask, and DIPEA (47 mg, 0.36 mmol) was added with stirring. The reaction was allowed to react at room temperature overnight, diluted with water (20 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to obtain the title compound.

[0281] 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.34(s,1H),7.67(d,J=8.9Hz,1H),7.62(s,1H), 7.53–7.48(m,1H),7.42(q,J=7.9Hz,1H),7.30(d,J=8.7Hz,1H),7.18(d,J=6.6Hz,2H), 7.00(s,1H),6.80(d,J=11.6Hz,1H),5.58(s,1H),4.14(s,6H),3.74(d,J=8.3Hz,3H),3 .25–2.90(m,2H),2.28(s,9H),1.73–1.66(m,6H),1.38–1.24(m,6H),1.25–1.14(m,8H).

[0282] Example 11 Synthesis of 3-((1S,2S))-1-(2-(S)-3'-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 11)

[0283] Step 1: Synthesis of 5-bromo-1-(difluoromethyl)-4-fluoro-1H-indazole

[0284] 5-Bromo-4-fluoro-1H-indazole (500 mg, 2.33 mmol) was dissolved in DCM (10 mL). A solution of KOH (782.82 mg, 13.95 mmol) in water (1.44 mL) was added dropwise at 0°C. (Chlorodifluoromethyl)trimethylsilane (368.90 mg, 2.33 mmol) was then added dropwise. The reaction was continued at 0°C for 6 h. DCM (5 mL) and H₂O (5 mL) were then added to dilute the reaction solution. The solution was extracted with DCM (5 mL x 3). The organic phase was dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:0-9:1) to obtain the title compound.

[0285] Step 2: Synthesis of tert-butyl (S)-3'-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylate

[0286] To the reaction flask were added (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol), 5-bromo-1-(difluoromethyl)-4-fluoro-1H 1-Indazole (85.03 mg, 0.32 mmol), (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (15.21 mg, 0.11 mmol), cuprous iodide (33.94 mg, 0.11 mmol), potassium carbonate (88.68 mg, 0.64 mmol), and NMP (5 mL) were added under nitrogen atmosphere and stirred at 130°C for 2 h. The reaction was stopped, and saturated brine (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20-40%) to obtain the title compound.

[0287] LC-MS(ESI):[M+H] + =652.3.

[0288] Step 3: Synthesis of (S)-1-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one

[0289] To the reaction flask was added (S)-3'-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'(6'H)-carboxylic acid tert-butyl ester (76 mg, 0.12 mmol), and then a dioxane hydrochloride solution (2 mL) was added. The mixture was stirred at room temperature for 1 h, and the mixture was evaporated under reduced pressure to dryness to obtain the target compound hydrochloride, which was used directly in the next step.

[0290] LC-MS(ESI):[M+H] + =552.3.

[0291] Step 4: Synthesis of 3-((1S,2S))-1-(2-(S)-3'-(3-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0292] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (80 mg, 0.19 mmol), (S)-1-(1-(difluoromethyl)-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl ... )-1,3-Dihydro-2H-imidazol-2-one hydrochloride (50 mg, 0.09 mmol), HOAt (17.37 mg, 0.13 mmol), EDCI (40.77 mg, 0.21 mmol) and DMF (5 mL) were added to a reaction flask, and DIPEA (219.89 mg, 1.70 mmol) was added with stirring. The mixture was reacted at room temperature overnight, and 10 mL of brine was added. The mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:3) to obtain the title compound.

[0293] 1 H NMR(500MHz,DMSO-d6)δ11.66(s,1H),9.20(d,J=64.5Hz,1H),8.13(t,J=59.3Hz,1H),7 .61(d,J=68.0Hz,2H),7.38(d,J=36.6Hz,2H),7.20(s,1H),7.02(d,J=52.1Hz,3H),6.83 –6.55(m,1H),5.59–5.27(m,1H),3.66(s,4H),2.99(s,1H),2.19(s,5H),1.73–1.43(m,7 H), 1.35 (d, J = 21.0Hz, 4H), 1.21 (d, J = 15.0Hz, 6H), 1.13 (s, 5H), 0.84 (d, J = 41.3Hz, 3H).

[0294] Example 12 Synthesis of 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 12)

[0295] Step 1: Synthesis of ethyl 7-bromoindolizine-2-carboxylate

[0296] Sodium bicarbonate (19.53 g, 232.52 mmol) was added to a solution of 4-bromo-2-methylpyridine (20 g, 116.26 mmol) and ethyl 3-bromopyruvate (34.01 g, 174.39 mmol) in acetonitrile (200 mL). The mixture was reacted at 90°C for 16 hours. The mixture was filtered through celite, and the residue was washed twice with ethyl acetate. The filtrate was washed with water (60 mL × 3) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:0-9:1) to obtain the title compound.

[0297] LC-MS(ESI):[M+H] + =268.1.

[0298] Step 2: Synthesis of ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate

[0299] Zinc powder (3.90 g, 59.68 mmol) was added to DMF (20 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred in an ice-water bath. Trimethylsilyl chloride (0.81 g, 7.46 mmol) and 1,2-dibromoethane (1.40 g, 7.46 mmol) were added dropwise, and the mixture was stirred at room temperature for 5 minutes. A solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (10.75 g, 44.76 mmol) in DMF (10 mL) was slowly added dropwise while stirring in an ice-water bath, and the mixture was allowed to react at room temperature for 30 minutes. Under nitrogen, ethyl 7-bromoindolizine-2-carboxylate (4.00 g, 14.92 mmol), [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (0.40 g, 1.49 mmol), and palladium acetate (0.33 g, 1.49 mmol) dissolved in DMF (10 mL) were added, and the temperature was raised to 50°C for 1 hour. After stirring in an ice-water bath, 5N dilute hydrochloric acid (12 mL) was added dropwise to acidify the mixture. The mixture was diluted with saturated brine (60 mL), dissolved in ethyl acetate (60 mL), and filtered through celite. The filtrate was extracted with ethyl acetate (120 mL × 3). The organic phase was collected, washed with saturated brine (120 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:0-9:1) to obtain the title compound.

[0300] LC-MS(ESI):[M+H] + =302.3;

[0301] 1 H NMR(500MHz,DMSO-d6)δ8.21(d,J=7.3Hz,1H),7.99(d,J=1.7Hz,1H),7.21(s,1H),6.65–6.59(m,2H),4.25(q,J=7.1Hz,2H), 3.74–3.66(m,2H),2.89–2.81(m,1H),1.69–1.62(m,2H),1.55–1.38(m,2H),1.30(t,J=7.1Hz,3H),1.24(s,3H),1.18(s,3H).

[0302] Step 3: Synthesis of (S)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester

[0303] The stereoisomers of the compound 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester (4.98 g) synthesized by the method in step 2 were separated by supercritical fluid chromatography, and the latter peak was taken to obtain the target compound.

[0304] Step 4: Synthesis of ethyl (S)-3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate

[0305] (S)-7-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester (2.7 g, 8.96 mmol), 2-bromoacetonitrile (1.18 g, 9.85 mmol), ferrous sulfate heptahydrate (1.25 g, 4.48 mmol) and NaI (1.34 g, 8.96 mmol) were added to DMSO (30 mL). 30% hydrogen peroxide (4.6 mL, 8.96 mmol) was added dropwise at 0°C. The mixture was reacted at 0°C for 10 min, diluted with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 3) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:0-3:2) to obtain the title compound.

[0306] LC-MS(ESI):[M+H] + =341.3.

[0307] Step 5: Synthesis of (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester

[0308] Compound (S)-ethyl 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylate (1.5 g, 4.41 mmol) and 1,3,2-dioxothiolane 2,2-dioxide (1.64 g, 13.22 mmol) were added to THF (10 mL). LiHMDS (39.7 mL, 39.66 mmol) was added dropwise at 0°C. The mixture was reacted at 0°C for 2 hours. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with water (20 mL x 3) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:0-3:2) to obtain the target compound.

[0309] LC-MS(ESI):[M+H] + =367.4.

[0310] Step 6: Synthesis of (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid

[0311] Compound (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid ethyl ester (1.58 g, 4.31 mmol) and lithium hydroxide monohydrate (0.9 g, 21.56 mmol) were added to 1,4-dioxane (12 mL) and water (6 mL). The reaction was carried out at 40°C for 2 h. The pH was adjusted to 4 with 2N dilute hydrochloric acid in an ice bath. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (MeOH:DCM (v / v) = 5%) to obtain the target compound.

[0312] LC-MS(ESI):[M+H] + =339.3.

[0313] Step 7: Synthesis of ethyl 2,2-dimethyl-3-oxopropionate

[0314] To the reaction flask, ethyl 3-hydroxy-2,2-dimethylpropionate (5 g, 34.2 mmol) and dichloromethane (100 mL) were added in batches. Dessmartin (21.76 g, 51.3 mmol) was added in batches at 0°C. After complete addition, the mixture was warmed to room temperature and stirred for 2 hours. Under an ice bath, saturated sodium thiosulfate solution was added to quench the mixture. Saturated sodium bicarbonate was then added to neutralize the large amount of acetic acid. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-5:1) to obtain the target compound.

[0315] Step 8: Synthesis of ethyl (S)-3-((1-cyanopropan-2-yl)amino)-2,2-dimethylpropanoate

[0316] To a reaction flask, (S)-3-aminobutyronitrile hydrochloride (300 mg, 2.49 mmol), methanol (10 mL), and diisopropylethylamine (322 mg, 2.49 mmol) were added sequentially. The reaction mixture was stirred for 20 minutes. Acetic acid (134 mg, 2.24 mmol) and ethyl 2,2-dimethyl-3-oxopropanoate (470 mg, 3.26 mmol) were then added and stirring continued for 2 hours. Sodium triacetoxyborohydride (1.05 g, 4.98 mmol) was then added and stirring continued at room temperature for 6 hours. The mixture was diluted with water and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, which was used directly in the next step.

[0317] Step 9: Synthesis of ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)-2,2-dimethylpropanoate

[0318] To the reaction flask, crude (S)-ethyl 3-((1-cyanopropyl-2-yl)amino)-2,2-dimethylpropanoate and di-tert-butyl dicarbonate (2 mL) were added sequentially. Stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-5:1) to obtain the title compound.

[0319] LC-MS(ESI):[M+H-Boc] + =213.1.

[0320] Step 10: Synthesis of tert-butyl (2S)-3-cyano-2,5,5-trimethyl-4-oxopiperidine-1-carboxylate

[0321] To a reaction flask, add (S)-ethyl 3-((tert-butoxycarbonyl)(1-cyanopropyl-2-yl)amino)-2,2-dimethylpropanoate (263 mg, 0.84 mmol), tetrahydrofuran (6 mL), and a 1M solution of potassium tert-butoxide in THF (1.3 mL, 1.26 mmol). After complete addition, stir at room temperature for 1 hour. Quench with saturated ammonium chloride solution and extract with ethyl acetate (3 x 15 mL). The combined organic phases are washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound, which is used directly in the next step.

[0322] LC-MS(ESI):[M+H] + =267.3.

[0323] Step 11: Synthesis of tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0324] (4-Fluoro-3,5-dimethylphenyl)hydrazine (200 mg, 1.3 mmol), (2S)-3-cyano-2,5,5-trimethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (173 mg, 0.65 mmol), and ethanol (10 mL) were added to a reaction flask. Under nitrogen protection, a dioxane hydrochloride solution (0.16 mL) was added, and the temperature was raised to 80°C for 1.5 hours. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 9:1-2:1) to obtain the title compound.

[0325] LC-MS(ESI):[M+H] +=403.4.

[0326] Step 12: Synthesis of (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (813-6)

[0327] To the reaction flask were added tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (173 mg, 0.43 mmol), DIPEA (277 mg, 2.15 mmol), and tetrahydrofuran (6 mL). Phenyl chloroformate (134 mg, 0.86 mmol) was added dropwise with stirring. After reacting at room temperature for 1 hour, 2,2-dimethoxyethane-1-amine (181 mg, 1.72 mmol) was added. Stirring was continued for 1 hour, and saturated brine was added. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to obtain the title compound.

[0328] LC-MS(ESI):[M+H] + =534.4.

[0329] Step 13: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0330] (S)-tert-Butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (213 mg, 0.4 mmol), methanesulfonic acid (34.52 mg, 0.36 mmol), and tetrahydrofuran (5 mL) were added to a reaction flask. The temperature was raised to react for 1 hour. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to obtain the title compound.

[0331] LC-MS(ESI):[M+H] + =470.3.

[0332] Step 14: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0333] (S)-2-(4-Fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (190 mg, 0.4 mmol), 5-bromo-4-fluoro-1-methyl-1H-indole (120 mg, 0.53 mmol), cuprous iodide (64.2 mg, 0.2 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (29 mg, 0.2 mmol) and NMP (5 mL) were added to the reaction flask under nitrogen protection, and the temperature was raised to 130 ° C. for 2 hours. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:EA (v / v) = 2:1-1:1) to obtain the title compound.

[0334] LC-MS(ESI):[M+H] + =618.4.

[0335] Step 15: Synthesis of (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0336] (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (250 mg, 0.4 mmol) and 4N hydrochloric acid dioxane solution (5.1 mL) were added to the reaction flask, reacted at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the hydrochloride salt of the target compound.

[0337] LC-MS(ESI):[M+H] + =518.4.

[0338] Step 16: Synthesis of 1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropane-1-carbonitrile

[0339] To a solution of (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid (100 mg, 0.30 mmol), (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (166 mg, 0.30 mmol) and HATU (169 mg, 0.44 mmol) in DMF (4 mL) was added DIPEA (764 mg, 5.91 mmol), and the mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (PE:EA (v / v) = 1:1-1:4) to obtain the title compound.

[0340] LC-MS(ESI):[M+H] + =838.6.

[0341] Step 17: Synthesis of (Z)-1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximidamide

[0342] To a solution of 1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropane-1-carbonitrile (140 mg, 0.17 mmol) in DMSO (10 mL) were added sodium bicarbonate (281 mg, 3.34 mmol) and hydroxylamine hydrochloride (232 mg, 3.34 mmol). The mixture was reacted at 60°C for 16 hours, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained by separation by silica gel column chromatography (PE:EA (v / v) = 1:1-1:4).

[0343] LC-MS(ESI):[M+H] + =871.6.

[0344] Step 18: Synthesis of 3-(1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0345] Compound (Z)-1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximidamide (116 mg, 0.13 mmol), CDI (43 mg, 0.19 mmol) and DBU (51 mg, 0.33 mmol) were added to DMSO (10 mL) and reacted at room temperature for 2 hours. The mixture was diluted with water (15 mL), extracted with ethyl acetate (8 mL × 3), and the organic phases were combined. The organic phases were washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:4 to 0:1) to obtain the title compound.

[0346] LC-MS(ESI):[M+H] + =897.6;

[0347] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.18(d,J=7.0Hz,1H),7.64(d,J=8.8Hz,1H),7.62–7. 43(m,1H),7.34(s,1H),7.16(d,J=6.3Hz,2H),7.08(s,2H),6.92(s,1H),6.73(dd,J=7.4,1. 8Hz,1H),6.41(d,J=32.5Hz,1H),5.75(s,1H),4.11(d,J=14.6Hz,3H),3.73(d,J=9.4Hz,2H) ,3.25–3.15(m,1H),2.34–2.05(m,12H),1.70(s,4H),1.42–1.26(m,9H),1.29–1.15(m,6H).

[0348] Example 13 Synthesis of 3-(1-(2-(((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 13)

[0349] Step 1: Synthesis of 1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropane-1-carbonitrile

[0350] To (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (120 mg, 0.22 mmol), (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)- ) To a solution of indolizine-2-carboxylic acid (98 mg, 0.29 mmol) and HATU (126 mg, 0.33 mmol) in DMF (2 mL) was added DIPEA (86 mg, 0.66 mmol), and the mixture was reacted at room temperature overnight. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL×3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then purified by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1) to obtain the title compound.

[0351] LC-MS(ESI):[M+H] + =862.6.

[0352] Step 2: Synthesis of (Z)-1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximidamide

[0353] To 1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropane-1- To a solution of formonitrile (130 mg, 0.15 mmol) in DMSO (4 mL) were added sodium bicarbonate (253 mg, 3.02 mmol) and hydroxylamine hydrochloride (210 mg, 3.02 mmol), and the mixture was reacted at 60°C for 16 hours. Water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1).

[0354] Step 3: Synthesis of 3-(1-(2-(((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0355] Compound (Z)-1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl) -N'-Hydroxycyclopropane-1-carboximidamide (89 mg, 0.13 mmol), CDI (32 mg, 0.2 mmol) and DBU (38 mg, 0.25 mmol) were added to DMSO (5 mL) and reacted at room temperature for 2 hours. Water (30 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was obtained by silica gel column chromatography (PE:EA (v / v) = 3:1-0:1).

[0356] 1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),8.31–8.09(m,2H),7.76–7.62(m,1H),7.62–7.45(m,1H),7.36 –7.26(m,1H),7.17–7.02(m,2H),7.00–6.82(m,1H),6.74–6.62(m,1H),6.49–6.30(m,1H),4.90–4.8 5(m,1H),3.97–3.80(m,2H),3.74–3.66(m,2H),3.42–3.38(m,1H),2.95–2.91(m,1H),2.26–2.17(m, 6H),1.73–1.62(m,3H),1.53–1.38(m,4H),1.33–1.24(m,11H),1.20–1.12(m,6H),0.87–0.84(m,2H).

[0357] Example 14 Synthesis of 3-(1-(7-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 14)

[0358] Step 1: Synthesis of 1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',-4',5',6'-tetrahydrospiro[cyclopropane-7'-pyrazolo[4,3]pyridine]-5'-carbonyl)indolizin-3-yl)cyclopropane-1-carbonitrile

[0359] To (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2'-,4',5',6'-tetrahydrospiro[cyclopropane-7'-pyrazolo[4,3-c]pyridin]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (160 mg, 0.31 mmol), (S)-1-(S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indazol-5-yl To a solution of oxazine-2-carboxylic acid (105 mg, 0.31 mmol) and HATU (177 mg, 0.47 mmol) in DMF (2 mL) was added DIPEA (100 mg, 0.78 mmol), and the reaction was allowed to react at room temperature overnight. Water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1).

[0360] LC-MS(ESI):[M+H] + =836.6.

[0361] Step 2: Synthesis of (Z)-1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximidamide

[0362] To 1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',-4',5',6'-tetrahydrospiro[cyclopropane-7'-pyrazolo[4,3]pyridine]-5'-carbonyl)indolizin-3-yl)cyclopropane-1-carbonitrile (135 To a solution of 4-nitropropene (5-nitropropene) in DMSO (5 mL) was added sodium bicarbonate (271 mg, 3.23 mmol) and hydroxylamine hydrochloride (225 mg, 3.23 mmol), and the mixture was reacted at 60 ° C for 16 hours. Water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL × 3). The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, the title compound was obtained by silica gel column chromatography (PE:EA (v / v) = 5:1-1:1).

[0363] LC-MS(ESI):[M+H] + =869.9.

[0364] Step 3: Synthesis of 3-(1-(7-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3'-(3-(4-fluoro-1-methyl-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0365] Compound (Z)-1-(7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(S)-3'-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)indolizin-3-yl)-N'-hydroxycyclopropane Propane-1-carboximidamide (110 mg, 0.13 mmol), CDI (41 mg, 0.25 mmol) and DBU (48 mg, 0.32 mmol) were added to DMSO (5 mL) and reacted at room temperature for 2 hours. Water (30 mL) was added to dilute the mixture, extracted with ethyl acetate (15 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1-0:1) to obtain the title compound.

[0366] 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),8.30(m,2H),7.66–7.61(m,1H),7.55–7.41(m,1H),7.35–7 .21(m,1H),7.19–7.03(m,2H),6.99–6.83(m,1H),6.75–6.66(m,1H),6.46–6.24(m,1H),5.82(s,1 H),4.13–4.06(m,3H),3.74–3.68(m,2H),3.48–3.32(m,2H),2.94–2.91(m,1H),2.25–2.18(m,6H ),1.79–1.59(m,3H),1.55–1.35(m,4H),1.31–1.24(m,9H),1.19–1.16(m,4H),0.85–0.82(m,2H).

[0367] Example 15 Synthesis of 3-(1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 15)

[0368] Step 1: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0369] Dissolve (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (1.80 g, 5.97 mmol) in methanol (18 mL). Add sodium hydroxide (0.60 g, 14.93 mmol) in water (4.5 mL) dropwise with stirring. React at 65°C for 2 hours. Cool to room temperature and adjust the pH to approximately 5 with 6N hydrochloric acid. A large amount of solid precipitates, which is filtered, and the filter cake is washed with water and dried to obtain the title compound.

[0370] LC-MS(ESI):[M+H] + =274.1.

[0371] Step 2: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0372] Compound (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (1.50 g, 5.49 mmol) was dissolved in N,N-dimethylacetamide (15 mL). Thionyl chloride (0.78 g, 6.59 mmol) was added dropwise with stirring at 0°C. The mixture was allowed to react at room temperature for 1 hour. N-Methylaniline (0.71 g, 6.59 mmol) and triethylamine (1.67 g, 16.46 mmol) were added with stirring at 0°C. The reaction was allowed to react at room temperature for 1 hour. The reaction was quenched with water (25 mL), resulting in the precipitation of a large amount of solid. The filter cake was washed with water and dried to obtain the title compound.

[0373] LC-MS(ESI):[M+H] + =363.3.

[0374] Step 3: Synthesis of (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0375] To a solution of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.90 g, 5.24 mmol) in 1,3-dimethyl-2-imidazolidinone (19 mL) was added 8N aqueous potassium hydroxide solution (2.0 mL, 15.73 mmol). Chloroacetonitrile (0.59 g, 7.86 mmol) was slowly added at 0°C, and the mixture was allowed to react at 30°C for 3 hours. The pH was adjusted to slightly acidic with 2N dilute hydrochloric acid, diluted with water (50 mL), and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with 20% brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (EA:PE (v / v) = 0-17%) to obtain the title compound.

[0376] LC-MS(ESI):[M+H] + =402.3.

[0377] Step 4: Synthesis of (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0378] To a solution of (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.0 g, 2.49 mmol) and vinyl sulfate (0.93 g, 7.47 mmol) in THF (15 mL) was slowly added dropwise lithium bistrimethylsilylamide (1 M, 4.3 mL, 9.96 mmol) at 0°C under a nitrogen atmosphere. The reaction was continued at 0°C for 3 hours. The mixture was quenched by the addition of 1 M dilute hydrochloric acid (15 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phases were washed sequentially with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product.

[0379] LC-MS(ESI):[M+H] + =428.2.

[0380] Step 5: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

[0381] To a solution of (S)-1-(1-cyanocyclopropyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (1.0 g, 2.34 mmol) in DMSO (8 mL) was added hydroxylamine hydrochloride (0.81 g, 11.69 mmol) and sodium bicarbonate (0.98 g, 11.69 mmol). The mixture was heated to 60°C for 2 hours. The mixture was diluted with water (25 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was added to a solution of CDI (0.7 g, 4.34 mmol) and DBU (0.83 g, 5.43 mmol) in DMSO (10 mL). The mixture was stirred at room temperature for 1 hour, diluted with water (30 mL), and extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the desired product.

[0382] LC-MS(ESI):[M+H] + =487.2.

[0383] Step 6: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0384] To a solution of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (1.0 g, 2.06 mmol) in ethylene glycol methyl ether (3 mL) was added KOH (1.15 g, 20.55 mmol) and the mixture was heated to 130°C and reacted overnight. The mixture was cooled to room temperature, the pH was adjusted to approximately 3 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The desired product was obtained by preparative HPLC.

[0385] LC-MS (ESI): [M+H]+=398.2.

[0386] Step 7: Synthesis of 3-(1-(2-((S)-3'-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0387] (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-yl)-1,3-dihydro-2H-imidazol-2-one (1 g, 1.85 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran- 4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.73 g, 1.85 mmol), EDCI (0.84 g, 4.28 mmol), and HOAT (0.34 g, 2.49 mmol) were dissolved in DMF (20 mL), followed by the addition of DIPEA (0.72 g, 5.54 mmol). The mixture was allowed to react at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative HPLC to yield the title compound.

[0388] 1H NMR (400MHz, CDCl3) δ11.27(s,1H),8.01(s,1H),7.56–7.50(m,1H),7.47–7.31(m,2H),7.27–7.08(m,2H),7.06–6.91(m, 2H),6.62(d,J=5.0Hz,1H),6.55–6.48(m,1H),6.27–6.23(m,1H),5.82–5.77(m,1H),4.12–3.93(m,1H),3.84–3.64(m,2H) ,3.58–3.42(m,2H),3.07–2.86(m,1H),2.22–2.09(m,6H),2.08–1.99(m,1H),1.75–1.67(m,2H),1.68–1.59(m,4H),1.58– 1.48(m,3H),1.44–1.28(m,2H),1.28(s,3H),1.25–1.19(m,4H),1.19–1.09(m,4H),1.07–0.88(m,1H),0.78–0.65(m,1H).

[0389] Example 16 Synthesis of 3-(1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 16)

[0390] Step 1: Synthesis of ethyl 2,2-dimethyl-3-oxopropionate

[0391] To a solution of ethyl 3-hydroxy-2,2-dimethylpropionate (5 g, 34.2 mmol) in dichloromethane (100 mL) at 0°C, Dess-Martin reagent (21.76 g, 51.3 mmol) was added portionwise and allowed to react at room temperature for 2 hours. The mixture was quenched by the addition of saturated sodium thiosulfate solution under ice-cooling, followed by the addition of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL x 3), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA (v / v) = 10:1 to 5:1) afforded the title compound.

[0392] Step 2: Synthesis of ethyl (S)-3-((1-cyanopropan-2-yl)amino)-2,2-dimethylpropanoate

[0393] (S)-3-Aminobutyronitrile hydrochloride (300 mg, 2.49 mmol), methanol (10 mL), and diisopropylethylamine (322 mg, 2.49 mmol) were added to a reaction flask and stirred for 20 minutes. Acetic acid (134 mg, 2.24 mmol) and ethyl 2,2-dimethyl-3-oxopropanoate (470 mg, 3.26 mmol) were then added and stirred for 2 hours. Sodium triacetoxyborohydride (1.05 g, 4.98 mmol) was then added and stirred at room temperature for 6 hours. The mixture was diluted with water and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound, which was used directly in the next step.

[0394] Step 3: Synthesis of ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanoprop-2-yl)amino)-2,2-dimethylpropanoate

[0395] Crude (S)-ethyl 3-((1-cyanopropyl-2-yl)amino)-2,2-dimethylpropanoate and di-tert-butyl dicarbonate (2 mL) were added to a reaction flask. Stirring was continued overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 10:1 to 5:1) to obtain the target compound.

[0396] LC-MS(ESI):[M+H-Boc] + =213.1.

[0397] Step 4: Synthesis of tert-butyl (2S)-3-cyano-2,5,5-trimethyl-4-oxopiperidine-1-carboxylate

[0398] To a solution of ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropyl-2-yl)amino)-2,2-dimethylpropanoate (263 mg, 0.84 mmol) in tetrahydrofuran (6 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.3 mL, 1.26 mmol). After reacting at room temperature for 1 hour, the mixture was quenched by the addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 15 mL), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound.

[0399] LC-MS(ESI):[M+H] + =267.3.

[0400] Step 5: Synthesis of (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0401] Dissolve (4-fluoro-3,5-dimethylphenyl)hydrazine (200 mg, 1.3 mmol) and tert-butyl (2S)-3-cyano-2,5,5-trimethyl-4-oxopiperidine-1-carboxylate (173 mg, 0.65 mmol) in ethanol (10 mL). Add 4.0 M hydrochloric acid in dioxane (0.16 mL) under a nitrogen atmosphere and heat to 80°C for 1.5 hours. Cool to room temperature, add saturated brine (30 mL), and extract with ethyl acetate (3 x 15 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography (PE:EA (v / v) = 10:1 to 3:1) to obtain the title compound.

[0402] LC-MS(ESI):[M+H] + =403.4.

[0403] Step 6: Synthesis of tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0404] (S)-tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (173 mg, 0.43 mmol) and DIPEA (277 mg, 2.15 mmol) were dissolved in tetrahydrofuran (6 mL). Phenyl chloroformate (134 mg, 0.86 mmol) was slowly added and the mixture was allowed to react at room temperature for 1 hour. 2,2-Dimethoxyethane-1-amine (181 mg, 1.72 mmol) was added and the reaction was continued at room temperature for 1 hour. The mixture was quenched with saturated brine (30 mL) and extracted with ethyl acetate (3 x 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1-2:1) to obtain the target compound.

[0405] LC-MS(ESI):[M+H] + =534.4.

[0406] Step 7: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0407] To a solution of (S)-tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (213 mg, 0.4 mmol) in tetrahydrofuran (5 mL) was added methanesulfonic acid (34.52 mg, 0.36 mmol) and heated to 60°C for 1 hour. After cooling to room temperature, saturated brine (30 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was separated by silica gel column chromatography (PE:EA (v / v) = 3:1-2:1) to obtain the title compound.

[0408] LC-MS(ESI):[M+H] + =470.3.

[0409] Step 8: Synthesis of (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0410] To a solution of (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (206 mg, 0.4 mmol) and 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (145 mg, 0.6 mmol) in NMP (5 mL) were added cuprous iodide (69.6 mg, 0.2 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (31 mg, 0.2 mmol) and potassium carbonate (181.9 mg, 1.32 mmol), and the mixture was heated to 130°C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1-2:1) to obtain the title compound.

[0411] LC-MS(ESI):[M+H] + =644.3.

[0412] Step 9: Synthesis of (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0413] To a 4N hydrochloric acid solution in dioxane (5.1 mL) was added tert-butyl (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (200 mg, 0.3 mmol), the mixture was reacted at room temperature for 1 hour, and the mixture was concentrated under reduced pressure to obtain the title compound.

[0414] LC-MS(ESI):[M+H] + =544.3.

[0415] Step 10: Synthesis of 3-(1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0416] (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (55 mg, 0.10 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4 5-(5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (40 mg, 0.10 mmol), EDCI (48 mg, 0.25 mmol), and HOAT (21 mg, 0.15 mmol) were dissolved in DMF (2 mL). DIPEA (39 mg, 0.30 mmol) was added and the mixture was allowed to react overnight at room temperature. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to preparative HPLC to obtain the target compound.

[0417] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.25(d,J=18.9Hz,1H),7.76–7.59(m,1H),7.49(d,J= 8.7Hz,2H),7.28–7.05(m,4H),6.92(d,J=38.9Hz,1H),6.72(d,J=32.3Hz,1H),5.83–5.22(m, 1H),3.82(s,2H),3.72(d,J=8.8Hz,2H),3.04(s,2H),2.25(s,6H),2.10–1.93(m,1H),1.84(s ,1H),1.68(s,4H),1.55(d,J=12.6Hz,4H),1.36(s,4H),1.26(d,J=16.9Hz,8H),1.19(s,6H).

[0418] Example 17 Synthesis of 3-[[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoroindazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 17)

[0419] Step 1: Synthesis of tert-butyl (S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylate

[0420] N-Methylpyrrolidone (5 mL), (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylic acid tert-butyl ester (500 mg, 1.07 mmol), 5-bromo-1-cyclopropyl-6-fluoroindazole (410 mg, 1.60 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (60 mg, 0.43 mmol), potassium carbonate (440 mg, 3.21 mmol) and cuprous iodide (70 mg, 0.21 mmol) were added to the reaction flask in sequence, placed under a nitrogen atmosphere, and heated to 100°C for 12 hours. After completion of the reaction, the product was cooled to room temperature and quenched with water (50 mL). The product was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated and purified by reverse-phase column chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 62.00%-92.00%, 15.00 min; flow rate: 60.00 ml / min) to obtain the title compound.

[0421] LC-MS(ESI):[M+H] + =642.4.

[0422] Step 2: Synthesis of 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one

[0423] (S)-tert-Butyl 3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylate (550 mg, 0.86 mmol) and 2M hydrochloric acid solution in dioxane (20 mL) were added sequentially to the reaction flask and stirred at 40°C for 1 hour. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the target compound.

[0424] LC-MS(ESI):[M+H] + =542.3.

[0425] Step 3: Synthesis of 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-5'-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indol-2-yl]carbonyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one

[0426] N,N-dimethylformamide (5 mL), 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one (460 mg, The following: 1,2-Dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (278 mg, 1.02 mmol), N,N-diisopropylethylamine (439 mg, 3.40 mmol), and HATU (484 mg, 1.27 mmol) were added sequentially to the reaction flask and reacted at 25°C for 3 hours. After completion of the reaction, the reaction solution was slowly poured into water (50 mL) to quench the reaction. The mixture was then extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%).

[0427] LC-MS(ESI):[M+H] + =797.3.

[0428] Step 4: Synthesis of [5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]acetonitrile

[0429] N,N-dimethylformamide (5 mL), 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-5'-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indol-2-yl]carbonyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1, 7'-Pyrazolo[4,3-c]pyridin-3'-yl]-2,3-dihydro-1H-imidazol-2-one (400 mg, 0.50 mmol) was added to the reaction flask, and the system was cooled to 0°C. Then, sodium hydride (200 mg, 5.02 mmol, 60%) was added under a nitrogen atmosphere. After stirring at 0°C for 0.5 hour, chloroacetonitrile (493 mg, 6.53 mmol) was added and stirring was continued at 0°C for 1.5 hours. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride (50 mL) to quench the mixture. Ethyl acetate (50 mL x 2) was added, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%) to obtain the target compound.

[0430] LC-MS(ESI):[M+H] + =836.4.

[0431] Step 5: Synthesis of 1-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropane-1-carbonitrile

[0432] To [5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane- To a solution of 1,7'-pyrazolo[4,3-c]pyridinyl]-5'-yl]carbonyl]indol-1-yl]acetonitrile (380 mg, 0.45 mmol) in tetrahydrofuran (5 mL) was added ethylene sulfate (140 mg, 1.14 mmol). The mixture was cooled to 0°C, and then a 1M solution of lithium bis(trimethylsilyl)amide in toluene (1.8 mL, 1.82 mmol) was slowly added dropwise. The reaction was continued at 0°C for 2 hours. After completion of the reaction, the reaction solution was slowly poured into saturated aqueous ammonium chloride (50 mL) for quenching. The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%) to obtain the target compound.

[0433] LC-MS(ESI):[M+H] + =862.3.

[0434] Step 6: Synthesis of 1-[2-[(S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-N-hydroxycyclopropane-1-carboximidamide

[0435] To a solution of 1-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoroindazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropane-1-carbonitrile (270 mg, 0.31 mmol) in dimethyl sulfoxide (5 mL) was added 50% aqueous solution of hydroxylamine (517 mg, 7.83 mmol), and the mixture was stirred at 25°C for 3 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound.

[0436] LC-MS(ESI):[M+H] + =895.4.

[0437] Step 7: Synthesis of 3-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropyl]-1,2,4-oxadiazol-5(4H)-one

[0438] Dimethyl sulfoxide (2 mL), 1-(2-((S)-3'-(3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-(( (S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl-1H-indol-1-yl-N-hydroxycyclopropane-1-carboximidamide (140 mg, 0.16 mmol), N,N'-carbonyldiimidazole (63 mg, 0.39 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (95 mg, 0.63 mmol) were added sequentially to a reaction flask and reacted at 25°C for 12 hours. After completion, the reaction solution was directly purified by reverse-phase column chromatography (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [A: H2O (0.05% NH3H2O); B: ACN]; B%: 10.00%-40.00%, 11.00 min; flow rate: 25.00 ml / min) to obtain the target compound.

[0439] LC-MS(ESI):[M+H] + =921.6;

[0440] 1 H NMR(400MHz, CDCl3)δ=11.41-11.30(m,1H),8.00(s,1H),7.87-7.69(m,1H),7.65-7.57(m,1H),7.56-7.47(m,1H),7.46 -7.31(m,1H),7.14-7.01(m,2H),6.73-6.40(m,2H),6.37-6.26(m,1H),6.25-6.02(m,1H),5.92-5.26(m,1H),4.27-3.9 3(m,1H),3.92-3.81(m,2H),3.80-3.49(m,2H),3.13-2.98(m,1H),2.29-2.23(m,6H),1.82-1.72(m,3H),1.70-1.57(m, 6H),1.48-1.39(m,2H),1.35-1.33(m,3H),1.32-1.27(m,4H),1.26-1.17(m,5H),1.11-0.93(m,1H),0.86-0.37(m,1H).

[0441] Example 18 Synthesis of 3-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoroindazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 18)

[0442] Step 1: Synthesis of tert-butyl (S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylate

[0443] (S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-3'-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylic acid tert-butyl ester (500 mg, 1.07 mmol), 5-bromo-1-cyclopropyl-7-fluoroindazole (409.19 mg, A mixture of 1,2-dimethyl-1,4-diaminobenzene (1,60 mg, 0.53 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (76.06 mg, 0.53 mmol), potassium carbonate (443.38 mg, 3.21 mmol), and cuprous iodide (203.67 mg, 1.07 mmol) was added to a reaction flask, followed by N-methylpyrrolidone (8 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), and aqueous ammonia (15 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 50%) to obtain the target compound.

[0444] LC-MS(ESI):[M+H] + =642.3.

[0445] Step 2: Synthesis of 3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one

[0446] Dissolve (S)-tert-butyl 3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4'-dihydrospiro(cyclopropyl-1,7'-pyrazolo[4,3-c]pyridine)-5'(6'H)-carboxylate (550 mg, 0.86 mmol) in 2 M dioxane hydrochloride (10 mL) and react at 40°C for 2 hours. After completion, concentrate under reduced pressure to obtain the target compound.

[0447] LC-MS(ESI):[M+H] + =542.2.

[0448] Step 3: Synthesis of 3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-5'-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indol-2-yl]carbonyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one

[0449] 3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-3'-yl]-2,3-dihydro-1H-imidazol-2-one (460 mg, 0.85 mmol) and 5-[(4S)-2, 2-Dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (255.36 mg, 0.93 mmol) was dissolved in N,N-dimethylformamide (8 mL), followed by the addition of N,N-diisopropylethylamine (329.32 mg, 2.55 mmol) and HATU (419.83 mg, 1.10 mmol). The mixture was reacted at 20°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 50%) to obtain the title compound.

[0450] LC-MS(ESI):[M+H] + =797.3.

[0451] Step 4: Synthesis of [5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]acetonitrile

[0452] 3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-1-[(4'S)-2'-(4-fluoro-3,5-dimethylphenyl)-5'-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indol-2-yl]carbonyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3 [-c]pyridin-3'-yl]-2,3-dihydro-1H-imidazol-2-one (300 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (8 mL) and cooled to 0°C. Sodium hydride (150.58 mg, 3.76 mmol, 60%) was added under a nitrogen atmosphere. After 0.5 hour, chloroacetonitrile (369.49 mg, 4.89 mmol) was added, and stirring was continued at 0°C for 2.5 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of ammonium chloride (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 50%) to obtain the title compound.

[0453] LC-MS(ESI):[M+H] + =836.5.

[0454] Step 5: Synthesis of 1-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropane-1-carbonitrile

[0455] [5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane [1,7'-pyrazolo[4,3-c]pyridinyl]-5'-yl]carbonyl]indol-1-yl]acetonitrile (300 mg, 0.36 mmol) and ethylene sulfate (111.35 mg, 0.90 mmol) were dissolved in tetrahydrofuran (6 mL), cooled to 0°C, and a 1M solution of lithium bis(trimethylsilyl)amide in toluene (1.4 mL, 1.44 mmol) was slowly added dropwise. The reaction was continued at 0°C for 2 hours. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride (30 mL) for quenching and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 50%) to obtain the target compound.

[0456] LC-MS(ESI):[M+H] + =862.3.

[0457] Step 6: Synthesis of 1-[2-[(S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-N-hydroxycyclopropane-1-carboximidamide

[0458] To a solution of 1-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoroindazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropane-1-carbonitrile (220 mg, 0.26 mmol) in dimethyl sulfoxide (5 mL) was added 50% aqueous hydroxylamine solution (0.5 mL, 16.32 mmol), and the mixture was reacted at 30°C for 3 hours. After the reaction was completed, the reaction solution was poured into water (60 mL), extracted with ethyl acetate (60 mL×2), and the organic phases were combined, washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound.

[0459] LC-MS(ESI):[M+H] + =895.4.

[0460] Step 7: Synthesis of 3-([5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-2-[[(4'S)-3'-[3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-5',6'-dihydro-4'H-spiro(cyclopropane-1,7'-pyrazolo[4,3-c]pyridine)-5'-yl]carbonyl]indol-1-yl]cyclopropyl]-1,2,4-oxadiazol-5(4H)-one

[0461] 1-(2-((S)-3'-(3-(1-cyclopropyl-7-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2'-(4-fluoro-3,5-dimethylphenyl)-4'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)-5-((S)-2,2-dimethyltetrahydro (-2H-pyran-4-yl)-1H-indol-1-yl)-N-hydroxycyclopropane-1-carboximidazole (100 mg, 0.11 mmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N'-carbonyldiimidazole (45.29 mg, 0.28 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (68.04 mg, 0.45 mmol) were added. The mixture was reacted at 30°C for 12 hours. After completion of the reaction, the reaction solution was directly purified by reverse-phase column chromatography (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 65.00%-95.00%, 10.00 min; flow rate: 25.00 ml / min) to obtain the target compound.

[0462] LC-MS(ESI):[M+H] + =921.5;

[0463] 1 H NMR(400MHz, DMSO-d6)δ=12.23-11.95(m,1H),8.21-8.01(m,1H),7.94-7.75(m,1H),7.64-7.60( m,1H),7.56-7.32(m,3H),7.21(d,J=8.4Hz,1H),7.17-6.97(m,3H),6.78-6.63(m,1H),5.98-5.1 8(m,1H),4.23-3.88(m,2H),3.78-3.61(m,3H),3.09-2.95(m,1H),2.23-2.13(m,6H),1.87-1.59 (m,6H),1.58-1.48(m,2H),1.36-1.30(m,4H),1.27(s,3H),1.21-1.06(m,8H),1.02-0.70(m,2H).

[0464] Example 19 Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 19)

[0465] Step 1: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-tetramethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0466] (S)-2-(4-Fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol), 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (97.56 mg, 0.43 mmol), cuprous iodide (13.52 mg, 0.04 mmol), (1S,2 S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (12.12 mg, 0.09 mmol), potassium carbonate (88.3 mg, 0.64 mmol) and NMP (3 mL) were added to a reaction flask, heated to 130 ° C under a nitrogen atmosphere for 2 hours, added with saturated brine (30 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (EA: PE (v / v) = 0% -60%) to obtain the title compound.

[0467] Step 2: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-one

[0468] (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-tetramethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (66 mg, 0.11 mmol) and 4 M hydrochloric acid dioxane solution (0.3 mL) were added to the reaction flask successively. After reacting at room temperature for 1 hour, the mixture was directly concentrated under reduced pressure to obtain the target compound.

[0469] Step 3: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0470] To (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-one (100 mg, 0.19 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazole- To a solution of 3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (76.79 mg, 0.19 mmol) and HATU (110.2 mg, 0.29 mmol) in DMF (2 mL) was added DIPEA (74.92 mg, 0.58 mmol), and the mixture was reacted at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by preparative HPLC to obtain the title compound.

[0471] 1H NMR (400MHz, CDCl3) δ8.18–8.09(m,1H),7.69–7.42(m,4H),7.30–7.28(m,3H),7. 19–7.06(m,3H),6.89–5.75(m,5H),4.14–4.01(m,2H),3.90–3.80(m,2H),3.66–3. 33(m,1H),3.17–2.96(m,1H),2.34–2.25(m,6H),1.85–1.73(m,4H),1.65–1.57(m ,4H),1.58–1.50(m,2H),1.45–1.41(m,3H),1.39–1.30(m,6H),1.28–1.22(m,3H).

[0472] Example 20 Synthesis of 3-[1-[2-((S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 20)

[0473] Step 1: Synthesis of (S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0474] N-Methylpyrrolidone (5 mL), (S)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), 5-bromo-1-cyclopropyl-6-fluoroindazole (407.44 mg, 1.60 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (60.59 mg, 0.43 mmol), potassium carbonate (441.48 mg, 3.19 mmol), and cuprous iodide (67.58 mg, 0.21 mmol) were added sequentially to a reaction flask, placed under a nitrogen atmosphere, and heated to 100°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched with water (300 mL). The mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound was isolated and purified by silica gel column chromatography (EA:PE (v / v) = 50%).

[0475] LC-MS(ESI):[M+H] + =644.4.

[0476] Step 2: Synthesis of (S)-1-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-3-[2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-4,7,7-trimethyl-2,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-1,3-dihydro-2H-imidazol-2-one

[0477] A dioxane hydrochloride solution (20 mL, 20.00 mmol) and (S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (550 mg, 0.85 mmol) were added sequentially to the reaction flask and stirred at 40°C for 1 hour. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the target compound.

[0478] LC-MS(ESI):[M+H] + =544.3.

[0479] Step 3: Synthesis of 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indole-2-carbonyl]-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-1,3-dihydro-2H-imidazol-2-one

[0480] N,N-dimethylformamide (5 mL), (S)-1-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-3-[2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-2,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-1,3-dihydro-2H-imidazol-2-one (460 mg, 0.85 mmol), 5-[(4S)-2,2-Dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indole-2-carboxylic acid (247.38 mg, 0.91 mmol), N,N-diisopropylethylamine (389.92 mg, 3.02 mmol), and HATU (430.17 mg, 1.13 mmol) were added sequentially to a reaction flask and reacted at 25°C for 3 hours. After completion, the reaction solution was slowly poured into water (100 ml) for quenching, followed by extraction with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was then isolated and purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%) to obtain the title compound.

[0481] LC-MS(ESI):[M+H] + =799.3.

[0482] Step 4: Synthesis of 2-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]acetonitrile

[0483] N,N-dimethylformamide (5 mL), 3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-1-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-5-[5-[(4S)-2,2-dimethyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-1H-indole-2-carbonyl]-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4, 3-c]pyridin-3-yl]-1,3-dihydro-2H-imidazol-2-one (400 mg, 0.50 mmol) was added to the reaction flask. The system was cooled to 0°C and, under nitrogen protection, sodium hydride (200.77 mg, 5.02 mmol) was added under a nitrogen atmosphere. After stirring at 0°C for 0.5 hour, chloroacetonitrile (492.65 mg, 6.53 mmol) was added and stirring continued at 0°C for 1.5 hours. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride (300 mL) to quench the mixture. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was then purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%) to obtain the title compound.

[0484] LC-MS(ESI):[M+H] + =838.5.

[0485] Step 5: Synthesis of 1-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]cyclopropane-1-carbonitrile

[0486] To a solution of 2-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoroindazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]acetonitrile (200 mg, 0.24 mmol) and ethylene sulfate (74.05 mg, 0.60 mmol) in tetrahydrofuran (10 mL) was slowly added lithium bis(trimethylsilyl)amide 1.0 M tetrahydrofuran solution (1.0 mL, 0.95 mmol) under cooling at 0°C, and stirring was continued at 0°C for 2 hours. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride (200 mL) for quenching and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (EA:PE (v / v) = 33%) to obtain the title compound.

[0487] LC-MS(ESI):[M+H] + =864.4.

[0488] Step 6: Synthesis of 1-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-N-hydroxycyclopropane-1-carboximidamide

[0489] To a solution of 1-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]cyclopropane-1-carbonitrile (85 mg, 0.10 mmol) in dimethyl sulfoxide (1 mL) was added 50% aqueous hydroxylamine solution (0.1 mL, 2.95 mmol), and the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), and then extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound.

[0490] LC-MS(ESI):[M+H] + =897.5.

[0491] Step 7: Synthesis of 3-[1-[2-((S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0492] To 1-[2-[(S)-3-[3-(1-cyclopropyl-6-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran To a solution of [4-[(1,8-[(1,8-diazabicyclo[5.4.0]undec-7-ene]] (90 mg, 0.10 mmol) and N,N'-carbonyldiimidazole (48.81 mg, 0.30 mmol) in dimethyl sulfoxide (1.5 mL)] was added 1,8-diazabicyclo[5.4.0]undec-7-ene (61.1 mg, 0.40 mmol) and allowed to react at 25°C for 12 hours. After completion, the reaction solution was directly purified by reverse-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [A: H2O (0.05% HCl); B: ACN]; B%: 62.00%-92.00%, 13.00 min; flow rate: 25.00 ml / min) to obtain the title compound.

[0493] LC-MS(ESI):[M+H] + =923.4;

[0494] 1H NMR(400MHz, DMSO-d6)δ=12.25-11.98(m,1H),8.26-8.03(m,1H),8.01-7.83(m,1H),7.82-7.69(m,1H), 7.61-7.41(m,2H),7.24-7.07(m,3H),7.05-6.92(m,1H),6.89-6.58(m,2H),5.86-5.14(m,1H),4.66-3.9 0(m,1H),3.79-3.66(m,3H),3.10-2.94(m,1H),2.59-2.49(m,2H),2.25(s,6H),1.90-1.80(m,1H),1.74 -1.62(m,1H),1.77-1.59(m,4H),1.56-1.39(m,5H),1.35(m,3H),1.28(m,3H),1.18(m,5H),1.13(m,4H).

[0495] Example 21 Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-(oxetane-3-yl)--1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0496] Step 1: Synthesis of tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-tetrahydromethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0497] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol), 5-bromo-4-fluoro-1-(oxetane-3-yl)-1H-indazole (173.2 mg, 0.64 mmol), cuprous iodide (40.55 mg, 0.13 mmol), (1S ,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (36.35 mg, 0.26 mmol), potassium carbonate (264.89 mg, 1.92 mmol) and NMP (5 mL) were added to the reaction flask, heated to 130 ° C under a nitrogen atmosphere for 2 hours, added with saturated brine (30 mL), extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (EA:PE (v / v) = 0%-60%) to obtain the target compound.

[0498] Step 2: Synthesis of (S)-1-(4-fluoro-1-(oxetane)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0499] To a solution of (S)-tert-butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-tetrahydromethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.15 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was reacted at room temperature for 1 hour and then concentrated under reduced pressure to obtain the title compound.

[0500] Step 3: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-(oxetan-3-yl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0501] To (S)-1-(4-fluoro-1-(oxetane)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, 0.21 mmol), 5-((S)-2,2-dimethyltetrahydro-2H- To a solution of (4-pyran-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (71 mg, 0.21 mmol) and HATU (110 mg, 0.27 mmol) in DMF (3 mL) was added DIPEA (69.8 mg, 0.54 mmol) and allowed to react at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative HPLC to yield the title compound.

[0502] 1 H NMR(400MHz, CDCl3)δ11.30(s,1H),8.33–8.23(m,1H),7.68–7.58(m,2H),7.56–7.49 (m,1H),7.40–7.28(m,5H),7.23–7.03(m,3H),6.89–6.08(m,3H),5.81–5.71(m,2H),5 .27–5.15(m,4H),4.19–4.05(m,2H),3.65–3.54(m,2H),3.44–3.22(m,1H),2.95–2.83 (m,1H),2.33–2.44(m,6H),1.87–1.80(m,3H),1.60–1.57(m,15H),1.23–1.09(m,3H).

[0503] Experimental Example 1 In vitro cell activity test

[0504] 1. Materials

[0505] (1) Cell lines

[0506] The cell line was constructed by Shanghai WuXi AppTec Co., Ltd., as shown in Table 1 below.

[0507] Table 1

[0508] (2) Reagents are shown in Table 2 below.

[0509] Table 2

[0510] (3) Instruments are shown in Table 3 below.

[0511] Table 3

[0512] (4) Compound information

[0513] Prepare the compound solution in DMSO at a working concentration of 100 μM or 10 μM. Perform 10 4-fold dilutions (maximum concentration after dilution is 1000 nM or 100 nM) using an automated pipetting workstation.

[0514] 2. Methods

[0515] (1) Experimental materials

[0516] The experimental buffer is shown in Table 4 below.

[0517] Table 4

[0518] The final concentrations of the detection reagents are shown in Table 5 below.

[0519] Table 5

[0520] (2) Experimental methods

[0521] (a) Preparation of compound plates:

[0522] The test compound was diluted 4-fold at 10 points with a starting concentration of 100 μM. The dilution was completed by the automatic pipetting workstation.

[0523] (b) Transfer compounds:

[0524] (i) Use a liquid handler to transfer 100 nL of 100x compound to a 384-well plate.

[0525] (ii) Centrifuge the 384-well plate at 1000 rpm for 5 seconds.

[0526] (c) Preparation of cell suspension

[0527] (i) Thaw a cryopreserved tube of HEK293 cells expressing hGLP-1R in 37°C warm water immediately.

[0528] (ii) Transfer the cell suspension to a 15 mL centrifuge tube and gently rinse with 10 mL of HBSS.

[0529] (iii) Centrifuge the tube at 1000 rpm at room temperature for 1 minute.

[0530] (iv) Discard the supernatant.

[0531] (v) Gently rinse with 10 ml of HBSS, pellet the cells by centrifugation, and resuspend the cells in assay buffer.

[0532] (vi) Measure cell density and activity using a cell counter.

[0533] (vii) Dilute the GLP-1R cell concentration to 1.0*10 5 / mL.

[0534] (viii) Transfer 10 μL of the diluted cell suspension into a 384-well plate.

[0535] (ix) Incubate at room temperature for 30 minutes.

[0536] (d) Detection:

[0537] (i) Add 10 μL of 800 nM serially diluted cAMP standard to empty wells of a 384-well plate.

[0538] (ii) Add 10 μL of cAMP detection reagent.

[0539] (iii) After incubation at room temperature for 60 minutes, the plate was read on a microplate reader.

[0540] The results are shown in Table 6, which shows the agonistic effects (EC 50 ).

[0541] Table 6. Agonist effect test results of compounds provided in some examples of the present invention

[0542] Results and Discussion: The compounds of the present invention exhibited superior agonist ability on GLP-1 receptor.

[0543] Experimental Example 2: Pharmacokinetic Study of the Compounds of the Invention in Mice

[0544] 1. Experimental Materials

[0545] C57BL / 6 mice: male, 6-8 weeks old, weighing 20-30 g, were purchased from Weitonglihua (Beijing) Laboratory Animal Technology Co., Ltd.

[0546] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0547] Instrument: AB LCMS-5500 tandem mass spectrometer

[0548] 2. Experimental methods

[0549] The compound was weighed and dissolved in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate system. All formulations were clear solutions and administered intravenously or orally to mice. Blood samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. At each PK sampling point, 30 μL of whole blood was collected into an EDTA-K2 anticoagulant blood collection tube and centrifuged at 4°C within 30 minutes to obtain plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or frozen until analysis.

[0550] Approximately 1 mg of compound was weighed and dissolved in DMSO, vortexed, and sonicated to obtain a 1 mg / mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile in water to obtain standard working solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL. Quality control working solutions at concentrations of 10, 20, 500, and 8,000 ng / mL were prepared using the same dilution method. Three μL of the standard working solutions at concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) were added to 30 μL of blank C57BL / 6 mouse plasma to obtain a total volume of 33 μL of standard curve samples with concentrations ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Quality control samples with concentrations of (1 ng / ml (low-1) and 2 ng / ml (low-2), 50 ng / ml (medium), 800 ng / ml (high)) were prepared separately.

[0551] Proteins were precipitated by adding 200 μL of acetonitrile containing the internal standard (dexamethasone) to 33 μL of standard sample, 33 μL of quality control sample, or 33 μL of unknown sample (30 μL of plasma and 3 μL of blank solution). The samples were then vortexed for 30 seconds and centrifuged at 4000 g at 4°C for 15 minutes. The supernatant was diluted threefold with water, and 10 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis using the following detection conditions:

[0552] Chromatographic column: Raptor Biphenyl 2.7μm 2.1×50mm

[0553] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), gradient elution according to the table below.

[0554] 3. Data processing

[0555] Using Phoenix™ Pharmacokinetic data were analyzed using a non-compartmental model using the software.

[0556] The results are shown in Table 7, which shows the pharmacokinetic parameters of mice.

[0557] Table 7. Experimental results of pharmacokinetic parameters of compounds provided in some examples of the present invention

[0558] Results and discussion: The compound of the present invention is better absorbed orally in mice and has higher exposure, half-life and bioavailability than LY3502970.

[0559] Experimental Example 3: Pharmacokinetic Study in Rats

[0560] 1. Experimental Materials

[0561] SD rats: male, 6-8 weeks old, weighing 200-300 g, were purchased from Sibeifu (Beijing) Experimental Animal Technology Co., Ltd.

[0562] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0563] Instrument: AB LCMS-5500 tandem mass spectrometer

[0564] 2. Experimental methods

[0565] The compound was weighed and dissolved in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate system. All formulations were clear solutions and administered intravenously or orally to rats. Blood samples were collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. At each PK sampling point, 200 μL of whole blood was collected into an EDTA-K2 anticoagulant blood collection tube and centrifuged at 4°C within 30 minutes to obtain plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or frozen until analysis.

[0566] Approximately 1 mg of the compound of the present invention was weighed and dissolved in DMSO, vortexed, and sonicated to obtain a 1 mg / mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile in water to obtain standard working solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL. Quality control working solutions were prepared using the same dilution method at concentrations of 10, 20, 500, and 8000 ng / mL. These quality control samples were prepared on the day of analysis using the same method as the standard curve samples. 5 μL of standard working solution at concentrations (5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) was added to 50 μL of blank SD rat plasma to create a total volume of 55 μL of standard curve samples with concentrations ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Separate quality control samples at concentrations of 1 ng / mL (low-1) and 2 ng / mL (low-2), 50 ng / mL (medium), and 800 ng / mL (high) were prepared.

[0567] Proteins were precipitated by adding 200 μL of acetonitrile containing the internal standard (dexamethasone) to 55 μL of standard sample, 55 μL of QC sample, or 55 μL of unknown sample (50 μL of plasma sample in 5 μL of 50% acetonitrile in water). The samples were then vortexed for 30 seconds and centrifuged at 4000 g, 4°C for 15 minutes. The supernatant was diluted threefold with water, and 5 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis using the following conditions:

[0568] Chromatographic column: HALO 90A Phenly-Hexyl, 2μm 2.1×30mm

[0569] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), gradient elution according to the table below.

[0570] 3. Data processing

[0571] Using Phoenix™ Pharmacokinetic data were analyzed using a non-compartmental model using the software.

[0572] The results are shown in Table 8, which shows the pharmacokinetic parameters of rats.

[0573] Table 8. Experimental results of pharmacokinetic parameters of compounds provided in some examples of the present invention

[0574] Results and discussion: The experimental results showed that the compound of the present invention was better absorbed orally in rats and had a higher exposure or half-life than LY3502970.

[0575] Experimental Example 4: Pharmacokinetic Study of the Compound of the Invention in Cynomolgus Monkeys

[0576] 1. Experimental Materials

[0577] Cynomolgus monkeys: male, 2-5 years old, weighing 2-6 kg, were purchased from Ankai Yibo (Zhanjiang) Biotechnology Co., Ltd. or Ankai Yibo (Zhaoqing) Biotechnology Co., Ltd.

[0578] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0579] Instrument: AB LCMS-5500 tandem mass spectrometer

[0580] 2. Experimental methods

[0581] Six 2-6 kg cynomolgus macaques were divided into two groups. One group received a single intravenous injection of 1 mg / kg, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after dosing. The other group received a single oral dose of 5 mg / kg, and blood was collected at 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after dosing. After pretreatment, plasma samples were analyzed by LC / MS / MS in MRM mode. Appropriate standard curves were established to quantify the target compound in the plasma samples and obtain drug concentration-time curves. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin software.

[0582] The results are shown in Table 9, which shows the pharmacokinetic parameters of cynomolgus monkeys.

[0583] Table 9. Experimental results of pharmacokinetic parameters of compounds provided in some examples of the present invention

[0584] Results and discussion: The compounds of the present invention were well absorbed orally in cynomolgus monkeys and had high exposure, half-life and bioavailability.

[0585] Experimental Example 5: Stability in Liver Microsomes

[0586] 1. Experimental Materials

[0587] 2. Experimental methods

[0588] Preparation of compound working solution: Prepare high concentration stock solution of test substance and control drug verapamil powder with DMSO, and dilute with DMSO to 100 μM working solution before use. The final concentration of test substance and verapamil is 1 μM.

[0589] Preparation of phosphate buffer (100 mM, pH 7.4): Weigh 7.098 g of disodium hydrogen phosphate and add it to 500 mL of pure water, then sonicate to dissolve it. This is Solution A. Weigh 3.400 g of potassium dihydrogen phosphate and add it to 250 mL of pure water, then sonicate to dissolve it. This is Solution B. Add Solution B to Solution A, and the pH will be 7.4.

[0590] Preparation of 10mM NADPH: Before the experiment, weigh an appropriate amount of NADPH and prepare a working solution with a concentration of 10mM using phosphate solution.

[0591] Preparation of incubation system: The incubation system was prepared according to the table below and preheated in a 37°C water bath for 10 minutes before use.

[0592] Transfer 25 μL of NADPH or phosphate buffered saline to the above incubation system and add 2.5 μL of 100 μM test substance or verapamil. Prepare duplicates for samples with NADPH; prepare single replicates for samples without NADPH.

[0593] At 0.5, 5, 15, 30, and 60 minutes, 30 μL of the suspension was collected, 150 μL of acetonitrile containing the internal standard was added to terminate the reaction, and the mixture was vortexed for 10 minutes.

[0594] Protein precipitation was then performed by centrifugation at 3220 g for 40 minutes. 100 μL of the supernatant was transferred to a sample plate and mixed with 100 μL of pure water for UPLC-MS / MS analysis.

[0595] 3. Data processing

[0596] All data calculations were performed using Microsoft Excel. Peak areas were determined by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0597] In vitro half-life (t 1 / 2 ) is calculated by slope: t 1 / 2 =0.693 / k

[0598] The in vitro clearance (unit: μL / min / mg) was calculated using the following formula:

[0599] CL int =0.693 / t 1 / 2*(Incubation system volume (μL) / Protein content (mg))

[0600] The results are shown in Table 10, which shows the experimental results of the stability of the compounds provided in some examples of the present invention in human liver microsomes.

[0601] Table 10. Experimental results of the stability of compounds provided in some examples of the present invention in human liver microparticles

[0602] Results and Discussion: The compound of the present invention exhibits good stability, which is significantly higher than that of LY3502970.

[0603] Experimental Example 6: Kinetic Solubility

[0604] Take 2.5μL of 20mM DMSO stock solution and add it to each 96-well plate (n=2) containing 497.5μL of simulated fasting intestinal fluid (FaSSIF pH 6.5) for a final concentration of 100μM (containing 0.5% DMSO). After adding a stirring bar to each well, seal it and shake it in a constant temperature shaker at 25℃ and 1100rpm for 2h. After shaking, filter the sample into the filter plate using a vacuum filter. Take 5μL of the filtrate, add 5μL of DMSO, and then add an appropriate amount of ultrapure water and acetonitrile mixed solution (1:1) containing internal standard to dilute the sample to the corresponding multiple. Mix well and prepare for LC-MS / MS analysis.

[0605] Take 5 μL of 100 μM DMSO standard solution, add 5 μL of different buffers, then add an appropriate amount of ultrapure water and acetonitrile mixed solution (1:1) containing internal standard to dilute the solution to the corresponding multiple, mix well, and perform LC-MS / MS analysis together with the sample.

[0606] The solubility values ​​of the test samples and standard controls are calculated according to the following formula:

[0607] The kinetic solubility calculation results of the test compounds are shown in Table 11:

[0608] Table 11. Kinetic solubility test results of compounds provided in some examples of the present invention

[0609] Results and Discussion: The compounds of the present invention exhibited good kinetic solubility, and their solubility was significantly higher than that of LY3502970.

[0610] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in: L1 is -C(=O)-, -S(=O)2- or -CR 10 R 11 -; L2 is -NR 12 -、 -C(=O)NR 13 -、 -NR 14 C(=O)NR 15 - or -CR 16 R 17 -; L3 is a key or -CR 18 R 19 -; L4 is a key or -CR 20 R 21 -; X1 is CH, NH, O or S; X2 is C or N; Y1 and Y2 are each independently CH or N; Y3 and Y4 are each independently C or N; R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace; R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl; R 3 is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace; R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 4 for R 5 and R 6 Each independently is H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent; or R 5 and R 6 Together with the carbon atoms to which they are attached, they can form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 1-3 substituted by an alkylamino substituent; R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 and R 25 Each independently represents H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino or nitro, provided that R 22 、R 23 、R 24 and R 25 At least one of them is not hydrogen; or R 22 and R 23 、R 24 and R 25 、R 23 and R 24 independently and optionally together with the carbon atom to which they are attached may form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 substituted by an alkylamino substituent; R 9 H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 substituted by a cycloalkyl substituent; R 12 、R 13 、R 14 and R 15 Each independently is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; Wherein, formula (I) is not the following compound:

2. The compound according to claim 1, wherein for 3. The compound according to claim 1 or 2, wherein R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace; R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl; R 3 is a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace; R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

4. The compound according to any one of claims 1 to 3, wherein R 1 Phenyl, The phenyl group, Can be optionally replaced by 1, 2 or 3 R 1a replace; R 1a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c , methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the ... 2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c each independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R 2b and R 2c Together with the phosphorus atoms to which they are attached, they can form R 3 is oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, The oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, Can be optionally replaced by 1, 2 or 3 R 3a replace; R 3a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, ethyl , n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

5. The compound according to any one of claims 1 to 4, wherein R 5 and R 6 Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent; or R 5 and R 6 Together with the carbon atom to which they are attached, they may form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino; R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 and R 25 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, Ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro, provided that R 22 、R 23 、R 24 and R 25 At least one of them is not hydrogen; or R 22 and R 23 、R 24 and R 25 、R 23 and R 24 independently and optionally together with the carbon atom to which they are attached can form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino; R 9 is H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, Methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently and optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R 12 、R 13 、R 14 and R 15 Each is independently H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

6. The compound according to any one of claims 1 to 5, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

9. The use according to claim 8, wherein The GLP-1 receptor agonist-mediated disease is diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease or dementia.

10. The use according to claim 9, wherein The diabetes mellitus is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of the adult.