Azacyclic derivatives, pharmaceutical compositions and uses thereof

Abstract

The present invention belongs to the field of medicine and relates to an azacyclic compound, a pharmaceutical composition thereof and its use in the preparation of a drug. Specifically, the compound of the present invention has a structure shown in formula (I), or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs. The compound of the present invention and its pharmaceutical composition can be used to prepare drugs for treating HIF-2α-mediated related diseases, such as cancer, inflammation, etc.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to an azacyclic compound, a pharmaceutical composition thereof and use thereof in preparing medicines. Specifically, the compound and the pharmaceutical composition thereof can be used as HIF-2α regulators and can be used to prepare medicines for treating cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic diseases and other related diseases. Background Art

[0002] HIFs are a class of nuclear transcription complexes that mediate intracellular hypoxia responses and are widely expressed in tissue cells to promote the adaptation process of the organism to hypoxia. HIFs mainly include HIF-1, HIF-2, and HIF-3, which are all heterodimers composed of oxygen-sensitive α subunits (HIF-1α, HIF-2α, and HIF-3α) and constitutive β subunits HIF-1β (also known as Aryl Hydrocarbon Receptor Nuclear Translocator, ARNT). Among the three α subunits, HIF-2α is the main regulator of pathological hypoxia response. When the oxygen concentration is normal, the half-life of HIF-2α is short, and two special proline Pro405 and Pro531 in the ODDD domain of HIF-2α are rapidly recognized and hydroxylated by hydroxylase. Hydroxylated HIF-2α binds to the VHL protein, is then ubiquitinated by the E3 ubiquitin ligase, and is ultimately rapidly degraded by the protease. In many malignant tumors, there are a large number of hypoxic areas or functionally defective VHL. At this time, HIF-2α accumulates in the cell and forms a heterodimer with the continuously expressed ARNT, and finally binds to different molecules of hypoxia response elements (HRE), thereby regulating the transcription of multiple target genes.

[0003] Both HIF-2α subunit and ARNT subunit belong to the Per-ARNT-Sim (PAS) subfamily of the basic helix-loop-helix (bHLH) family. The two subunits have similar structures, mainly including the N-terminal bHLH (DNA Bonding Domain, DBD, DNA binding region), and two adjacent PASA and PASB domains (Ligand Bonding Domain, LBD, ligand binding region); the C-terminus binds to transcriptional cofactors to regulate the transcription of downstream genes. Studies have found that there is a cavity of about 290Å3 inside the PASB domain of the HIF-2α subunit. After binding to the regulator, it can affect the formation of heterodimerization between the HIF-2α subunit and the ARNT subunit, thereby blocking or activating DNA binding and target gene transcription. HIF-2α downstream target genes such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and glycolytic enzymes are related to tumors, inflammation, and blood diseases. Therefore, the development of HIF-2α regulators has important clinical significance. Summary of the invention

[0004] The present invention provides a novel azacyclic derivative, a pharmaceutical composition thereof and its use. The compound or its pharmaceutical composition can be effectively used to prepare a drug for preventing, treating or alleviating HIF-2α-mediated related diseases, such as cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic diseases, etc.

[0005] Specifically, in one aspect, the present invention provides a compound having a structure as shown in formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0006] (I),

[0007] in,

[0008] X 1 N or CR 1 ;

[0009] X 2 and X 5 are each independently N or CH;

[0010] X 3 CR 5 or N;

[0011] X 4 CR 4 or N;

[0012] A is C 6-14 Aryl or 5-12 membered heteroaryl;

[0013] R 1 For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n1 C(=O)OR 8 、-(CR a R b ) n1 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Alkoxy C 1-6 The alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d 、-C(=O)R 8 、-C(=O)R 8 、-S(=O)2R 8 、C(=O)NR c R d , C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by aryl and 5-12 membered heteroaryl substituents;

[0014] R 2 For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n2 C(=O)OR 8 、-(CR a R b ) n2 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 Alkyl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Alkoxy C 1-6 The alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, Cl, Br, I, OH, CN, NO2, NH2, COOH, CF3, NR c R d 、-C(=O)R 8 、-S(=O)2R8 、C(=O)NR c R d , C 6-12 substituted by aryl and 5-12 membered heteroaryl substituents;

[0015] R 3 For H, D, F, Cl, Br, I, OH, CN, NO2, -S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)OR 8 、-(CR a R b ) n1 C(=O)OH, -CH(=O), -S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 、-NR c C(=O)NR c R d , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-12 aryl or 5-12 membered heteroaryl, wherein the C 6-12 The aryl and 5-12 membered heteroaryl groups are each independently optionally substituted by 1, 2, 3 or 4 groups selected from F, Cl, Br, I, OH, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 substituted by a haloalkoxy substituent;

[0016] Each R 4 and R 5 are independently H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n2 C(=O)OR 8 、-(CR a R b ) n2C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-6 alkyl;

[0017] Each R 6 and R 7 independently F, Cl, Br, I, OH, CN, NH2, NO2, C(=O)OR 8 ,C(=O)OH,-CH(=O),-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-C(=O)R 8 , C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy;

[0018] Each R 8 Independently for C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12aryl or 5-12 membered heteroaryl, and R 8 Optionally selected from 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 substituted by aryl and 5-12 membered heteroaryl substituents;

[0019] Each R a and R b are independently H, F, Cl, Br, I, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy;

[0020] Each R c and R d Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0021] m is 1, 2 or 3; and

[0022] Each n1 and n2 is independently 0, 1, 2, 3 or 4;

[0023] The premise is that R 2 and R 3 cannot be H at the same time, and the compound of formula (I) does not contain compound , and .

[0024] In some embodiments, A is C 6-12 In some embodiments, A is C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C 11 Aryl, C 12 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl.

[0025] In some embodiments, the 5-10 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the 5-10 membered heteroaryl includes 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 3-pyridinyl, 4-pyridin ... pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl oxazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl or [1,2,4]triazolo[1,5-a]pyridinyl.

[0026] In some embodiments, the C 1-6 The haloalkyl group is C 1-6 One or more H in the alkyl group is independently selected from F, Cl, and Br. 1-6 The haloalkyl group is trifluoromethyl, trifluoroethyl, monofluoromethyl, difluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl or 1,1-dibromoethyl.

[0027] In some embodiments, the C 1-4 The haloalkyl group is C 1-4 One or more H in the alkyl group is independently selected from F, Cl, and Br. 1-4The haloalkyl group is trifluoromethyl, trifluoroethyl, monofluoromethyl, difluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl or 1,1-dibromoethyl.

[0028] In some embodiments, the heterocyclic group comprises 1, 2 or 3 heteroatoms selected from O, N, and S. In some embodiments, the heterocyclic group comprises oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholinyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl or 1,1-dioxo-1,3-thiomorpholine.

[0029] In some embodiments, A is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, benzofurazan, or pyrazolyl.

[0030] In some embodiments, R 1 For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n1 C(=O)OR 8 、-(CR a R b ) n1 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NRc S(=O)2NR c R d 、-C(=O)R 8 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Alkoxy C 1-4 Alkyl, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Alkoxy C 1-4 The alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d 、-C(=O)R 8 、-C(=O)R 8 、-S(=O)2R 8 、C(=O)NR c R d , C 3-12 Cycloalkyl, 3-6 membered heterocyclic group, C 6-12 substituted by aryl and 5-6 membered heteroaryl substituents; wherein R a , R b , R c , R d , n1 and R 8 Each has the definition as described in the present invention.

[0031] In some embodiments, R 1 For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n1 C(=O)OR 8 、-(CR a R b ) n1 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b )n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, methoxymethyl, ethoxymethyl or ethoxyethyl, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl are each independently optionally substituted by 1, 2, 3 or 4 radicals selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d 、-C(=O)R 8 、-C(=O)R 8 、-S(=O)2R 8 、C(=O)NR c R d , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl substituents; wherein R a , R b , R c , R d , n1 and R 8 Each has the definition as described in the present invention.

[0032] In some embodiments, R 2For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n2 C(=O)OR 8 、-(CR a R b ) n2 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Alkoxy C 1-4 Alkyl, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Alkoxy C 1-6 The alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 groups selected from F, Cl, Br, I, OH, CN, NO2, NH2, COOH, CF3, NR c R d 、-C(=O)R 8 、-S(=O)2R 8 、C(=O)NR c R d , C 6-12 substituted by aryl and 5-6 membered heteroaryl substituents; wherein R a , Rb , R c , R d , n2 and R 8 Each has the definition as described in the present invention.

[0033] In some embodiments, R 2 For H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n2 C(=O)OR 8 、-(CR a R b ) n2 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c R d 、-NR c S(=O)2NR c R d 、-C(=O)R 8, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, methoxymethyl, ethoxymethyl or ethoxyethyl, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, methoxymethyl, ethoxymethyl or ethoxyethyl alkenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl are each independently optionally substituted by 1, 2, 3 or 4 radicals selected from F, Cl, Br, I, OH, CN, NO2, NH2, COOH, CF3, NR c R d 、-C(=O)R 8 、-S(=O)2R 8 、C(=O)NR c R d , phenyl, pyridyl, pyrimidyl, thienyl, pyrazolyl and imidazolyl substituents; wherein R a , R b , R c , R d , n2 and R 8 Each has the definition as described in the present invention.

[0034] In some embodiments, R 3 For H, D, F, Cl, Br, I, OH, CN, NO2, -S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)OR 8 、-(CR a R b ) n1 C(=O)OH, -CH(=O), -S(=O)2NR c R d 、-NR c R d 、-NR cS(=O)2NR c R d 、-C(=O)R 8 、-NR c C(=O)NR c R d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl or pyrazolyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl and pyrazolyl are each independently optionally substituted by 1, 2, 3 or 4 groups selected from F, Cl, B r, I, OH, CN, NO2, COOH, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl; wherein R a , R b , R c , R d , n1 and R 8 Each has the definition as described in the present invention.

[0035] In some embodiments, each R 4 and R 5 are independently H, D, F, Cl, Br, I, OH, CN, NO2, -(CR a R b ) n2 C(=O)OR 8 、-(CR a R b ) n2 C(=O)OH、-CH(=O、-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、-(CR a R b ) n1 C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-NR c Rd 、-NR c S(=O)2NR c R d 、-C(=O)R 8 , C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Alkoxy C 1-4 alkyl;

[0036] Each R 6 and R 7 independently F, Cl, Br, I, OH, CN, NH2, NO2, C(=O)OR 8 ,C(=O)OH,-CH(=O),-S(=O)2R 8 、-OR 8 、-SR 8 、-S(=O)R 8 、C(=O)NR c R d 、-NR c C(=O)NR c R d 、-S(=O)2NR c R d 、-C(=O)R 8 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C 1-4 Haloalkyl or C 1-4 Haloalkoxy;

[0037] Among them, R a , R b , R c , R d , n1 and R 8 Each has the definition as described in the present invention.

[0038] In some embodiments, each R 8 Independently for C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-12 aryl or 5-6 membered heteroaryl, and R 8 Optionally selected from 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-12 substituted by aryl and 5-6 membered heteroaryl substituents; wherein R c and R d Each has the definition as described in the present invention.

[0039] In some embodiments, each R 8 R is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, propyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl or imidazolyl, and R 8 Optionally selected from 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, CN, NO2, COOH, CF3, NR c R d , methyl, ethyl, n-propyl, isopropyl, tert-butyl, -fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl substituents, wherein R c and R d Each has the definition as described in the present invention.

[0040] In some embodiments, each R a and R b are independently H, F, Cl, Br, I, OH, CN, NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy;

[0041] Each R c and R dand tert-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, and imidazolyl.

[0042] In some embodiments, the compound of the present invention is a structure of formula (IX), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0043] (IX),

[0044] Wherein, A is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, thienyl, benzofurazan or pyrazolyl, R 1 , R 2 , R 3 , R 6 and R 7 Each has the definition as described in the present invention.

[0045] In some embodiments, the compound of the present invention is a structure of formula (II), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0046] (II)

[0047] Among them, R 1 , R 2 , R 3 , R 6 and R 7 Each has the definition as described in the present invention.

[0048] In some embodiments, the compound of the present invention is a structure of formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0049] (III) (IV) (V) (VI) (VII) or (VIII)

[0050] Wherein, R1, R2, R3, R6 and R7 each have the meanings as described in the present invention.

[0051] In some embodiments, the compound of the present invention is a structure of formula (II-1), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0052] (II-1),

[0053] Among them, R 1 , R 2 , R 8 , R 6 and R 7 Each has the definition as described in the present invention.

[0054] In some embodiments, the compounds described herein have one of the following structures, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

[0055] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or

[0056] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0057] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0058] In some embodiments, the adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof.

[0059] In some embodiments, the pharmaceutical composition may be in liquid, solid, semisolid, gel or spray form.

[0060] In another aspect, the present invention provides use of the compound or pharmaceutical composition of the present invention in preparing a drug for preventing, treating or alleviating HIF-2α-mediated related diseases.

[0061] In some embodiments, the HIF-2α-mediated related disease is cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic disease.

[0062] In some embodiments, the cancer is renal cancer, glioblastoma, breast cancer, non-small cell lung cancer, prostate cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.

[0063] In some embodiments, the inflammation is inflammation of the digestive system, and optionally, the inflammation of the digestive system is Crohn's disease or ulcerative colitis. On the other hand, the present invention relates to an intermediate for preparing a compound represented by the structure of formula (I), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX).

[0064] On the other hand, the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX). Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0065] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.

[0066] Detailed description of the present invention

[0067] Definition of terms

[0068] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be recognized by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way 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 the present application (including but not limited to defined terms, term applications, described techniques, etc.), the present application shall prevail.

[0069] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0070] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0071] Unless otherwise indicated, the structural formulae and compounds described herein include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Therefore, compounds of single stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention also fall within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include one or more different isotopically enriched atoms.

[0072] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents. It should be understood that the term "independently optionally substituted with..." can be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents selected from a specific group, the substituents can be substituted at each position in the same or different manner.

[0073] The description methods used in the present invention, "each...is independently" and "...are each independently" and "...are independently" are interchangeable and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0074] In the compounds described in the present invention, when any variable (such as R c , R d If a compound (e.g., ) occurs more than once in any combination, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permissible as long as such combinations result in stable compounds. It is understood that one of ordinary skill in the art can select substituents for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized using readily available starting materials using techniques in the art and the methods set forth below.

[0075] The term "room temperature" refers to ambient temperature, which may be 10°C-35°C, or 15°C-30°C, or 20°C-30°C.

[0076] In the present invention, "C q1-q2 " represents the number of carbon atoms in the group being described, for example, C 1-6 Alkyl means an alkyl group containing 1 to 6 carbon atoms; 3-6The cycloalkyl group represents a cycloalkyl group containing 3 to 6 carbon atoms.

[0077] The term "q3-q4-membered" or "q3-q4-atom-consisting" refers to the number of ring atoms of the described ring, for example, a 3- to 6-membered heterocyclyl group refers to a heterocyclyl group containing 3-6 ring atoms.

[0078] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms. In another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl, n-pentyl, 2-pentyl, and the like.

[0079] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon sp 2 Double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-10 carbon atoms; in one embodiment, the alkenyl group contains 2-6 carbon atoms; in another embodiment, the alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), propenyl (-C=CHCH3), isopropenyl (-C(CH3)=CH2), and the like.

[0080] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2-6 carbon atoms; in another embodiment, the alkynyl group contains 2-10 carbon atoms; the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0081] 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 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1 or 2 hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 Hydroxyalkyl, i.e. C 1-6 Alkyl substituted by one or more hydroxyl groups, preferably, C 1-6 Hydroxyalkyl means, that is, C 1-6 In some embodiments, hydroxyalkyl represents C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, CH2OH-, CH2OHCH2CH2CH2-, CH2OHCH2-, CH2OHCH2CHOHCH2-, CH(CH3)OHCH2CHOHCH2-, and the like.

[0082] The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, such examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0083] The term "halogen" means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0084] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. 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-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), and the like.

[0085] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, and the like.

[0086] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein. In some embodiments, alkoxyalkyl refers to a C 1-6 Alkoxy C 1-6 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-4 Alkyl; in other embodiments, alkoxyalkyl represents C 1-4 Alkoxy C 1-3 Alkyl; in some embodiments, alkoxyalkyl represents C 1-3 Alkoxy C 1-3 Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.

[0087] The terms "cycloalkyl" or "cycloalkane" are used interchangeably and refer to a monovalent saturated monocyclic carbon ring system of 3 to 12 carbon atoms. The -CH2- group in the carbon ring may be optionally replaced by -C(O)-. In one embodiment, the cycloalkyl contains 3 to 6 carbon atoms, i.e., C 3-6 In another embodiment, the cycloalkyl group contains 3-5 carbon atoms, i.e., C 3-5 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of carbocyclic rings in which the -CH2- group may be replaced by -C(O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0088] The term "heterocyclyl" refers to a monovalent non-aromatic saturated or partially unsaturated monocyclic ring system having 3-12 ring atoms, and the system contains at least 1 carbon atom and 1, 2 or 3 heteroatoms selected from O, N, and S. Unless otherwise specified, the heterocyclyl group can be a carbon group or a nitrogen group, and the -CH2- group can be optionally replaced by -C(O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide, and the nitrogen atom of the ring can be optionally oxidized to N-oxygen compound. In some embodiments, the heterocycle contains 4-7 ring atoms, that is, it represents a 4-7 membered heterocycle; in other embodiments, the heterocycle contains 4-7 ring atoms, that is, it represents a 4-7 membered heterocycle. Examples of heterocycles include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, 1,1-dioxo-1,3-thiomorpholine, and the like. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl. Examples of heterocyclic groups in which the nitrogen atom is oxidized to an N-oxygen compound include, but are not limited to, 1,1-dioxo-1,3-thiomorpholine.

[0089] The term "aryl" refers to a monovalent aromatic ring group formed by removing a hydrogen atom from a ring carbon atom of an aromatic ring. Examples of aryl groups may include phenyl, naphthyl, anthracenyl, and the like.

[0090] The term "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. In one embodiment, a 5-10 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the term "heteroaryl" refers to a heteroaromatic ring group or a 5-membered heteroaryl containing 5 ring atoms, wherein 1, 2, 3 or 4 heteroatoms independently selected from O, S and N are contained. Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0091] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0092] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0093] The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature such as ion exchange methods to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0094] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0095] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0096] The "nitrogen oxide" of the present invention refers to when the compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. The special example of N-oxide is the N-oxide of tertiary amine or the N-oxide of nitrogen-containing heterocyclic nitrogen atom. The corresponding amine can be treated with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0097] As used herein, the term "treating" any disease or condition refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof) in some embodiments. In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0098] The "cancer" mentioned in the present invention includes, but is not limited to, the following diseases: renal cancer, glioblastoma, breast cancer, lung cancer, prostate cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma, ovarian cancer, bladder cancer, brain cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, vaginal cancer, cervical cancer, endometrial cancer, thyroid cancer and skin cancer, etc.; lymphoid hematopoietic system tumors, including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma, etc.; myeloid hematopoietic system tumors, including acute and chronic myeloid leukemia and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma, glioma, etc.

[0099] The cyclopentadiene compounds provided by the present invention can effectively regulate the activity of HIF-2α protein. The regulation referred to here means that some compounds are inhibitors and some compounds are agonists. The terms "inhibitor" and "antagonist" are used interchangeably, and they refer to compounds that inhibit target proteins or enzymes (e.g., HIF-2α). Therefore, the terms "antagonist" and "inhibitor" are defined in the context of the biological effect of the target protein. Although the preferred antagonists herein interact specifically with the target (e.g., bind to HIF-2α), compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway to which the target protein belongs are also specifically included in this scope. The term "agonist" used herein refers to a compound that has the biological function of starting or enhancing the target protein by binding to the target protein. Therefore, the term "agonist" is defined in the context of the biological effect of the target protein. Although the preferred agonists herein interact specifically with the target (e.g., bind to HIF-2α), compounds that start or enhance the biological activity of the target by interacting with other members of the signal transduction pathway are also specifically included. "Signal transduction" is a process by which stimulatory or inhibitory signals are transmitted into a cell and elicit an intracellular response within the cell. A modulator of a "signal transduction pathway" refers to a compound that modulates the activity of one or more cellular proteins that are targeted to the same specific signal transduction pathway. A modulator can enhance (agonist) or inhibit (antagonist) the activity of a signaling molecule.

[0100] Pharmaceutical compositions, preparations, administration and uses of the compounds of the present invention

[0101] The present invention provides a compound of the present invention or a pharmaceutical composition thereof having a regulating effect on HIF-2α. The pharmaceutical composition of the present invention comprises a compound represented by formula (I), (II) or (II-1), a compound listed in the present invention, or a compound of the embodiment. The amount of the compound in the composition of the present invention can effectively treat or alleviate a patient's HIF-2α-related disease or condition, including cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic disease.

[0102] As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, which, as used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, Comprehensive content of the documents here, show that different adjuvants can be used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0103] When used for treatment, a therapeutically effective amount of the compounds of the present invention, especially the compounds of formula (I), (II) or (II-1) and their pharmaceutically acceptable salts, can be administered as raw chemicals or as active ingredients of pharmaceutical compositions. Therefore, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the compounds of the present invention, especially the compounds of formula (I), (II) or (II-1) or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents or excipients, etc. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit (e.g., a reduction in cancer cells). When a single active ingredient is administered alone, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that causes a therapeutic effect when administered in combination, sequentially or simultaneously. The compounds of the present invention, especially the compounds of formula (I), (II) or (II-1) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. According to another aspect of the present invention, a method for preparing a pharmaceutical preparation is also provided, which comprises mixing a compound of the present invention, especially a compound of formula (I), (II) or (II-1) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0104] The amount of active ingredient combined with one or more adjuvants to prepare a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. The amount of active ingredient that the compound of formula (I), (II) or (II-1)) is mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the treatment time, and the patient's age, sex, body weight and condition. The preferred unit dosage form is a unit dosage form containing the daily dose or divided dose of the active ingredient described above or a suitable fraction thereof. Treatment can be started with a small dose that is significantly lower than the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the optimal effect is achieved in this case. In general, the concentration level at which the compound is most ideally administered is generally effective in anti-tumor aspects without causing any harmful or toxic side effects.

[0105] The pharmaceutical composition is suitable for administration by any suitable route, for example, by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such preparations can be prepared by any known method in the field of pharmacy, for example, by mixing the active ingredient with a carrier or excipient. Oral administration or injection is preferred.

[0106] According to the method of the present invention, compound and composition can be any dosage and any administration route to be effectively used for processing or alleviating the severity of the disease. Necessary accurate amount will change according to the patient's situation. Compound or composition can be used in combination with one or more other therapeutic agents.

[0107] The present invention also provides use of the compound of the present invention or the pharmaceutical composition of the present invention in preparing a drug for preventing, treating or alleviating HIF-2α-mediated related diseases.

[0108] The compounds of the present invention or their pharmaceutical compositions can be used as HIF-2α modulators. When HIF-2α activation and / or one or more downstream processes associated with HIF-2α activation or overactivation are associated with a disease, condition or disorder, the compounds of the present invention or their pharmaceutical compositions are very useful for treating the disease, condition or disorder or reducing its severity. In addition, the present invention provides methods for treating a disease, condition or disorder or reducing its severity, wherein HIF-2α activation or overactivation is associated with the disease state.

[0109] The HIF-2α-mediated related diseases include, but are not limited to, cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic diseases.

[0110] The "cancer" mentioned herein includes, but is not limited to, the following diseases: renal cancer, glioblastoma, breast cancer, lung cancer, prostate cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma, ovarian cancer, bladder cancer, brain cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, vaginal cancer, cervical cancer, endometrial cancer, thyroid cancer and skin cancer, etc.; lymphatic hematopoietic system tumors, including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma, etc.; myeloid hematopoietic system tumors, including acute and chronic myeloid leukemia and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma, glioma, etc. Preferably, the compound of the present invention or the pharmaceutical composition of the present invention can be prepared for preventing, treating or alleviating cancers related to renal cancer, glioblastoma, breast cancer, lung cancer, prostate cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma in patients.

[0111] The inflammation mentioned herein includes but is not limited to inflammation of the digestive system. The compounds of the present invention can preferably be prepared for preventing, treating or alleviating inflammation of the patient's digestive system, wherein the inflammation of the digestive system includes but is not limited to Crohn's disease or ulcerative colitis.

[0112] General Synthesis Methods of Compounds of the Invention

[0113] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0114] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise indicated, reagents are conventional reagents and can be purchased from the market. Silica gel columns are used as chromatographic columns. NMR spectra are CDC13 or DMSO-d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. Coupling constants J are expressed in Hertz (Hz).

[0115] The following abbreviations are used throughout this invention:

[0116]

[0117] The following synthetic schemes describe procedures for preparing compounds disclosed herein.

[0118] Synthesis Scheme 1

[0119]

[0120] Compound (Ia) can be prepared by the synthesis method of Synthesis Scheme 1, wherein R 2 , R 3 , R 6 , R 7 and R 8 Each has the definition as described in the present invention. Compound (Ia-1) reacts with compound (Ia-2) under appropriate conditions (such as under the action of zinc chloride and N,N-diisopropylethylamine, and reflux in 1,2-dichloroethane solution) to obtain compound (Ia-3); compound (Ia-3) undergoes reduction reaction under appropriate conditions (such as under the action of palladium hydroxide and hydrogen) to obtain compound (Ia-4); compound (Ia-4) reacts with formic acid to obtain compound (Ia-5); compound (Ia-5) reacts with POCl3 under appropriate conditions (such as reflux) to obtain compound (Ia-6); compound (Ia-6) reacts with NBS to obtain compound (Ia-7); compound (Ia-7) and compound (Ia-8) undergo coupling reaction under appropriate conditions (such as under the action of Pd(dppf)Cl2, and a base such as sodium carbonate is added at the same time) to obtain compound (Ia).

[0121] Synthesis Scheme 2

[0122]

[0123] Compound (Ib) can be prepared by the synthesis method of Synthesis Scheme 2, wherein R 2 , R 3 , R 6 and R 7 Each has the definition as described in the present invention. Compound (Ib-1) is reacted under appropriate conditions (such as under the action of borane and reflux in tetrahydrofuran solvent) to obtain compound (Ib-2); compound (Ib-2) and compound (Ib-3) are amidated under appropriate conditions (such as under the action of HATU or DIPEA and in dichloromethane solution) to obtain compound (Ib-4); compound (Ib-4) is reacted with POCl3 under appropriate conditions (such as reflux) to obtain compound (Ib).

[0124] Synthesis Scheme 3

[0125]

[0126] Compound (Ib) can be prepared by the synthesis method of Synthesis Scheme 3, wherein R 2 , R 3 , R 6 and R 7 Each has the definition as described in the present invention. Compound (Ib-5) reacts with compound (Ib-6) under alkaline conditions (such as sodium hydride) to obtain compound (Ib-4); compound (Ib-4) reacts with POCl3 under appropriate conditions (such as reflux) to obtain compound (Ib).

[0127] The preparation methods of other compounds of the present invention can be prepared by methods similar to the above-mentioned synthesis scheme, or by methods similar to the following examples.

[0128] Example

[0129] Example 1: Synthesis of ethyl 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (Compound 1)

[0130]

[0131]

[0132] Step 1: Preparation of 4-(methylsulfonyl)pyridine-2-carbonitrile

[0133] Take 4-bromopyridine-2-carbonitrile (5.0 g, 27.3 mmol), sodium methanesulfinate (3.3 g, 32.7 mmol) and cuprous iodide (15.6 g, 81.9 mmol) and add them to 100 mL of dimethyl sulfoxide under argon protection. React at 100°C for 3 h. Cool to room temperature, add 200 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and chromatograph the residue with silica gel column (PE: EA (v: v) = 4: 1) to obtain 4.2 g of the target compound (yield 84%). 1 H NMR (400 MHz, CDCl3): δ 9.04 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 3.15 (s, 3H).

[0134] Step 2: Preparation of ethyl 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)acrylate

[0135] Take 4-(methylsulfonyl)pyridine-2-carbonitrile (4.2 g, 23.1 mmol), sodium 3-ethoxy-3-oxopropanoate (5.7 g, 36.9 mmol) and zinc chloride (1.6 g, 11.5 mmol) and add them to 200 mL of 1,2-dichloroethane solution, add N,N-diisopropylethylamine (300 mg, 2.3 mmol), and reflux for 10 h in a water separator at 120°C. Cool to room temperature, add 200 mL of water, extract three times with dichloromethane, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and column chromatography (PE: EA (v; v) = 3: 1) to obtain 3 g of the target compound (yield 48%). 1 H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.86 (d, J = 5.0 Hz, 1H), 5.49 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.13 (s, 3H), 1.35 (t, J = 7.1 Hz,3H).

[0136] Step 3: Preparation of ethyl 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)propanoate

[0137] Take ethyl 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)acrylate (3 g, 11.1 mmol), palladium hydroxide (450 mg) and acetic acid (7 mL) and add them to 100 mL of methanol solution. Under the action of hydrogen, react at room temperature for 5 h, filter and spin dry the filtrate to obtain 2.5 g of ethyl 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)propanoate (yield 83%). 1 H NMR (400MHz, CDCl3): δ 8.77 (d, J = 5.0 Hz, 1H), 7.87 (s, 1H), 7.61 (d, J = 5.0 Hz,1H), 4.48 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.02 (s, 3H), 2.86 (m, 1H), 2.69(m, 1H), 1.20 (t, J = 7.1 Hz, 3H).

[0138] Step 4: Preparation of ethyl 3-formamido-3-(4-(methylsulfonyl)pyridin-2-yl)propanoate

[0139] Take ethyl 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)propanoate (2.5 g, 9.2 mmol) and add it to 20 mL of formic acid, reflux at 100°C for 12 h. Cool to room temperature and remove formic acid to obtain 2.5 g of the target compound (yield 91%). 1 H NMR(400 MHz, CDCl3): δ 8.75 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H),7.81 (s, 1H), 7.66 (d, J = 5.0 Hz, 1H), 5.72 – 5.48 (m, 1H), 4.03 (q, J = 7.1Hz, 2H), 3.16 – 3.11 (m, 1H), 3.02 (s, 3H), 2.88 – 2.83 (m, 1H).

[0140] Step 5: Preparation of ethyl 2-(7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate

[0141] Take ethyl 3-formamido-3-(4-(methylsulfonyl)pyridin-2-yl)propanoate (2.5 g, 8.3 mmol) and add it to 50 mL toluene solution, add phosphorus oxychloride (5.1 g, 33.3 mmol), and reflux at 100°C for 12h. Cool to room temperature, spin off toluene, add saturated sodium bicarbonate solution, adjust the pH to 8, extract with ethyl acetate three times, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and chromatograph the residue with silica gel column (PE: EA (v: v) = 4: 1) to obtain ethyl 2-(7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate 1.4 g (yield 59%). 1 H NMR (400MHz, CDCl3): δ 8.21 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H), 6.87 (d,J = 7.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.94 (s, 2H), 3.02 (s, 3H), 1.22(t, J = 7.2 Hz, 3H).

[0142] Step 6: Preparation of ethyl 2-(3-bromo-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate

[0143] Take ethyl 2-(7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (1.4 g, 4.9 mmol) and add it to 20 mL DMF solution, add NBS (1.1 g, 5.4 mmol), and react at 55°C for 2 h. Cool to room temperature, add 100 mL water, extract with ethyl acetate three times, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and the residue is chromatographed on a silica gel column (PE: EA (v: v) = 4: 1) to obtain ethyl 2-(3-bromo-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate 1.3 g (yield 72%). 1 H NMR (400 MHz, CDCl3): δ 8.13 – 8.07 (m,1H), 7.87 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 4.13 (q, J = 7.1 Hz,2H), 3.92 (s, 2H), 3.03 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).

[0144] Step 7: Preparation of ethyl 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate

[0145] Take ethyl 2-(3-bromo-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (150 mg, 0.43 mmol), (3,5-difluorophenyl)boric acid (82 mg, 0.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (31 mg, 0.043 mmol) and sodium carbonate (91 mg, 0.86 mmol) and add them to 20 mL toluene and 1 mL water under argon protection. Reflux for 3 h. The mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by vortexing. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 4: 1~2: 1) to obtain 160 mg of ethyl 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (yield 94%). 1 H NMR (400 MHz, CDCl3): δ 8.34 – 8.19 (m, 2H), 7.39 – 7.30(m, 2H), 7.02 – 7.00 (m, 1H), 6.98 – 6.91 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 3.11 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0146] Example 2: Synthesis of 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetic acid (Compound 2)

[0147]

[0148]

[0149] Lithium hydroxide (55 mg, 1.3 mmol) was added to a mixture of 0.7 mL of water and 0.7 mL of ethanol, and ethyl 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (50 mg, 0.13 mmol) was added. The mixture was reacted at room temperature for 1 h. The ethanol was removed by vortexing, and the pH was adjusted to 6 with 1 N HCl until solids precipitated. The mixture was filtered, the filter cake was washed with water, and dried to obtain 42 mg of the target compound (yield 88%). 1H NMR (400 MHz, Methanol-d4): δ 8.53 – 8.51 (m,1H), 8.34 (s, 1H), 7.60 – 7.41 (m, 2H), 7.24 – 7.05 (m, 2H), 4.09 (s, 2H), 3.18 (s, 3H).

[0150] Example 3: Synthesis of 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)ethane-1-ol (Compound 3)

[0151]

[0152]

[0153] Take ethyl 2-(3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (50 mg, 0.13 mmol) and add it to 5 mL tetrahydrofuran solution, slowly drop 1 N lithium tri-sec-butylborohydride (0.26 mL). React at room temperature for 1 h, quench the reaction with saturated ammonium chloride, add 20 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v;v) = 1: 1) to obtain 32 mg of the target compound (yield 70%). 1 H NMR (400 MHz, CDCl3): δ 8.24 (d, J= 7.5 Hz, 1H), 8.21 (s, 1H), 7.35 – 7.32 (m, 2H), 7.01 – 6.90 (m, 2H), 4.24(s, 1H), 4.07 (t, J = 5.7 Hz, 2H), 3.18 (t, J = 5.7 Hz, 2H), 3.09 (s, 3H).

[0154] Example 4: Synthesis of ethyl 2-(3-(3-cyano-5-fluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate (Compound 4)

[0155]

[0156] The synthesis method is as shown in Example 1, except that the raw material (3,5-difluorobenzene)boric acid in step 7 of Example 1 is replaced by (3-cyano-5-fluorophenyl)boric acid. 1H NMR (400 MHz, CDCl3): δ 8.31 – 8.22 (m, 2H), 7.93 (s, 1H), 7.82 – 7.79 (m, 1H), 7.479 – 7.45 (m, 1H), 7.09 – 7.07 (m, 1H), 4.22 (q, J =7.2 Hz, 2H), 4.05 (s, 2H), 3.12 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0157] Example 5: Synthesis of ethyl 2-(3-(3,5-difluorophenyl)-7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate (Compound 5)

[0158]

[0159]

[0160] Step 1: Preparation of ethyl 3-amino-3-(4-bromopyridin-2-yl)acrylate

[0161] The synthesis method is as follows: Step 2 of Example 1, except that 4-(methylsulfonyl)pyridine-2-carbonitrile is replaced by 4-bromopyridinecarbonitrile. 1 H NMR (400 MHz, CDCl3): δ 8.44 (d, J = 5.3 Hz, 1H), 7.92 (s, 1H), 7.51 (d,J = 5.3 Hz, 1H), 5.30 (s, 1H), 4.20 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0162] Step 2: Preparation of ethyl 3-amino-3-(4-bromopyridin-2-yl)propanoate

[0163] Take 3-amino-3-(4-bromopyridin-2-yl) ethyl acrylate (11.2 g, 41.3 mmol) and add it to 50 mL of glacial acetic acid, and add sodium borohydride (4.7 g, 124 mmol) in batches. React at room temperature for 12 hours, quench the reaction with saturated sodium bicarbonate solution, add 200 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue with silica gel column chromatography (PE: EA (v / v) = 1: 1) to obtain the target compound 3-amino-3-(4-bromopyridin-2-yl) ethyl propionate 9.4 g (84%). 1H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 5.2Hz, 1H), 7.59 (s, 1H), 7.34 (d, J = 5.3 Hz, 1H), 4.41 – 4.38 (m, 1H), 4.13(q, J = 7.1 Hz, 2H), 2.88 – 2.83 (m, 1H), 2.79 – 2.67 (m, 1H), 1.23 (t, J =7.1 Hz, 3H).

[0164] Step 3: Preparation of ethyl 3-(4-bromopyridin-2-yl)-3-carboxamidopropanoate

[0165] The synthesis method is as follows: Step 4 of Example 1, except that 3-amino-3-(4-(methylsulfonyl)pyridin-2-yl)propanoic acid ethyl ester is replaced with 3-amino-3-(4-bromopyridin-2-yl)propanoic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 8.07 (s,1H), 7.55 – 7.46 (m, 2H), 7.46 – 7.37 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.73– 3.55 (m, 1H), 3.40 – 3.34 (m, 1H), 2.79 – 2.61 (m, 1H), 1.33 (t, J = 7.1Hz, 3H).

[0166] Step 4: Preparation of ethyl 2-(7-bromoimidazo[1,5-a]pyridin-1-yl)acetate

[0167] The synthesis method is as follows: Step 5 of Example 1, except that 3-formamido-3-(4-(methylsulfonyl)pyridin-2-yl)propanoic acid ethyl ester is replaced with 3-(4-bromopyridin-2-yl)-3-formamidopropanoic acid ethyl ester. 1 H NMR (400 MHz, CDCl3): δ 8.03(s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.63 (s, 1H), 6.59 (d, J = 7.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0168] Step 5: Preparation of ethyl 2-(7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate

[0169] Take ethyl 2-(7-bromoimidazole [1,5-a] pyridin-1-yl)acetate (283 mg, 1 mmol), 2-thiopheneboronic acid (192 mg, 1.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (73 mg, 0.1 mmol) and sodium carbonate (106 mg, 2 mmol) and add them to a mixture of 30 mL toluene and 3 mL water, and protect with argon. Reflux for 2 h. Cool to room temperature, add 50 mL water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and purify the residue by column chromatography (PE: EA = 2: 1~1: 1) to obtain the target compound ethyl 2-(7-(thiophene-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate 267 mg (yield 93%). 1 H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.60 (s, 1H), 7.32 – 7.29 (m, 2H), 7.10 – 7.06 (m, 1H), 6.86 (d, J = 7.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.94(s, 2H), 1.28 (t, J = 7.3 Hz, 3H).

[0170] Step 6: Preparation of ethyl 2-(3-bromo-7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate

[0171] Synthesis method: Referring to step 6 of Example 1, ethyl 2-(7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate

[0172] Replaced with ethyl 2-(7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate. 1 H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 1H), 7.51 (s, 1H), 7.27 – 7.24 (m, 2H), 7.07 –7.01 (m, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.87 (s,2H), 1.21 (t, J = 7.2 Hz, 3H).

[0173] Step 7: Preparation of ethyl 2-(3-(3,5-difluorophenyl)-7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate

[0174] The synthesis method refers to step 7 of Example 1, replacing ethyl 2-(3-bromo-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)acetate with ethyl 2-(3-bromo-7-(thiophen-2-yl)imidazo[1,5-a]pyridin-1-yl)acetate. 1 H NMR(400 MHz, CDCl3): δ 8.15 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.29 – 7.24 (m,4H), 7.05 – 7.02 (m, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.82 – 6.76 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.93 (s, 2H), 1.22 (d, J = 7.1 Hz, 3H).

[0175] Example 6: Synthesis of 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine-1-ol (Compound 6)

[0176]

[0177]

[0178] Step 1: Preparation of 4-bromo-3-methylpyridine 1-oxide

[0179] Take 4-bromo-3-methylpyridine hydrochloride (10 g, 48 mmol) and add it to 200 mL of dichloromethane solution, and add m-chloroperbenzoic acid (12.4 g, 72 mmol) in batches. React at room temperature for 12 hours, quench the reaction with saturated sodium bicarbonate solution, add 200 mL of water, extract with dichloromethane three times, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and chromatograph the residue with silica gel column (DCM ~ DCM: EA (v:v =1:1)) to obtain 6.4 g of the target compound (yield 71%). MS (ESI), m / z: M + 189.1.

[0180] Step 2: Preparation of 4-bromo-3-methylpyridine-2-carbonitrile

[0181] 4-Bromo-3-methylpyridine 1-oxide (6.4 g, 34 mmol) was dissolved in 100 mL DMF, trimethylsilyl cyanide (4.0 g, 41 mmol), triethylamine (6.9 g, 68 mmol) and dimethylcarbamoyl chloride (3.8 g, 36 mmol) were added respectively, and the mixture was heated to 100°C for 5 h. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, and 200 mL of water was added. The mixture was extracted with ethyl acetate three times, the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was chromatographed on a silica gel column (PE: EA (v: v) = 10: 1) to obtain 3.5 g (yield 52%) of the target compound 4-bromo-3-methylpyridine-2-carbonitrile. 1 H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 5.1 Hz, 1H), 2.66 (s, 3H).

[0182] Step 3: Preparation of (4-bromo-3-methylpyridin-2-yl)methanamine

[0183] Prepare 4-bromo-3-methoxypyridine-2-carbonitrile (3.5 g, 17.8 mmol) and dissolve it in 100 mL of anhydrous THF. Slowly drip borane tetrahydrofuran solution (1 N, 53 mL, 53 mmol) at 0°C and react at room temperature for 12 hours. Slowly drip methanol to quench the reaction, stir at room temperature for 1 hour, and spin off the organic solution to obtain the target compound (4-bromo-3-methylpyridin-2-yl)methylamine 3.5 g (yield 99%). MS (ESI), m / z: M + 202.1.

[0184] Step 4: Preparation of N-((4-bromo-3-methylpyridin-2-yl)methyl)-3,5-difluorobenzamide

[0185] Dissolve (4-bromo-3-methylpyridin-2-yl)methylamine (740 mg, 3.7 mmol) in 100 mL of dichloromethane, add 3,5-difluorobenzoic acid (701 mg, 4.4 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluoro (2.8 g, 7.4 mmol) and N,N-diisopropylethylamine (1.9 g, 14.8 mmol) respectively, and react at room temperature for 12 h. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by vortexing. The residue was purified by silica gel column chromatography (PE: EA (v:v) = 7: 1) to obtain 341 mg of the target compound N-((4-bromo-3-methylpyridin-2-yl)methyl)-3,5-difluorobenzamide (yield 27%). 1 H NMR (400 MHz, CDCl3) δ8.32 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.45 – 7.42 (m, 2H), 7.30 (d, J = 5.3 Hz, 1H), 7.00 – 6.94 (m, 1H), 4.70 (s, 2H), 2.41 (s, 3H).

[0186] Step 5: Preparation of 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine

[0187] Take N-((4-bromo-3-methylpyridin-2-yl)methyl)-3,5-difluorobenzamide (341 mg, 1 mmol) and add it to 50 mL toluene solution, add phosphorus oxychloride (1.53 g, 10 mmol), and reflux at 100°C for 12h. Cool to room temperature, spin off toluene, add saturated sodium bicarbonate solution, adjust pH to 8, add 50 mL water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by column chromatography (PE: EA (v: v) = 10: 1) to obtain 270 mg (yield 83%) of 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine. 1 HNMR (400 MHz, CDCl3): δ 8.07 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.37 – 7.29(m, 2H), 6.91 – 6.86 (m, 1H), 6.64 (d, J = 7.5 Hz, 1H), 2.50 (s, 3H).

[0188] Step 6: Preparation of 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridin-1-ol

[0189] 7-Bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine (100 mg, 0.31 mmol) was added to 20 mL of 1,4-dioxane solution, and selenium dioxide (344 mg, 3.1 mmol) and tert-butyl hydroperoxide (70% content, dissolved in water, 400 mg, 3.1 mmol) were added. The mixture was reacted at 50°C for 5 h. The mixture was cooled to room temperature and quenched by pouring 10 mL of ice water. The mixture was filtered through diatomaceous earth and the filter cake was washed three times with ethyl acetate. The organic layers were combined and washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. 58 mg of 7-Bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine-1-ol (yield 55%) was obtained by column chromatography (PE: EA (v: v) = 5: 1). 1 H NMR (400 MHz, CDCl3): δ 11.69 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.61 (d, J = 5.1 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.10– 7.05 (m, 1H), 2.90 (s, 3H).

[0190] Example 7: Synthesis of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 7)

[0191]

[0192]

[0193] Step 1: Synthesis of 1,7-dibromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine

[0194] 7-Bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine (32 mg, 0.1 mmol) was added to 20 mL of carbon tetrachloride solution, and N-bromosuccinimide (40 mg, 0.2 mmol) and benzoyl peroxide (2.4 mg, 0.01 mmol) were added. The mixture was refluxed for 2 h under argon protection. The mixture was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain 21 mg of the target compound 1,7-dibromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine (yield 55%). 1 H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 7.6 Hz, 1H), 7.28 – 7.25 (m, 2H), 6.98 – 6.90 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.09 (s, 2H).

[0195] Step 2: Synthesis of methyl (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)acetate

[0196] Take 1,7-dibromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine (21 mg, 0.043 mmol) and add 3 mL of acetonitrile solution, add acetic acid (5 mg, 0.081 mmol) and triethylamine (10 mg, 0.1 mmol), and react at 60°C for 1 h. The organic solution is removed by rotation. The crude product of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)acetate is obtained.

[0197] Step 3: Synthesis of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol

[0198] The crude product of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)acetic acid methyl ester was dissolved in 3 mL of methanol and sodium hydroxide (42 mg, 1.04 mmol) and refluxed for 1 h. The mixture was cooled to room temperature, saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was chromatographed on a silica gel column (PE: EA (v: v) = 5: 1) to obtain 10 mg (yield 56%) of the target compound (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 7). 1 H NMR (400 MHz, MeOH-d4): δ 8.36(d, J = 7.6 Hz, 1H), 7.42 – 7.39 (m, 2H), 7.18 – 7.09 (m, 1H), 6.82 (d, J =7.6 Hz, 1H), 5.18 (s, 2H).

[0199] Example 8: Synthesis of 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 8)

[0200]

[0201]

[0202] 7-Bromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine (210 mg, 0.52 mmol) was added to 20 mL of dimethyl sulfoxide solution, sodium methanesulfinate (80 mg, 0.78 mmol) and cuprous iodide (494 mg, 2.6 mmol) were added, and the mixture was reacted at 100°C for 12 h under argon protection. The mixture was cooled to room temperature and quenched by pouring into ice water. The mixture was filtered through diatomaceous earth, and the filter cake was washed three times with ethyl acetate, extracted, and the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain 160 mg of the target compound 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 8) (yield 76%). 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 7.37 – 7.32 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 6.97 – 6.93 (m, 1H), 3.13 (s, 3H), 2.91 (s, 3H).

[0203] Example 9: Synthesis of 1-bromo-3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 9)

[0204]

[0205]

[0206] 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (100 mg, 0.32 mmol) was added to 20 mL of carbon tetrachloride solution, and N-bromosuccinimide (68 mg, 0.34 mmol) and benzoyl peroxide (3.8 mg, 0.015 mmol) were added. The mixture was refluxed for 2 h under argon protection. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain 50 mg of the target compound 1-bromo-3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 9) (yield 40%). 1 H NMR (400 MHz, Methanol-d4): δ 8.39 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 6.3 Hz, 2H), 7.28 –7.07 (m, 2H), 3.20 (s, 3H), 3.16 (s, 3H).

[0207] Example 10: Synthesis of 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-ol (Compound 10)

[0208]

[0209] The synthesis method refers to step 6 of Example 6, except that 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine is replaced by 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine. 1 H NMR (400MHz, CDCl3) δ 11.47 (s, 1H), 8.78 (d, J = 4.9 Hz, 1H), 8.26 (d, J = 4.9 Hz, 1H), 7.53 – 7.43 (m, 2H), 7.11 – 7.07 (m, 1H), 3.22 (s, 3H), 3.19 (s, 3H).

[0210] Example 11: Synthesis of 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carbaldehyde (Compound 11)

[0211]

[0212]

[0213] Phosphorus oxychloride (742 mg, 4.5 mmol) was placed in a 10 mL sealed tube and placed in an ice-water bath. 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (100 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (330 mg, 4.5 mmol) and the mixture was slowly dripped into the sealed tube. Heat to 100°C and react for 3 h. The mixture was cooled to room temperature, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by vortexing. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 4: 1) to obtain 98 mg (yield 87%) of the target compound 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carbaldehyde (Compound 11). 1 H NMR (600 MHz, CDCl3): δ 10.41 – 10.14 (m, 1H), 8.27 (d, J = 8.3Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.04 (t, J = 8.3 Hz,1H), 3.32 (s, 3H), 3.23 (s, 3H).

[0214] Example 12: Synthesis of (3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)methanol (Compound 12)

[0215]

[0216]

[0217] 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carboxaldehyde (50 mg, 0.14 mmol) was added to 5 mL of ultra-dry tetrahydrofuran, and sodium borohydride (27 mg, 0.71 mmol) was slowly added. The reaction was allowed to react at room temperature for 1 h, and saturated ammonium chloride was slowly added dropwise to quench the reaction. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. Column chromatography (PE: EA (v: v) = 2: 1) was performed to obtain 44 mg of the target compound (3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)methanol (Compound 12) (yield 89%). 1 H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.6 Hz, 1H), 7.37 –7.28 (m, 2H), 7.24 (s, 1H), 7.03 – 6.92 (m, 1H), 5.15 (s, 2H), 3.14 (s, 3H),3.09 (s, 3H).

[0218] Example 13: Synthesis of 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazole[1,5-a]pyridine-1-carboxylic acid (Compound 13)

[0219]

[0220]

[0221] Take 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carbaldehyde (50 mg, 0.14 mmol) and add it to 2 mL of tert-butyl alcohol and 1 mL of 2-methyl-2-butene. Sodium hypochlorite (66 mg, 0.78 mmol) and sodium hydrogen phosphate monohydrate (94 mg, 0.78 mmol) were dissolved in 2 mL of water and slowly dripped into the mixture. The mixture was reacted at room temperature for 12 hours. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by vortexing. The residue was purified by silica gel column chromatography (PE: EA = 1: 1 - DCM: MeOH = 20: 1) to obtain 27 mg (yield 53%) of the target compound 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazole[1,5-a]pyridine-1-carboxylic acid (Compound 13). 1 H NMR (400 MHz, Methanol-d4): δ 8.28 (s, 1H), 7.45 – 7.34 (s,3H), 7.12 (t, J = 9.0 Hz, 1H), 3.23 (s, 3H), 3.17 (s, 3H).

[0222] Example 14: Synthesis of methyl 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carboxylate (Compound 14)

[0223]

[0224]

[0225] 2-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carboxylic acid (25 mg, 0.07 mmol) was added to 1 mL DCM and 0.5 mL MeOH, and trimethylsilylated diazomethane (39 mg, 0.34 mmol) was slowly added dropwise under ice bath, and the mixture was reacted at room temperature for 2 h. 10 mL of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA = 2: 1) to obtain the target compound 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carboxylic acid methyl ester (Compound 14) 9 mg (yield 34%). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.04 – 6.96 (m, 1H), 4.03 (s,3H), 3.23 (s, 3H), 3.20 (s, 3H).

[0226] Example 15: Synthesis of 7-bromo-3-(3,5-difluorophenyl)-8-methyl-1-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 15)

[0227]

[0228]

[0229] Step 1: Preparation of 1,7-dibromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine

[0230] The synthesis method is as follows: Step 1 of Example 7, except that 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine is replaced with 7-bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine. 1 H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 7.5 Hz, 1H), 7.30 – 7.27 (m, 2H), 6.92 – 6.89 (m, 1H), 6.64 (d, J = 7.5 Hz, 1H), 2.80 (s, 3H).

[0231] Step 2: Preparation of 7-bromo-3-(3,5-difluorophenyl)-8-methyl-1-(methylsulfonyl)imidazo[1,5-a]pyridine

[0232] Synthesis Method: Refer to the synthesis of Example 8, except that 7-bromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine is replaced with 1,7-dibromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine. 1 H NMR(400 MHz, Methanol-d4): δ 8.43 – 8.32 (m, 1H), 7.49 (d, J = 6.8 Hz, 2H), 7.24– 7.12 (m, 1H), 7.02 (d, J = 7.5 Hz, 1H), 3.46 (s, 3H), 2.86 (s, 3H).

[0233] Example 16: Synthesis of 3-(3,5-difluorophenyl)-8-methyl-1,7-bis(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 16)

[0234]

[0235] Synthesis Method: Refer to the synthesis of Example 8, and replace 7-bromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine with 1,7-dibromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine. Under this condition, 7-bromo-3-(3,5-difluorophenyl)-8-methyl 3-(3,5-difluorophenyl)-8-methyl-1,7-bis(methylsulfonyl)imidazo[1,5-a]pyridine can also be obtained at the same time (yield 11%). 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(dd, J = 7.5, 0.9Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.31 – 7.29 (m, 2H), 7.06 – 7.00 (m, 1H), 3.58 (s, 3H), 3.31 (s, 3H), 3.18 (s, 3H).

[0236] Example 17: Synthesis of 3-fluoro-5-(1-(hydroxymethyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridin-3-yl)benzonitrile (Compound 17)

[0237]

[0238] Synthesis method: Refer to the synthesis of Example 12, except that 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-carbaldehyde is replaced with 3-fluoro-5-(1-formyl-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridin-3-yl)benzonitrile. 1 H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 7.6 Hz, 1H), 8.01 (s,1H), 7.89 (d, J = 9.4 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.6 Hz,1H), 4.96 (s, 2H), 3.34 (s, 3H), 2.75 (s, 3H).

[0239] Example 18: Synthesis of (3-(3,5-difluorophenyl))-7-(methylsulfonyl)imidazo[1,5-a]pyridin-1-yl)methanol (Compound 18)

[0240]

[0241] The starting material is 4-bromopyridine-2-carbonitrile, and the synthesis method is sequentially referred to steps 3, 4, 5 of Example 6, Example 8, Example 11 and Example 12. 1 H NMR (400 MHz, CDCl3): δ 8.39 (s, 1H), 8.28 (d, J = 7.6Hz, 1H), 7.38 – 7.32 (m, 2H), 7.15 – 7.05 (m, 1H), 7.00 – 6.95 (m, 1H), 5.07(s, 2H), 3.11 (s, 3H).

[0242] Example 19: Synthesis of 3-(3,5-difluorophenyl)-7-(methylsulfonyl)imidazo[1,5-a]pyridine-1-ol (Compound 19)

[0243]

[0244] The starting material is 4-bromopyridine-2-carbonitrile, and the synthesis steps are sequentially referred to steps 3, 4, 5 of Example 6, Example 8 and step 6 of Example 6. 1 H NMR (400 MHz, CDCl3): δ 11.21 (s, 1H), 8.99 (d, J = 5.0Hz, 1H), 8.79 (s, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.14 –7.09 (s, 1H), 3.18 (s, 3H).

[0245] Example 20: Synthesis of (3,5-difluorophenyl)-8-methyl-7-(methylthio)imidazo[1,5-a]pyridine-1-ol (Compound 20)

[0246]

[0247]

[0248] Step 1: Preparation of 3-(3,5-difluorophenyl)-8-methyl-7-(methylthio)imidazo[1,5-a]pyridine

[0249] 7-Bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine (143 mg, 0.46 mmol) was added to 5 mL N,N-dimethylformamide, sodium thiomethoxide (39 mg, 0.56 mmol) was added, and the mixture was reacted at 100°C for 4 h. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA = 10: 1) to obtain 120 mg (yield 89%) of 3-(3,5-difluorophenyl)-8-methyl-7-(methylthio)imidazo[1,5-a]pyridine. 1 H NMR (400 MHz, CDCl3): δ 8.06(d, J = 7.5 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.23 – 7.19 (m, 1H), 7.02 –7.00 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 2.55 (s, 3H), 2.50 (s, 3H).

[0250] Step 2: Preparation of (3,5-difluorophenyl)-8-methyl-7-(methylthio)imidazo[1,5-a]pyridin-1-ol

[0251] Take (3,5-difluorophenyl)-8-methyl-7-(methylthio)imidazo[1,5-a]pyridine-1-ol (27.5 mg, 0.1 mmol) and add it to 5 mL of 1,4-dioxane, add selenium dioxide (27 mg, 0.24 mmol), and react at 100°C for 2 h. Cool to room temperature, add 10 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain 10 mg of the target compound (yield 32%). 1 H NMR (400 MHz, CDCl3): δ 11.63 (s, 1H), 8.39 (d, J = 5.4Hz, 1H), 7.60 (d, J = 5.4 Hz, 2H), 7.39 – 7.31 (m, 1H), 7.17 – 7.15 (m, 1H), 2.89 (s, 3H), 2.55 (s, 3H).

[0252] Example 21: Synthesis of 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)-1-nitroimidazo[1,5-a]pyridine (Compound 21)

[0253]

[0254]

[0255] Take 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (79 mg, 0.26 mmol) and add it to 5 mL of acetonitrile under argon protection. Dissolve tetrafluoroborate nitrosocyanate (90 mg, 0.77 mmol) in 5 mL of acetonitrile and drop it into the mixed system to react at room temperature for 2 h. Quench the reaction with 1 mL of ethanol, add 20 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v:v) = 3: 1) to obtain the target compound (yield 41%). 1 H NMR (400 MHz, CDCl3): δ8.18 – 8.10 (m, 2H), 7.87 – 7.78 (m, 2H), 7.06 (d, J = 7.4 Hz, 1H), 3.15 (s,3H), 2.85 (s, 3H).

[0256] Example 22: Synthesis of 3-(3,5-difluorophenyl)-1-fluoro-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (Compound 22)

[0257]

[0258]

[0259] Take 3-(3,5-difluorophenyl)-8-methyl-7-(methylsulfonyl)imidazo[1,5-a]pyridine (127 mg, 0.41 mmol) and add it to 5 mL N,N-dimethylformamide under argon protection. Dissolve 1-fluoro-2,4,6-trimethylpyridine boron tetrafluoride (187 mg, 0.82 mmol) in N,N-dimethylformamide and drop it into the mixed system. React at 60°C for 2 h. Cool to room temperature, add 2 mL of 1 N sodium hydroxide solution, add 20 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA = 5: 1) to obtain 66 mg of the target compound (yield 47%). 1H NMR (600 MHz, CDCl3): δ 8.11 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 6.65– 6.64 (m, 1H), 3.12 (d, J = 2.6 Hz, 3H), 2.57 (s, 3H).

[0260] Example 23: Synthesis of ethyl 3-(3,5-difluorophenyl)imidazole[1,5-a]pyridine-8-carboxylate (Compound 23)

[0261]

[0262]

[0263] Step 1: Preparation of 3-bromo-2-(bromomethyl)pyridine

[0264] Take 2-methyl-3-bromopyridine (5 g, 29 mmol) and add it to 100 mL of carbon tetrachloride solution, add N-bromosuccinimide (7.7 g, 43.6 mmol) and benzoyl peroxide (1.87 g, 5.8 mmol), protect with argon, and reflux for 12 hours. Cool to room temperature, add 100 mL of water, extract three times with dichloromethane, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain 2.4 g of the target compound (yield 33%). 1 H NMR (600 MHz, CDCl3): δ 8.54 (d, J = 3.7 Hz, 1H), 8.01 – 7.85 (m, 1H), 7.13 – 7.12 (m, 1H), 4.72 (s, 2H).

[0265] Step 2: Preparation of N-((3-bromopyridin-2-yl)methyl)-3,5-difluorobenzamide

[0266] Take 3-bromo-2-(bromomethyl)pyridine (2.4 g, 9.5 mmol) and 3,5-difluorobenzamide (1.6 g, 10.5 mmol) and add them to 100 mL of anhydrous tetrahydrofuran solution. Add sodium hydride (60%, 573 mg, 14.3 mmol) in batches and reflux for 24 h. Cool in an ice-water bath and slowly drip saturated ammonium chloride to quench the reaction. Add 100 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 5: 1) to obtain 1.38 g of the target compound (yield 44%). 1 H NMR (400 MHz, CDCl3): δ 8.55 – 8.54 (m, 1H), 8.01 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.50 –7.39 (m, 2H), 7.23 – 7.16 (m, 1H), 7.03 – 6.91 (m, 1H), 4.79 (d, J = 3.9 Hz, 2H).

[0267] Step 3: Preparation of 8-bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine

[0268] Take N-((3-bromopyridin-2-yl)methyl)-3,5-difluorobenzamide (1.38 g, 4.2 mmol) and add it to 50 mL of toluene solution, add phosphorus oxychloride (6.48 g, 42 mmol), and reflux at 100°C for 12 h. Cool to room temperature, spin off toluene, add saturated sodium bicarbonate solution, adjust the pH to 8, add 100 mL of water, extract with ethyl acetate three times, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain 1.06 g (yield 81%) of the target compound. 1 H NMR (400 MHz, CDCl3): δ 8.23 ​​(d, J =7.2 Hz, 1H), 7.68 (s, 1H), 7.35 – 7.33 (m, 2H), 7.02 (d, J = 6.9 Hz, 1H), 6.97 – 6.82 (m, 1H), 6.55 (t, J = 7.1 Hz, 1H).

[0269] Step 4: Preparation of ethyl 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylate

[0270] 8-Bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine (1.06 g, 3.43 mmol), di(cyanobenzene)palladium dichloride (31 mg, 0.082 mmol), 1,1'-bis(di-phenylphosphino)ferrocene (114 mg, 0.21 mmol) and triethylamine (694 mg, 6.86 mmol) were added to 50 mL of ethanol, and carbon monoxide (15 bar) was introduced. The mixture was reacted at 140°C for 12 h. The mixture was cooled to room temperature and carbon monoxide gas was slowly released. 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by vortexing. The residue was purified by silica gel column chromatography (PE: EA (v / v) = 5:1) to obtain 0.93 g (yield 89%) of ethyl 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylate. 1 H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 7.1 Hz, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.68– 7.66 (m, 1H), 7.35 – 7.33 (m, 2H), 6.94 – 6.88 (m, 1H), 6.74 (t, J = 7.0Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H).

[0271] Example 24: Synthesis of (3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 24)

[0272]

[0273]

[0274] Take 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (400 mg, 1.32 mmol) and add it to 30 mL of ultra-dry tetrahydrofuran, slowly add tetrahydrofuran solution of lithium aluminum tetrahydride (2.5 mol / L, 1 mL, 2.64 mmol). React at room temperature for 1 h. Slowly add aqueous solution to quench the reaction, extract with ethyl acetate three times, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA = 3: 1) to obtain 320 mg of the target compound (yield 93%). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.2 Hz,1H), 7.64 (s, 1H), 7.41 – 7.30 (m, 2H), 6.91 – 6.86 (m, 2H), 6.69 (t, J = 6.9Hz, 1H), 4.92 (s, 2H).

[0275] Example 25: Synthesis of 3-(3,5-difluorophenyl)imidazole[1,5-a]pyridine-8-carboxylic acid (Compound 25)

[0276]

[0277]

[0278] 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (52 mg, 0.17 mmol) was added to 2 mL of tetrahydrofuran, and 2 mL of 2 N sodium hydroxide was added dropwise. The mixture was reacted at room temperature for 1 h. The tetrahydrofuran solution was removed by vortexing, the pH was adjusted to 7 with dilute hydrochloric acid, the mixture was filtered, the filter cake was washed three times with water, and dried to obtain 40 mg of the target compound 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid (Compound 25) (yield 86%). 1 H NMR (600 MHz, DMSO-d6): δ 8.77 (d, J = 7.2 Hz,1H), 7.95 (s, 1H), 7.65 (d, J = 6.7 Hz, 1H), 7.59 – 7.57 (m, 2H), 7.45 – 7.30(m, 1H), 6.89 (t, J = 7.0 Hz, 1H).

[0279] Example 26: Synthesis of 3-(3,5-difluorophenyl)imidazole[1,5-a]pyridine-8-carbaldehyde (Compound 26)

[0280]

[0281]

[0282] (3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-yl)methanol (220 mg, 0.85 mmol) was added to 10 mL of dichloromethane, and Dess martin reagent (726 mg, 1.7 mmol) was added, and the mixture was reacted at room temperature for 3 h. 20 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 4: 1) to obtain 204 mg of the target compound 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxaldehyde (Compound 26) (yield 93%). 1 H NMR (600 MHz, CDCl3): δ 10.06(s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 7.44 (d, J = 6.2 Hz, 1H), 7.34 (d, J = 5.8 Hz, 2H), 6.96 – 6.89 (m, 1H), 6.85 (t, J = 6.9 Hz, 1H).

[0283] Example 27: Synthesis of (1,7-dibromo-3-(3-chloro-5-fluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 27)

[0284]

[0285] The synthesis method refers to steps 1-5 of Example 6 and steps 1-3 of Example 7, except that 3,5-difluorobenzoic acid in step 4 of Example 6 is replaced by 3-chloro-5-fluorobenzoic acid. 1 H NMR (600 MHz, Methanol-d4): δ 8.36 (d, J =7.5 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.54 – 7.52 (m, 1H), 7.41 – 7.39 (m,1H), 6.85 (d, J = 7.5 Hz, 1H), 5.21 (s, 3H).

[0286] Example 28: Synthesis of 3-fluoro-5-(8-(hydroxymethyl)-7-methylimidazo[1,5-a]pyridin-3-yl)benzonitrile (Compound 28)

[0287]

[0288]

[0289] The synthesis method refers to steps 1-5 of Example 6 and step 6 of Example 23, and the starting material is 4-methyl-3-bromopyridine.

[0290] Step 7: Preparation of 3-fluoro-5-(8-(hydroxymethyl)-7-methylimidazo[1,5-a]pyridin-3-yl)benzonitrile

[0291] Take 3-(3-cyano-5-fluorophenyl)-7-methylimidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (32 mg, 0.1 mmol) and add it to 2 mL of anhydrous toluene. Dissolve lithium borohydride (4.4 mg, 0.2 mmol) in 1 mL of anhydrous ether and slowly drip into the reaction system. Raise the temperature from room temperature to 100 °C. Continue to react for half an hour after the temperature stabilizes. Cool to room temperature, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and purify the residue with silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain the target compound 3-fluoro-5-(8-(hydroxymethyl)-7-methylimidazo[1,5-a]pyridin-3-yl)benzonitrile (Compound 28) 18 mg (yield 64%). 1 H NMR (600 MHz, CDCl3): δ 7.83– 7.74 (m, 2H), 7.25 – 7.24 (m, 2H), 7.08 – 6.99 (m, 1H), 6.62 (d, J = 7.3Hz, 1H), 4.90 (s, 2H), 2.38 (s, 3H).

[0292] Example 29: Synthesis of (3-(3,5-difluorophenyl)-7-methylimidazo[1,5-a]pyridin-8-yl)methanol (Compound 29)

[0293]

[0294] The synthesis method refers to Example 28, and the 3-fluoro-5-cyanobenzoic acid in step 4 is replaced by 3,5-difluorobenzoic acid. 1 H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.3 Hz, 1H), 7.62 (s, 1H), 7.33 –7.30 (m, 2H), 6.95 – 6.77 (m, 1H), 6.52 (d, J = 7.3 Hz, 1H), 4.91 (s, 2H),2.37 (s, 3H).

[0295] Example 30: Synthesis of (1-bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 30)

[0296]

[0297]

[0298] Step 1: Preparation of ethyl 1-bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylate

[0299] Take 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (52 mg, 0.17 mmol) and add NBS (36 mg, 0.2 mmol) to 5 mL of dichloromethane, and react at room temperature for 3 h. Extract three times with dichloromethane, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 6: 1) to obtain 41 mg of the target compound (yield 62%). MS (ESI), m / z: M + 383.0.

[0300] Step 2: Preparation of (1-bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol

[0301] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 1-bromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 7.2 Hz, 1H), 7.33 – 7.30 (m, 2H), 7.00 – 6.82 (m, 2H), 6.69 (t, J = 6.9 Hz, 1H), 5.14 (d, J = 6.0 Hz, 2H).

[0302] Example 31: Synthesis of (1-bromo-7-chloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 31)

[0303]

[0304] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7. 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J= 5.1 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 5.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 5.41 (s, 2H).

[0305] Example 32: Synthesis of (1-bromo-7-chloro-3-(3,4-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 32)

[0306]

[0307] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method refers to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method refers to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of 4-chloro-3-methylpyridin-2-yl)methylamine with 3,4-difluorobenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.47 – 7.50 (m, 1H), 7.38 – 7.34 (m, 1H), 6.68 (d, J =7.6 Hz, 1H), 5.26 (s, 2H).

[0308] Example 33: Synthesis of (1-bromo-7-chloro-3-(3-fluoro-4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 33)

[0309]

[0310] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 3-fluoro-4-trifluoromethylbenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz,1H), 7.80 (t, J = 7.7 Hz, 1H), 7.65 (t, J = 9.0 Hz, 2H), 6.75 (d, J = 7.6 Hz,1H), 5.28 (s, 2H).

[0311] Example 34: Synthesis of (1-bromo-7-chloro-3-(2-fluoro-5-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 34)

[0312]

[0313] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 2-fluoro-5-trifluoromethylbenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 6.3, 2.3Hz, 1H), 7.83 – 7.78 (m, 1H), 7.64 (dd, J = 7.6, 4.4 Hz, 1H), 7.41 (t, J =9.2 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.29 (s, 2H).

[0314] Example 35: Synthesis of (1-bromo-7-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 35)

[0315]

[0316] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 3-trifluoromethylbenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.7 Hz, 1H),8.02 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H),7.69 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 5.27 (s, 2H).

[0317] Example 36: Synthesis of (1-bromo-7-chloro-3-(2,3-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 36)

[0318]

[0319] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 2, 3-difluorobenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 3.9 Hz, 1H), 7.59 – 7.35 (m, 3H), 7.35 – 7.30 (m, 1H), 5.36 (s, 2H).

[0320] Example 37: Synthesis of (1-bromo-7-chloro-3-(3-fluoro-5-methoxyphenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 37)

[0321]

[0322] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method is sequentially referred to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method is sequentially referred to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 3-fluoro-5-methoxybenzoic acid. 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.7 Hz,1H), 7.38 (t, J = 2.2 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz,1H), 5.42 (s, 2H), 4.00 (s, 3H).

[0323] Example 38: Synthesis of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanamine (Compound 38)

[0324]

[0325]

[0326] Step 1: Synthesis of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanamine

[0327] Dissolve bis(tert-butyloxycarbonyl)amine (186 mg, 0.85 mmol) in 5 mL DMF solution, add potassium tert-butoxide (128 mg, 1.1 mmol), and react at room temperature for 1 h. Dissolve 1,7-dibromo-8-(bromomethyl)-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine (300 mg, 0.57 mmol) in 10 mL tetrahydrofuran solution, slowly dropwise add it to the mixed system, and react at 65°C for 12 h. Cool to room temperature, add 50 mL water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, spin off the organic solution, and purify the residue with silica gel column chromatography (PE: EA (v: v) = 5: 1) to obtain 85 mg of the intermediate (yield 26%). Dissolve the intermediate in 5 mL 1,4-dioxane solution, react with 1N HCl at room temperature for 2 h, and spin off the organic solution. Recrystallization was performed using petroleum ether:ethyl acetate = 5:1 to obtain 38 mg (69%) of (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanamine. 1H NMR (400 MHz, Methanol-d4) δ 8.89 (s,1H), 7.54 – 7.44 (m, 3H), 7.28 – 7.20 (m, 1H), 5.15 (s, 2H), 3.68 (s, 2H).

[0328] Example 39: Synthesis of (1-bromo-7-chloro-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 39)

[0329]

[0330] The starting material is 4-chloro-3-methylpyridine hydrochloride. The synthesis method refers to steps 1-3 in Example 6 to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl)methylamine, which is then reacted with 3-fluoro-5-(trifluoromethyl)benzoic acid. The synthesis method refers to steps 4 and 5 in Example 6 and the synthesis of Example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl)methylamine with 3,5-difluorobenzoic acid. 1 H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 5.7 Hz, 2H), 7.02 – 6.85 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H).

[0331] Example 40: Synthesis of ethyl 1-bromo-7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylate (Compound 40)

[0332]

[0333]

[0334] Step 1: Preparation of (E)-3-((3-ethoxy-3-oxopropyl)amino)but-2-enoic acid ethyl ester

[0335] Ethyl acetoacetate (106.2 g, 0.7 mol), ethyl 3-aminopropionate (91.0 g, 0.7 mol) and potassium carbonate (232.2 g, 1.7 mol) were dissolved in 500 mL of toluene and separated by water at 120°C for 12 h. The mixture was cooled to room temperature, filtered, and washed with DCM. The mixture was concentrated in vacuo to obtain a yellow liquid (150.0 g, 72.1%).

[0336] Step 2: Preparation of ethyl 2-methyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate

[0337] (E)-3-((3-ethoxy-3-oxopropyl)amino)but-2-enoic acid ethyl ester (150 g, 0.6 mol) was dissolved in toluene, and NaH (22.6 g, 0.9 mol) was added in batches and refluxed for 12 h. Then the mixture was cooled to room temperature and the pH was adjusted to 4-5 with 15% hydrochloric acid solution. The mixture was extracted with EA and dried to obtain a yellow solid (48.0 g, 40.0%).

[0338] Step 3: Preparation of ethyl 2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate

[0339] 2-Methyl-4-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester (48 g, 0.2 mol) and Pb(OAc)4 (295.0 g, 0.7 mol) were dissolved in acetic acid and refluxed at 120°C for 12 h. Then the mixture was cooled to room temperature, acetic acid was removed by vortexing, EA was extracted, and the mixture was separated by column chromatography (EA: PE = 1: 3) to obtain a yellow solid (12.5 g, 27.4%). 1 H NMR (400 MHz, Chloroform-d)δ 8.06 (d, J = 9.5 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H), 4.33 (q, J = 7.1 Hz,2H), 2.75 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0340] Step 4: Preparation of 4-chloro-2-methylnicotinate

[0341] Ethyl 2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (12.5 g, 70.0 mmol) was dissolved in phosphorus oxychloride and refluxed at 110°C for 12 h. Then the mixture was cooled to room temperature, the phosphorus oxychloride was removed by rotation, EA was extracted, and the mixture was separated by column chromatography (EA: PE = 1: 5) to obtain a yellow solid (9.0 g, 62.9%).

[0342] Step 5: Preparation of ethyl 2-(bromomethyl)-4-chloronicotinate

[0343] 4-Chloro-2-methylnicotinic acid ethyl ester (9.0 g, 43.5 mmol), NBS (8.4 g, 47.7 mmol) and BPO (1.05 g, 4.2 mmol) were dissolved in carbon tetrachloride, protected by argon, and reacted at 65°C for 12 hours. Then cooled to room temperature, the carbon tetrachloride was removed by rotation, EA was extracted, and separated by column chromatography (EA: PE = 1: 10) to obtain a yellow solid (12.0 g, 90.1%).

[0344] Step 6: Preparation of ethyl 2-(aminomethyl)-4-chloronicotinate

[0345] Dissolve bis(tert-butyloxycarbonyl)amine (2.28 g, 10.5 mmol) and potassium tert-butoxide (1.5 g, 13.8 mmol) in THF and react at room temperature for 1 h. Then add 2-(bromomethyl)-4-chloronicotinic acid ethyl ester (2.0 g, 6.9 mmol) to the reaction system and reflux at 65 ° C for 12 h. Then cool to room temperature, add water, extract with EA, and separate with column chromatography (EA: PE = 1: 10) to obtain a yellow solid (1.8 g, 62.5%). Dissolve the intermediate in 5 mL of 1,4-dioxane solution, react with 1N HCl at room temperature for 4 h, and spin off the organic solution. Then spin off 1,4-dioxane and dry to obtain a white solid (0.9 g, 96%).

[0346] Step 7: Preparation of ethyl 4-chloro-2-((3-fluoro-5-methylbenzamido)methyl)nicotinate

[0347] Ethyl 2-(aminomethyl)-4-chloronicotinate (500 mg, 2.3 mmol), 3-fluoro-5-methylbenzoic acid (374 mg, 2.3 mmol), EDCI (643 mg, 3.4 mmol) and DMAP (311 mg, 2.6 mmol) were dissolved in DCM and reacted at room temperature for 6 h. Then water was added, extracted with DCM, and separated by column chromatography (EA: PE = 1: 3) to obtain a yellow solid (240 mg, 29.3%). 1 H NMR(400 MHz, Chloroform-d) δ 8.32 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J= 8.3 Hz, 2H), 7.06 (d, J = 9.3 Hz, 1H), 5.12 (d, J = 4.8 Hz, 2H), 4.47 (q, J= 7.1 Hz, 2H), 2.45 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0348] Step 8: Preparation of ethyl 7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylate

[0349] 4-Chloro-2-((3-fluoro-5-methylbenzamide)methyl)nicotinic acid ethyl ester (240 mg, 0.68 mmol) was dissolved in toluene, phosphorus oxychloride (10 ml) was added, and the mixture was reacted at 110°C for 12 h. Then, the toluene and phosphorus oxychloride were removed by rotation, and the mixture was extracted with EA and subjected to column chromatography (EA: PE = 1: 3) to obtain a yellow solid (160 mg, 29.3%).

[0350] Step 9: Preparation of ethyl 1-bromo-7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylate

[0351] Ethyl 7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylate (160 mg, 0.72 mmol) and NBS were dissolved in DCM and reacted at room temperature for 4 h. Then water was added, extracted with DCM, and separated by column chromatography (EA: PE = 1:5) to obtain a yellow solid (170 mg, 54.1%). 1 H NMR (400 MHz, Chloroform-d) δ 7.16 (s, 1H), 7.11 (dd, J = 7.2, 1.5 Hz, 1H), 7.05 – 1.03 (m, 2H), 6.74 (dd, J = 7.2, 1.5 Hz,1H), 4.51 (q, J = 7.2, 2H), 2.42 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0352] Example 41: Synthesis of (1-bromo-7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 41)

[0353]

[0354] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 7.02 (t, J = 9.2 Hz, 2H), 6.95 – 6.82 (m, 1H), 6.73 –6.62 (m, 1H), 5.17 (s, 2H), 2.42 (s, 3H).

[0355] Example 42: Synthesis of 1-bromo-7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylic acid (Compound 42)

[0356]

[0357] The synthesis method refers to Example 25, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 7-chloro-3-(3-fluoro-5-methylphenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.3 Hz, 1H), 7.17 (s, 1H), 7.04 (t, J = 8.1 Hz, 2H), 6.76 (d, J = 7.2 Hz, 1H), 2.43 (s, 3H).

[0358] Example 43: Synthesis of ethyl 3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-bromo-7-chloroimidazo[1,5-a]pyridine-8-carboxylate (Compound 43)

[0359]

[0360] The synthesis method refers to Example 40, except that the raw material 3-fluoro-5-methylbenzoic acid in Step 7 in Example 40 is replaced with benzo[c][1,2,5]oxadiazole-5-carboxylic acid. 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 1.3 Hz,1H), 7.90 (dd, J = 9.2, 1.2 Hz, 1H), 7.64 (dd, J = 9.3, 1.4 Hz, 1H), 7.20 (d,J = 7.1 Hz, 1H), 6.85 (d, J = 7.1 Hz, 1H), 4.54 (q, J = 7.2 Hz, 2H), 1.49 (t,J = 7.1 Hz, 3H).

[0361] Example 44: Synthesis of ethyl 1-bromo-7-chloro-3-(naphthalen-2-yl)imidazo[1,5-a]pyridine-8-carboxylate (Compound 44)

[0362]

[0363] The synthesis method refers to Example 40, and the raw material 3-fluoro-5-methylbenzoic acid in Step 7 in Example 40 is replaced by 2-naphthoic acid. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 1.7 Hz, 1H), 7.96 – 7.86 (m,3H), 7.63 – 7.57 (m, 3H), 7.12 (d, J = 7.1 Hz, 1H), 6.72 (d, J = 7.1 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H).

[0364] Example 45: Synthesis of (1-bromo-7-chloro-3-(naphthalen-2-yl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 45)

[0365]

[0366] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 1-bromo-7-chloro-3-(naphthalen-2-yl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 1.8 Hz, 1H), 7.92 – 7.88 (m, 4H), 7.69 – 7.51 (m, 3H), 6.89 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 7.1 Hz, 1H), 5.19 (s, 2H).

[0367] Example 46: Synthesis of ethyl 1-bromo-7-chloro-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridine-8-carboxylate (Compound 46)

[0368]

[0369] The synthesis method refers to Example 40, except that the raw material 3-fluoro-5-methylbenzoic acid in Step 7 in Example 40 is replaced by 3-(methylsulfonyl)benzoic acid. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 1.8 Hz, 1H), 8.08 (dt, J = 7.9, 1.4 Hz, 1H), 7.87 (dt, J = 7.9, 1.4 Hz, 1H), 7.69 (t, J = 7.8Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.53 (q, J = 7.1Hz, 2H), 3.11 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0370] Example 47: Synthesis of (1-bromo-7-chloro-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 47)

[0371]

[0372] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 1-bromo-7-chloro-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR(400 MHz, CDCl3) δ 8.17 – 7.98 (m, 2H), 7.89 – 7.82 (m, 1H), 7.67 (t, J = 7.8Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 7.1 Hz, 1H), 5.20 (s, 2H), 3.11 (s, 3H).

[0373] Example 48: Synthesis of (7-chloro-1-methyl-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 48)

[0374]

[0375]

[0376] Step 1: Preparation of ethyl 7-chloro-1-methyl-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridine-8-carboxylate

[0377] Dissolve 1-bromo-7-chloro-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (80 mg, 0.18 mmol) in 2 mL DMF. Add trimethylcyclotriboroxane (27 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg, 0.027 mol) and potassium carbonate (74 mg, 0.54 mol) respectively. Under argon protection, react at 100 ° C for 3 h. Cool to room temperature, add 20 mL of water, extract three times with ethyl acetate, combine the organic layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, spin off the organic solution, and purify the residue by silica gel column chromatography (PE: EA (v: v) = 2: 1) to obtain 30 mg of the intermediate (yield 43%).

[0378] Step 2: Preparation of (7-chloro-1-methyl-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridin-8-yl)methanol

[0379] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 7-chloro-1-methyl-3-(3-(methylsulfonyl)phenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR(400 MHz, CDCl3) δ 8.10 – 8.02 (m, 2H), 7.84 (d, J = 7.7 Hz, 1H), 7.67 (t, J= 7.8 Hz, 1H), 7.20 – 7.06 (m, 1H), 6.72 (d, J = 6.6 Hz, 1H), 4.99 (s, 2H), 3.09 (d, J = 11.3 Hz, 3H).

[0380] Example 49: Synthesis of ethyl 1-bromo-7-chloro-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridine-8-carboxylate (Compound 49)

[0381]

[0382] The synthesis method refers to Example 40, and the raw material 3-fluoro-5-methylbenzoic acid in Step 7 in Example 40 is replaced by 1-methyl-1H-pyrazole-4-carboxylic acid. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 1.3 Hz, 2H), 7.07 (dd, J = 10.2, 7.1 Hz, 1H), 6.71 (dd, J = 7.1, 3.9 Hz, 1H), 4.50 (q, J = 7.1Hz, 2H), 4.00 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0383] Example 50: Synthesis of (1-bromo-7-chloro-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 50)

[0384]

[0385] The synthesis method refers to Example 24, and the raw material 3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester is replaced with 1-bromo-7-chloro-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester. 1 H NMR(400 MHz, CDCl3) δ 7.70 – 7.65 (m, 2H), 6.83 (dd, J = 15.6, 7.0 Hz, 1H), 6.67(dd, J = 7.1, 4.0 Hz, 1H), 5.13 (s, 2H), 4.00 (s, 3H).

[0386] Example 51: Synthesis of ethyl 1-bromo-7-chloro-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyridine-8-carboxylate (Compound 51)

[0387]

[0388] The synthesis method refers to steps 1-8 of Example 40, except that the raw material 3-fluoro-5-methylbenzoic acid in step 7 of Example 40 is replaced by benzoic acid. 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.64 – 7.52 (m, 3H), 7.49 – 7.46 (m, 3H), 6.73 (d, J = 7.2 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.49(t, J = 7.1 Hz, 3H).

[0389] Example 52: Synthesis of 1-bromo-7-chloro-3-phenylimidazo[1,5-a]pyridine-8-carboxylic acid ethyl ester (Compound 52)

[0390]

[0391] The synthesis method is as in Example 40, except that the raw material 3-fluoro-5-methylbenzoic acid in step 7 of Example 40 is replaced with benzoic acid. The synthesis method of ethyl 2-(aminomethyl)-4-chloronicotinate and benzoic acid is as in Example 40. 1 H NMR(400 MHz, CDCl3) δ 7.62 – 7.36 (m, 5H), 7.09 (d, J = 7.1 Hz, 1H), 6.70 (d, J= 7.1 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0392] Example 53: Synthesis of methyl (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)acetate (Compound 53)

[0393]

[0394] The synthesis method is detailed in step 2 of Example 7 to obtain methyl (1,7-dibromo-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)acetate (Compound 53). 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.33 –7.28 (m, 3H), 7.02 – 6.94 (m, 1H), 5.71 (s, 2H), 2.17 (d, J = 2.0 Hz, 3H).

[0395] Example 54: Synthesis of (7-bromo-1-chloro-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol (Compound 54)

[0396]

[0397]

[0398] Step 1: Synthesis of 7-bromo-1-chloro-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine

[0399] 7-Bromo-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine (323 mg, 1 mmol) was added to 20 mL of dichloromethane solution, and N-chlorosuccinimide (200 mg, 1.5 mmol) was added to react at room temperature for 12 h. 20 mL of water was added, and dichloromethane was extracted three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain 182 mg of the target compound (yield 51%).

[0400] Step 2: Synthesis of 7-bromo-8-(bromomethyl)-1-chloro-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine

[0401] 7-Bromo-1-chloro-3-(3,5-difluorophenyl)-8-methylimidazo[1,5-a]pyridine (182 mg, 0.508 mmol) was added to 20 mL of carbon tetrachloride solution, and N-bromosuccinimide (99 mg, 0.559 mmol) and benzoyl peroxide (12 mg, 0.05 mmol) were added. The mixture was refluxed for 5 h under argon protection. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with dichloromethane three times. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by rotation. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain 56 mg of the target compound (yield 25%).

[0402] Step 3: Synthesis of (7-bromo-1-chloro-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridin-8-yl)methanol

[0403] The synthesis method is similar to Step 3 and Step 4 of Example 7, except that 7-bromo-8-(bromomethyl)-1-chloro-3-(3,5-difluorophenyl)imidazo[1,5-a]pyridine is used as the starting material. 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz,1H), 7.70 – 7.64 (m, 1H), 7.28 (s, 1H), 6.96 – 6.91(m, 1H), 6.69 (d, J = 7.6Hz, 1H), 5.24 (s, 2H).

[0404] Experimental Example 1

[0405] In vitro activity experiment: The present invention uses Luciferase detection technology to verify the inhibitory or stimulatory effect of the compound of the present invention on HIF-2α gene expression.

[0406] 1. Purpose of the experiment

[0407] The inhibitory or agonistic effects of the compounds of the present invention on HIF-2α gene expression in 786-O cells were determined.

[0408] 2. Experimental Materials

[0409] Human clear cell kidney cells (786-O); RPMI-1640 medium (Thermofisher, C11875500BT) containing 10% fetal bovine serum (Thermofisher, 10099141C); 96-well transparent plate (Corning, polo-00895); dual reporter gene detection kit (Promeg, E1960); Opti-MEM reagent (Thermofisher, 31985070); Lipo-fectamine 2000 transfection reagent (Thermofisher, 11668019); recombinant plasmids: PGL4.42 HRE-luc2: 500 ng (MiaoLingBio, P3135), pGL4.75 Renilla: 50 ng (MiaoLingBio, P0211); inhibitor positive molecule: PT-2385 ((S) -3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile), agonist positive molecule: ZG2033 (N-(3,5-dimethoxyphenyl)benzo[d]isothiazol-3-amine).

[0410] 3. Experimental methods

[0411] Human clear cell kidney cell 786-O cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were prepared in 96-well plates one day before transfection, with a cell density of 7000 cells / well. After 24 hours of adherent growth, transient transfection was performed using the dual reporter gene co-transfection method. The transfection reagent was Lipo-fectamine2000, and the transfection reagent and plasmid were diluted with Opti-MEM reagent respectively. PGL4.42 HRE-luc2 was 500 ng per well; pGL4.75 Renilla was 50 ng per well. Different concentrations of compounds were added after 5 hours of co-transfection. After incubation for 24 hours, the Luciferase dual reporter gene detection kit was used to detect the luminescence signal. Each sample was replicated in 3 wells. Data processing: First, the ratio of Firefly luciferase / Renilla luciferase in each tube was calculated, and then the ratio of the control group was taken as 1 to obtain the relative luciferase activity of different treatment groups, that is, the regulatory activity of gene transcription in the treatment group. Graphpad was used to calculate the inhibitory or agonistic activity.

[0412] 4. Experimental results

[0413] The results of the Luciferase assay for these compounds are shown in Table 1. The compounds with inhibitory activity are shown in Table 1, where “A” refers to IC 50 Less than or equal to 1 μM, “B” refers to IC 50 Between 1 μM and 5 μM, “C” refers to IC 50 Greater than 5μM.

[0414] Table 2 lists compounds with agonist activity, where "A" refers to EC 50 Less than or equal to 1 μM, “B” refers to EC 50 Between 1 μM and 5 μM, “C” refers to EC 50 Greater than 5 μM.

[0415] The specific results are shown in Table 1 and Table 2:

[0416] Table 1

[0417]

[0418] The data in Table 1 show that the compounds of the present invention have good inhibitory activity on the transcription level of HIF-2α protein.

[0419] Table 2

[0420]

[0421] The data in Table 2 show that the compounds of the present invention have good agonist activity at the transcription level of HIF-2α protein.

[0422] Experimental Example 2

[0423] In vitro activity experiment: The present invention uses TR-FRET detection technology to verify the inhibitory or stimulating effect of the compound of the present invention on the binding of HIF-2α protein and ARNT protein.

[0424] 1. Purpose of the experiment

[0425] The inhibitory or agonistic effects of the compounds of the present invention on HIF-2α protein and ARNT protein were determined.

[0426] 2. Experimental materials, as shown in Table 3:

[0427] Table 3

[0428]

[0429] 3. Experimental methods

[0430] Purified protein complexes of FLAG-tagged ARNT (Sino-Biological; ME14OC2821) and His-tagged HIF-2α (Pharmaron Inc) in assay buffer were dispensed into 384-well plates and compounds were added. After MAb AntiFLAG M2-Eu cryptate (Cisbio, 61FG2KLA) and Streptavidin-D2 (Cisbio, 610SADAB) were added to each well at 5 nM, the plates were centrifuged at 1000 rpm for 1 min and the plates were equilibrated in the dark at room temperature for 12 h. The plates were read and the fluorescence ratio of 665 nm / 615 nm was obtained on an EnVision multi-label plate reader (PerkinElmer). The inhibition / agonism ratio was calculated by:

[0431]

[0432] : Average RR value of positive control.

[0433] : Average RR value of negative control.

[0434] 4. Experimental results

[0435] Table 4 lists compounds with inhibitory activity, where "A" means that when the compound concentration is 100 μM, the inhibitory effect is greater than or equal to 50%; "B" means when the compound concentration is 100 μM, the inhibitory effect is between 0% and 50%.

[0436] Table 5 lists compounds with agonist activity, where "A" means that when the compound concentration is 100 μM, the agonist effect is greater than or equal to 50%; "B" means that when the compound concentration is 100 μM, the agonist effect is between 20% and 50%. "C" means that when the compound concentration is 100 μM, the agonist effect is between 0 and 20%.

[0437] Table 4

[0438]

[0439] The data in Table 4 show that the compounds of the present invention have good inhibitory activity on the transcription level of HIF-2α protein.

[0440] Table 5

[0441]

[0442] The data in Table 5 show that the compounds of the present invention have good agonist activity at the transcription level of HIF-2α protein.

[0443] The present invention illustrates the compounds, compositions, preparation methods and applications of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned methods, that is, it does not mean that the present invention must rely on the above-mentioned detailed methods to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the products of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A compound, or a stereoisomer thereof, having one of the following structures, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutical composition comprising the compound of claim 1, optionally further comprising a pharmaceutically acceptable adjuvant.

3. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a drug for preventing, treating or alleviating HIF-2α-mediated related diseases.

4. The use according to claim 3, wherein HIF-2α-mediated diseases include cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic diseases.

5. The use according to claim 4, wherein The cancers are renal cancer, glioblastoma, breast cancer, lung cancer, prostate cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.

6. The use according to claim 4, wherein The inflammation is inflammation of the digestive system.

7. The use according to claim 6, characterized in that The inflammation of the digestive system is Crohn's disease or ulcerative colitis.

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