Tetrahydropyrazolopyridine derivative and use thereof

Abstract

The present invention relates to the field of drugs and to a tetrahydropyrazolopyridine derivative and a use thereof. Specifically, the present invention relates to a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound of formula (I). The compound and a pharmaceutical composition thereof of the present invention, as GLP-1R agonists, can be used for preparing drugs for preventing or treating GLP-1R-related diseases, especially for preparing drugs for treating diabetes.

Description

Tetrahydropyrazole-pyridine derivatives and their uses Technical Field

[0001] This invention belongs to the pharmaceutical field. Specifically, this invention relates to a new class of tetrahydropyrazole-pyridine derivatives as GLP-1R agonists, pharmaceutical compositions thereof, and the use of such compounds and pharmaceutical compositions thereof in the preparation of medicaments for treating GLP-1R-related diseases. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin consisting of 30 or 31 amino acids, secreted by L cells in the small intestine. GLP-1 exerts a wide range of effects through its receptor, including promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. Therefore, GLP-1 analogs have shown efficacy in reducing HbA1c and weight loss and have been developed as effective therapeutic agents for the treatment of diabetes and obesity. GLP-1 analogs have also demonstrated efficacy in improving cardiovascular outcomes and preserving renal function in patients with diabetes, thus providing therapeutic opportunities for a variety of metabolic disorders and related diseases. Recently, liraglutide and semaglutide have shown reductions in liver fat and promoted NASH regression in clinical trials, indicating potential utility against NASH. However, most of these GLP-1 analogs require invasive subcutaneous administration. Semaglutide in certain formulations can be administered orally, but still suffers from inconvenient dosing regimens and poor bioavailability. Improving the metabolic stability and bioavailability of GLP-1 analogs is challenging, likely due to their peptide nature.

[0003] GLP-1 receptor is a proven ideal target for treating metabolic diseases such as obesity, diabetes, and fatty liver. Several GLP-1R agonist peptide drugs, such as dulaglutide and semaglutide, have been approved for marketing abroad for the treatment of diabetes and weight loss. However, these peptides require injection, resulting in poor patient accessibility; they are also costly, have poor accessibility, and impose a heavy medical burden; they require refrigeration, making them inconvenient to carry and store; and for diseases with complex etiologies requiring multiple drug combinations, such as non-alcoholic fatty liver disease, they are difficult to combine with existing oral small molecule drugs in combination therapy. Therefore, there is an urgent need to develop small molecule oral GLP-1R agonists. Summary of the Invention

[0004] This invention provides a tetrahydropyrazolopyridine derivative or a pharmaceutical composition thereof, which can act as GLP-1R agonists. The compounds or pharmaceutical compositions thereof described in this invention can treat diseases and / or conditions, particularly diabetes, by activating GLP-1R activity; therefore, this invention also relates to the use of the compounds or pharmaceutical compositions thereof in the preparation of such medicaments.

[0005] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0006] in,

[0007] Ring A is selected from C 6-10 Aryl, 8-12 heterocyclic or 8-12 heteroaryl;

[0008] R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0009] R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylamino-C 1-6 Alkyl-, di(C) 1-6 alkyl)amino-C 1-6 Alkyl-, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0010] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 ring atoms, wherein the C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-8 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs;

[0011] Each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups;

[0012] R 4 R 5 and R 6 Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0013] R 7 It is a 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic group, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -C 1-6 Alkylene C 3-8 cycloalkyl and -C 1-6 Substituents of alkylene groups (heterocyclic groups consisting of 3-10 atoms);

[0014] Each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR f C 1-6 Alkyl, C 7-15 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C)1-6 Alkyl)amino, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0015] R a R b R c and R d Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0016] R e and R f Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0017] n is 0, 1, 2, 3, 4 or 5;

[0018] t can be 0, 1, 2, 3, 4, or 5;

[0019] p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0020] In some embodiments, ring A is selected from phenyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, pyridinopyrrolyl, pyridinopyrazolyl, pyridinoimidazolyl, pyrimidinopyrrolyl, pyrimidinopyrazolyl, pyrimidinoimidazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinopyrrolyl, pyrazinotriazolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, furanopyrrolyl, furanoimidazolyl, thienopyrrolyl, thienoimidazolyl, tetrahydrobenzopyrrolyl, tetrahydrobenzimidazolyl, indolinyl, spiro[cyclopropyl-1,3'-indolinyl], pyrrolotriazine, pyridinotriazolyl, or tetrahydroisoquinolinyl; wherein The phenyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, pyridopyrrolyl, pyridopyrazolyl, pyrididazolyl, pyrimidopyrrolyl, pyrimidopyrazolyl, pyrimididazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinopyrrolyl, pyrazinotriazolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, furanopyrrolyl, furanoimidazolyl, thienopyrrolyl, thienopyrazolyl, tetrahydrobenzopyrrolyl, tetrahydrobenzimidazolyl, indolinyl, spiro[cyclopropyl-1,3'-indolinyl], pyrrolotriazinyl, pyridotriazolyl, and tetrahydroisoquinolinyl groups are each independently and optionally divided by n R groups. 3 Replaced;

[0021] Each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl and C 3-6 Substituents of cycloalkyl groups.

[0022] In some implementations, ring A is selected from the following substructures: The substructures of ring A are each independently and optionally divided by n R. 3 Replaced;

[0023] Each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c-S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein... Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylene The following groups are selected independently and optionally, and are each of the following groups: cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, and -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR fIt is substituted by substituents of oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH(OH)CH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0024] In some implementation schemes, R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl or 3-8 membered heterocyclic groups;

[0025] R 4 R 5 and R 6 Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0026] In some implementation schemes, R 1The following are the possible values: H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

[0027] R 4 R 5 and R 6 Each of the following is independently H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxygen Heterocyclic butyl, azaheterocyclic butyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -C H2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridyl Each azinyl group is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy and trifluoromethoxy.

[0028] R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy-C 1-4 Alkyl-, C 1-4 Hydroxyalkyl, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkylamino-C 1-4 Alkyl-, di(C) 1-4 alkyl)amino-C 1-4 Alkyl-, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino and di(C) 1-4 Substituents of alkyl)amino groups;

[0029] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 ring atoms, wherein the C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-6 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs;

[0030] Each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR f C 1-4 Alkyl, C7-15 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 Cycloalkyl or 3-8 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino and di(C) 1-4 The substituents of alkyl)amino groups are replaced.

[0031] In some implementation schemes, R 2a and R 2bEach of the following is independently represented as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methoxymethylene, methoxyethylidene, hydroxymethyl, hydroxy methylethyl, methylamino, ethylamino, dimethylamino, methylaminomethylene, ethylaminomethylene, dimethylaminomethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl Propylene, allyl, ethynyl, propyneyl, 1-propynyl, 1-yntyneyl, 2-yntyneyl, 3-yntyneyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetra Each of the following groups is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino and ethylamino;

[0032] Or R 2a and R 2b Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each optionally and independently substituted by 1, 2, 3, or 4 R groups;

[0033] Each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR f Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the -(CH2) group... t -OR d -(CH2) t -, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziroxy, pyrroleyl, tetrahydrofuranyl The tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, and dimethylamino.

[0034] In some implementation schemes, R 7 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, -C 1-4 Alkylene C 3-6 cycloalkyl and -C 1-4 Substituents of alkylene groups (heterocyclic groups consisting of 3-8 atoms).

[0035] In some implementation schemes, R 7The compounds are oxacyclobutyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, dihydroimidazoyl, 2-oxabicyclo[4.1.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 1-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, tetrahydrofuranyl, tetrahydropyranyl, thiotetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl, thiophene, thiazolyl, oxazolyl, and pyridinyl. , pyrimidinyl, pyrazinyl or pyridazinyl, wherein the oxadiazyl, azabicyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, dihydroimidazoyl, 2-oxabicyclo[4.1.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 1-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, tetrahydrofuranyl, tetrahydropyranyl, thiotetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl Thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally divided by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, and -CH2N. The substituents of H2, -CH2CH2NH2, -CH2CN, -CH2CH2CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, methylenecycloheptyl, methylenecyclooctane, methyleneaziridine, methyleneoxacyclobutyl, methylenepyrrolyl, methylenetetrahydrofuranyl, methylenepiperidinyl, ethylpiperidinyl, methylenepiperazinyl, and methylenemorpholinyl are substituted.

[0036] In some implementation schemes, R a R b R c and R d Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 1-4Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0037] R e and R f Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0038] In some implementation schemes, R a R b R c and R dEach of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclo... Butyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy;

[0039] R e and R f Each of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0040] In some embodiments, the compound of the present invention is a compound of formula (IV), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0041] Ring A is selected from 8-12 membered heterocyclic groups or 8-12 membered heteroaryl groups;

[0042] Ring B is selected from

[0043] R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0044] R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylamino-C 1-6 Alkyl-, di(C) 1-6 alkyl)amino-C 1-6 Alkyl-, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0045] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 ring atoms, wherein the C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-8 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs;

[0046] Each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups;

[0047] R 4 R 5 and R 6 Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0048] R 7 It is a 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic group, C 6-10The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -C 1-6 Alkylene C 3-8 cycloalkyl and -C 1-6 Substituents of alkylene groups (heterocyclic groups consisting of 3-10 atoms);

[0049] Each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR f C 1-6 Alkyl, C 7-15 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0050] R a R b R c and R d Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0051] n is 0, 1, 2, 3, 4 or 5;

[0052] t can be 0, 1, 2, 3, 4, or 5;

[0053] p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0054] On one hand, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or formula (IV) of the present invention, or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof.

[0055] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable diluent, carrier, or excipient.

[0056] On the other hand, the present invention relates to the use of compounds of formula (I) or formula (IV) or pharmaceutical compositions thereof in the preparation of medicaments for the prevention, treatment or relief of GLP-1R-related diseases.

[0057] In some embodiments, the GLP-1R-related diseases described in this invention are diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, or diabetic nephropathy.

[0058] In another aspect, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) or formula (IV).

[0059] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0060] Detailed Description of the Invention

[0061] Definitions and general terms

[0062] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0063] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0064] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0065] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0066] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0067] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0068] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structures described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0069] The stereochemical definitions and rules used in this invention generally follow 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.

[0070] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0071] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0072] As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0073] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0074] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0075] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0076] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C1. 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C1 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, denoted as C1 1-3Alkyl groups. 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-B) u、-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)CH2CH3) ), 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, n-octyl, etc.

[0077] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-6 carbon atoms, denoted as C 2-6 Alkenyl group; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms, denoted as C1 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0078] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, denoted as C1. 2-6 Alkynyl group; in yet another embodiment, the alkynyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0079] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0080] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3Alkoxy group. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0081] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, the haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3 Haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, monofluoromethoxy (-OCH2F), difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), 2-fluoroethoxy (-OCH2CH2F), etc.

[0082] The term "alkylamino" or "alkylamino" may also be expressed as "N-alkylamino," wherein each amino group is independently substituted by an alkyl group, wherein the alkyl group has the meaning as described in this invention. Examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), etc. The alkylamino group may optionally be substituted by one or more substituents described in this invention.

[0083] The term "di(alkyl)amino" may also be expressed as "N,N-dialkylamino," wherein the amino group is independently substituted by two alkyl groups, wherein the alkyl groups have the meaning as described in this invention. Examples include, but are not limited to, N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group may optionally be substituted by one or more substituents described in this invention.

[0084] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one, two, three, or four hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a hydroxyl C 1-6 Alkyl, i.e., C 1-6 The alkyl group is replaced by one or more hydroxyl groups, preferably, the hydroxyl group is C. 1-6 Alkyl represents C 1-6 The alkyl group is replaced by a hydroxyl group. In some embodiments, hydroxyalkyl indicates a hydroxyl C 1-4 Alkyl. In some embodiments, hydroxyalkyl means hydroxyl C. 1-3 Alkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH(OH)CH3, -CH2CH2OH, -C(CH3)2OH, -CH2CH(OH)CH2CH2OH, etc.

[0085] The terms "alkoxyalkyl" and "alkoxyalkylene" are used interchangeably to indicate that an alkyl group can be replaced by one or more identical or different alkoxy groups, wherein the alkoxy and alkyl groups have the meanings as described in this invention. Examples of such groups include, but are not limited to, methoxymethylene, ethoxymethylene, methoxyethylene, ethoxyethylene, etc.

[0086] The terms "alkylaminoalkyl" and "alkylaminoalkylene" are used interchangeably to indicate that an alkyl group can be replaced by one or more identical or different alkylamino groups, wherein the alkylamino and alkyl groups have the meanings as described in this invention. Examples of such groups include, but are not limited to, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, etc.

[0087] The terms "di(alkyl)aminoalkyl" and "di(alkyl)aminoalkylene" are used interchangeably to indicate that the alkyl group can be replaced by one or more identical or different di(alkyl)amino groups, wherein the di(alkyl)amino and alkyl groups have the meanings as described in this invention. Examples of such groups include, but are not limited to, dimethylaminomethylene, dimethylaminomethylene, diethylaminomethylene, diethylaminoethylene, etc.

[0088] The term "aminoalkyl" indicates that an alkyl group is replaced by one or more amino groups, wherein the alkyl group has the meaning as described in this invention. In some embodiments, aminoalkyl means amino C 1-6 Alkyl, i.e., C 1-6 The alkyl group is replaced by one or more amino groups, preferably, the amino group is C10. 1-6 Alkyl represents C 1-6 The alkyl group is replaced by an amino group. Examples of such substitutions include, but are not limited to, aminomethyl (-CH2NH2), aminoethyl (e.g., -CH2CH2NH2), etc.

[0089] The term "cyanoalkyl" indicates that an alkyl group is substituted with one or two cyano substituents, wherein "cyano" is -CN, and alkyl has the meaning described herein. In some embodiments, cyanoalkyl indicates an alkyl group substituted with one or two cyano groups. In some embodiments, cyanoalkyl indicates a cyanoC group. 1-6 Alkyl, i.e., C 1-6 The alkyl group is replaced by one or more cyano groups, preferably, the cyano group is C 1-6 Alkyl represents C 1-6 The alkyl group is replaced by a cyano group. Examples of such substitutions include, but are not limited to, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, etc.

[0090] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbocyclic system with 3-12 carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group comprises 3-10 carbon atoms, i.e., C2... 3-10 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-7 carbon atoms, i.e., C64-C75. 3-7 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-6 carbon atoms, i.e., C64-C ... 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 carbon atoms, i.e., C64-C74-C6 ... 3-5 Cycloalkyl. In another embodiment, the cycloalkyl group is a monocyclic cycloalkyl group containing 3-7 carbon atoms, i.e., C10-C2 ... 3-7 Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentadienyl, bicyclo[1.1.0]butyl, bicyclo[3.1.0]hexyl, etc. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0091] The term "alkylenecycloalkylene" means that a cycloalkyl group is attached to the remainder of the molecule via an alkylene group, wherein both the alkylene group and the cycloalkyl group have the meaning as described in this invention. The alkylene group and the cycloalkyl group in "alkylenecycloalkylene" may optionally be substituted with one or more substituents described in this invention.

[0092] The term "heterocycle" or "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic ring. When a heterocycle is attached to other parts of a molecule via a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms, represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms, represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in still other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms, represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in still other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms, represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in still other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms, represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. In still other embodiments, the heterocycle or heterocyclic group is a monocyclic ring consisting of 3-7 atoms, represented as a 3-7 membered monocyclic heterocycle or a 3-7 membered monocyclic heterocyclic group. Examples of the heterocycles include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, pyrazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazoline, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. The heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, aziridine, oxazolidine, pyrrolidine, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazoline, pyrazolidine, pyrazolidine, pyrazolidine, oxazolidine, imidazoline, piperidinyl, piperazinyl, or morpholinyl.

[0093] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10 aryl groups. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene.

[0094] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl group; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzofuran, benzothiazole, benzopyridinyl, benzoimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolylalkyl, 2,3-dihydrobenzofuran, benzo[2,3-b][1,4]dioxin, pyrido[2,3-b][1,4]dioxin, benzo[2,3-b][1,4]oxazine, pyrido[2,3-b][1,4]oxazine, etc.

[0095] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0096] The term "oxo" means =O.

[0097] The term "cyano" means -CN or -C≡N.

[0098] The term "thiol" represents -SH.

[0099] The term "hydroxyl group" represents -OH.

[0100] The term "carboxyl group" represents -C(=O)OH.

[0101] The term "composed of jk atoms" or "of jk elements" means that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k and any natural number between them. For example, "composed of 3-8 atoms" or "3-8 elements", "composed of 3-6 atoms" or "3-6 elements", "composed of 5-10 atoms" or "5-10 elements", or "composed of 5-6 atoms" or "5-6 elements" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0102] The terms "alkylenecycloalkyl", "alkyleneheterocyclic", "alkylenearyl", and "alkyleneheteroaryl" indicate that a cycloalkyl, heterocyclic, aryl, or heteroaryl group is attached to the remainder of the molecule via an alkylene group, wherein the alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups all have the meanings described herein. The alkylene, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in the terms "alkylenecycloalkyl", "alkyleneheterocyclic", "alkylenearyl", and "alkyleneheteroaryl" may optionally be substituted by one or more substituents described herein.

[0103] The term "prodrug" as used in this invention refers to the conversion of a compound into a compound represented by formula (I) or (IV) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0104] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0105] As used in this invention, "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups. This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions.

[0106] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0107] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound. As used herein, the term "treatment" refers to any disease or condition, in some embodiments meaning to improve the disease or condition (i.e., slow down or stop or alleviate the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means to alleviate or improve at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In other embodiments, "treatment" means to regulate the disease or condition from a physical (e.g., stabilizing perceptible symptoms) or physiological (e.g., stabilizing bodily parameters) or both. In other embodiments, "treatment" means to prevent or delay the onset, occurrence, or worsening of the disease or condition.

[0108] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0109] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0110] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0111] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0112] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0113] The compounds of formula (I) or formula (IV) described in this invention may exist in the form of salts.

[0114] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0115] Description of the compounds of the present invention

[0116] The present invention provides a compound, or a pharmaceutical composition thereof, which can act as an agonist of GLP-1R.

[0117] The present invention further relates to the use of the said compound or a pharmaceutical composition thereof in the preparation of a medicament that treats diseases and / or conditions by activating GLP-1R activity through the said compound.

[0118] The excellent properties of the compounds of this invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0119] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0120] Among them, R 1 R 2a R 2b R 3 R 4 R 5 R 6 R 7 Ring A and n each have the definitions described in this invention.

[0121] In some implementations, when ring A is At that time, R 3 for

[0122] In some implementations, ring A is At that time, there is at least one R 3 It is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0123] In some implementations, ring A is R 3 When R is methyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 7 It is not tetrahydropyranyl.

[0124] In some implementations, ring A is selected from C. 6-10 aryl, 8-12-membered heterocyclic, or 8-12-membered heteroaryl; wherein the 8-12-membered heterocyclic and 8-12-membered heteroaryl are each independently and optionally divided by n R 3 Replaced; of which, R 3 And n has the definition as described in this invention.

[0125] In some embodiments, ring A is selected from 8-12-membered bicyclic heterocyclic groups or 8-12-membered bicyclic heteroaryl groups; wherein the 8-12-membered bicyclic heterocyclic group and the 8-12-membered bicyclic heteroaryl group are each independently and optionally divided by n R groups. 3 Replaced; of which, R 3 And n has the definition as described in this invention.

[0126] In some embodiments, ring A is selected from phenyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, pyridinopyrrolyl, pyridinopyrazolyl, pyridinoimidazolyl, pyrimidinopyrrolyl, pyrimidinopyrazolyl, pyrimidinoimidazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinopyrrolyl, pyrazinotriazolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, furanopyrrolyl, furanoimidazolyl, thienopyrrolyl, thienoimidazolyl, tetrahydrobenzopyrrolyl, tetrahydrobenzimidazolyl, indolinyl, spiro[cyclopropyl-1,3'-indolinyl], pyrrolotriazine, pyridinotriazolyl, and tetrahydroisoquinolinyl; wherein The phenyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, pyridopyrrolyl, pyridopyrazolyl, pyrididazolyl, pyrimidopyrrolyl, pyrimidopyrazolyl, pyrimididazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyrazinopyrrolyl, pyrazinotriazolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, furanopyrrolyl, furanoimidazolyl, thienopyrrolyl, thienopyrazolyl, tetrahydrobenzopyrrolyl, tetrahydrobenzimidazolyl, indolinyl, spiro[cyclopropyl-1,3'-indolinyl], pyrrolotriazinyl, pyridotriazolyl, and tetrahydroisoquinolinyl groups are each independently and optionally divided by n R groups. 3 Replaced; of which, R 3 And n has the definition as described in this invention.

[0127] In other implementations, ring A is selected from the following substructures: The substructures of ring A are each independently and optionally divided by n R. 3 Replaced; of which, R 3 And n has the definition as described in this invention.

[0128] In some implementations, ring A is selected from... When, wherein the ring A is independently and optionally divided by n R 3 Replaced; of which, R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NRb R c -NR b S(O)2R c , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein... Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylene The following groups are selected independently and optionally, and are each of the following groups: cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, and -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f The substituents of oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH(OH)CH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted; among which, R a R b Rc R e R f p has the definition as described in this invention.

[0129] In some implementation schemes, R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups.

[0130] In some implementation schemes, R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 3-8 membered heterocyclic groups.

[0131] In other implementations, R 1 The following are possible values: H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

[0132] In some implementation schemes, R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylamino-C 1-6 Alkyl-, di(C)1-6 alkyl)amino-C 1-6 Alkyl-, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0133] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 ring atoms, wherein the C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-8 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs; wherein the Rs have the definition as described in this invention.

[0134] In some implementation schemes, R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy-C 1-4 Alkyl-, C 1-4 Hydroxyalkyl, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 1-4 Alkylamino-C 1-4 Alkyl-, di(C) 1-4alkyl)amino-C 1-4 Alkyl-, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino and di(C) 1-4 Substituents of alkyl)amino groups;

[0135] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-6 ring atoms, wherein the C 3-6 The cycloalkyl group and the heterocyclic group consisting of 3-6 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs; wherein the Rs have the definition as described in this invention.

[0136] In other implementations, R 2a and R 2bEach of the following is independently represented as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methoxymethylene, methoxyethylidene, hydroxymethyl, hydroxy methylethyl, methylamino, ethylamino, dimethylamino, methylaminomethylene, ethylaminomethylene, dimethylaminomethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl Propylene, allyl, ethynyl, propyneyl, 1-propynyl, 1-yntyneyl, 2-yntyneyl, 3-yntyneyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetra Each of the following groups is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, dimethylamino and ethylamino;

[0137] Or R 2a and R 2b Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl groups is independently and optionally substituted by 1, 2, 3, or 4 R groups; wherein the R groups have the definitions described herein.

[0138] In some implementations, each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, or -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR f C 1-6 Alkyl, C 7-15 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups; wherein, R d , t, R e R f p has the definition as described in this invention.

[0139] In some implementations, each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, or -(CH2). t -OR d -(CH2) p -C(=O)R e-(CH2) p -C(=O)OR f C 1-4 Alkyl, C 7-15 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 Cycloalkyl or 3-8 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, di(C) 1-4 Alkyl)amino, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino and di(C) 1-4 Substituents of alkyl)amino groups; wherein, R d , t, R e R f p has the definition as described in this invention.

[0140] In other embodiments, each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, or -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p -C(=O)OR fMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziroxybutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein the -(CH2) group... t -OR d -(CH2) t -, Methyl, Ethyl, n-propyl, Isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, Vinyl, Propylene, Allyl, Ethynyl, Propylene, 1-Propylene, 1-Oynylbutyl, 2-Oynylbutyl, 3-Oynylbutyl, Methoxy, Ethoxy, Isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, Difluoromethoxy, Methylamino, Ethylamino, Dimethylamino, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Oxacyclobutyl, Azacyclobutyl, Pyrrolidinyl, Tetrahydrofuranyl, Tetrahydro The pyranyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, and dimethylamino; wherein, R d , t, R e R f p has the definition as described in this invention.

[0141] In some implementation schemes, each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a-S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups; wherein, R a R b R c R e R f p has the definition as described in this invention.

[0142] In some implementation schemes, each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a-C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups; wherein, R a R b R c R e R fp has the definition as described in this invention.

[0143] In other implementations, each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c , Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein... Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylene The following groups are selected independently and optionally, and are each of the following groups: cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, and -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f The substituents of oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH(OH)CH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted; among which, R a R b R c R e R f p has the definition as described in this invention.

[0144] In some implementation schemes, R 4 R 5 and R 6 Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced.

[0145] In some implementation schemes, R 4 R 5 and R 6 Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0146] In other implementations, R 4 R 5 and R 6Each of the following is independently H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxygen Heterocyclic butyl, azaheterocyclic butyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -C H2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridyl Each azinyl group is independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy and trifluoromethoxy.

[0147] In some implementation schemes, R 7 It is a 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic group, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -C 1-6 Alkylene C 3-8 cycloalkyl and -C 1-6Substituents of alkylene groups (heterocyclic groups consisting of 3-10 atoms).

[0148] In some implementation schemes, R 7 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, -C 1-4 Alkylene C 3-6 cycloalkyl and -C 1-4 Substituents of alkylene groups (heterocyclic groups consisting of 3-8 atoms).

[0149] In other implementations, R 7The compounds are oxacyclobutyl, azacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, dihydroimidazoyl, 2-oxabicyclo[4.1.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 1-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, tetrahydrofuranyl, tetrahydropyranyl, thiotetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl, thiophene, thiazolyl, oxazolyl, and pyridinyl. , pyrimidinyl, pyrazinyl or pyridazinyl, wherein the oxadiazyl, azabicyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyridazinyl, dihydroimidazoyl, 2-oxabicyclo[4.1.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 1-oxaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, tetrahydrofuranyl, tetrahydropyranyl, thiotetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, furanyl Thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally divided by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, and -CH2N. The substituents of H2, -CH2CH2NH2, -CH2CN, -CH2CH2CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, methylenecycloheptyl, methylenecyclooctane, methyleneaziridine, methyleneoxacyclobutyl, methylenepyrrolyl, methylenetetrahydrofuranyl, methylenepiperidinyl, ethylpiperidinyl, methylenepiperazinyl, and methylenemorpholinyl are substituted.

[0150] In some implementation schemes, R a R b R c and R d Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced.

[0151] In some implementation schemes, R a R b R c and R d Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl or 5-10 heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0152] In other implementations, R a R b R c and R dEach of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclo... Butyl, cyclopentyl, cyclohexyl, oxacyclobutyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0153] In some implementation schemes, R e and R f Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 The substituents of the haloalkoxy group are replaced.

[0154] In some implementation schemes, R e and R f Each is independently H, D, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-4Alkyl, C 1-4 Haloalkyl, C 3-6 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The substituents of the haloalkoxy group are replaced.

[0155] In other implementations, R e and R f Each of the following is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, and trifluoromethoxy.

[0156] In some embodiments, the compound of the present invention is a compound of formula (II), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0157] Among them, X, Y, Z, R 1 R 2a R 2b R 3a R 4 R 5 R 6 and R 7 Each has the definition described in this invention.

[0158] In some embodiments, the compound of the present invention is a compound of formula (III), or a stereoisomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (III).

[0159] Among them, X, Y, Z, R 1 R 2a R 2b R 3b R 4 R 5 R 6 and R 7 Each has the definition described in this invention.

[0160] In some implementations, X is CR x Or N; where R x It has the definition as described in this invention.

[0161] In some implementations, Y is CR y Or N; where R y It has the definition as described in this invention.

[0162] In some implementations, Z is CR z Or N; where R z It has the definition as described in this invention.

[0163] In some implementation schemes, R x R y and R z Each of the following is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0164] In some implementation schemes, R x R y and R z Each of the following is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups.

[0165] In other implementations, R x R y and R zEach of the following can be independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, -SF5, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, or trifluoromethoxy.

[0166] In some implementation schemes, R 3a and R 3b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups; wherein, R a R b R c R e R f p has the definition as described in this invention.

[0167] In some implementation schemes, R 3a and R 3b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; wherein the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p-C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkyl and C 3-6 Substituents of cycloalkyl groups; wherein, R a R b R c R e R f p has the definition as described in this invention.

[0168] In other implementations, R 3a and R 3b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)OR a -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R cMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl Cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, azacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, or isopropyl... Butyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, methoxy, ethoxy, isopropoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziridine, pyrroleyl, tetrahydro Furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, and -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f The substituents of oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH(OH)CH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are substituted; among which, R a R b R c R e R f p has the definition as described in this invention.

[0169] On the other hand, the compounds described in this invention have the following structures, or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, but are by no means limited to:

[0170] On the one hand, the compounds described in this invention are compounds represented by formula (IV), or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof.

[0171] Ring A is selected from 8-12 membered heterocyclic groups or 8-12 membered heteroaryl groups;

[0172] Ring B is selected from

[0173] R 1 is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups;

[0174] R 2a and R 2b Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 1-6 Alkylamino-C 1-6 Alkyl-, di(C) 1-6 alkyl)amino-C 1-6 Alkyl-, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0175] Or R 2a and R 2b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl or heterocyclic group consisting of 3-8 ring atoms, wherein the C 3-8 The cycloalkyl group and the heterocyclic group consisting of 3-8 ring atoms are each independently and optionally replaced by 1, 2, 3 or 4 Rs;

[0176] Each R 3 Independently, it is H, D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a -C(=O)R a -C(=O)ORa -NR b R c -C(=O)NR b R c -NR b C(=O)R c -S(O)R a -S(O)2R a -S(O)2NR b R c -NR b S(O)2R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl or 5-12 heteroaryl; wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl, -C 1-6 Alkylene C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3, or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). p -C(=O)R e -(CH2) p -C(=O)OR f Oxygen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl and C 3-8 Substituents of cycloalkyl groups;

[0177] R 4 R 5 and R 6Each of the following can be independently identified as H, D, -F, -Cl, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0178] R 7 It is a 3-12 membered heterocyclic group, C 6-10 Aryl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic group, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, -C 1-6 Alkylene C 3-8 cycloalkyl and -C 1-6 Substituents of alkylene groups (heterocyclic groups consisting of 3-10 atoms);

[0179] Each R is independently D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2). t -OR d -(CH2) p -C(=O)R e -(CH2) p-C(=O)OR f C 1-6 Alkyl, C 7-15 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 Cycloalkyl or 3-10 membered heterocyclic groups; wherein the -(CH2) group is... t -OR d -(CH2) t -、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino, di(C) 1-6 Alkyl)amino, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino and di(C) 1-6 Substituents of alkyl)amino groups;

[0180] R a R b R c and R d Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl or 5-12 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0181] R e and R f Each is independently H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 The cycloalkyl group and the 3-10 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substituents of haloalkoxy groups;

[0182] n is 0, 1, 2, 3, 4 or 5;

[0183] t can be 0, 1, 2, 3, 4, or 5;

[0184] p can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0185] On the other hand, the compounds described in this invention have the following structures, or stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs, but are by no means limited to:

[0186] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0187] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable diluent, carrier, or excipient.

[0188] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of GLP-1R-related diseases.

[0189] In some embodiments, the GLP-1R-related diseases described in this invention are diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, or diabetic nephropathy.

[0190] On the other hand, the present invention also provides a method for preventing or treating GLP-1R-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0191] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), formula (II), formula (III) or formula (IV).

[0192] Pharmaceutical compositions, formulations, administration and uses of the compounds of this invention

[0193] The pharmaceutical compositions of the present invention are characterized by compounds of formula (I), (II), (III), or (IV), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers. The amounts of compounds in the pharmaceutical compositions of the present invention are effective in treating or alleviating GLP-1R-mediated diseases in patients.

[0194] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0195] As described in this invention, pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional adjuvants that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, is also within the scope of this invention.

[0196] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0197] In preparing the pharmaceutical compositions provided by this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in a carrier, such as a capsule, sachet, paper, or other container. If the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, serving as a carrier, container, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterilely packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0198] The compounds or pharmaceutical compositions of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0199] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0200] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0201] The compounds or pharmaceutical compositions of the present invention are also coupled with soluble polymers that act as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0202] The administration regimen of the compounds or pharmaceutical compositions of this invention will vary depending on a variety of known factors, such as the pharmacokinetic characteristics and patterns of the specific agent and the route of administration; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract, or halt the progression of a disease.

[0203] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is in the range of approximately 0.001 to 1000 mg / kg body weight per day, preferably between approximately 0.01 and 100 mg / kg body weight. The compounds of the present invention can be administered once daily, or can be administered in two, three, or four divided doses daily.

[0204] Each unit dose of a suitable dosage form (pharmaceutical composition) may contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.

[0205] The compounds and compositions described in this invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of this invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of this invention can be included in a single formulation along with other therapeutic agents or in a separate formulation.

[0206] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0207] The compounds, pharmaceutical salts, hydrates, or pharmaceutical compositions thereof involved in this invention are effective in preventing, treating, or alleviating diseases mediated by GLP-1R, particularly diabetes.

[0208] In some embodiments, the compounds of the present invention or pharmaceutical compositions thereof are effective in preventing, treating or alleviating GLP-1R-related conditions in patients, including, but not limited to: diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, or diabetic nephropathy.

[0209] General Synthesis Process

[0210] To describe this invention, the following embodiments will be used to further illustrate the technical solution of this invention. These embodiments are only used to illustrate specific implementation methods of this invention so that those skilled in the art can understand it, but are not intended to limit the scope of protection of this invention. In the specific implementation methods of this invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0211] Unless otherwise specified, the substituents are defined as described in this invention. The following reaction schemes and examples are provided to further illustrate the content of this invention.

[0212] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0213] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples represents 15°C–30°C; in some examples, room temperature is 20°C–30°C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification. Unless otherwise specified, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0214] When this invention relates to one or more of the following reagents or solvents, the solvents can be used in experiments after being treated as follows: anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium; anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride; ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0215] The reaction can be carried out under positive pressure of nitrogen or argon or over anhydrous solvent with a drying tube attached (unless otherwise indicated). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected via syringe. All glassware is dried.

[0216] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0217] 1 H NMR spectra were recorded using a Bruker 400MHz, 600MHz, or 599MHz nuclear magnetic resonance spectrometer. 1¹H NMR spectra are performed using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets), qt (quartet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0218] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV).

[0219] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0220] The following abbreviations or English terms are used throughout this invention: EtOAc,EA ethyl acetate h hours DCM dichloromethane min minutes PE petroleum ether oC degrees Celsius MeOH methanol g grams DMSO dimethyl sulfoxide mmol millimoles DMSO-d6 deuterated dimethyl sulfoxide M, mol / L moles per liter CDCl3 deuterated chloroform mg milligrams DMF N,N-dimethylformamide mL milliliters THF tetrahydrofuran HOBt 1-hydroxybenzotriazole EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DIPEA N,N-diisopropylethylamine μL microliters HCl hydrochloride nL nanoliters TLC thin-layer chromatography plate μM micromoles NMP N-methylpyrrolidone nM nanomoles DBU 1,8-diazobispyrocyclo[5.4.0]undecyl-7-ene T3P 1-propylphosphonic anhydride HATU N,N,N'N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate

[0221] Synthesis Scheme 1

[0222] Compound (Ia) can be synthesized according to the method of synthetic scheme 1; wherein R 1 R 2a R 2b R 3a R 4 R 5 R 6 and R 7It has the definition as described in this invention. Compound (I-1) reacts with compound (I-2) under suitable conditions (such as the action of potassium carbonate or cesium carbonate) to give compound (I-3); compound (I-3) reacts with compound (I-4) under suitable conditions (such as the action of a catalyst such as iodide ketone) to give compound (I-5); compound (I-5) reacts with acidic conditions (such as the action of HCl) to give compound (I-6); compound (I-6) reacts with compound (I-7) under suitable conditions (such as the action of HATU or DIPEA) to give compound (Ia).

[0223] Synthesis Scheme 2

[0224] Compound (Ib) can be synthesized according to the method of synthetic scheme 2; wherein R 1 R 3a R 4 R 5 R 6 and R 7 It has the definition as described in this invention. Compound (I-8) reacts with pinacol diboronate under suitable conditions (e.g., with potassium acetate and palladium catalyst) to give compound (I-9); compound (I-9) reacts with compound (I-10) under suitable conditions (e.g., with potassium carbonate and palladium catalyst) to give compound (I-11); compound (I-11) reacts under alkaline conditions (e.g., with sodium hydroxide) to give compound (I-12); compound (I-12) reacts with compound (I-13) under suitable conditions (e.g., with HATU and DIPEA) to give compound (I-14); compound (I-14) reacts with bromoacetonitrile under suitable conditions (e.g., with sodium hydride) to give compound (I-15). Compound (I-15) reacts with 4-methyl-1,3,2-dioxathiapentane 2,2-dioxide under alkaline conditions (such as the action of bis(trimethylsilylamino)lithium) to give compound (I-16); compound (I-16) reacts with hydroxylamine hydrochloride under suitable conditions (such as at 60°C) to give compound (I-17). Compound (I-17) reacts with N,N'-carbonyldiimidazole under suitable conditions (such as the action of DBU) to give compound (Ib).

[0225] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. Example

[0226] Intermediate 1: (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0227] It was prepared by referring to the synthesis method of intermediate 18 of compound 101a in patent application WO2021155841A1.

[0228] Intermediate 2: 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

[0229] It was prepared by referring to the synthesis method of intermediate 47 in Example 39 of patent application WO2022017338A1.

[0230] Example 1: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0231] Step 1: Synthesis of 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine

[0232] 5-Bromo-1H-pyrazolo[3,4-b]pyridine (0.2 g, 1.01 mmol), cyclopropylboronic acid (0.17 g, 2.02 mmol), 2,2'-bipyridine (0.16 g, 1.01 mmol), copper acetate (0.18 g, 1.01 mmol), and sodium carbonate (0.21 g, 2.02 mmol) were added to a reaction flask, followed by the addition of acetonitrile (10 mL). After purging the oxygen, the mixture was heated to 80 °C and stirred for 26 h. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a white solid product (0.1 g, 41.59%).

[0233] 1H NMR (400MHz, CDCl3) δ8.60(d,J=1.9Hz,1H),8.18(d,J=1.9Hz,1H),7.91(s,1H),3.90–3.85(m,1H),1.38–1.30(m,2H),1.23–1.18(m,2H).

[0234] Step 2: Synthesis of (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-carboxylic acid tert-butyl ester

[0235] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.3 g, 0.68 mmol), 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine (0 0.24 g (1.02 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.097 g, 0.68 mmol), and potassium carbonate (0.23 g, 1.70 mmol) were dissolved in NMP (6 mL). Cuprous iodide (0.13 g, 0.68 mmol) was added under nitrogen protection, and the nitrogen atmosphere was replaced again. The mixture was heated to 130 °C and stirred for 5 h. After the reaction was complete, water (70 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid (0.4 g, 98.33%).

[0236] MS(ESI,pos.ion)m / z:599.3[M+H] + ;

[0237] 1H NMR (400MHz, CDCl3) δ8.69(s,1H),8.26(d,J=2.3Hz,1H),8.01(s,1H),7.11(d,J=6.2Hz,2H),6.72(d,J=3.1Hz,1H),6.37(s,1H),5.37–5.25(m,1H ),4.51–4.34(m,1H),3.91(tt,J=7.3,3.8Hz,1H),3.17(s,1H),2.87–2.7 8(m,2H),2.25(s,6H),1.52(s,9H),1.38–1.35(m,5H),1.25–1.20(m,2H).

[0238] Step 3: Synthesis of (S)-1-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0239] (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.33 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of 4 mol / L 1,4-dioxane hydrogen chloride solution (0.99 mL, 3.96 mmol). The mixture was stirred at room temperature for 6 h. After the reaction was complete, the solvent was removed under reduced pressure to give a white solid product (0.178 g, 99.59%). MS (ESI, pos.ion) m / z: 499.3 [M+H] + .

[0240] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0241] Dissolve (S)-1-(1-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (0.20 g, 0.38 mmol) in DMF (5 mL), and add DIPEA (0.20 g, 0.38 mmol) with stirring. 1.52 mmol), and stirred for another 30 minutes; then HATU (0.22 g, 0.57 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.15 g, 0.38 mmol) were added, and the mixture was stirred at room temperature for 9 h. After the reaction was complete, the starting material was detected by TLC to be completely reacted. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100:1) to give a white solid product (0.081 g, 24.91%). MS(ESI,pos.ion)m / z:892.3[M+H] + ;

[0242] 1 H NMR (400MHz, CDCl3) δ11.33(s,1H),8.71(s,1H),8.30(s,1H),8.02(s,1H),7.59(d,J=8.6Hz,1H),7.53(s,1H),7.27(d,J=1 0.0Hz,1H),7.15(d,J=5.8Hz,1H),6.78(d,J=2.3Hz,1H),6.71(d,J=5.2Hz,1H),6.40(d,J=2.2Hz,1H),5.80(d,J=6.4Hz,1H) ,4.48(d,J=9.6Hz,1H),3.91–3.87(m,3H),3.64–3.58(m,1H),3.19–3.12(m,1H),3.02(s,2H),2.94(s,1H),2.27(s,6H),2. 08(s,2H),1.91(d,J=4.9Hz,1H),1.77–1.74(m,2H),1.56(d,J=6.5Hz,3H),1.35(s,6H),1.29(s,5H),1.19(d,J=5.3Hz,4H).

[0243] Example 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0244] Step 1: Synthesis of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-2-carboxylate

[0245] At room temperature, ethyl 5-bromoindole-2-carboxylic acid (10 g, 37.30 mmol), pinacol diboronate (14.21 g, 55.95 mmol), and potassium acetate (10.98 g, 111.90 mmol) were added to 1,4-dioxane (100 mL), and the mixture was purged with nitrogen three times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (3.05 g, 3.73 mmol) was added, and the mixture was purged with nitrogen three times. The mixture was heated to 100 °C and stirred for 5 hours. After the reaction was complete, the reaction was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layer was collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to give a white solid product (11 g, 93.58%).

[0246] MS(ESI,pos.ion)m / z:316.1[M+H] + ;

[0247] Step 2: Synthesis of ethyl 5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole-2-carboxylate

[0248] In a reaction flask, ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole-2-carboxylate (800 mg, 2.54 mmol), 6-bromo-2-methyl-2,3-dihydropyridazin-3-one (480.09 mg, 2.54 mmol), potassium carbonate (1053.16 mg, 7.62 mmol), 1,4-dioxane (29.01 mL), and water (10 mL) were added. Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (207.43 mg, 0.25 mmol) was added, and the mixture was stirred at 90 °C for 6 hours. Cool to room temperature, quench the reaction with ammonium chloride aqueous solution (30 mL), extract with ethyl acetate (40 mL × 2), wash with saturated brine (30 mL), dry with anhydrous sodium sulfate, filter, remove some solvent from the filtrate under reduced pressure, filter the precipitated solid to obtain a brown solid product (550 mg, 72.88%).

[0249] Step 3: Synthesis of 5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole-2-carboxylic acid

[0250] Ethyl 5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole-2-carboxylate (470 mg, 1.58 mmol) and methanol (25.28 mL) were added to a reaction flask, followed by the addition of a solution of sodium hydroxide (139.04 mg, 3.48 mmol) and water (10 mL). The mixture was stirred at 60 °C for 3 h. The solvent was removed under reduced pressure, and the product was extracted with water (20 mL) and methyl tert-butyl ether (30 mL). The aqueous phase was adjusted to pH 3 by adding dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL × 3). The product was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1-4 / 1) to give a gray solid product (400 mg, 93.97%).

[0251] MS(ESI,pos.ion)m / z:270.0[M+H] + .

[0252] Step 4: Synthesis of (S)-6-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-5-yl)-2-methylpyridazin-3(2H)-one

[0253] 5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole-2-carboxylic acid (300 mg, 1.11 mmol), HATU (633.08 mg, 1.67 mmol), triethylamine (449.28 mg, 4.44 mmol), and DMF (21.10 mL) were added to a reaction flask. The mixture was stirred at room temperature for 1 hour under nitrogen protection. Then, (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (583.84 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 11 hours. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1-20 / 1) to give a yellow solid product (500 mg, 60.58%).

[0254] MS(ESI,pos.ion)m / z:741.3[M+H] + .

[0255] Step 5: Synthesis of (S)-2-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)acetonitrile

[0256] Add (S)-6-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-5-yl)-2-methylpyridazin-3(2H)-one (500 mg, 0.67 mmol) and DMF (10.55 mL) to a reaction flask. Under ice bath conditions, add 60% sodium hydride (80.40 mg, 2.01 mmol) and react for 0.5 hours. Then, add bromoacetonitrile (120.55 mg, 1.01 mmol) dropwise and stir at room temperature for 10 hours. Add bromoacetonitrile (120.55 mg, 1.01 mmol) and heat to 40 °C with stirring for 3 hours. Quench the reaction by adding ammonium chloride aqueous solution (10 mL) dropwise to the reaction system under ice bath conditions. Extract with ethyl acetate (20 mL × 2), wash with saturated brine (10 mL × 2), dry with anhydrous sodium sulfate, filter, remove solvent from the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 40 / 1-20 / 1) to give a pale yellow solid product (230 mg, 43.70%).

[0257] MS(ESI,pos.ion)m / z:780.2[M+H] + .

[0258] Step 6: Synthesis of (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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboxynitrile

[0259] Add (S)-2-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole- 1-(4R)-4-methyl-1,3,2-dioxathiapentane-2,2-dioxide (186.49 mg, 1.35 mmol) and tetrahydrofuran (11.25 mL) were added dropwise under nitrogen protection at 0 °C. The mixture was stirred at room temperature for 18 hours under nitrogen protection, then heated to 40 °C and stirred for another 15 hours. The reaction was quenched by adding 10 mL of ammonium chloride aqueous solution to the reaction mixture in an ice bath. The mixture was extracted with ethyl acetate (20 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1-20 / 1) to give a pale yellow solid crude product (40 mg, 18.12%). MS(ESI,pos.ion)m / z:820.3[M+H] + .

[0260] Step 7: Synthesis of (1S,2S,Z)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-N'-hydroxy-2-methylcyclopropyl-1-carboximide

[0261] (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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carboxyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropane-1-carboxynitrile (100 mg, 0.12 mmol), sodium bicarbonate (50.41 mg, 0.60 mmol), hydroxylamine hydrochloride (41.69 mg, 0.60 mmol), and DMSO (2.73 mL) were added to the reaction flask. The reaction was carried out under nitrogen protection and stirred at 60 °C for 21 hours. Cool to room temperature, add water (20 mL) to quench the reaction, stir for 1 hour, filter, concentrate the filtrate under reduced pressure, and dry to obtain a pale yellow solid product (100 mg, 96.13%).

[0262] Step 8: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0263] Add (1S,2S,Z)-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-6-oxo) (1,6-dihydropyridazine-3-yl)-1H-indol-1-yl)-N'-hydroxy-2-methylcyclopropyl-1-carboximide (100 mg, 0.12 mmol), N,N'-carbonyldiimidazole (48.65 mg, 0.30 mmol), DBU (45.67 mg, 0.30 mmol), and DMSO (4.55 mL) were stirred at room temperature for 17 hours under nitrogen protection. The reaction was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by preparative purification (dichloromethane / ethyl acetate (v / v) = 4 / 1-1 / 1) to give a pale yellow solid product (16 mg, 15.53%). MS (ESI, pos.ion) m / z: 879.3 [M+H] + ;

[0264] 1 H NMR (400MHz, CDCl3) δ11.33(s,1H),8.19(s,1H),8.11(s,1H),7.89–7.84(m,2H),7.75(d,J=8.7Hz,1H),7.53– 7.47(m,1H),7.32(d,J=8.8Hz,1H),7.16(d,J=5.7Hz,2H),7.07(d,J=5.3Hz,1H),6.84(s,1H),6.67(s,1H),6.3 9(s,1H),4.50(d,J=9.7Hz,1H),4.15(s,3H),3.97(s,3H),3.69–3.62(m,1H),3.24–3.15(m,1H),3.08(d,J=14 .2Hz,2H),2.31(s,6H),2.01-1.98(m,1H),1.66(d,J=6.5Hz,2H),1.60(d,J=6.1Hz,3H),1.24(d,J=5.7Hz,3H).

[0265] Example 3: 3-((1S,2S)-1-(2-((S)-3-(3-(2-(cyclopropylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0266] Step 1: Synthesis of (6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)(cyclopropyl) methyl ketone

[0267] 6-Bromo-1,2,3,4-Tetrahydroisoquinoline hydrochloride (0.2 g, 0.8 mmol) and triethylamine (0.16 g, 1.6 mmol) were dissolved in dichloromethane (8 mL). After stirring for 15 min, cyclopropylformyl chloride (0.1 g, 0.96 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, the reaction solution was directly evaporated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to give a white solid product (0.2 g, 88.72%). MS (ESI, pos.ion) m / z: 280.00 [M+H] + .

[0268] Step 2: Synthesis of (S)-3-(3-(2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0269] (6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)(cyclopropyl) methyl ketone (0.18 g, 0.65 mmol), (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.19 g, 0.43 mmol), potassium carbonate (0.12 g, 0.86 mmol), trans-(1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine (0.092 g, 0.65 mmol), and cuprous iodide (0.12 g, 0.65 mmol) were dissolved in N-methylpyrrolidone (8 mL) and reacted overnight at 130 °C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered to obtain the filtrate, which was diluted with water (20 mL), extracted with ethyl acetate (3 × 10 mL), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a yellow powder product (0.26 g, 94.29%). MS (ESI, pos.ion) m / z: 641.00 [M+H] + .

[0270] Step 3: Synthesis of (S)-1-(2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0271] (S)-3-(3-(2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.245 g, 0.38 mmol) was dissolved in dioxane (3 mL, 4 mol / L) of hydrogen chloride and stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was directly evaporated to dryness to give a yellow oily product (0.22 g, 99.70%).

[0272] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(2-(cyclopropaneformyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0273] (S)-1-(2-(cyclopropanecarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (0.22 g, 0.38 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.17 g, 0.42 mmol), HATU (0.22 g, 0.57 mmol), and N,N-diisopropylethylamine (0.15 g, 1.14 mmol) were dissolved in N,N-dimethylformamide (8 mL) and reacted overnight at room temperature with stirring. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a white powder product (0.24 g, 67.40%). MS(ESI,pos.ion)m / z:934.00[M+H] + ;

[0274] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.28(s,1H),8.23(s,1H),8.10(d,J=9.4Hz,2H),7.88(d,J=8.9Hz,1H),7.67(d,J=8.8Hz,1H),7.61–7.45(m,3 H),7.19(d,J=6.4Hz,2H),7.11–7.07(m,2H),6.95(s,1H),5.59(d,J=7.2H z,1H),4.40(d,J=12.1Hz,1H),3.90–3.82(m,1H),3.76(s,4H),3.17(s,2H ),2.91(d,J=14.9Hz,1H),2.78(s,1H),2.26(s,6H),2.23(s,2H),1.84(t, J=7.6Hz,1H),1.78(t,J=6.7Hz,1H),1.73–1.65(m,1H),1.59(d,J=6.7Hz, 1H),1.45(d,J=6.6Hz,3H),1.40(s,1H),1.35(s,2H),1.23(s,1H),1.22–1 .16(m,5H),1.13(s,3H),1.10–1.03(m,2H),0.85(dt,J=15.4,7.2Hz,1H).

[0275] Example 4: 3-(2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)propyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

[0276] Step 1: Synthesis of 2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylpropionitrile

[0277] 0.17 g (0.21 mmol) of 2-(2-((4S)-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-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((4S)-2,2-dimethyloxacyclohexane-4-yl)-1H-indol-1-yl)acrylonitrile (3 mL) was dissolved in N,N-dimethylformamide. After cooling to 0℃, sodium hydride (0.017g, 0.42mmol) was added. After reacting for 15min, iodomethane (0.045g, 0.32mmol) was added. After reacting for 3h, the temperature was lowered to 0℃, and the reaction was quenched by adding 2N hydrochloric acid (5mL). The mixture was diluted with ethyl acetate (20mL), washed with saturated brine (5mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA=2:1-1:10) to obtain an off-white product (0.13g, 75%).

[0278] MS(ESI,pos.ion)m / z:838.0[M+H] + .

[0279] Step 2: Synthesis of 2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-N-hydroxy-2-methylpropanediamine

[0280] 2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylpropyl Nitrile (0.13 g, 0.16 mmol), hydroxylamine hydrochloride (0.056 g, 0.80 mmol), and sodium bicarbonate (0.067 g, 0.80 mmol) were dissolved in dimethyl sulfoxide (3 mL). The mixture was then heated to 60 °C and reacted for 14 h. The reaction was quenched by adding saturated brine (5 mL), extracted with ethyl acetate (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oily product (0.12 g, 88%).

[0281] MS(ESI,pos.ion)m / z:871.0[M+H] + .

[0282] Step 3: Synthesis of 3-(2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)propyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

[0283] 2-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-N-hydroxy-2-methylpropanedin (0.13 g, 0.15 g) The product (0.75 mmol) was dissolved in dimethyl sulfoxide (3 mL), and then DBU (0.11 g, 0.75 mmol) and N,N'-carbazyl diimidazole (0.12 g, 0.75 mmol) were added. After reacting for 5 h, the mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 1:1) to give a white solid product (0.02 g, 15%). MS (ESI, pos.ion) m / z: 897.40 [M+H] + ;

[0284] 1H NMR(400MHz, CDCl3)δ10.95(s,1H),8.17–7.78(m,1H),7.54–7.44(m,2H),7.26–6.9 9(m,3H),6.81–6.45(m,2H),6.32–6.11(m,1H),5.55(d,J=7.0Hz,1H),4.89(d,J=8. 0Hz,1H),3.85(s,2H),3.72–3.33(m,2H),3.03–2.93(m,3H),2.29(s,6H),2.11–2.0 0(m,3H),1.89(s,4H),1.65–1.51(m,6H),1.45(d,J=6.3Hz,2H),1.35–1.21(m,10H).

[0285] Example 5: 4-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indol-5-yl)morpholin-3-one

[0286] Step 1: Synthesis of 3-((1S,2S)-1-(5-bromo-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0287] (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (5.36 g, 9.71 mmol) was dissolved in DMF (70 mL), and then DIPE was added. A (5.98 g, 46.25 mmol) was stirred at room temperature for 1 hour, followed by the addition of 5-bromo-1-(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (3.5 g, 9.25 mmol) and HATU (5.28 g, 13.88 mmol). The reaction was stirred at room temperature for 22 hours. After the reaction was complete, the mixture was diluted with water (600 mL), extracted with ethyl acetate (300 mL × 2), the organic phases were combined, washed with saturated brine (300 mL), the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 70 / 1) to give a brown solid product (7.488 g, 92.39%).

[0288] MS(ESI,pos.ion)m / z:874.80[M+H] + .

[0289] Step 2: Synthesis of 4-(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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indol-5-yl)morpholin-3-one

[0290] 3-((1S,2S)-1-(5-bromo-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one 0.1 g (0.11 mmol), 3-morpholinone (0.017 g, 0.17 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.016 g, 0.11 mmol), and potassium carbonate (0.046 g, 0.33 mmol) were dissolved in NMP (5 mL). Cuprous iodide (0.021 g, 0.11 mmol) was added under nitrogen protection, and the atmosphere was purged with nitrogen again. The mixture was heated to 130 °C and stirred for 15 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a white solid product (0.047 g, 45.94%). MS (ESI, negative ion) m / z: 894.0 [MH] - ;

[0291] 1 H NMR (400MHz, CDCl3) δ11.31(s,1H),8.13(s,1H),7.72(d,J=8.8Hz,1H),7.63(s,1H),7.52(s,2H),7.31(s, 1H),7.16(d,J=6.1Hz,2H),6.76(s,1H),6.64(d,J=1.9Hz,1H),6.35(d,J=3.0Hz,1H),5.85–5.80(m,1H),4. 43(s,2H),4.11(t,J=5.0Hz,2H),3.83(d,J=3.7Hz,2H),3.70–3.62(m,2H),3.20–3.04(m,3H),2.31(s,6H) ,1.95(t,J=5.1Hz,1H),1.69(d,J=6.7Hz,1H),1.59(t,J=6.8Hz,3H),1.28–1.26(m,4H),1.24–1.22(m,4H).

[0292] Example 6: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0293] 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyridin-2(1H)-one (0.027 g, 0.12 mmol), 3-((1S,2S)-1-(5-bromo-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-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 (0.1 g, 0.11 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0072 g, 0.011 mmol), and potassium carbonate (0.33 mmol, 0.046 g) were dissolved in dioxane (10 mL) and water (2 mL) and refluxed at 100 °C overnight under a nitrogen atmosphere with stirring. After the reaction was completed, the mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH (v / v) = 60 / 1) to obtain a brown powder product (0.07 g, 68.88%).

[0294] MS(ESI,pos.ion)m / z:890.00[M+H] + ;

[0295] 1H NMR (400MHz, Chloroform-d): δ11.65(s,2H),8.28(s,1H),7.85(d,J=12.2Hz,2H),7.67(d,J=10.3Hz,2H),7.52(d,J=10.5Hz,2H),7 .41(t,J=8.2Hz,1H),7.35(d,J=6.5Hz,1H),7.18(d,J=6.4Hz,2H),7.09(s,1H),6.98(d,J=19.6Hz,2H),6.45(d,J=9.6Hz,1H),6.31( d,J=9.3Hz,1H),6.15(t,J=6.6Hz,1H),4.43(d,J=34.8Hz,1H),3.83(d,J=17.5Hz,1H),3.65(s,1H),2.92(s,1H),2.24(d,J=13.9Hz ,6H),1.80(d,J=28.6Hz,2H),1.62(d,J=29.5Hz,2H),1.45(d,J=6.6Hz,2H),1.34(s,1H),1.23(s,3H),0.86(dd,J=15.6,7.5Hz,2H).

[0296] Example 7: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0297] Step 1: Synthesis of 5-bromo-1-cyclopropyl-1H-pyrazolo[4,3-b]pyridine

[0298] 5-Bromo-1H-pyrazole[4,3-b]pyridine (1.0 g, 5.05 mmol), cyclopropylboronic acid (0.87 g, 10.1 mmol), 2,2'-bipyridine (0.79 g, 5.05 mmol), copper acetate (0.92 g, 5.05 mmol), and sodium carbonate (1.07 g, 10.1 mmol) were added to a reaction flask, followed by the addition of acetonitrile (20 mL). After purging the flask with oxygen, the mixture was heated to 80 °C and stirred for 39 h. After the reaction was complete, insoluble impurities were removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a white solid product (1.1 g, 91.49%).

[0299] MS(ESI,pos.ion)m / z:237.9[M+H] + ;

[0300] 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.82(d,J=8.7Hz,1H),7.44(d,J=8.7Hz,1H),3.67–3.62(m,1H),1.33–1.13(m,4H).

[0301] Step 2: Synthesis of (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-carboxylic acid tert-butyl ester

[0302] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.45 mmol), 5-bromo-1-cyclopropyl-1H-pyrazolo[4,3-b]pyridine (0.11 g, 0.45 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.064 g, 0.45 mmol), and potassium carbonate (0.16 g, 1.13 mmol) were dissolved in NMP (5 mL). Cuprous iodide (0.086 g, 0.45 mmol) was added under nitrogen protection, and the nitrogen atmosphere was replaced again. The mixture was heated to 130 °C and stirred for 5 h. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid product (0.239 g, 88.13%). MS (ESI, pos.ion) m / z: 599.1 [M+H] + ;

[0303] 1 H NMR(400MHz, CDCl3)δ8.51(d,J=9.1Hz,1H),8.10(s,1H),8.04(d,J=9.1Hz,1H),7 .57(d,J=3.1Hz,1H),7.10(d,J=6.2Hz,2H),6.33(d,J=2.2Hz,1H),5.36-5.24(m, 1H),4.50–4.34(m,1H),3.76–3.59(m,1H),3.15(s,1H),2.82(s,2H),2.21(s,6H) ,1.51(s,9H),1.31(d,J=6.7Hz,3H),1.27(d,J=5.5Hz,2H),1.22(d,J=5.6Hz,2H).

[0304] Step 3: Synthesis of (S)-1-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0305] (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.23 g, 0.38 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of 0.95 mL (3.8 mmol) of 4 mol / L 1,4-dioxane hydrogen chloride solution. The mixture was stirred at room temperature for 11 h. After the reaction was complete, the solvent was removed under reduced pressure to give a white solid product (0.20 g, 97.30%). MS (ESI, pos.ion) m / z: 499.1 [M+H] + ;

[0306] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0307] Dissolve (S)-1-(1-cyclopropyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (0.20 g, 0.37 mmol) in DMF (5 mL), and add DIPEA (0.20 g) with stirring. Add 1.56 mmol), and continue stirring for 1 h; then add HATU (0.22 g, 0.58 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.16 g, 0.39 mmol), and stir at room temperature for 26 h. After the reaction is complete, dilute with water (50 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine, remove the solvent under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to give a white solid product (0.21 g, 60.54%). MS (ESI, pos.ion) m / z: 892.0 [M+H] + ;

[0308] 1 H NMR (400MHz, CDCl3) δ11.36(s,1H),8.59(d,J=9.1Hz,1H),8.12–8.09(m,2H),7.62(d,J=3.4Hz,1H),7.60(d,J=8.7Hz,1H),7.54 (s,1H),7.14(d,J=6.1Hz,2H),6.72(s,1H),6.33(d,J=3.1Hz,1H),5.84(q,J=6.4Hz,1H),4.50(dd,J=13.4,4.6Hz,1H),3.90–3. 83(m,3H),3.72–3.66(m,1H),3.64–3.55(m,1H),3.22–3.12(m,1H),3.06–3.03(m,2H),2.25(s,6H),1.80–1.74(m,3H),1.64–1. 62(m,2H),1.51(d,J=6.6Hz,3H),1.36(s,3H),1.30(s,3H),1.27(d,J=7.6Hz,4H),1.18(d,J=3.2Hz,3H),0.95(d,J=6.7Hz,2H).

[0309] Example 8: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0310] Step 1: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0311] 3-((1S,2S)-1-(5-bromo-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2 4-Oxadiazol-5(4H)-one (2.5 g, 2.85 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.23 g, 0.29 mmol), pinacol diboronate (1.09 g, 4.28 mmol), and potassium acetate (0.84 g, 8.55 mmol) were dissolved in 1,4-dioxane (35 mL). The mixture was purged with nitrogen and then heated to 100 °C with stirring for 6 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 6 / 1) to give a brown solid product (1.54 g, 58.46%). MS (ESI, pos.ion) m / z: 922.90 [M+H] + .

[0312] Step 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0313] 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2, 4-Oxadiazol-5(4H)-one (0.10 g, 0.11 mmol), 5-bromo-1-methylpyrimidin-2(1H)-one (0.031 g, 0.17 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.009 g, 0.011 mmol), and potassium carbonate (0.046 g, 0.33 mmol) were added to a reaction flask. Under nitrogen protection, 1,4-dioxane (10 mL) and water (3 mL) were added, and the atmosphere was purged with nitrogen again. The mixture was heated to 100 °C and stirred. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a yellow-green solid product (0.09 g, 91.78%). MS (ESI, pos.ion) m / z: 905.34 [M+H] + ;

[0314] 1 H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.97(s,1H),8.65(s,1H),8.28(s,1H),7.91(s,1H),7.67(d, J=8.8Hz,1H),7.59–7.48(m,3H),7.18(d,J=5.6Hz,2H),7.06(s,1H),7.03(s,1H),6.95(s,1H),5.59 (d,J=6.5Hz,1H),4.37(d,J=10.2Hz,1H),3.55(s,3H),3.29–3.14(m,1H),2.92–2.88(m,1H),2.26( s,6H),1.86–1.74(m,2H),1.71–1.63(m,1H),1.45(d,J=5.8Hz,3H),1.34(s,1H),1.24–1.10(m,8H).

[0315] Example 9: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0316] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4- Oxadiazole-5(4H)-one (0.1 g, 0.11 mmol), 6-bromo-1-methyl-1,2-dihydropyridin-2-one (0.031 g, 0.17 mmol), potassium carbonate (0.030 g, 0.22 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (0.090 g, 0.011 mmol) were placed in a two-necked flask, and dioxane (3 mL) and water (1 mL) were added. The mixture was then purged three times with nitrogen. The reaction mixture was then allowed to react overnight at 90 °C under nitrogen protection. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, extracted with water and EA (30 mL × 3), washed with saturated brine (30 mL × 3), and purified by column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to obtain a white solid product (60 mg, 96.13%). MS (ESI, pos.ion) m / z: 903.90 [M+H] + ;

[0317] 1H NMR (400MHz, DMSO-d6) δ11.85–11.72(m,1H),8.29(s,1H),7.80(s,1H),7.68(d,J=8.8Hz,1H),7.59(d,J=8.6Hz,1H),7.52(t, J=7.9Hz,1H),7.45(d,J=8.2Hz,2H),7.18(d,J=6.4Hz,2H),7.09(d,J=3.4Hz,2H),6.96(s,1H),6.44(d,J=9.1Hz,1H),6.15(d, J=6.9Hz,1H),5.60(d,J=6.3Hz,1H),4.41(d,J=12.5Hz,1H),3.83(d,J=24.3Hz,2H),3.28(s,3H),2.91(d,J=15.2Hz,1H),2.2 6(s,7H),1.86(d,J=7.8Hz,1H),1.79(s,1H),1.71(s,1H),1.45(d,J=6.6Hz,3H),1.24(s,2H),1.21–1.16(m,3H),1.14(s,2H).

[0318] Example 10: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazole-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2-oxo-1,2-dihydropyridin-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0319] At room temperature, 3-((1S,2S)-1-(5-bromo-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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (0.10 g, 0.12 g) was prepared. 0.032 g, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridin-2(1H)-one (0.076 g, 0.36 mmol), potassium phosphate (0.076 g, 0.36 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (0.0098 g, 0.012 mmol) were dissolved in a mixed solution of 1,4-dioxane (6 mL) and water (1 mL), purged three times with nitrogen, and reacted at 90 °C for 24 h. After the reaction was complete, water (10 mL) was added, followed by extraction with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative plate (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid product (0.037 g, 35.83%).

[0320] HRMS:calcd.For C 48 H 42 F2N 11 O5[M+H] + :890.3338,found:890.3333;

[0321] 1H NMR (400MHz, CDCl3) δ11.31(s,1H),8.11(s,1H),7.81(d,J=9.7Hz,1H),7.72(d,J=7.4Hz,1H),7.62–7.31(m,4H),7.18(d,J=6.1 Hz,1H),7.08(d,J=6.1Hz,1H),6.79(s,1H),6.74(d,J=9.4Hz,1H),6.63(s,1H),6.48(s,1H),6.33(d,J=3.0Hz,1H),6.10(s,1H) ,5.83(t,J=6.6Hz,1H),5.37(s,1H),5.18(d,J=6.9Hz,1H),4.55–4.44(m,1H),3.77(s,1H),3.70–3.60(m,3H),3.50(d,J=49.6H z,3H),3.18(d,J=11.2Hz,1H),3.06(d,J=13.9Hz,1H),2.28(s,1H),1.44(d,J=5.1Hz,1H),1.28(s,6H),0.88(d,J=20.2Hz,4H).

[0322] Example 11: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0323] Step 1: Synthesis of 4-bromo-N-cyclopropyl-2-nitrobenzene

[0324] 4-Bromo-1-fluoro-2-nitrobenzene (2 g, 9.09 mmol), cyclopropylamine (2.59 g, 45.45 mmol), and DIPEA (2.35 g, 18.18 mmol) were dissolved in ethanol (20 mL), and the mixture was heated to 55 °C and stirred for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a red solid product (2.3 g, 98.41%). MS (ESI, pos.ion) m / z: 257.00 [M+H] + ;

[0325] 1H NMR (400MHz, CDCl3) δ8.32(d,J=2.3Hz,1H),8.07(s,1H),7.55(dd,J=9.1,2.3Hz,1 H),7.26(d,J=9.1Hz,1H),2.62–2.56(m,1H),0.99–0.90(m,2H),0.72–0.65(m,2H).

[0326] Step 2: 4-Bromo-N 1 Synthesis of cyclopropylphenyl-1,2-diamine

[0327] 4-Bromo-N-cyclopropyl-2-nitrobenzene (1 g, 3.89 mmol) was dissolved in methanol (20 mL), and after purging with hydrogen, Raney nickel (0.23 g, 3.89 mmol) was added. The mixture was then purged with hydrogen again, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the insoluble matter was removed by filtration, and the solvent was removed from the filtrate under reduced pressure to give a reddish-brown oily product (0.86 g, 97.35%). MS (ESI, pos.ion) m / z: 227.05 [M+H] + .

[0328] Step 3: Synthesis of 5-bromo-1-cyclopropyl-1H-benzo[d]imidazole

[0329] 4-bromo-N 1 Cyclopropylphenyl-1,2-diamine (0.86 g, 3.79 mmol) was dissolved in DMF (6 mL), stirred until homogeneous, and then trimethyl orthoformate (2.01 g, 18.95 mmol) and hydrochloric acid (0.46 g, 3.79 mmol) were added. The mixture was stirred at room temperature for 20 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a brown oily product (0.28 g, 31.18%). MS (ESI, pos.ion) m / z: 237.00 [M+H] + ;

[0330] 1 H NMR (400MHz, CDCl3) δ7.94(d,J=0.9Hz,1H),7.93(s,1H),7.49–7.40(m,2H),3.44–3.29(m,1H),1.22–1.14(m,2H),1.08–1.02(m,2H).

[0331] Step 4: Synthesis of (S)-3-(3-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0332] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.3 g, 0.68 mmol), 5-bromo-1-cyclopropyl-1H-benzo[d]imidazole (0.24 g, 1.02 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.097 g, 0.68 mmol), and potassium carbonate (0.23 g, 1.70 mmol) were dissolved in NMP (5 mL). Cuprous iodide (0.13 g, 0.68 mmol) was added under nitrogen protection, and the nitrogen atmosphere was replaced again. The mixture was heated to 130 °C and stirred for 15 hours. After the reaction was complete, water (70 mL) was added for dilution, and ethyl acetate (50 mL × 2) was used for extraction. The organic phases were combined and washed with saturated brine. The solvent was removed under reduced pressure, and the residue was purified and separated by column chromatography (dichloromethane / ethyl acetate (v / v) = 2 / 1) to give a brown solid product (0.366 g, 90.12%).

[0333] MS(ESI,pos.ion)m / z:598.3[M+H] + ;

[0334] 1 H NMR(400MHz, CDCl3)δ8.06(s,1H),7.85(s,1H),7.70–7.61(m,2H),7.13(d ,J=6.1Hz,2H),6.72(d,J=2.4Hz,1H),6.30(s,1H),5.37–5.24(m,1H),4.5 0–4.35(m,1H),3.46–3.43(m,1H),3.16(s,1H),2.83–2.78(m,2H),2.24(s ,6H),1.52(s,9H),1.36(d,J=6.6Hz,3H),1.24–1.19(m,2H),1.08(s,2H).

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

[0336] (S)-3-(3-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.366 g, 0.61 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of 1,4-dioxane hydrogen chloride solution (3.05 mL, 12.2 mmol, 4 mol / L). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the solvent was removed under reduced pressure to give a brown solid product (0.33 g, 100.91%).

[0337] Step 6: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0338] Dissolve (S)-1-(1-cyclopropyl-1H-benzo[d]imidazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (0.33 g, 0.61 mmol) in DMF (3 mL), and add DIPEA (0.39 g, 3 mL) with stirring. 0.05 mmol), and stirred for 1 h; then HATU (0.35 g, 0.92 mmol) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.25 g, 0.61 mmol) were added, and the reaction was stirred at room temperature for 17 h. After the reaction was complete, water (70 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid product (0.21 g, 60.54%). MS (ESI, pos.ion) m / z: 891.0 [M+H] + ;

[0339] 1 H NMR (400MHz, CDCl3) δ11.39(s,1H),9.13(s,1H),8.21–8.10(m,2H),7.93(d,J=9.0Hz,1H),7.60(d,J=8.7Hz,1H),7. 54(s,1H),7.27(s,1H),7.12(d,J=6.0Hz,2H),6.90(s,1H),6.73(s,1H),6.40(s,1H),5.85–5.80(m,1H),4.51(dd,J =13.5,4.5Hz,1H),3.92–3.87(m,2H),3.69–3.59(m,2H),3.23–3.12(m,1H),3.06–3.02(m,2H),2.27(s,6H),1.84–1 .74(m,4H),1.71–1.65(m,3H),1.53(d,J=6.9Hz,3H),1.38(s,3H),1.32(s,3H),1.28(s,4H),1.19(d,J=5.4Hz,3H).

[0340] Example 12: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0341] Add 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indol-1-yl)-2-methyl Cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.11 mmol), 6-bromo-3-pyridazine alcohol (28.87 mg, 0.17 mmol), potassium carbonate (45.6 mg, 0.33 mmol), dioxane (5.80 mL), and water (2 mL) were added. The mixture was purged with nitrogen several times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (44.9 mg, 0.055 mmol) was added. The mixture was purged with nitrogen several times, and the mixture was stirred at 80 °C for 4.5 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 40 / 1-25 / 1) to give a yellow solid product (70 mg, 72.51%). MS (ESI, pos.ion) m / z: 890.9 [M+H] + ;

[0342] 1H NMR (400MHz, CDCl3) δ11.43–11.20(m,2H),8.10–7.94(m,2H),7.87–7.66(m,3H),7.51(d,J=2.8Hz,1H) ,7.22–7.17(m,2H),7.11–6.98(m,2H),6.82(d,J=5.7Hz,1H),6.64–6.44(m,1H),6.34–6.08(m,1H),5.8 3(q,J=6.5Hz,1H),4.58–4.36(m,1H),3.68–3.44(m,2H),3.22–3.03(m,2H),2.31–2.27(m,6H),1.99(t, J=6.1Hz,1H),1.66(s,3H),1.62–1.60(m,2H),1.30–1.26(m,2H),1.25–1.24(m,3H),1.11–1.08(m,2H).

[0343] Example 13: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0344] Add 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl) to the reaction flask -1,2,4-oxadiazol-5(4H)-one (102 mg, 0.11 mmol), 4-bromo-2-methylpyridazine-3(2H)-one (31.19 mg, 0.17 mmol), potassium carbonate (45.61 mg, 0.33 mmol), dioxane (5.8 mL), and water (2 mL) were added. The mixture was purged with nitrogen several times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (44.9 mg, 0.055 mmol) was added. The mixture was purged with nitrogen several times, and the mixture was stirred at 80 °C for 4.5 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 4 / 1-1 / 1) to give a yellow solid product (60 mg, 59.98%). MS (ESI, pos.ion) m / z: 904.90 [M+H] + ;

[0345] 1 H NMR (400MHz, CDCl3) δ11.34–11.30(m,1H),8.42–8.32(m,1H),8.10–7.99(m,1H),7.89–7.84(m,1H) ),7.711–7.61(m,2H),7.51(s,1H),7.36–7.28(m,2H),7.22–7.07(m,2H),6.82(s,1H),6.63–6.48( m,1H),6.33–6.08(m,1H),5.83–5.28(m,1H),4.91–4.46(m,1H),3.90–3.88(m,3H),3.67–3.42(m, 2H),319–3.02(m,2H),2.30–2.27(m,6H),1.98–1.66(m,3H),1.61–1.54(m,3H),1.29–1.07(m,7H).

[0346] Example 14: 3-((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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

[0347] Step 1: Synthesis of ethyl (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate

[0348] Ethyl 5-((4S)-2,2-dimethyloxa-4-yl)-1H-indole-2-carboxylate (200 mg, 0.66 mmol) and DMF (5.3 mL) were added to a reaction flask. Sodium hydride (79.2 mg, 1.98 mmol, 60%) was added under ice bath conditions, and the reaction was allowed to proceed for 0.5 hours. Bromoacetonitrile (158.3 mg, 1.32 mmol) was then added dropwise, and the mixture was stirred at room temperature for 20 hours. The reaction was quenched by adding 20 mL of ammonium chloride aqueous solution to the reaction system under ice bath conditions. The mixture was extracted twice with ethyl acetate (20 mL), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-5 / 1) to give a pale yellow solid product (120 mg, 53.12%).

[0349] MS(ESI,pos.ion)m / z:341.1[M+H] + .

[0350] Step 2: Synthesis of ethyl (S,Z)-1-(2-amino-2-(hydroxyimino)ethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0351] Ethyl (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (300 mg, 0.88 mmol), sodium bicarbonate (369.6 mg, 4.4 mmol), hydroxylamine hydrochloride (305.8 mg, 4.4 mmol), and DMSO (4.6 mL) were added to a reaction flask. The mixture was stirred at 60 °C for 6 hours under nitrogen protection. After cooling to room temperature, water (20 mL) was added to quench the reaction, and the mixture was stirred for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain a pale yellow crude solid (310 mg, 94.19%).

[0352] Step 3: Synthesis of ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-1H-indole-2-carboxylate

[0353] Ethyl (S,Z)-1-(2-amino-2-(hydroxyimino)ethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ester (310 mg, 0.83 mmol), CDI (336.5 mg, 2.07 mmol), DBU (315.9 mg, 2.07 mmol), and DMSO (4.6 mL) were added to the reaction flask. The mixture was stirred at room temperature for 9 hours under nitrogen protection. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 40 / 1-20 / 1) to give a pale yellow solid product (300 mg, 90.48%). MS(ESI,pos.ion)m / z:400.0[M+H] + .

[0354] Step 4: Synthesis of (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-1H-indole-2-carboxylic acid

[0355] Ethyl (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-1H-indole-2-carboxylate (300 mg, 0.75 mmol) and methanol (19.0 mL) were added to a reaction flask, followed by the addition of 5 mL of a solution of sodium hydroxide (75 mg, 1.88 mmol). The mixture was stirred at 60 °C for 2.5 hours. The solvent was removed under reduced pressure, and the pH was adjusted to approximately 3 with dilute hydrochloric acid. The solvent was removed again under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10 / 1-5 / 1) to obtain a pale yellow solid product (120 mg, 43.02%).

[0356] MS(ESI,neg.ion)m / z:370.0[MH] - ;

[0357] 1H NMR (599MHz, CDCl3) δ10.69(s,1H),8.39(s,1H),7.60(d,J=8.7Hz,1H),7.56(s,1H),7.43(s,1H),7.39(dd,J=8.7,1.0Hz,1H),5.54(s,2H),3.99–3 .91(m,1H),3.87(td,J=11.6,3.9Hz,1H),3.07(ddd,J=12.6,10.8,4.0Hz, 1H),1.86–1.75(m,3H),1.69(t,J=12.9Hz,1H),1.39(s,3H),1.33(s,3H).

[0358] Step 5: Synthesis of 3-((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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

[0359] Add (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-1H-indole-2-carboxylic acid (90 mg, 0.24 mmol), HATU (136.9 mg, 0.36 mmol), triethylamine (121.4 mg, 1.2 mmol), and DMF (10 g) to the reaction flask under nitrogen protection. The mixture was stirred at room temperature for 0.5 hours, and then (S)-1-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (132.5 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 17 hours under nitrogen protection. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 4 / 1-1 / 1) to give a pale yellow solid product (90 mg, 42.74%). MS (ESI, pos.ion) m / z: 869.0 [M+H] + ;

[0360] 1H NMR (400MHz, CDCl3) δ10.77(s,1H),8.09–8.04(m,1H),7.56–7.28(m,5H),7.17–7. 09(m,2H),6.90–6.83(m,1H),6.63–6.50(m,1H),6.33–6.18(m,1H),5.86–5.69(m, 1H),5.26–5.20(m,2H),4.88–4.72(m,1H),3.88–3.40(m,4H),3.14–3.01(m,3H),2 .30–2.27(m,6H),1.79–1.56(m,8H),1.36(s,3H),1.30(s,3H),1.25–1.22(m,3H).

[0361] Example 15: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0362] 0.028 g, 0.12 mmol of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-2(1H)-one, 3-((1S,2S)-1-(5-bromo-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-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 (0.1 g, 0.11 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0072 g, 0.011 mmol), and potassium carbonate (0.33 mmol, 0.046 g) were dissolved in dioxane (10 mL) and water (2 mL) and refluxed overnight at 100 °C under a nitrogen atmosphere. After the reaction was complete, water (20 mL) was added, followed by extraction with ethyl acetate (10 mL × 3). The organic layers were then combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a white powder product (0.09 g, 87.19%). MS (ESI, pos.ion) m / z: 903.90 [M+H] + ;

[0363] 1 H NMR (400MHz, Chloroform-d): δ11.79(s,1H),8.29(s,1H),8.10(d,J=2.7Hz,2H),7.84(d,J=9.7Hz,2H),7.68(d,J=8 .8Hz,1H),7.53(d,J=5.7Hz,2H),7.19(d,J=6.3Hz,2H),7.09(d,J=2.7Hz,1H),7.02(s,1H),6.95(s,1H),6.51(d,J=9 .5Hz,1H),5.59(d,J=6.8Hz,1H),4.39(d,J=13.4Hz,1H),3.85(s,5H),3.53(s,6H),2.91(d,J=15.1Hz,1H),2.78(d,J =5.0Hz,1H),2.23(s,1H),1.83(s,1H),1.77(s,1H),1.45(d,J=6.7Hz,3H),1.20(d,J=6.5Hz,4H),0.91–0.80(m,3H).

[0364] Example 16: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0365] Step 1: Synthesis of 5-bromo-1-cyclopropyl-4-fluoro-1H-benzi[d]imidazole

[0366] 6-Bromo-7-fluoro-1H-benzo[d]imidazole (215 mg, 1.0 mmol), cyclopropylboronic acid (171.8 mg, 2 mmol), copper acetate (181.63 mg, 1 mmol), 2,2'-bipyridine (156.18 mg, 1 mmol), sodium carbonate (211.98 mg, 2 mmol), and acetonitrile (12.72 mL) were added to a reaction flask and stirred at 80 °C for 8 hours under an oxygen atmosphere. The reaction was quenched by adding 10 mL of ammonium chloride aqueous solution dropwise to the reaction system under ice bath conditions. The mixture was extracted twice with 20 mL of ethyl acetate, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1-20 / 1) to obtain a pale yellow solid crude product (250 mg, 98.01%).

[0367] MS(ESI,pos.ion)m / z:254.9[M+H] + ;

[0368] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.40 (dd, J = 10.1, 4.1Hz, 1H), 7.25 (d, J = 8 .6Hz,1H),3.38(tt,J=7.1,3.7Hz,1H),1.21–1.17(m,2H),1.08–1.03(m,2H).

[0369] Step 2: Synthesis of (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0370] Add (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (400 mg, 0.91 mmol) and 5-bromo-1-cyclopropyl-4-fluoro-1H-benzo[d]imidazole (243.74 mg) to the reaction flask. Under nitrogen protection, cuprous iodide (34.66 mg, 0.18 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (51.78 mg, 0.36 mmol) were added, followed by stirring at 130 °C for 21 hours. The mixture was cooled to room temperature, the reaction was quenched with water (20 mL), extracted twice with ethyl acetate (40 mL), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1-1 / 2) to give a yellow solid product (110 mg, 19.72%). MS (ESI, pos.ion) m / z: 616.1 [M+H] + .

[0371] Step 3: Synthesis of (S)-1-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0372] (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (110 mg, 0.18 mmol) and ethyl acetate (11.09 mL) were added dropwise, followed by the addition of 4 M ethyl acetate hydrochloride solution (0.45 mL, 1.80 mmol). The mixture was stirred at room temperature for 5 hours. Then, 4 M ethyl acetate hydrochloride solution (0.45 mL, 1.80 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The solvent was removed under reduced pressure to give a yellow solid product (98 mg, 99.36%). MS (ESI, pos.ion) m / z: 516.0 [M+H] + .

[0373] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-benzo[d]imidazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0374] In a reaction flask, 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 (72 mg, 0.17 mmol), HATU (96.96 mg, 0.26 mmol), triethylamine (86.01 mg, 0.85 mmol), and DMF (10 g) were added. The mixture was stirred at room temperature for 0.5 hours under nitrogen protection. Then, (S)-1-(1-cyclopropyl-4-fluoro-1H- A DMF (5.27 mL) solution of benzo[d]imidazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (86.73 mg, 0.16 mmol) was stirred at room temperature for 10 hours under nitrogen protection to remove the solvent under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 4 / 1-1 / 1) to give a pale yellow solid product (30 mg, 18.86%).

[0375] MS(ESI,pos.ion)m / z:909.00[M+H] + ;

[0376] 1H NMR (400MHz, CDCl3) δ11.37(s,1H),8.01–7.97(m,1H),7.60(d,J=8.5Hz,1H),7.54(s,1H),7.48(s,1H),7.38–7.21 (m,2H),7.18–7.07(m,2H),6.74–6.72(m,1H),6.65–6.51(m,1H),6.32–6.09(m,1H),5.84–5.29(m,1H),4.90–4.46 (m,1H),3.88–3.84(m,2H),3.66–3.39(m,2H),3.23–2.95(m,3H),2.30–2.26(m,6H),1.82–1.73(m,3H),1.70(d,J= 6.8Hz,1H),1.64–1.52(m,4H),1.36(s,3H),1.30(s,3H),1.28–1.24(m,3H),1.23–1.21(m,3H),1.15–1.09(m,3H).

[0377] Example 17: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0378] 6-Bromo-2-methylpyridazin-3(2H)-one (0.025 g, 0.13 mmol), 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole-1,2,4-oxadiazol-5(4H)-one (0.1 g) 0.11 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0072 g, 0.011 mmol), and potassium carbonate (0.33 mmol, 0.046 g) were dissolved in dioxane (10 mL) and water (2 mL). The mixture was stirred and refluxed overnight at 100 °C under a nitrogen atmosphere. After the reaction was complete, water (20 mL) was added, followed by extraction with ethyl acetate (10 mL × 3). The organic layers were then combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a white powder (0.09 g, 87.19%).

[0379] MS(ESI,pos.ion)m / z:904.90[M+H] + ;

[0380] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.25(d,J=20.4Hz,2H),8.10(d,J=9.4Hz,1H),7.88(d,J=8.9Hz,1H),7.67(d,J=8.8H z,1H),7.57(d,J=8.6Hz,1H),7.51(t,J=8.0Hz,1H),7.19(d,J=6.4Hz,2H),7.12–7.06(m,2H),7.05(s,1H),6.95(s,1H),5. 59(d,J=7.2Hz,1H),4.40(d,J=12.1Hz,1H),3.89–3.82(m,1H),3.76(s,4H),3.21–3.06(m,1H),2.91(d,J=14.9Hz,1H),2.2 6(s,6H),2.23(s,2H),1.81(dt,J=24.7,7.8Hz,2H),1.72–1.57(m,2H),1.45(d,J=6.6Hz,3H),1.20(dd,J=13.5,8.1Hz,4H).

[0381] Example 18: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0382] Step 1: Synthesis of (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol

[0383] 1,1-Cyclopropanediethanol (5 g, 48.96 mmol), imidazole (5.0 g, 73.44 mmol), and DCM (75.5 mL) were added to a reaction flask, followed by tert-butyldimethylchlorosilane (7.38 g, 48.96 mmol). The mixture was stirred under reflux for 16 hours. The reaction was quenched with water (80 mL), allowed to stand for separation, and the organic phase was washed with saturated brine (80 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-4 / 1) to give a colorless liquid product (4.29 g, 40.50%).

[0384] Step 2: Synthesis of 5-bromo-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4-fluoro-1H-indazole

[0385] 5-Bromo-4-fluoroindazole (1.0 g, 4.65 mmol), (1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol (2.01 g, 9.3 mmol), triphenylphosphine (2.44 g, 9.3 mmol), and THF (44.98 mL) were added to a reaction flask and stirred until homogeneous. Then, diethyl azodicarbonate (1.62 g, 9.3 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction was quenched with water (20 mL), extracted with ethyl acetate (40 mL × 2), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1-10 / 1) to give a pale yellow liquid product (700 mg, 36.41%).

[0386] MS(ESI,pos.ion)m / z:413.0[M+H]+ ;

[0387] 1 H NMR (400MHz, CDCl3) δ8.06(s,1H),7.43(dd,J=8.8,6.2Hz,1H),7.32(d,J=8.9Hz,1H),4.40( s,2H),3.27(s,2H),0.93(s,9H),0.74(t,J=5.4Hz,2H),0.51(d,J=5.4Hz,2H),0.02(s,6H).

[0388] Step 3: Synthesis of (S)-3-(3-(1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0389] Add (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (400 mg, 0.91 mmol) and 5-bromo-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4- Fluoro-1H-indazole (413.8 mg, 1.00 mmol), potassium carbonate (377.3 mg, 2.73 mmol), and NMP (10 g) were added under nitrogen protection, along with cuprous iodide (173.3 mg, 0.91 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (258.9 mg, 1.82 mmol). The mixture was heated to 130 °C and stirred for 15 hours. After cooling to room temperature, the reaction was quenched with water (20 mL), extracted twice with ethyl acetate (40 mL), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1-1 / 1) to give a pale yellow viscous liquid product (100 mg, 14.26%).

[0390] 1H NMR(400MHz, CDCl3)δ8.13(s,1H),7.48(d,J=8.9Hz,1H),7.45–7.37(m,1H),7.14( d,J=6.1H,2H),6.58(s,1H),6.31(s,1H),5.37–5.25(m,1H),4.44–4.43(m,2H),3. 37–3.18(m,4H),2.88–2.79(m,2H),2.28(d,J=1.2Hz,6H),1.52(s,9H),1.38(d,J= 6.7Hz,3H),0.95(s,9H),0.75(t,J=5.4Hz,2H),0.52(t,J=5.3Hz,2H),0.05(s,6H).

[0391] Step 4: Synthesis of (S)-1-(4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0392] Add the mixture (S)-3-(3-(1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methyl)-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (277.1 mg, 0.42 mmol) and ethyl acetate (11.1 mL) to a reaction flask, and add dropwise 4M ethyl acetate hydrochloride solution (1.05 mL, 4.2 mmol). Stir at room temperature for 4 hours. Remove the solvent under reduced pressure, add triethylamine to adjust the pH to about 8, remove the solvent under reduced pressure again, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1-10 / 1) to obtain a pale yellow solid product (135 mg, 57.44%).

[0393] MS(ESI,pos.ion)m / z:560.1[M+H] + ;

[0394] 1H NMR (400MHz, CDCl3) δ8.15 (s, 1H), 7.42–7.36 (m, 2H), 7.10 (d, J = 6.2Hz, 2H), 6.55(d,J=1.7Hz,1H),6.24(d,J=3.0Hz,1H),4.43(s,2H),4.28(d,J=5.6Hz,1 H),3.41–3.35(m,1H),3.29(s,2H),3.15–3.11(m,1H),2.95–2.83(m,2H),2.2 7(s,6H),1.39(d,J=6.3Hz,3H),0.74(t,J=5.4Hz,2H),0.58(t,J=5.4Hz,2H).

[0395] Step 5: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0396] Add 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 (85 mg, 0.21 mmol), HATU (119.8 mg, 0.32 mmol), triethylamine (106.2 mg, 1.05 mmol), and DMF (10 g) to a reaction flask, and incubate at room temperature under nitrogen protection. After stirring for 0.5 hours, a solution of (S)-1-(4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (117.5 mg, 0.21 mmol) in DMF (5.27 mL) was added. The mixture was stirred at room temperature for 11 hours under nitrogen protection. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 4 / 1-1 / 1) to give a pale yellow solid product (150 mg, 76.19%).

[0397] HRMS:calcd.for C 52 H55 F2N 10 O6[M+H] + :953.4274,found:953.4275;

[0398] 1 H NMR (400MHz, CDCl3) δ11.35–11.30(m,1H),8.20–8.11(m,1H),7.67–7.58(m,1H),7.57–7.46(m,2H),7.41–7.32(m,1H),7.29–7.27(m,1H),7 .19–7.08(m,2H),6.74–6.73(m,1H),6.63–6.49(m,1H),6.34–6.10(m ,1H),5.84–5.28(m,1H),4.91–4.50(m,1H),4.47–4.42(m,2H),3.91–3 .82(m,2H),3.65–3.60(m,1H),3.51(s,1H),3.34–3.31(m,2H),3.24– 3.10(m,1H),3.04–2.99(m,2H),2.30–2.28(m,6H),1.97–1.87(m,1H), 1.84–1.64(m,6H),1.71–1.60(m,3H),1.37(s,3H),1.31(s,3H),1.16(dd,J=54.3,5.8Hz,3H),0.77(q,J=5.8Hz,2H),0.62(t,J=5.5Hz,2H).

[0399] Example 19: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0400] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazolyl Azoxyl-5(4H)-one (0.1 g, 0.11 mmol), 5-bromo-1-(difluoromethyl)-1,2-dihydropyridin-2-one (0.049 g, 0.22 mmol), potassium carbonate (0.030 g, 0.22 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (0.009 g, 0.011 mmol) were placed in a two-necked flask, and dioxane (4 mL) and water (1 mL) were added. The mixture was then purged three times with nitrogen. The reaction mixture was then allowed to react overnight at 90 °C under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, and then water (50 mL) and EA were added for extraction (30 mL × 3). The solution was washed with saturated saline (30 mL × 3), mixed with silica gel, and purified by column chromatography with dichloromethane / methanol (v / v) = 30 / 1 as the eluent to obtain a white solid product (63 mg, 61.85%).

[0401] MS(ESI,neg.ion)m / z:937.90[MH] - ;

[0402] 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.27(s,1H),8.08–7.98(m,2H),7.96(s,1H),7.92(d,J=6.6Hz,1H),7.66(d,J=8.8Hz,1H),7.59(d,J =9.0Hz,1H),7.51(dd,J=13.8,8.1Hz,2H),7.17(d,J=6.3Hz,2H),7.08–7.01(m,1H),6.94(s,1H),6.66(d,J=9.7Hz,1H),5.58(d,J=6.8Hz,1 H),4.37(d,J=13.0Hz,1H),3.84(s,1H),3.63(d,J=13.0Hz,1H),2.90(d,J=14.9Hz,1H),2.23(d,J=14.4Hz,6H),1.99(q,J=7.6Hz,1H),1.8 0(d,J=24.5Hz,1H),1.83–1.77(m,2H),1.44(d,J=6.6Hz,2H),1.36–1.32(m,1H),1.22(s,3H),1.18(t,J=7.2Hz,4H),0.84(t,J=6.6Hz,1H).

[0403] Example 20: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0404] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclo Propyl)-1,2,4-oxadiazol-5(4H)-one (0.11 g, 0.12 mmol), 5-bromo-1-isopropylpyridine-2(1H)-one (0.039 g, 0.18 mmol), potassium carbonate (0.050 g, 0.36 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) chloride (0.016 g, 0.024 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL), and the reaction was carried out at 100 °C for 4 h under nitrogen protection. After the reaction was complete, water (10 mL) was added, followed by extraction with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid product (0.073 g, 65.71%). MS (ESI, pos.ion) m / z: 932.0 [M+H] + ;

[0405] 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.10(s,1H),7.76–7.61(m,4H),7.51(d,J=2.9Hz,2H),7.42(d,J=9 .2Hz,1H),7.17(d,J=6.1Hz,2H),7.08(d,J=6.1Hz,1H),6.79(s,1H),6.63(t,J=2.2Hz,1H),6.48(s,1H) ,6.33(d,J=3.1Hz,1H),4.49(d,J=13.3Hz,1H),3.65(s,2H),3.17(d,J=13.5Hz,1H),3.05(d,J=14.3Hz ,2H),2.29(dd,J=14.6,2.1Hz,8H),1.45(d,J=6.3Hz,8H),1.25(t,J=5.9Hz,9H),1.09(d,J=5.4Hz,1H).

[0406] Example 21: 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0407] Step 1: Synthesis of (S,E)-N-((4-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

[0408] 4-Bromopyridine-2-carboxaldehyde (3 g, 16.13 mmol), (S)-2-methylpropane-2-sulfinamide (2.15 g, 17.74 mmol), and cesium carbonate (6.31 g, 19.36 mmol) were dissolved in dichloromethane (30 mL), and the mixture was heated to 40 °C and reacted for 1 h. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA(v / v) = 10 / 1-1 / 1) to give a yellow oily compound (4.5 g, 96.48%). MS (ESI, pos.ion) m / z: 289.0 [M+H] + ;

[0409] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.67 (d, J = 6.1Hz, 1H), 8.56 (d, J = 5.2Hz, 1H), 8.18 (d, J = 1.5Hz, 1H), 7.57 (dd, J = 5.2, 1.8Hz, 1H), 1.30 (s, 9H).

[0410] Step 2: Synthesis of (S)-N-((4-bromopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide

[0411] (S,E)-N-((4-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (4.5 g, 15.56 mmol) was dissolved in methanol (30 mL), and then sodium borohydride (0.88 g, 23.34 mmol) was added. The reaction was carried out at room temperature. After 30 min of reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1-1 / 4) to give a white solid product (1.5 g, 33.10%).

[0412] MS(ESI,pos.ion)m / z:291.00[M+H]+ ;

[0413] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.37 (d, J = 5.3Hz, 1H), 7.54 (s, 1H), 7.38 (dd, J = 5.2, 1.4Hz, 1H), 4.51–4.33 (m, 2H), 4.28 (t, J = 5.6Hz, 1H), 1.28 (s, 9H).

[0414] Step 3: Synthesis of (4-bromopyridin-2-yl)methylamine

[0415] (S)-N-((4-bromopyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (4 g, 13.74 mmol) was dissolved in methanol (50 mL), cooled to 0 °C, and then 4 mol / L ethyl hydrochloride solution (17.18 mL, 68.7 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solution was concentrated and evaporated to dryness. Then, 20 mL of 2N NaOH aqueous solution was added, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 1-2 / 1) to give a yellow liquid compound (1.5 g, 58.39%). MS (ESI, pos.ion) m / z: 187.1 [M+H] + ;

[0416] 1 H NMR (599MHz, CDCl3) δ (ppm) 8.36 (d, J = 5.3Hz, 1H), 7.51 (d, J = 0.9Hz, 1H), 7.33 (dd, J = 5.2, 1.4Hz, 1H), 3.97 (s, 2H), 2.13 (s, 2H).

[0417] Step 4: Synthesis of N-((4-bromopyridin-2-yl)methyl)cyclopropaneformamide

[0418] (4-Bromopyridin-2-yl)methylamine (0.3 g, 1.60 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.32 g, 3.2 mmol) and cyclopropaneformyl chloride (0.18 g, 1.76 mmol) were added. The reaction was carried out at room temperature. After 1 h of reaction, the mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1 to 1 / 9) to give a yellow solid product (0.3 g, 73%). MS (ESI, pos.ion) m / z: 255.0 [M+H] + ;

[0419] 1 H NMR (599MHz, CDCl3) δ (ppm) 8.38 (d, J = 5.3 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J = 5.3, 1.4 Hz, 1H), 6.85(s,1H),4.59(d,J=5.3Hz,2H),1.54–1.45(m,1H),1.05–1.00(m,2H),0.85–0.75(m,2H).

[0420] Step 5: Synthesis of 7-bromo-3-cyclopropylimidazo[1,5-a]pyridine

[0421] N-((4-bromopyridin-2-yl)methyl)cyclopropaneformamide (0.18 g, 0.71 mmol) was dissolved in dichloromethane (6 mL), and then (1E)-1-methoxy-N-(triethylammonium)sulfonylmethylimine ester (0.85 g, 3.55 mmol) was added. The reaction was carried out at room temperature. After 2 h of reaction, the mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 1 to 10 / 1) to give a yellow oily liquid compound (0.12 g, 71.73%). MS (ESI, pos.ion) m / z: 237.0 [M+H] + ;

[0422] 1 H NMR (599MHz, CDCl3) δ (ppm) 7.87 (d, J = 7.5 Hz, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 6.63 (dd, J = 7.5, 1. 6Hz, 1H), 2.01 (ddd, J=7.8, 5.0, 2.6Hz, 1H), 1.29 (dd, J=17.1, 9.9Hz, 2H), 1.09 (d, J=3.6Hz, 2H).

[0423] Step 6: Synthesis of (S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0424] Tert-butyl(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.45 mmol), 7-bromo-3-cyclopropylimidazo[1,5-a]pyridine (0.12 g, 0.50 mmol), cuprous iodide (0.043 g, 0.23 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1.13 mmol), and potassium carbonate (0.19 g, 1.35 mmol) were dissolved in N-methylpyrrolidone (5 mL). After evacuation, the mixture was heated to 130 °C for reaction. After reacting for 3 hours, the mixture was diluted with ethyl acetate (40 mL), extracted with saturated brine (10 mL × 4), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1-1 / 4) to give a yellow solid product (0.2 g, 73.87%). MS (ESI, pos.ion) m / z: 598.3 [M+H] + .

[0425] Step 7: Synthesis of (S)-1-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one

[0426] (S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.33 mmol) was dissolved in dichloromethane (4 mL), and then 4 mol / L ethyl hydrogen chloride solution (0.83 mL, 3.30 mmol) was added. The reaction was carried out at room temperature. After 1 h of reaction, the solution was concentrated and evaporated to dryness, diluted with water (10 mL), and the pH was adjusted to 7-8 with sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (15 mL × 2), the organic phases were combined, and the solvent was removed under reduced pressure to give a yellow solid product (0.16 g, 96%).

[0427] Step 8: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0428] 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 (0.14 g, 0.34 mmol) was dissolved in DMF (4 mL), and HATU (0.26 g, 0.68 mmol) and triethylamine were added. (0.34 g, 3.40 mmol) and (S)-1-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (0.17 g, 0.34 mmol) were reacted at room temperature. After reacting for 13 h, the mixture was diluted with ethyl acetate (30 mL), washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to give a blue-white solid product (0.1 g, 32.85%).

[0429] HRMS:calcd.for C 50 H 52 FN 10 O5[M+H] + :891.4101,found:891.4140;

[0430] 1H NMR (400MHz, CDCl3) δ11.41–11.28(m,1H),8.30–7.76(m,3H),7.64–7.61(m,1H),7.54–7.50(m,1H),7.33–7 .28(m,1H),7.28–7.25(m,1H),7.11–7.01(m,2H),6.73–6.71(m,1H),6.41–6.26(m,1H),5.82–5.80(m,1H), 4.90–4.87(m,1H),4.52–4.50(m,1H),3.90–3.86(m,2H),3.64–3.58(m,1H),3.03(d,J=12.6Hz,3H),2.28–2 .23(m,7H),1.92–1.64(m,6H),1.55–1.50(m,4H),1.37–1.33(m,5H),1.32–1.26(m,5H),1.20–1.08(m,3H).

[0431] Example 22: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(6-cyclopropyl-7-oxo-4,6-diazaspiro[2.4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0432] Step 1: Synthesis of 4-bromo-N-(1-formylcyclopropyl)benzamide

[0433] 4-Bromobenzoic acid (0.2 g, 0.99 mmol) was dissolved in DMF (5 mL), followed by the addition of HOBt (0.16 g, 1.19 mmol), EDCI (0.34 g, 1.78 mmol), DIPEA (0.38 g, 2.97 mmol), and 1-aminocyclopropane-1-carboxamide (0.12 g, 1.19 mmol). After the addition was complete, the mixture was stirred at room temperature. After the reaction was completed as monitored by TLC, the reaction solution was extracted with water and EA (30 mL × 3), washed with saturated brine (30 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a white solid product (0.23 g, 81.65%).

[0434] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.98 (s, 1H), 7.91–7.78 (m, 2H), 7.67 (d, J = 8.4H z,2H),7.33(s,1H),7.02(s,1H),1.31(q,J=4.2Hz,2H),0.95(q,J=4.2Hz,2H).

[0435] Step 2: Synthesis of 5-(4-bromophenyl)-4,6-diazaspiro[2.4]hepten-4-en-7-one

[0436] 4-Bromo-N-(1-formylcyclopropyl)benzamide (0.2 g, 0.71 mmol) was dissolved in tert-butanol (4 mL) at room temperature, followed by the addition of potassium tert-butoxide (0.25 g, 2.27 mmol), and the reaction was heated to 85 °C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (10 mL), and then saturated ammonium chloride solution (10 mL) was added. A solid precipitated from the system. The mixture was stirred overnight, and the solid was collected by filtration and dried to give a white solid product (167 mg, 89.17%). MS (ESI, pos.ion) m / z: 265.90 [M+H] + ;

[0437] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.88 (d, J = 8.4Hz, 2H), 7.74 (d, J = 8.3Hz, 2H), 1.71 (q, J = 4.2Hz, 2H), 1.50 (q, J = 4.1Hz, 2H).

[0438] Step 3: Synthesis of 5-(4-bromophenyl)-6-cyclopropyl-4,6-diazaspiro[2.4]hept-4-en-7-one

[0439] 5-(4-bromophenyl)-4,6-diazaspiro[2,4]hepta-4-en-7-one (0.2 g, 0.75 mmol), cyclopropylboronic acid (0.13 g, 1.5 mmol), 2,2'-bipyridine (0.12 g, 0.75 mmol), copper acetate (0.14 g, 0.75 mmol), and sodium carbonate (0.16 g, 0.75 mmol) were dissolved in acetonitrile (8 mL) and reacted overnight at 85 °C under an oxygen atmosphere. After the reaction was complete, the reaction solution was directly evaporated to dryness, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1 to 1 / 1) to give a white solid product (0.18 g, 78.19%). MS (ESI, pos.ion) m / z: 306.05 [M+H] + .

[0440] Step 4: Synthesis of (S)-3-(3-(4-(6-cyclopropyl-7-oxo-4,6-diazaspiro[2.4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazole[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0441] 5-(4-bromophenyl)-6-cyclopropyl-4,6-diazaspiro[2,4]hepten-4-en-7-one (0.18 g, 0.59 mmol), (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid. tert-butyl ester (0.17 g, 0.39 mmol), potassium carbonate (0.16 g, 1.17 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (0.055 g, 0.39 mmol), and cuprous iodide (0.074 g, 0.39 mmol) were dissolved in N-methylpyrrolidone (10 mL). The mixture was refluxed overnight at 130 °C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was diluted with water (20 mL), extracted with ethyl acetate (3 × 10 mL), and the organic layer was obtained. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA (v / v) = 1 / 1) to give a white solid (0.2 g, 50.93%).

[0442] MS(ESI,pos.ion)m / z:666.30[M+H] + .

[0443] Step 5: Synthesis of (S)-6-cyclopropyl-5-(4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)4,6-diazaspiro[2,4]hepten-4-en-7-one

[0444] (S)-3-(3-(4-(6-cyclopropyl-7-oxo-4,6-diazaspiro[2,4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazole[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.30 mmol) was dissolved in dioxane (4 mL, 4 mol / L) containing hydrogen chloride and stirred at room temperature for 30 min. After the reaction was completed, the pH was adjusted to alkaline by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (3 × 10 mL) to obtain an organic layer. The layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a pale yellow solid product (0.16 g, 94.16%). MS(ESI,pos.ion)m / z:566.20[M+H] + .

[0445] Step 6: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(4-(6-cyclopropyl-7-oxo-4,6-diazaspiro[2.4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0446] The following ingredients were added: (S)-6-cyclopropyl-5-(4-(3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)phenyl)-4,6-diazaspiro[2,4]hepten-4-en-7-one (0.16 g, 0.28 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 (0.14 g, 0.34 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.16 g, 0.42 mmol), and N,N-diisopropylethylamine (0.11 g, 0.84 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted overnight with stirring at room temperature. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (3 × 10 mL), and an organic layer was obtained. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 80 / 1) to give a white solid product (0.20 g, 73.72%).

[0447] MS(ESI,pos.ion)m / z:959.30[M+H] + ;

[0448] 1H NMR (400MHz, Chloroform-d) δ (ppm) 11.36 (s, 1H), 8.01 (d, J=8.6Hz, 2H), 7.93 (d, J= 8.8Hz,2H),7.61(d,J=8.6Hz,1H),7.54(d,J=1.7Hz,1H),7.13(d,J=6.1Hz,2H),6.9 0(d,J=3.3Hz,1H),6.73(s,1H),6.41(d,J=3.3Hz,1H),5.82(q,J=6.6Hz,1H),5.49– 5.16(m,1H),4.51(dd,J=13.6,5.1Hz,1H),3.97–3.91(m,2H),3.77(d,J=4.7Hz,2H) ,3.06(s,1H),3.00(td,J=7.0,3.4Hz,2H),2.28(d,J=2.2Hz,6H),2.23(d,J=2.2Hz, 2H),2.13(q,J=4.7Hz,2H),1.89(q,J=4.7Hz,2H),1.81(td,J=7.1,6.3,3.3Hz,2H), 1.75(d,J=3.9Hz,1H),1.68(d,J=4.1Hz,1H),1.53(d,J=6.9Hz,4H),1.38(s,3H),1. 32(s,3H),1.28(d,J=4.3Hz,2H),1.20(d,J=5.5Hz,3H),1.09(dd,J=6.5,4.2Hz,2H).

[0449] HRMS:calcd.for C 54 H 56 FN 10 O6[M+H] + :959.4368,found:959.4383.

[0450] Example 23: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0451] Step 1: Synthesis of 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-c]pyridine

[0452] At room temperature, 5-bromo-1H-pyrazolo[3,4-c]pyridine (0.5 g, 2.52 mmol), cyclopropylboronic acid (0.43 g, 5.04 mmol), 2,2'-bipyridine (0.39 g, 2.52 mmol), copper acetate (0.46 g, 2.52 mmol), and sodium carbonate (0.53 g, 5.04 mmol) were dissolved in acetonitrile (5 mL), oxygen was displaced, and the mixture was heated to 80 °C for 4 h. After the reaction was complete, 10 mL of water was added to quench the reaction, and then the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a yellow solid product (0.34 g, 56.56%).

[0453] MS(ESI,pos.ion)m / z:237.9[M+H] + .

[0454] Step 2: Synthesis of (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-carboxylic acid tert-butyl ester

[0455] At room temperature, (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-carboxylic acid tert-butyl ester (0.25 g, 0.57 mmol) was dissolved in NMP (3 mL), followed by the addition of 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-c]pyridine (0.20 g, 0.85 mmol), potassium carbonate (0.24 g, 1.71 mmol), cuprous iodide (0.11 g, 0.57 mmol), and (1S,2S)-(+)-N,N'-dimethylcyclohexane-1,2-diamine (0.081 g, 0.57 mmol). The mixture was then heated to 130 °C and reacted for 2.5 h. After the reaction was complete, 10 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a yellow solid product (0.28 g, 82.60%). MS (ESI, pos.ion) m / z: 599.1 [M+H] +

[0456] Step 3: Synthesis of (S)-1-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0457] At room temperature, (S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-carboxylic acid tert-butyl ester (0.25 g, 0.42 mmol) was dissolved in 1,4-dioxane (5 mL), and 4M dioxane hydrochloride solution (0.32 mL, 1.26 mmol) was added. The reaction was carried out at room temperature for 8 h. After the reaction was complete, the reaction solution was evaporated to dryness, 20 mL of water was added, and the pH was adjusted to 6-7 with sodium bicarbonate. Extraction was performed with ethyl acetate (20 mL × 2), followed by washing with saturated brine, drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to remove the solvent, yielding a white solid (0.20 g, 96.07%). MS (ESI, pos.ion) m / z: 499.5 [M+H] + ;

[0458] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0459] At room temperature, 0.16 g (0.40 mmol) of 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 was dissolved in DMF (4 mL), and DIPEA (0.21 g, 1.6 mmol) and HATU (0.23 g) were added. 0.60 mmol) was added, stirred at room temperature for 10 min, and then (S)-1-(1-cyclopropyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (0.2 g, 0.40 mmol) was added. The reaction was carried out at room temperature for 8 h. After the reaction was complete, 10 mL of water was added to quench the reaction, and then the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to prepare a white solid product (0.12 g, 33.54%). MS(ESI,pos.ion)m / z:892.0[M+H] + ;

[0460] HRMS:calcd.For C 49 H 51 FN 11 O5[M+H] + :892.4059,found:892.4067;

[0461] 1H NMR(400MHz,DMSO-d6)δ(ppm)11.75(s,1H),9.11(s,1H),8.49(s,1H),8.25(s,1H),7.66–7.51(m,2 H),7.40(d,J=8.4Hz,1H),7.27(d,J=8.6Hz,1H),7.19(d,J=6.2Hz,2H),6.98(d,J=12.7Hz,2H),5.61 (d,J=5.9Hz,1H),4.40(d,J=13.5Hz,1H),3.95(d,J=6.1Hz,2H),3.18(s,2H),3.03(d,J=13.0Hz,2H) ,2.90(d,J=16.6Hz,2H),2.20(s,7H),2.05–1.94(m,1H),1.26(d,J=15.3Hz,8H),1.22–1.04(m,12H)

[0462] Example 24: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2-oxo-2,3-dihydro-1H-imidazol-1-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,6-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0463] Step 1: Synthesis of 6-bromo-2-cyclopropylpyridazine-3(2H)-one

[0464] 6-Bromo-3-pyridazine (93 mg, 0.53 mmol), cyclopropylboronic acid (91.05 mg, 1.06 mmol), copper acetate (96.26 mg, 0.53 mmol), 2,2'-bipyridine (82.78 mg, 0.53 mmol), sodium carbonate (112.35 mg, 1.06 mmol), and acetonitrile (6.36 mL) were added to a reaction flask and stirred at 80 °C for 16 hours under an oxygen atmosphere. The reaction was quenched by adding 10 mL of ammonium chloride aqueous solution to the reaction system, extracted twice with 20 mL of ethyl acetate, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 2 / 1-1 / 1) to give a pale yellow solid product (83 mg, 72.62%).

[0465] 1H NMR (400MHz, CDCl3) δ7.23(d,J=9.6Hz,1H),6.81(d,J=9.6Hz,1H),4.09–3.99(m,1H),1.18–1.09(m,2H),1.07–1.00(m,2H).

[0466] Step 2: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2-oxo-2,3-dihydro-1H-imidazol-1-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0467] Add 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl)- 1,2,4-Oxadiazol-5(4H)-one (100 mg, 0.11 mmol), 6-bromo-2-cyclopropylpyridazine-3(2H)-one (35.48 mg, 0.17 mmol), potassium carbonate (45.61 mg, 0.33 mmol), dioxane (5.8 mL), and water (2 mL) were added. The mixture was purged with nitrogen several times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (8.98 mg, 0.011 mmol) was added. The mixture was purged with nitrogen several times, and the mixture was stirred at 80 °C for 4.5 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 2 / 1-1 / 2) to give a pale yellow solid product (40 mg, 39.65%).

[0468] HRMS:calcd.for C 50 H 45 F2N 12 O5[M+H] +:931.3598,found:931.3599;

[0469] 1 H NMR (400MHz, CDCl3) δ11.31–11.26(m,1H),8.14–7.94(m,2H),7.87–7.65(m,3H),7.52(s ,1H),7.26–7.04(m,4H),6.82(s,1H),6.64–6.47(m,1H),6.34–6.09(m,1H),5.86–5.31(m ,1H),4.93–4.47(m,1H),4.36–4.28(m,1H),3.71–3.51(m,2H),3.24–3.01(m,2H),2.31- 2.27(m,6H),2.00–1.82(m,1H),1.63–1.58(m,3H),1.30–1.23(m,9H),1.19–1.04(m,4H).

[0470] Example 25: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(2H)-one

[0471] Step 1: Synthesis of 5-bromo-1-cyclopropylpyridine-2(1H)-one

[0472] 5-Bromo-1,2-dihydropyridin-2-one (0.2 g, 1.15 mmol), cyclopropylboronic acid (0.99 g, 11.5 mmol), copper acetate (0.42 g, 2.3 mmol), 2,2'-bispyridine (0.36 g, 2.3 mmol), and sodium carbonate (0.37 g, 3.45 mmol) were placed in a 25 mL two-necked flask, and acetonitrile (7 mL) was added. The mixture was purged three times with oxygen, and then heated to 70 °C under an oxygen atmosphere. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) as eluent to give a yellow oily product (0.15 g, 60.96%).

[0473] MS(ESI,pos.ion)m / z:213.90[M+H] + ;

[0474] 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=2.7Hz,1H),7.33(dd,J=9.7,2.8Hz,1H),6.48( d,J=9.7Hz,1H),3.33(tt,J=7.6,4.2Hz,1H),1.16(q,J=6.8Hz,2H),0.92–0.85(m,2H).

[0475] Step 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(2H)-one

[0476] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxazolyl Diazole-5(4H)-one (0.1 g, 0.11 mmol), 5-bromo-1-cyclopropylpyridin-2(1H)-one (0.047 g, 0.22 mmol), potassium carbonate (0.030 g, 0.22 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichloromethane complex (0.090 g, 0.011 mmol) were placed in a 25 mL two-necked flask, and dioxane (3 mL) and water (1 mL) were added. The mixture was then purged three times with nitrogen. The reaction mixture was then allowed to react overnight at 90 °C under nitrogen protection. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, extracted with water and EA (30 mL × 3), washed with saturated saline (30 mL × 3), mixed with silica gel, and purified by column chromatography using dichloromethane / methanol (v / v) = 30 / 1 as the eluent, yielding a white solid product (59 mg, 58.54%). MS (ESI, pos.ion) m / z: 929.90 [M+H] + ;

[0477] HRMS:calcd.for C 51 H 46 F2N 11 O5[M+H] + :930.3646,found:930.3648.

[0478] 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.29(s,1H),7.87(s,1H),7.84–7.78(m,1H),7.74(d,J=2.6Hz,1H),7.68(d,J=8.8Hz,1H),7.53(q,J =8.7,8.3Hz,3H),7.19(d,J=6.1Hz,2H),7.09(d,J=3.0Hz,1H),7.01(s,1H),6.95(d,J=8.5Hz,1H),6.49(d,J=9.4Hz,1H),5.59(d,J=7.0Hz, 1H),4.39(d,J=13.2Hz,1H),3.86(s,2H),3.40(dt,J=7.0,3.3Hz,1H),2.91(d,J=14.7Hz,1H),2.25(d,J=14.3Hz,6H),1.81(d,J=18.4Hz,2 H),1.66(s,1H),1.59(s,1H),1.45(d,J=6.6Hz,2H),1.25(d,J=6.4Hz,3H),1.17(t,J=6.3Hz,5H),1.03(d,J=7.4Hz,2H),1.01–0.96(m,2H).

[0479] Example 26: 3-((1S,2S)-1-(2-((S)-3-(3-(2-(cyclopropanoyl)isoindoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indo-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0480] Step 1: Synthesis of (5-bromoisoindoline-2-yl)(cyclopropyl)methyl ketone

[0481] 5-Bromo-2,3-dihydro-1H-isoindoline (0.5 g, 2.52 mmol) and TEA (0.76 g, 7.56 mmol) were dissolved in DCM (10 mL). Cyclopropylformyl chloride (0.32 g, 3.02 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was quenched with sodium bicarbonate aqueous solution, extracted with dichloromethane (20 mL), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a brown solid (0.5 g, 74.42%). MS (ESI, pos.ion) m / z: 266.00, 267.99 [M+H] + ;

[0482] 1 H NMR (400MHz, CDCl3) δ7.49–7.41(m,2H),7.18(t,J=9.0Hz,1H),4.99(d,J=13.5Hz,2 H),4.79(d,J=16.5Hz,2H),1.76–1.68(m,1H),1.13–1.04(m,2H),0.88–0.86(m,2H).

[0483] Step 2: Synthesis of (S)-3-(3-(2-(cyclopropylformyl)isoindoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0484] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.45 mmol), (5-bromoisoindoline-2-yl)(cyclopropyl) methyl ketone (0.12 g, 0.45 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.064 g, 0.45 mmol), and potassium carbonate (0.19 g, 1.35 mmol) were dissolved in NMP (8 mL). Cuprous iodide (0.086 g, 0.45 mmol) was added under nitrogen protection, and the mixture was heated to 130 °C and stirred for 4.5 hours. After the reaction was complete, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified and separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a colorless oily product (0.23 g, 81.01%).

[0485] MS(ESI,pos.ion)m / z:627.1[M+H] + ;

[0486] Step 3: Synthesis of (S)-1-(2-(cyclopropylformyl)isoindoline-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride

[0487] (S)-3-(3-(2-(cyclopropylformyl)isoindoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.23 g, 0.37 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 4 mol / L 1,4-dioxane hydrogen chloride solution (0.93 mL, 3.7 mmol). The mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solvent was removed under reduced pressure to give a white solid product (0.2 g, 96.79%). MS (ESI, pos.ion) m / z: 527.1 [M+H] + ;

[0488] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(2-(cyclopropanoyl)isoindoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indoline-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0489] Dissolve (S)-1-(2-(cyclopropylformyl)isoindoline-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one hydrochloride (0.22 g, 0.39 mmol) in DMF (8 mL), add DIPEA (0.20 g, 1.56 mmol) with stirring, and continue stirring for 30 minutes. Then add 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2) S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (0.16 g, 0.39 mmol) and HATU (0.22 g, 0.58 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined and washed with saturated brine. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 1 / 1) to give a gray solid product (0.16 g, 44.72%). MS (ESI, pos.ion) m / z: 920.0 [M+H] + ;

[0490] HRMS:calcd.For C 52 H 55 FN9O6[M+H] + :920.4259,found:920.4262

[0491] 1H NMR (400MHz, CDCl3) δ11.33(d,J=9.3Hz,1H),7.69–7.61(m,1H),7.58(d,J=8.5Hz,1H),7.54–7.49(m,2H),7.41(s,1H),7.27–7.22(m,1H),7.1 4(d,J=6.1Hz,2H),6.75(d,J=3.0Hz,1H),6.71(s,1H),6.34(t,J=3.3Hz,1H),5.83–5.74(m,1H),5.08(d,J=14.7Hz,2H),4.86(d,J=12.7Hz,2H) ,4.50–4.47(m,1H),3.90–3.84(m,2H),3.61(td,J=13.7,3.7Hz,1H),3 .22–3.11(m,1H),3.06–3.04(m,2H),2.27(s,6H),1.92(t,J=4.8Hz,1H) ,1.79–1.74(m,4H),1.66(s,3H),1.54(d,J=5.6Hz,3H),1.36(s,3H),1. 30(s,3H),1.20(d,J=5.4Hz,3H),1.12–1.07(m,2H),0.90–0.86(m,2H).

[0492] Example 27: 3-((1S,2S)-1-(5-(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-(6-methyl-7-oxo-4,6-diazaspiro[2.4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0493] Step 1: Synthesis of 4-bromo-N-(1-formylcyclopropyl)benzamide

[0494] 4-Bromobenzoic acid (0.2 g, 0.99 mmol) was dissolved in DMF (5 mL), followed by the addition of HOBt (0.16 g, 1.19 mmol), EDCI (0.34 g, 1.78 mmol), DIPEA (0.38 g, 2.97 mmol), and 1-aminocyclopropane-1-carboxamide (0.12 g, 1.19 mmol). After the addition was complete, the mixture was stirred at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was extracted with water and EA (30 mL × 3), washed with saturated brine (30 mL × 3), and purified by column chromatography with silica gel, using dichloromethane / methanol (v / v) = 50:1 as the eluent, to give a white solid (0.23 g, 81.65%).

[0495] 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),7.91–7.78(m,2H),7.67(d,J=8.4Hz,2H),7.33(s,1H),7.02(s,1H),1.31(q,J=4.2Hz,2H),0.95(q,J=4.2Hz,2H)

[0496] Step 2: Synthesis of 5-(4-bromophenyl)-4,6-diazaspiro[2.4]hepten-4-en-7-one

[0497] 4-Bromo-N-(1-formylcyclopropyl)benzamide (0.2 g, 0.71 mmol) was dissolved in tert-butanol (4 mL) at room temperature, followed by the addition of potassium tert-butoxide (0.25 g, 2.27 mmol). The reaction mixture was heated to 85 °C after the addition was complete. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and 10 mL each of water and saturated ammonium chloride solution were added. The mixture was stirred overnight, filtered, and the residue was washed 2-3 times with water and dried to give a white solid product (167 mg, 89.17%). MS (ESI, pos.ion) m / z: 265.90 [M+H] + ;

[0498] 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.4Hz,2H),7.74(d,J=8.3Hz,2H),1.71(q,J=4.2Hz,2H),1.50(q,J=4.1Hz,2H)

[0499] Step 3: Synthesis of 5-(4-bromophenyl)-6-methyl-4,6-diazaspiro[2.4]hepten-4-en-7-one

[0500] 5-(4-bromophenyl)-4,6-diazaspiro[2,4]hepten-4-en-7-one (0.15 g, 0.57 mmol) was dissolved in DMF (6 mL), purged three times with nitrogen, and then sodium hydrogen (0.034 g, 0.85 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 60 min. Iodomethane (0.24 g, 1.71 mmol) was added to the reaction solution, and the reaction was continued at room temperature. After the reaction was completed by TLC monitoring, water and EA were added for extraction (30 mL × 3), followed by washing with saturated brine (30 mL × 3), and the sample was purified by column chromatography with silica gel mixed in, using dichloromethane / ethyl acetate (v / v) = 20 / 1 as the eluent, to give a white solid product (0.143 g, 90.54%). MS (ESI, pos.ion) m / z: 279.0 [M+H] +

[0501] Step 4: 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-(3-(4-(6-methyl-7-oxo-4,6-diazaspiro[2.4]hept-4-en-5-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0502] At room temperature, 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)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (0.18 g, 0.24 mmol), 5- (4-Bromophenyl)-6-methyl-4,6-diazaspiro[2.4]hepten-4-en-7-one (0.10 g, 0.36 mmol), iodide ionone (0.091 g, 0.48 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.10 g, 0.72 mmol) and potassium carbonate (0.066 g, 0.48 mmol) were placed in a 25 mL two-necked flask, purged with nitrogen three times, NMP (8 mL) was added, purged with nitrogen three times, and then the reaction solution was heated at 130 °C overnight. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, filtered to remove inorganic salts, and the filtrate was extracted with water and EA (50 mL × 3), washed with saturated brine (50 mL × 3), mixed with silica gel, and purified by column chromatography using DCM / EA (v / v) = 30 / 1 as the eluent to obtain a white solid product (0.065 g, 28.44%). MS (ESI, pos.ion) m / z: 933.0 [M+H] +

[0503] HRMS:calcd.for C 52 H 54 FN 10 O5[M+H] + :933.4206,found:933.4220

[0504] 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),7.91(d,J=8.4Hz,2H),7.86(d,J=8.5Hz,2H),7.52(s,1H),7.47(s,1H),7.39(d,J=8.5Hz,1 H),7.25(d,J=8.7Hz,1H),7.16(d,J=6.0Hz,2H),7.05(s,1H),6.95(s,1H),5.58(d,J=7.2Hz,1H),4.37(d,J=13.1Hz,1H),3.71(s ,1H),3.18(s,3H),3.13(s,1H),3.02(s,2H),2.88(d,J=16.3Hz,2H),2.21(s,6H),1.98(p,J=7.1Hz,2H),1.75(d,J=4.1Hz,2H),1 .54(d,J=4.2Hz,2H),1.38(d,J=6.5Hz,2H),1.26(s,3H),1.22(s,6H),1.17(s,3H),1.13(d,J=5.9Hz,2H),0.84(t,J=6.5Hz,1H);

[0505] Example 28: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0506] Steps: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl)-5-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0507] 5-Bromo-3-methylpyridin-2(1H)-one (0.025 g, 0.13 mmol), 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (0.1 g, 0.11 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.014 g, 0.022 mmol), and potassium carbonate (0.046 g, 0.33 mmol) were dissolved in dioxane (8 mL) and water (2 mL). The reaction was carried out overnight at 100 °C under a nitrogen atmosphere with stirring. After the reaction was completed, the mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give a brown powder product (0.022 g, 22.46%).

[0508] MS(ESI,pos.ion)m / z:903.90[M+H] + ;

[0509] HRMS:calcd.for C 49 H 44 F2N 11 O5[M+H]+:904.3495.found:903.3513.

[0510] 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.27(s,1H),7.82(s,1H),7.75(s,2H),7.67(d,J=8 .8Hz,1H),7.50(d,J=5.6Hz,4H),7.17(d,J=6.4Hz,2H),7.08(d,J=6.7Hz,1H),7.01–6.92 (m,2H),5.58(s,1H),4.38(d,J=13.4Hz,1H),3.85(s,2H),3.18(s,2H),2.76(d,J=5.0Hz, 2H),2.25(s,7H),2.06(s,3H),1.43(d,J=6.6Hz,3H),1.16(d,J=7.6Hz,4H),1.12(s,3H).

[0511] Example 29: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0512] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclo Propyl)-1,2,4-oxadiazol-5(4H)-one (0.12 g, 0.13 mmol), 5-bromo-4-methylpyridin-2(1H)-one (0.037 g, 0.20 mmol), potassium carbonate (0.054 g, 0.39 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride (0.017 g, 0.026 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL), and the reaction was carried out at 100 °C for 7 h under nitrogen protection. After the reaction was complete, 10 mL of water was added, followed by extraction with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid product (0.006 g, 5.10%). MS (ESI, pos.ion) m / z: 904.0 [M+H] + ;

[0513] HRMS:calcd.For C 49 H 44 F2N 11 O5[M+H] + :904.3495,found:904.3508.

[0514] Example 30: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(4-fluoro-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0515] 5-Bromo-4-fluoropyridin-2(1H)-one (0.04 g, 0.21 mmol), 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(4,4,5 ... Methyl-1,3,2-dioxaborane-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (0.13 g, 0.14 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.018 g, 0.028 mmol), and potassium carbonate (0.058 g, 0.42 mmol) were dissolved in dioxane (8 mL) and water (2 mL). The mixture was stirred and refluxed overnight at 100 °C under a nitrogen atmosphere. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were then combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane / methanol (v / v) = 0–4%) to give a brown powder (0.08 g, 6.25%). MS(ESI,pos.ion)m / z:907.90[M+H] + .

[0516] HRMS:calcd.for C 48 H 41 F3N 11 O5[M+H] + :908.3244.found:908.3253.

[0517] 1H NMR(599MHz,DMSO-d6)δ12.01(s,1H),11.78(s,1H),8.28(s,1H),7.75(s,1H),7.67(t,J=8.6Hz,1H),7.62(s,1H),7.55–7.48(m,2H),7 .40(d,J=8.1Hz,1H),7.19(d,J=4.3Hz,1H),7.09(d,J=8.2Hz,1H),7.03(d,J=22.2Hz,1H),6.95(s,1H),6.27(d,J=13.1Hz,1H),5.33(t, J=4.9Hz,1H),4.40(d,J=12.1Hz,1H),4.04(t,J=6.6Hz,1H),3.85(d,J=7.6Hz,1H),3.10(s,1H),2.90(d,J=15.3Hz,1H),2.78(s,2H),2. 44–2.11(m,6H),1.99(dt,J=12.7,7.0Hz,1H),1.76(s,1H),1.53–1.39(m,3H),1.32–1.27(m,2H),1.21–1.17(m,2H),0.90–0.76(m,3H).

[0518] Example 31: 3-((1S,2S)-1-(2-((S)-3-(3-(1-(cyclopropanecarbonyl)indololin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0519] Step 1: Synthesis of (5-bromoindoline-1-yl)(cyclopropyl)methyl ketone

[0520] 5-Bromo-2,3-dihydro-1H-indole (0.5 g, 2.52 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (0.76 g, 7.56 mmol) and 4-dimethylaminopyridine (0.062 g, 0.50 mmol), and finally cyclopropylformyl chloride (0.40 g, 3.78 mmol). The reaction was carried out at room temperature. After 16 h of reaction, the product was directly concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1 to 4 / 1) to give a white solid product (0.5 g, 74.42%). MS (ESI, pos.ion) m / z: 265.9 [M+H]+ ;

[0521] 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.29 (d, J = 9.3Hz, 2H), 4.29 (t, J = 8.0Hz, 2H), 3 .22(t,J=7.9Hz,2H),1.75(s,1H),1.20–1.06(m,2H),0.91(td,J=6.7,3.7Hz,2H).

[0522] Step 2: Synthesis of (S)-3-(3-(1-(cyclopropanecarbonyl)indoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0523] (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.45 mmol), 5-bromo-1-cyclopropanecarbonyl-2,3-dihydro-1H-indole (0.24 g, 0.90 mmol), cuprous iodide (0.043 g, 0.23 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1.13 mmol), and potassium carbonate (0.19 g, 1.35 mmol) were dissolved in N-methylpyrrolidone (8 mL). After vacuuming and purging with inert gas three times, the mixture was heated to 130 °C for reaction. After reacting for 4 hours, the product was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was then subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1 to 1 / 1) to give a yellow solid product (0.25 g, 88%). MS (ESI, pos.ion) m / z: 627.1 [M+H] + ;

[0524] 1H NMR (400MHz, CDCl3) δ8.22(s,1H),7.55(s,1H),7.18(d,J=7.1Hz,1H),7.09(d,J=6.2Hz,2H),6.65(d,J=2.9Hz,1H),6.26(s,1H),5.43–5.17(m,1H), 4.41(d,J=62.7Hz,3H),3.22(d,J=55.6Hz,3H),2.81(s,2H),2.23(s,6H), 1.78(s,1H),1.51(s,9H),1.33(d,J=6.7Hz,3H),1.16(s,2H),0.92(s,2H).

[0525] Step 3: Synthesis of (S)-1-(1-(cyclopropanecarbonyl)indoline-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0526] (S)-3-(3-(1-(cyclopropanecarbonyl)indoline-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.2 g, 0.32 mmol) was dissolved in dichloromethane (5 mL), and hydrogen chloride (0.8 mL, 3.2 mmol, 4 M / L in dioxane) was added. The reaction was carried out at room temperature. After 1 h of reaction, the product was directly concentrated and filtered to give a yellow solid product (0.15 g, 89.26%).

[0527] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-(cyclopropanecarbonyl)indololin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0528] 0.16 mol of 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 was dissolved in N,N-dimethylformamide (6 mL), and then 0.22 g of HATU (0.57 mL) was added. The product was prepared by reacting (0.2 g, 0.38 mmol) with triethylamine (0.38 g, 3.8 mmol) at room temperature. After 17 h of reaction, the product was diluted with ethyl acetate (50 mL), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was further subjected to silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1 to 10 / 1) to give a yellow solid product (0.2 g, 57.24%).

[0529] HRMS: calcd.for C 52 H 55 FN9O6[M+H] + :920.4252,found:920.4283.

[0530] 1 H NMR (599MHz, CDCl3) δ11.35–11.30(m,1H),8.26(s,1H),7.67–7.46(m,3H),7.29–7.19(m,2H),7. 14–7.04(m,2H),6.71–6.55(m,2H),6.29(s,1H),5.83–5.26(m,1H),4.49–4.30(m,3H),3.92–3.8 3(m,2H),3.63–3.59(m,1H),3.46–3.21(m,2H),3.19–3.00(m,3H),2.27–2.23(m,6H),1.85–1.71 (m,5H),1.70–1.62(m,2H),1.55–1.49(m,4H),1.39–1.24(m,8H),1.23–1.16(m,3H),0.93(s,2H).

[0531] Example 32: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0532] Steps: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0533] 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl) was added to the reaction flask. -1,2,4-oxadiazol-5(4H)-one (150 mg, 0.16 mmol), 5-bromo-2-hydroxy-3-(trifluoromethyl)pyridine (58.08 mg, 0.24 mmol), potassium carbonate (66.3 mg, 0.48 mmol), dioxane (5.8 mL), and water (2 mL) were added. The mixture was purged with nitrogen several times. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (65.33 mg, 0.08 mmol) was added. The mixture was purged with nitrogen several times, and the mixture was stirred at 90 °C for 6 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane / methanol (v / v) = 40 / 1-20 / 1) to give a yellow solid product (70 mg, 44.96%).

[0534] HRMS:calcd.for C 49 H 41 F5N 11 O5[M+H]+:958.3207,found:958.3206.

[0535] 1 H NMR (400MHz, CDCl3) δ11.31–11.25(m,1H),8.18(s,1H),8.11–7.94(m,1H),7. 80–7.71(m,3H),7.51–7.38(m,3H),7.16–7.06(m,2H),6.80(s,1H),6.62–6.4 7(m,1H),6.33-6.11(m,1H),5.83–5.32(m,1H),4.89–4.47(m,1H),3.63(s,2H ),3.24–2.97(m,2H),2.29-2.27(m,6H),1.67–1.48(m,5H),1.29–1.09(m,8H).

[0536] Example 33: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0537] Step 1: Synthesis of 5-bromo-1-ethylpyridin-2(1H)-one

[0538] At room temperature, 5-bromopyridin-2-ol (0.5 g, 2.87 mmol) and cesium carbonate (2.81 g, 8.61 mmol) were added to DMF (10 mL), and iodoethane (1.34 g, 8.61 mmol) was added under nitrogen protection. The reaction was carried out at room temperature for 1 h after the addition was complete. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) to give a brown oily product (0.26 g, 44.78%).

[0539] MS(ESI,pos.ion)m / z:202.0[M+H] +;

[0540] 1 H NMR (400MHz, DMSO-d6) δ 8.04 (d, J = 2.8 Hz, 1H), 7.50 ( dd, J = 9.6, 2.8 Hz, 1H), 6.36 ( d, J = 9.6 Hz, 1H), 3.88 ( q, J = 7.1 Hz, 2H), 1.20 ( t, J = 7.1 Hz, 3H).

[0541] Step 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0542] At room temperature, 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl 1,2,4-oxadiazol-5(4H)-one (0.15 g, 0.16 mmol), 5-bromo-1-ethylpyridin-2(1H)-one (0.048 g, 0.24 mmol), potassium carbonate (0.066 g, 0.48 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) dichloride (0.021 g, 0.032 mmol) were dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL), and the reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction was complete, 10 mL of water was added, followed by extraction with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid product (0.05 g, 33.51%). MS (ESI, pos.ion) m / z: 918.3 [M+H] + ;

[0543] 1H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.10–8.06(m,1H),7.87(s,1H),7.83(d,J=9.6Hz,1H),7.68(d,J=8.8Hz,1H),7.5 5(s,1H),7.52(d,J=7.9Hz,2H),7.18(d,J=6.0Hz,2H),7.08(s,1H),7.01(s,1H),6.94(s,1H),6.80(s,1H),6.50(d,J=9 .4Hz,1H),5.59(d,J=7.3Hz,1H),4.05–4.00(m,2H),2.91(d,J=16.3Hz,2H),2.26(s,6H),2.23(s,2H),2.08–1.94(m,2H ), 1.45 (d, J = 6.9Hz, 3H), 1.35 (d, J = 9.0Hz, 2H), 1.28 (s, 2H), 1.19 (d, J = 7.4Hz, 3H), 1.13 (s, 3H), 0.85 (t, J = 6.8Hz, 2H).

[0544] Example 34: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-(difluoromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0545] Step 1: Synthesis of 5-bromo-1-(difluoromethyl)-6-methylpyridin-2(1H)-one

[0546] 5-Bromo-6-methyl-1,2-dihydropyridin-2-one (0.5 g, 2.66 mmol), sodium difluorochloroacetate (2.03 g, 13.3 mmol), and lithium bromide (1.15 g, 13.3 mmol) were dissolved in N,N-dimethylformamide (10 mL). After cooling to 0 °C, sodium hydride (0.27 g, 6.65 mmol) was added, and the mixture was heated to 80 °C. After reacting for 16 h, the mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 1 to 4 / 1) to give a white solid product (0.09 g, 14%).

[0547] MS(ESI,pos.ion)m / z:237.9[M+H] + ; 1 H NMR (599MHz, CDCl3) δ8.00(t,J=58.9Hz,1H),7.43(d,J=9.8Hz,1H),6.36(d,J=9.8Hz,1H),2.63(s,3H).

[0548] Step 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-(difluoromethyl)-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0549] 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2, 4-Oxadiazol-5(4H)-one (0.1 g, 0.11 mmol), 5-bromo-1-(difluoromethyl)-6-methyl-1,2-dihydropyridin-2-one (0.052 g, 0.22 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex (0.018 g, 0.022 mmol) and potassium carbonate (0.046 g, 0.33 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and the mixture was heated to 100 °C after evacuation. After reacting for 4 hours, the product was diluted with ethyl acetate (20 mL), washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was then subjected to silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1 to 10 / 1) to give a white solid product (0.05 g, 48%).

[0550] HRMS:calcd.for C 50 H 44 F4N 12 O5[M+H] +:954.3458,found:954.3464.

[0551] 1 H NMR (400MHz, CDCl3) δ11.33–11.27(m,1H),8.34–7.99(m,2H),7.68(m,1H),7 .53(m,3H),7.32(m,1H),7.24(m,1H),7.13(m,2H),6.80–6.60(m,2H),6.51(m ,1H),6.22(m,1H),5.67(m,1H),4.56–4.42(m,1H),3.80–3.34(m,3H),3.13(m ,2H),2.45(s,3H),2.29(m,6H),1.98(m,1H),1.72–1.55(m,5H),1.26(m,6H).

[0552] Example 35: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0553] Step 1: Synthesis of 6-bromo-2-(difluoromethyl)-2H-pyridazin-3-one

[0554] 6-Bromo-3-pyridazine (0.1 g, 0.57 mmol) and lithium bromide (0.15 g, 1.71 mmol) were dissolved in DMF (3 mL), cooled to 0 °C under nitrogen protection, and stirred. After stirring for 30 minutes, sodium hydride (0.027 g, 0.68 mmol) and sodium difluorochloroacetate (0.17 g, 1.14 mmol) were added. After the addition was complete, the mixture was heated to 80 °C and stirred for 17 hours. After the reaction was completed, the reaction system was quenched with ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to give a white solid product (0.035 g, 27.22%).

[0555] 1H NMR (400MHz, CDCl3) δ (ppm) 7.60 (t, J = 58.4Hz, 1H), 7.34 (d, J = 9.8Hz, 1H), 6.85 (d, J = 9.8Hz, 1H).

[0556] Step 2: 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0557] 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-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indol-1-yl)-2-methylcyclopropyl) 1,2,4-Oxadiazol-5(4H)-one (0.1 g, 0.11 mmol), 6-bromo-2-(difluoromethyl)-2H-pyridazin-3-one (0.030 g, 0.13 mmol), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (0.0072 g, 0.011 mmol), and potassium carbonate (0.038 g, 0.28 mmol) were dissolved in 1,4-Dioxane (6 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 5 hours under nitrogen protection. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a gray solid product (0.028 g, 27.46%).

[0558] HRMS:calcd.for C 48 H 41 F2N 12 O5[M+H] + :941.3259,found:941.3265.

[0559] 1H NMR(400MHz, CDCl3)δ(ppm)11.30–11.26(m,1H),8.18(s,1H),8.10(s,1H),7.98–7.60(m,5H),7.51(s, 1H),7.17(d,J=6.1Hz,1H),7.08–7.01(m,1H),6.84(s,1H),6.66–6.44(m,1H),6.34–6.08(m,1H),5.89 –5.78(m,1H),4.47(dd,J=13.5,4.5Hz,1H),3.70–3.51(m,2H),3.24–3.12(m,1H),3.09–3.04(m,1H),2 .29(d,J=14.6Hz,6H),1.98(t,J=6.3Hz,1H),1.69–1.53(m,6H),1.16–1.07(m,3H),0.91–0.83(m,3H).

[0560] Example 36: 1-((5-(3-((S)-5-(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-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-fluoro-1H-indazol-1-yl)methyl)cyclopropane-1-carboxaldehyde

[0561] Add 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)- 4-Methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (37 mg, 0.039 mmol) and DCM (7.55 mL) were added, followed by the addition of PDC (29.3 mg, 0.078 mmol), and the mixture was stirred at room temperature for 10 hours. PDC (29.3 mg, 0.078 mmol) was then added, and the mixture was stirred at room temperature for 24 hours. The solvent was removed by vacuum distillation, and the crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 2 / 1-1 / 1), followed by scraping purification to give a pale yellow solid product (10 mg, 27.08%).

[0562] HRMS:calcd.for C 52 H 52 F2N 10 O6[M+H] + :951.4112,found:951.4118.

[0563] 1H NMR (400MHz, CDCl3) δ11.35–11.31(m,1H),8.68–8.63(m,1H),8.13–8.04(m,1H),7.68–7.27(m,5H),7 .19–7.01(m,2H),6.74–6.72(m,1H),6.62–6.47(m,1H),6.34–6.09(m,1H),5.89–5.79(m,1H),4.75–4 .68(m,2H),4.51–4.42(m,1H),3.89–3.77(m,2H),3.65–3.59(m,1H),3.21–3.01(m,3H),2.31–2.27(m ,6H),1.80–1.53(m,10H),1.45–1.42(m,3H),1.36–1.35(m,3H),1.23–1.08(m,3H),0.92–0.85(m,4H).

[0564] Example 37 3-((1S,2S))-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl))-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0565] Step 1: Synthesis of 7-bromo-3-cyclopropylimidazo[1,2-b]pyridazine

[0566] 5-Bromopyridazine-3-amine (0.10 g, 0.57 mmol) was dissolved in ethanol (8 mL), and α-bromocyclopropaneethyl ketone (0.093 g, 0.57 mmol) was added. The mixture was stirred at 80 °C. After the reaction was complete, the reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 9 / 1) to give the target compound as a white solid (0.03 g, 21.93%). MS (ESI, pos.ion) m / z: 238.0 [M+H] + .

[0567] Step 2: Synthesis of (S)-3-(3-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl))-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0568] 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridyl-5-carboxylic acid tert-butyl ester (0.15 g, 0.34 mmol) was dissolved in N-methylpyrrolidone (10 mL), and 7-bromo-3-cyclopropylimidazo[1,2-b]pyridazine (0.081 g, 0.34 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.24 g, 1.70 mmol), potassium carbonate (0.14 g, 1.02 mmol), and iodide ketone (0.065 g, 0.34 mmol) were added. The reaction was carried out under nitrogen protection and stirred at 130 °C. After the reaction was complete, the solid was removed by diatomaceous earth extraction. The reaction was quenched with an appropriate amount of water (50 mL), and extracted with ethyl acetate (3 × 25 mL). The organic layer was collected, washed with saturated brine (25 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 3) to give the target compound (0.13 g, 63.91%) as a pale yellow oil. MS (ESI, pos.ion) m / z: 599.3 [M+H] + .

[0569] Step 3: Synthesis of (S)-1-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl))-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one

[0570] (S)-3-(3-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl))-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.13 g, 0.22 mmol) was dissolved in ethyl acetate (10 mL) and stirred at room temperature until the reaction was complete. After the reaction was complete, the reaction solvent was removed by rotary evaporation, and the mixture was dissolved in saturated sodium bicarbonate aqueous solution (15 mL). The solution was then extracted with ethyl acetate (3 × 20 mL), and the organic layer was collected, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and rotary evaporated under reduced pressure to give the target compound (0.10 g, 92.37%) as a pale yellow solid. MS(ESI,pos.ion)m / z:499.2[M+H] + .

[0571] Step 4: Synthesis of 3-((1S,2S))-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl))-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0572] Dissolve (S)-1-(3-cyclopropylimidazo[1,2-b]pyridazin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl))-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (0.08 g, 0.16 mmol) in N,N-dimethylformamide (8 mL), and add N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) and O -(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.09 mg, 0.24 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 (0.07 mg, 0.16 mmol), under nitrogen protection, stirred at room temperature. After the reaction was complete, an appropriate amount of water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was collected, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The residue was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a pale green solid target compound (0.087 g, 60.78%). MS (ESI, pos.ion) m / z: 892.3 [M+H] + ;

[0573] 1H NMR(400MHz,Chloroform-d)δ(ppm)11.30–11.24(m,1H),9.91(s,1H),8.80–8.67(m,1H),7.75–7.68(m,1H),7.60(dd,J=8.6,4. 9Hz,1H),7.54–7.48(m,1H),7.29(s,1H),7.26(s,1H),7.10–7.00(m,2H),6.73–6.69(m,1H),6.49–6.34(m,1H),5.80(s,1H),4. 52(dd,J=13.5,4.9Hz,1H),3.93–3.84(m,2H),3.60(t,J=12.8Hz,1H),3.23–3.13(m,1H),3.09–3.02(m,2H),2.28–2.24(m,6H), 1.86–1.75(m,3H),1.71–1.62(m,2H),1.53(d,J=14.2Hz,3H),1.37(d,J=7.5Hz,3H),1.32–1.27(m,10H),1.20(d,J=4.9Hz,3H).

[0574] 19 F NMR(376MHz,Chloroform-d)δ-119.29,-119.35.

[0575] HRMS:calcd.For C 49 H 51 FN 11 O5[M+H] + :892.4059,found:892.4069

[0576] Example 38: 3-((1S,2S)-1-(2-((S)-3-(3-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0577] Step 1: Synthesis of N-((4-bromopyridin-2-yl)methyl)-2-cyclopropylacetamide

[0578] 4-Bromo-2-aminomethylpyridine (0.11 g, 0.59 mmol), cyclopropionic acid (0.065 g, 0.65 mmol), HATU (0.34 g, 0.89 mmol), and DIPEA (0.38 g, 2.95 mmol) were dissolved in DMF (5 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain a colorless oily product (0.1 g, 63.18%). MS (ESI, pos.ion) m / z: 269.1, 271.1 [M+H] + .

[0579] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.40–8.38(m,1H),7.55(dd,J=5.3,1.8Hz,1H),7.50(d,J=1.4Hz,1H),4 .36(d,J=6.0Hz,2H),2.09(d,J=7.1Hz,2H),1.08–0.93(m,1H),0.51–0.41(m,2H),0.20–0.13(m,2H).

[0580] Step 2: Synthesis of 7-bromo-3-(cyclopropylmethyl)imidazo[1,5-a]pyridine

[0581] N-((4-bromopyridin-2-yl)methyl)-2-cyclopropylacetamide (0.3 g, 1.11 mmol) was dissolved in DCM (10 mL), stirred until homogeneous, and then Burgess reagent (0.79 g, 3.33 mmol) was added. The mixture was stirred at room temperature for 13 hours. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a colorless oily product (0.2 g, 71.45%). MS (ESI, pos.ion) m / z: 251.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.66 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.32 (s, 1H), 6.59 (dd, J = 7.5, 1 .8Hz,1H),2.93(d,J=6.6Hz,2H),1.25–1.16(m,1H),0.65–0.58(m,2H),0.28(q,J=5.0Hz,2H).

[0582] Step 3: Synthesis of (S)-3-(3-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0583] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-C]pyridine-5-carboxylic acid tert-butyl ester (0.3 g, 0.68 mmol), 7-bromo-3-(cyclopropylmethyl)imidazo[1,5-a]pyridine (0.20 g, 0.82 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.097 g, 0.68 mmol), and potassium carbonate (0.28 g, 2.04 mmol) were dissolved in NMP (10 mL). Cuprous iodide (0.13 g, 0.68 mmol) was added under nitrogen protection, and the nitrogen atmosphere was replaced again. The mixture was heated to 130 °C and stirred for 6 hours. After the reaction was complete, water (50 mL) was added for dilution, and ethyl acetate (25 mL × 2) was used for extraction. The organic phases were combined and washed with saturated brine (30 mL × 2). The solvent was removed under reduced pressure, and the residue was purified and separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to give a brown solid product (0.38 g, 91.42%).

[0584] MS(ESI,pos.ion)m / z:612.3[M+H] + ;

[0585] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.84 (d, J=7.5Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.09 (d, J= 6.2Hz,2H),7.02(s,1H),6.69(d,J=3.1Hz,1H),6.33(s,1H),5.38–5.21(m,1H),4.50–4. 30(m,1H),3.15(s,1H),2.98(s,2H),2.80(d,J=3.1Hz,2H),2.24(s,3H),2.23(s,3H),1. 51(s,9H),1.32(d,J=6.7Hz,3H),1.24–1.19(m,1H),0.63(d,J=7.2Hz,2H),0.32(s,2H).

[0586] Step 4: Synthesis of (S)-1-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one

[0587] (S)-3-(3-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.38 g, 0.62 mmol) was dissolved in 1,4-dioxane (10 mL), stirred until homogeneous, and then a 4 mol / L solution of 1,4-dioxane hydrogen chloride (0.019 mL, 0.062 mmol) was added. The reaction was stirred at room temperature. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, the pH was adjusted to 7-8 by adding sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to give a pale yellow solid (0.255 g, 80.24%). MS(ESI,pos.ion)m / z:512.3[M+H] + ;

[0588] Step 5: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0589] 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 (0.1 g, 0.24 mmol), (S)-1-(3-(cyclopropylmethyl)imidazo[1,5-a]pyridin-7-yl)-3-(2-(4 (-Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (0.12 g, 0.24 mmol), HATU (0.14 g, 0.36 mmol), and DIPEA (0.093 g, 0.72 mmol) were dissolved in DMF (4 mL) and the reaction was stirred at room temperature. After the reaction was complete, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with saturated brine (20 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 3:1) to give a pale yellow solid product (0.12 g, 54.56%).

[0590] MS(ESI,pos.ion)m / z:905.3[M+H] + ;

[0591] 1 H NMR(400MHz, CDCl3)δ(ppm)11.35(s,1H),7.91–7.71(m,1H),7.61–7.58(m,1H),7.55–7.50(m,2H),7.43–7.35(m,1H),7.33–7.25(m, 1H),7.14–7.03(m,3H),6.75–6.70(m,2H),6.36–6.14(m,1H),5.79(q,J=6.4Hz,1H),4.49(dd,J=13.7,4.6Hz,1H),3.93–3.80(m,2H) ,3.61(td,J=13.5,3.4Hz,1H),3.22–3.12(m,1H),3.08–3.04(m,2H),2.99(d,J=6.5Hz,2H),2.28–2.23(m,6H),1.96(s,1H),1.83–1. 73(m,4H),1.54(d,J=6.7Hz,3H),1.36(s,3H),1.30(s,3H),1.27(s,3H),1.19(d,J=5.7Hz,3H),0.65–0.60(m,2H),0.35–0.27(m,2H).

[0592] Example 39: 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0593] Step 1: Synthesis of 7-bromo-3-cyclopropylimidazo[1,2-a]pyridine

[0594] 4-Bromopyridine-2-amine (0.35 g, 2.02 mmol), α-bromocyclopropaneethyl ketone (0.33 g, 2.02 mmol), and DIPEA (0.52 g, 4.04 mmol) were dissolved in toluene (6 mL), and the mixture was heated to 100 °C and stirred for 24 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a pale yellow solid product (0.3 g, 62.55%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.88 (dd, J=7.1, 0.6Hz, 1H), 7.72–7.62 (m, 1H), 7.34 (s, 1H), 6.8 2(dd,J=7.1,1.9Hz,1H),2.02(tt,J=8.2,5.1Hz,1H),1.02–0.97(m,2H),0.96–0.92(m,2H).

[0595] Step 2: Synthesis of (S)-3-(3-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0596] (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.5 g, 1.13 mmol), 7-bromo-3-cyclopropylimidazo[1,2-a]pyridine (0.29 g, 1.24 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1.13 mmol), and potassium carbonate (0.47 g, 3.39 mmol) were dissolved in NMP (8 mL). Cuprous iodide (0.22 g, 1.13 mmol) was added under nitrogen protection, and the nitrogen atmosphere was replaced again. The mixture was heated to 130 °C and stirred for 15 hours. After the reaction was complete, water (50 mL) was added for dilution, and ethyl acetate (30 mL × 2) was used for extraction. The organic phases were combined and washed with saturated brine (20 mL × 2). The solvent was removed under reduced pressure, and the residue was purified and separated by column chromatography (dichloromethane / ethyl acetate (v / v) = 2:1) to give a grayish-white solid product (0.409 g, 60.42%).

[0597] MS(ESI,pos.ion)m / z:598.3[M+H] + ;

[0598] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.06 (d, J = 7.4Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J = 7.3, 1.9Hz ,1H),7.38(s,1H),7.08(d,J=6.2Hz,2H),6.74(d,J=3.2Hz,1H),6.34(d,J=2.1Hz,1H) ,5.37–5.24(m,1H),4.50–4.34(m,1H),3.15(s,1H),2.88–2.73(m,2H),2.23(s,3H),2 .22(s,3H),2.09–2.00(m,1H),1.67(s,9H),1.33(d,J=6.7Hz,3H),1.04–0.96(m,4H).

[0599] Step 3: Synthesis of (S)-1-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one

[0600] (S)-3-(3-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.4 g, 0.67 mmol) was dissolved in 1,4-dioxane (8 mL), followed by the addition of 1.68 mL (6.7 mmol) of 4 mol / L 1,4-dioxane hydrochloride solution. The mixture was stirred at room temperature for 22 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product was diluted with water (30 mL). The pH was adjusted to alkaline with sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a brown solid product (0.3 g, 90.09%).

[0601] MS(ESI,pos.ion)m / z:498.2[M+H] + ;

[0602] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.06 (d, J = 7.4Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 7.3Hz, 1 H),7.37(s,1H),7.07(d,J=6.2Hz,2H),6.71(d,J=3.2Hz,1H),6.28(d,J=3.0Hz,1H ),4.14(q,J=7.0Hz,1H),3.42–3.36(m,1H),3.14–3.05(m,1H),2.83–2.76(m,2H), 2.23(d,J=1.2Hz,6H),2.05–2.01(m,1H)1.27(d,J=6.6Hz,3H),1.02–0.96(m,4H).

[0603] Step 4: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0604] 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 (0.1 g, 0.24 mmol), (S)-1-(3-cyclopropylimidazo[1,2-a]pyridin-7-yl)-3-(2-(4-fluoro-3, 5-Dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (0.12 g, 0.24 mmol) and HATU (0.14 g, 0.36 mmol) were dissolved in DMF (5 mL), and then DIPEA (0.093 g, 0.72 mmol) was added. The mixture was stirred at room temperature for 10 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined and washed with saturated brine (20 mL × 2). The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 2:1) to give a pale yellow solid product (0.11 g, 50.80%).

[0605] MS(ESI,pos.ion)m / z:891.3[M+H] + ;

[0606] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.10–8.08 (m, 1H), 7.59 (d, J = 8.5Hz, 1H), 7.53 (s, 1H), 7.49–7.42 (m, 1H), 7.39–7.36 (m ,1H),7.31–7.25(m,1H),7.12–7.01(m,2H),6.81–6.62(m,2H),6.36–6.14(m,1H),5.83–5.23(m,1H),4.90–4.45(m, 1H),3.87–3.81(m,2H),3.65–3.37(m,1H),3.21–2.96(m,3H),2.23(d,J=16.2Hz,6H),2.04–1.98(m,1H),1.91(t,J =5.0Hz,1H),1.82–1.61(m,5H),1.53(d,J=6.5Hz,3H),1.38–1.24(m,9H),1.19(d,J=5.4Hz,2H),1.08–0.96(m,4H).

[0607] Example 40: 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0608] Step 1: Synthesis of 5-bromo-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine

[0609] 5-Bromo-7-azaindole (200 mg, 1.02 mmol), cyclopropylboronic acid (175.2 mg, 2.04 mmol), copper acetate (185.3 mg, 1.02 mmol), 2,2'-bipyridine (159.3 mg, 1.02 mmol), sodium carbonate (216.2 mg, 2.04 mmol), and acetonitrile (12.72 mL) were added to a reaction flask and stirred at 80 °C for 5 hours under an oxygen atmosphere. The reaction was quenched by adding 20 mL of ammonium chloride aqueous solution to the reaction system in an ice bath. The mixture was extracted twice with 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 20 / 1-10 / 1) to give a pale yellow solid product (130 mg, 54.01%).

[0610] MS(ESI,pos.ion)m / z:237.0[M+H] + ;

[0611] 1H NMR (400MHz, CDCl3) δ (ppm) 8.39 (d, J = 2.1Hz, 1H), 8.00 (d, J = 2.1Hz, 1H), 7.21 (d, J = 3.5Hz, 1H) ,6.34(d,J=3.5Hz,1H),3.51(tt,J=7.3,3.8Hz,1H),1.15(q,J=7.1Hz,2H),1.07–1.01(m,2H).

[0612] Step 2: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0613] Add 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)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (100) to the reaction flask 49.8 mg, 0.14 mmol), 5-bromo-1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (49.8 mg, 0.21 mmol), potassium carbonate (58.0 mg, 0.42 mmol), and NMP (4.86 mL) were added under nitrogen protection. Cuprous iodide (26.7 mg, 0.14 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (39.8 mg, 0.28 mmol) were added, and the mixture was heated to 120 °C and stirred for 4 hours. The reaction was quenched by adding 10 mL of ammonium chloride aqueous solution after cooling to room temperature. The mixture was extracted twice with 20 mL of ethyl acetate, washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 4 / 1-2 / 1) to give a pale yellow solid product (60 mg, 49.48%). HRMS:calcd.for C 50 H 52 FN 10 O5[M+H] + :891.4101,found:891.4098.

[0614] 1H NMR(400MHz, CDCl3)δ(ppm)11.33–11.29(m,1H),8.46–8.31(m,1H),8.12–7.89(m,1H),7.62–7.51(m,2H),7 .32–7.29(m,1H),7.28–7.25(m,1H),7.18–7.06(m,2H),6.74–6.58(m,2H),6.49–6.37(m,1H),6.35–6.11(m ,1H),5.84–5.28(m,1H),4.90–4.46(m,1H),3.92–3.78(m,2H),3.69–3.46(m,2H),3.22–2.99(m,3H),2.29- 2.25(m,6H),1.83–1.68(m,4H),1.60–1.55(m,3H),1.36–1.35(m,3H),1.30–1.28(m,6H),1.22–1.04(m,7H).

[0615] Example 41: 3-((1S,2S))-1-(2-((4S)-3-(3-(3-(2,2-difluorocyclopropyl))imidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0616] Step 1: Synthesis of N-((4-bromopyridin-2-yl)methyl)-2,2-difluorocyclopropane-1-carboxamide

[0617] (4-Bromopyridin-2-yl)methylamine hydrochloride (0.55 g, 2.46 mmol) was dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (1.63 mL, 9.84 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.40 g, 3.69 mmol), and 2,2-difluorocyclopropane-1-carboxylic acid (0.30 g, 2.46 mmol) were added. The reaction was carried out under nitrogen protection and stirred at room temperature. After the reaction was completed, an appropriate amount of water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic layer was collected, washed with saturated brine (2 × 25 mL), and dried over anhydrous sodium sulfate. The residue was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give a white solid target compound (0.44 g, yield 62.13%).

[0618] Step 2: Synthesis of 7-bromo-3-(2,2-difluorocyclopropyl)imidazo[1,5-a]pyridine

[0619] N-((4-bromopyridin-2-yl)methyl)-2,2-difluorocyclopropane-1-carboxamide (0.43 g, 1.48 mmol) was dissolved in dichloromethane (10 mL), and Burgess reagent (0.53 mg, 2.22 mmol) was added. The reaction was carried out under nitrogen protection and stirred at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give the target compound (0.26 g, yield 64.45%) as a pale yellow oil.

[0620] 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.80(dt,J=7.5,1.0Hz,1H),7.66–7.63(m,1H),7.36(d,J=0.9Hz,1H ),6.73(dd,J=7.5,1.9Hz,1H),2.90–2.83(m,1H),2.44–2.37(m,1H),2.10(ddd,J=11.8,5.1,3.8Hz,1H).

[0621] Step 3: Synthesis of (4S)-3-(3-(3-(2,2-difluorocyclopropyl))imidazo...

Claims

1. A compound which is a compound of Formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound of Formula (I), ###0001### (I) wherein Ring A is selected from the following substructures: wherein the substructures of ring A are each independently optionally substituted with n R 3 substituted; each R 3 independently H, D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, -SF5, -OR a , -C(=O)R a , -C(=O)OR a , -NR b R c , -C(=O)NR b R c , -NR b C(=O)R c , -S(O)R a , -S(O)2R a , -S(O)2NR b R c , -NR b S(O)2R c , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, methoxy, ethoxy, i-propoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; wherein said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, methoxy, ethoxy, i-propoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2) p -C(=O)R e , -(CH2) p -C(=O)OR f , oxo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH(OH)CH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R 1 H, D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl or 3-10 membered heterocyclyl; R 2a and R 2b form, together with the atoms on which they are attached, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1, 2, 3, or 4 R each R is independently D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, -(CH2) t -OR d , -(CH2) p -C(=O)R e , -(CH2) p -C(=O)OR f , methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, methoxy, ethoxy, iso-propoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl; wherein each of said -(CH2) t -OR d , -(CH2) t -, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, ethenyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, methoxy, ethoxy, iso-propoxy, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, difluoromethoxy, methylamino, ethylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, iso-propoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, and dimethylamino; R 4 , R 5 , and R 6 are each independently H, D, -F, -CI, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-12 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 7 is dihydropyridinyl, tetrahydropyranyl or piperidinyl, wherein each of said dihydropyridinyl, tetrahydropyranyl and piperidinyl is independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, trifluoromethoxy, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2CN, -CH2CH2CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, methylenecycloheptyl, methylenecyclooctane, methylenazetidinyl, methylenoxetanyl, methylenepyrrolidinyl, methylenetetrahydrofuranyl, methylenepiperidinyl, ethylenepiperidinyl, methylenepiperazinyl and methylenemorpholinyl; R a , R b , R c , and R d are each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-12 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-12 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R e and R f each independently H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and 3-10 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; n is 1, 2, 3, 4, or 5; t is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The compound according to claim 1, wherein R 1 H, D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl or 3-8 membered heterocyclyl; R 4 , R 5 , and R 6 are each independently H, D, -F, -CI, -Br, -I, -CN, -OH, -NH2, -SF5, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

3. The compound according to claim 1 or 2, wherein R 1 H, D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxy, ethoxy, i-propoxy, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl; R 4 , R 5 , and R 6 are each independently H, D, -F, -CI, -Br, -I, -CN, -OH, -NH2, -SF5, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -CI, -Br, -I, -OH, -NH2, -CN, -SH, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, and trifluoromethoxy.

4. The compound according to any one of claims 1-3, wherein R a , R b , R c , and R d are each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; R e and R f each independently H, D, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or 3-8 membered heterocyclyl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

5. The compound according to any one of claims 1-4, wherein R a , R b , R c , and R d are each independently H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, and trifluoromethoxy; R e and R f each independently H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from D, -F, -Cl, -Br, -I, -OH, -NH2, -CN, -SH, oxo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, methoxy, ethoxy, i-propoxy, difluoromethoxy, and trifluoromethoxy.

6. A compound having the following structure, or a stereoisomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, 7. A pharmaceutical composition comprising a compound according to any one of claims 1-6; further comprising a pharmaceutically acceptable diluent, carrier or excipient.

8. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention, treatment or alleviation of a GLP-1R associated disease.

9. Use according to claim 8, wherein, The GLP-1R associated disease is diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight conditions, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, cardiac dysrhythmias, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, dementia, Parkinson's disease, or diabetic nephropathy.

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