Bicyclic compounds and their applications

Abstract

The present invention relates to compounds according to formula (I). The present invention also provides compositions and formulations containing such compounds, and methods of using and making such compounds. TIFF2024540259000090.tif41118

Description

[Technical field]

[0001] The present invention relates to bicyclic compounds, compositions and formulations containing such compounds, and methods of using and making such compounds. [Background technology]

[0002] HIFs (Hypoxia inducible factors) are members of the transcription factor family, a pathway by which the body senses changes in oxygen. They are also called hypoxia inducible factors, and mediate the cellular hypoxic response by controlling more than 40 downstream hypoxia-adaptive genes. It mainly consists of two parts, HIFα (HIF-1α, HIF-2α, HIF-3α) and HIF-1β, where HIF-1β is always present in the cell nucleus, while HIFα is in the cytoplasm. Under oxygen-sufficient conditions, HIFα is eventually degraded by the proteasome through pathways such as hydroxylation by PHD prolyl hydroxylase and ubiquitination tagging by VHL (Von Hippel-Lindau Syndrome) ubiquitinase. However, when hypoxia or metabolic pathway is abnormal, HIFα cannot be degraded and accumulates in the nucleus, binds with HIF-1β to form heterodimers, activates hypoxia response elements (HREs) in downstream gene promoters, and further regulates related gene transcription to enable cells to survive under hypoxic conditions. These genes are related to tumor angiogenesis, cell proliferation, survival, metabolism, invasion and metastasis, drug resistance, inflammation and immunity, etc. Here, HIF-2α can mediate chronic hypoxia and be persistently activated under physiological hypoxic conditions, and plays a more important role in tumor development and progression.

[0003] Current research has shown that the mechanisms by which HIF-2α mediates tumor development and progression mainly include: 1. Under conditions such as hypoxia or VHL mutation, HIF-2α accumulates in the cell nucleus due to blocked metabolic pathways, and forms heterodimers with HIF-1β, which further activates hypoxia response elements (HREs), upregulates downstream cancer-related genes such as VEGFA, CXCR4, and Cyclin D1, and promotes tumor angiogenesis; 2. HIF-2α is also involved in the transmission of immunosuppressive signals by upregulating CD73 expression, so that targeting HIF-2α can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells, and NK cells.

[0004] Activation of the HIF-2α pathway is closely related to the development and progression of renal cell carcinoma, glioma, neuroblastoma, and pheochromocytoma. The VHL protein is an important component of E3 ubiquitin ligase and mediates protein degradation by the proteasome. The VHL gene has a high mutation rate of 57% or heterozygous deletion of 98% in renal cell carcinoma (RCC), which leads to pseudohypoxia and induces HIF-2α activation in the nucleus. Clear cell renal cell carcinoma (ccRCC) accounts for 70% to 75% of primary renal cell malignant tumors, and more than 90% of ccRCC patients have VHL protein deficiency. In the absence of angiogenesis, glioma induces local high expression of HIF-2α by destabilizing the blood supply and creating a hypoxic microenvironment, promoting tumor growth. In pheochromocytomas and paragangliomas, the AA mutation rate at positions 529-532 of HIF-2α is as high as 81%, which directly affects the hydroxylation degradation of HIF-2α and leads to persistent activation of HIF-2α.

[0005] Heterodimerization by HIF-2α activation and HIF-1β is an important factor in downstream activation, and the PAS domains of both are binding sites for heterodimerization, and Pe Based on this, Loton's development team developed the HIF-2α small molecule inhibitor PT2977, which exerts an antitumor effect by inhibiting the binding of HIF-2α to HIF-1β.

[0006] Based on the very important and close relationship of HIF-2α pathway with tumor development and migration, there is a great need to develop more and more efficient novel molecular entities. Summary of the Invention

[0007] The present invention first provides a compound of formula (I) or a stereoisomer, tautomer, pharma- ceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, [ka] Where: [ka] represents a single bond or a double bond, X1, X2, X3, and X4 are each independently selected from C or N, and at least one of X1, X2, X3, and X4 is N; W is selected from C, N, O or S; R1 is C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy groups, C6-C 10 Aryl groups, 5-18 membered heteroaryl groups, C5-C 10 a cycloalkyl group, and a 5- to 10-membered heterocyclyl group, wherein the 5- to 18-membered heteroaryl group and the 5- to 10-membered heterocyclyl group each contain 1, 2 or 3 heteroatoms independently selected from N, O and S; and the C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10Alkoxy groups, C6-C 10 Aryl groups, 5-18 membered heteroaryl groups, C5-C 10 The cycloalkyl group and the 5-10 membered heterocyclyl group are optionally selected from H, halogen, -OH, -CN, oxo group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C3-C5 cycloalkyl group, C2-C6 alkynyl group, C1-C6 halogenated alkyl group, cyano substituted C1-C6 alkyl group, cyano substituted C1-C6 halogenated alkyl group, C1-C6 halogenated alkoxy group, -C1-C6 alkylene-OR c , -C1-C6 alkylene-C=OR c , -NO2, -OR c , -SR c , -NR a R b , -C(=O)R c , -C(=O)OR c , -C(=O)NR a R b , -NC(=O)R c , -S(=O)R c , -S(=O)2R c , -S(=O)2NR a R b , -S(=O)(=NR a )R b , -P(=O)R a R b or -P(=S)R a R b may be substituted with one or more substituents selected from R3 is H, deuterium, halogen, -NO2, -CN, -OH, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C5 halogenated alkyl groups, C1-C 10 Alkoxy group, -OC(=O)-C 1-3 Alkyl group, -C(=O)-OC 1-3 Alkyl group or C2-C 10 alkynyl groups, 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C5 halogenated alkyl groups, C1-C 10Alkoxy group, -OC(=O)-C 1-3 Alkyl group, -C(=O)-OC 1-3 Alkyl groups, C2-C 10 The alkynyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, a C1-C5 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, or a C1-C5 halogenated alkyl group;

[0008] R4 and R5 each independently represent H, a halogen, -NO2, or -NR a R b , -OH, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 halogenated alkyl group, C2-C 10 Alkenyl groups, C2-C 10 alkynyl group, C3-C5 cycloalkyl group and 3-6 membered heterocyclyl group, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 halogenated alkyl group, C2-C 10 Alkenyl groups, C2-C 10 The alkynyl group, the C3-C5 cycloalkyl group and the 3-6 membered heterocyclyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, an oxo group, a C1-C5 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group or a C1-C5 halogenated alkyl group; or R4 and R5 together form an oxo group; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl group; R6 is H, -CN, halogen, -NO2, -OH, -NO2, -NR a R b , oxo group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 halogenated alkyl group, C2-C 10 Alkenyl groups, C2-C 10 alkynyl group, C3-C5 cycloalkyl group and 3-6 membered heterocyclyl group, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 halogenated alkyl group, C2-C 10 Alkenyl groups, C2-C 10The alkynyl group, the C3-C5 cycloalkyl group and the 3- to 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, an oxo group, a C1-C5 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group or a C1-C5 halogenated alkyl group, or two R6 together with the C atom to which they are bonded form a substituted or unsubstituted C3-C5 cycloalkyl group or a 3- to 5-membered heterocyclyl group; or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl group; R f is absent, H, -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C3-C 10 Cycloalkyl group, oxo group, -NR a R b wherein C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups and C3-C 10 The cycloalkyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, a C1-C5 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, or a C1-C5 halogenated alkyl group; R j is -C1-C6 alkylene-C(=O)R c , -C1-C6 alkylene-C(=O)OR c , -C2F5, -C(=O)R c , -C(=O)OR c , -SR c , -S(=O)R c , -S(=O)2R c or -S(=O)(=NR a )R cwherein the C1-C6 alkylene group is optionally substituted with one or more substituents selected from H, halogen, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 halogenated alkyl, C1-C4 alkoxy and C1-C4 halogenated alkoxy; R a and R b are independently H, CN, or C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Alkoxy groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C 6-C 10 an aryl group or a 5- to 10-membered heteroaryl group; R c is C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C6 cycloalkyl groups and -NR a R b wherein C1-C 10 Alkyl groups, C1-C 10 The alkoxy group and the C3-C6 cycloalkyl group may be optionally substituted with one or more substituents selected from H, halogen, CN, -NH2, an oxo group, a C1-C4 halogenated alkyl group, a C1-C4 halogenated alkoxy group, and a C3-C6 cycloalkyl group;

[0009] n is 0 or 1, m is 0, 1, 2, 3 or 4; The condition is that the compound is 3-fluoro-5-(4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 3-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfoxy)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxy)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-Fluoro-5-(5-fluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (193), (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile, and Not 1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol.

[0010] In some embodiments, the compound has formula (II-1) or formula (II-2): [ka] As shown in the figure.

[0011] In some embodiments, R3 is H, deuterium, C1-C 10 Alkyl groups, C2-C 10 alkenyl groups, 10 Alkyl groups and C2-C 10 The alkenyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, amino groups, and C1-C5 halogenated alkyl groups.

[0012] In some embodiments, R3 is selected from H, deuterium, a C1-C3 alkyl group, and a C2-C5 alkenyl group, and the C1-C3 alkyl group and the C2-C5 alkenyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, and a C1-C5 halogenated alkyl group.

[0013] In some embodiments, R3 is selected from H, deuterium, or a C1-C3 alkyl group, which may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, and a C1-C5 halogenated alkyl group.

[0014] In some embodiments, R3 is selected from H, deuterium, or a C1-C3 alkyl group.

[0015] In some embodiments, R3 is H or deuterium.

[0016] In some embodiments, R3 is H.

[0017] In some embodiments, R4 and R5 are each independently selected from H, a halogen, or a C1-C6 alkyl group, and the C1-C6 alkyl group may be optionally substituted with one or more substituents selected from H, a halogen, -CN, -OH, an amino group, or an oxo group.

[0018] In some embodiments, R4 and R5 are each independently selected from H, halogen, or a C1-C6 alkyl group.

[0019] In some embodiments, R4 and R5 are each independently selected from H or halogen.

[0020] In some embodiments, R4 and R5 are each independently selected from H or F.

[0021] In some embodiments, R f is selected from H, -CN, -NH2, halogen, -NO2, a C1-C3 alkyl group, a cyclopropyl group, or a C1-C3 halogenated alkyl group, and the C1-C3 alkyl group, cyclopropyl group, or a C1-C3 halogenated alkyl group may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an amino group, a C1-C3 alkyl group, a C2-C4 alkenyl group, and a C1-C3 halogenated alkyl group.

[0022] In some embodiments, R f is selected from H, -CN, halogen, a C1-C3 alkyl group, or a C1-C3 halogenated alkyl group.

[0023] In some embodiments, R f is H, —CN or halogen.

[0024] In some embodiments, R f is H or a halogen.

[0025] In some embodiments, R f is H, -CN, -F, -Cl, -Br or -CF3.

[0026] In some embodiments, R f is H.

[0027] In some embodiments, W is C or O.

[0028] In some embodiments, said W is C.

[0029] In some embodiments, R6 is H, -CN, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 halogenated alkyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, or C1-C6 halogenated alkyl group may optionally be substituted with one or more substituents selected from H, halogen, -CN, -OH, an oxo group, and an amino group.

[0030] In some embodiments, R6 is H, halogen, or a C1-C6 alkyl group, which may be optionally substituted with one or more substituents selected from H, halogen, -CN, -OH, an oxo group, and an amino group.

[0031] In some embodiments, R6 is H, halogen, or a C1-C6 alkyl group.

[0032] In some embodiments, R6 is H, halogen, or a C1-C3 alkyl group.

[0033] In some embodiments, R6 is H or halogen.

[0034] In some embodiments, R6 is H, F, Cl, or Br.

[0035] In some embodiments, R6 is H or F.

[0036] In some embodiments, R is C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10 is a cycloalkyl group or a 5- to 10-membered heterocyclyl group, The 5- to 10-membered heteroaryl group and the 5- to 10-membered heterocyclyl group each contain 1, 2 or 3 heteroatoms independently selected from N, O and S, and the C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10 The cycloalkyl group or the 5- to 10-membered heterocyclyl group may optionally be selected from the group consisting of halogen, -OH, -CN, an oxo group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkyl group, a cyano-substituted C1-C6 alkyl group, a cyano-substituted C1-C6 halogenated alkyl group, -C1-C6 alkylene-OR c , -C1-C6 alkylene-C=OR c , -NO2, C(=O)OR c or -S(=O)2R c may be substituted with one or more substituents selected from:

[0037] In some embodiments, R is C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10 a cycloalkyl group or a 5-10 membered heterocyclyl group, the 5-10 membered heteroaryl group and the 5-10 membered heterocyclyl group containing 1 or 2 N heteroatoms, the C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10The cycloalkyl group or the 5- to 10-membered heterocyclyl group may be optionally substituted with one or more substituents selected from a halogen, a hydroxy group, a cyano group, an amino group, a C1-C6 alkyl group, a C3-C5 cycloalkyl group, a C1-C6 halogenated alkyl group, a cyano-substituted C1-C6 alkyl group, a cyano-substituted C1-C6 halogenated alkyl group, or a C1-C6 halogenated alkoxy group.

[0038] In some embodiments, R is C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10 a cycloalkyl group or a 5-10 membered heterocyclyl group, the 5-10 membered heteroaryl group and the 5-10 membered heterocyclyl group containing 1 or 2 N heteroatoms, the C6-C 10 Aryl groups, 5-10 membered heteroaryl groups, C5-C 10 The cycloalkyl group or the 5- to 10-membered heterocyclyl group may be optionally substituted with one or more substituents selected from halogen, cyano group, cyano-substituted C1-C6 halogenated alkyl group, cyano-substituted C1-C6 alkyl group, or C1-C6 halogenated alkyl group.

[0039] In some embodiments, R1 is a phenyl group, a pyridyl group, a naphthyl group, a 10-membered heteroaryl group, C 8- C 10 A cycloalkyl group or an 8-10 membered heterocyclyl group, the 10 membered heteroaryl group and the 8-10 membered heterocyclyl group containing 1 or 2 N heteroatoms, the phenyl group, the pyridyl group, the naphthyl group, the 10 membered heteroaryl group, the C8-C 10 The cycloalkyl group or the 8-10 membered heterocyclyl group may be optionally substituted with one or more substituents selected from halogen, cyano group or C1-C6 halogenated alkyl group.

[0040] In some embodiments, R1 is a phenyl group, which may be optionally substituted with one or more substituents selected from halogen, -CN, or a C1-C6 halogenated alkyl group.

[0041] In some embodiments, R1 is a phenyl group, which may be optionally substituted with one or more substituents selected from halogen, -CN, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.

[0042] In some embodiments, R j is -C1-C6 alkylene-C(=O)R c , -C1-C6 halogenated alkylene -C(=O)R c , -C1-C6 halogenated alkylene -C(=O)OR c , -C2F5, -C1-C6 cyano-substituted alkylene-C(=O)R c , -C(=O)R c , -C(=O)OR c , -SR c , -S(=O)R c , -S(=O)2R c or -S(=O)(=NR a )R c is selected from.

[0043] In some embodiments, R j is -C2F5, -C1-C6 halogenated alkylene -C(=O)R c , -C1-C6 halogenated alkylene -C(=O)OR c , -C(=O)OR c , -C(=O)R c , -SR c , -S(=O)2R c or -S(=O)(=NR a )R c is selected from.

[0044] In some embodiments, R j -SR c , -S(=O)2R c or -S(=O)(=NR a )R c It is.

[0045] In some embodiments, R c is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and -NH2, and the C1-C6 alkyl group, the C1-C6 alkoxy group, and the C3-C6 cycloalkyl group may be optionally substituted with one or more substituents selected from H, halogen, CN, -NH2, a C1-C4 halogenated alkyl group, and a C3-C6 cycloalkyl group.

[0046] In some embodiments, R c is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, and -NH2, and the C1-C6 alkyl group and the C1-C6 alkoxy group may be optionally substituted with one or more substituents selected from H, halogen, CN, -NH2, and a C1-C4 halogenated alkyl group.

[0047] In some embodiments, R c is selected from a C1-C6 alkyl group, said C1-C6 alkyl group being optionally substituted with one or more substituents selected from H, halogen, and CN.

[0048] In some embodiments, R a is selected from H, CN, or a C1-C4 alkyl group.

[0049] In some embodiments, R b is selected from H, CN, or a C1-C4 alkyl group.

[0050] In some embodiments, R j teeth, [ka] is selected from.

[0051] In some embodiments, R j teeth, [ka] is selected from.

[0052] In some embodiments, the compound has formula (III-1), formula (III-2), formula (III-3), or formula (III-4): [ka] As shown in the figure.

[0053] Here, R1, R3, R4, R5, R6, R f , R j , m, n, and W are as described in the above embodiment.

[0054] In some embodiments, the compound is as shown in formula (VI-1): [ka] Here, R1, R3, R4, R5, R6, R f , R c , X1, X2, X3, X4, m, n, and W are as described in the above embodiment.

[0055] In some embodiments, the compound is as shown in formula (VI-2): [ka] Here, R1, R3, R4, R5, R6, R f , R a , R c , X1, X2, X3, X4, m, n, and W are as described in the above embodiment.

[0056] In some embodiments, the compound has formula (VII-1), formula (VII-2), formula (VII-3) or formula (VII-4): [ka] As shown in Here, R1, R3, R4, R5, R6, R f , R j , m, and n are as described in the above embodiment.

[0057] In some embodiments, the compound has formula (VIII-1), formula (VIII-2), formula (VIII-3), or formula (VIII-4): [ka] As shown in Here, R1, R3, R4, R5, R6, R f , R c , R a , m, and n are as described in the above embodiment.

[0058] In some embodiments, the compound has formula (VIII-5), formula (VIII-6), formula (VIII-7), or formula (VIII-8): [ka] As shown in Here, R1, R3, R4, R5, R6, R f , R c , m, and n are as described in the above embodiment.

[0059] In some embodiments, the compound has formula (IX-1) or formula (IX-2): [ka] As shown in Here, R1, R4, R5, R6, R f , R c , R a , m are as described in the above embodiment.

[0060] In some embodiments, the compound has formula (X-1), formula (X-2), formula (X-3), formula (X-4), formula (X-5), formula (X-6), formula (X-7), or formula (X-8): [ka] As shown in Here, R1, R6, R j , m are as described in the above embodiment.

[0061] In some embodiments, the compound has formula (XI-1) or formula (XI-2): [ka] As shown in Here, R4, R5, R6, R f , R c , R a , m is as described in the above embodiment, R x and R z are each independently a halogen, -OH, -CN, an oxo group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkyl group, a cyano-substituted C1-C6 alkyl group, a cyano-substituted C1-C6 halogenated alkyl group, -C1-C6 alkylene-OR c , -C1-C6 alkylene-C=OR c , -NO2, -C(=O)OR c and -S(=O)2R c is arbitrarily selected from.

[0062] The present invention further provides a compound, or a pharma- ceutically acceptable salt thereof, comprising: 1) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzonitrile, 2) 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 4) (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 5) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 6) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 7) (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 8) (S)-3-((R)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 9) 5-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 10) (S)-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 11) (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 12) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 13) (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile, 14) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 15) 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide, 16) (S)-3-(ethylsulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol,

[0063] 17) 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 18) N-(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide, 19) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl) -5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile, 20) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 21) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 22) (S)-5-(3-((difluoromethyl)sulfonyl)-2,5,5-trifluoroether-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 23) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 24) 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 25) 1-(3-chloro-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 26) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 27) (S)-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 28) (S)-2-Chloro-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 29) (S)-4-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 30) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 31) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 32) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol,

[0064] 33) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 34) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 35) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 36) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 37) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 38) (S)-4-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 39) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 40) (S)-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 41) 4-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 42) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 43) (S)-2-(difluoromethyl)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 44) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 45) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 46) (S)-4-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 47) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile, 48) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroethyl acetate, 49) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetonitrile,

[0065] 50) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide, 51) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(thiazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 52) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indole Ru-4-ol, 53) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(oxazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 54) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2,2-difluoroacetonitrile, 55) 2-(((S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile, 56) (S)-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide methyl, 57) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl) propionitrile, 58) (S)-1-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)cyclopropane-1-nitrile, 59) N-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide, 60) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carboxylate ethyl. 61) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 62) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-formamide, 63) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 64) (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 65) (R)-2-(difluoromethyl)-4-(4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile,

[0066] 66) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-3-fluorobenzonitrile, 67) (4S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 68) (S)-1-((R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 69) (S)-1-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 70) (S)-1-(2,4-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 71) (S)-2-((5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl)-5-fluorobenzonitrile, 72) (S)-1-(2,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 73) N-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxy)(trifluoromethyl)-16-sulfino)cyanamide, 74) N-((difluoromethyl)((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxo)-16-sulfino)cyanamide, 75) (S)-2-(5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorophenyl)acetonitrile, 76) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(fluoromethyl)benzonitrile, 77) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 78) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 79) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 80) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 81) (S)-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-5,6-dihydrocyclopentadiene[b]pyrrol-1(4H)-yl)-yl 2-fluorobenzonitrile, 82) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindol-8-ol,

[0067] 83) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, 84) (7R,8S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7-fluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindolizin-8-ol, 85) 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro perfluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,7-tetrahydropyran[3,4-b]pyrrol-4-ol, 86) 2-(difluoromethyl)-4-((4S,5R)-3-((difluoromethyl)sulfonyl)-5-fluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 87) 2-(difluoromethyl)-4-((4S,5R)-5-fluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 88) (S)-5,5-difluoro-1-(imidazo[1,2-a]pyridin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 89) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 90) (S)-8-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluoro-1-naphthonitrile, 91) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 92) (S)-5,5-Difluoro-1-(quinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 93) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 94) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 95) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 96) 1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 97) (4S)-1-(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 98) (4S)-5,5-Difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol,

[0068] 99) (4S)-5,5-Difluoro-3-(methylsulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 100) 5,5-difluoro-3-((fluoromethyl)sulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 101) (4S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrafluoroethylene Lahydro-1H-indol-4-ol, 102) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 103) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-((trifluoromethyl)thio)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 104) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 105) 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,7-dihydropyran[3,4-b]pyrrol-1(5H)-yl)benzonitrile, 106) 2-Fluoro-5-(2,5,5-trifluoro-4-hydroxy-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, or 107) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile.

[0069] The present invention further provides methods for preparing the compounds, and any of the compounds according to formula (I) of the present invention or the compounds described in the specific examples can be prepared by organic synthesis techniques known to those skilled in the art or known to those skilled in the art based on the contents described herein, using commercially available starting materials, compounds known in the literature, or intermediates that are readily prepared, and can be obtained using preparation methods similar to those in the specific examples.

[0070] Specifically, in another embodiment, the present invention relates to a method for producing a compound represented by general formula (IX-1), comprising reacting a compound represented by formula (A-1) with a reducing agent, [ka] Here, R1, R4, R5, R6, R f , R c , R a , m are as defined in the previous embodiment.

[0071] In another embodiment, the present invention relates to a method for preparing a compound represented by general formula (IX-2), comprising reacting a compound represented by formula (A-2) with a reducing agent, [ka] Here, R1, R4, R5, R6, R f , R c , R a , m is as defined in the previous embodiment, and further, R1 is [ka] and R x , R z is as defined in the previous embodiment.

[0072] Here, the reducing agent may be a common reducing agent such as sodium borohydride, lithium borohydride, etc., and the corresponding chiral monomers at the hydroxyl group position of the skeleton structure of the compound of formula (IX-1) and the compound of formula (IX-2) can be obtained by chiral reduction (e.g., Noyori asymmetric reduction, CBS asymmetric reduction, etc.) of the compound of formula (A-1) and the compound of formula (A-2).

[0073] In some embodiments, the reducing agent used in the chiral reduction is [(R,R)-Ts-DPEN]RuCl(p-cymene)].

[0074] In some alternative embodiments, the compound of formula (A-1) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , R a , m is as defined in the previous embodiment; [ka]

[0075] The compound represented by formula (B-1) is a A compound represented by formula (B-2) can be produced under conditions of an oxidizing agent (e.g., iodobenzene diacetate) together with an oxidizing agent (e.g., cyanamide, etc.), and the compound represented by formula (B-2) can be oxidized to produce a compound represented by formula (A-1).

[0076] In some other embodiments, the compound of formula (A-1) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , Ra , m is as defined in the previous embodiment; [ka]

[0077] The compound represented by formula (B-1) can be produced by oxidation reactions (e.g., metachloroperbenzoic acid, peroxy The compound represented by formula (B-3) is obtained by reacting the compound represented by formula (B-3) with an imidization reagent (e.g., ammonium carbamate, trifluoroacetamide, etc.) in the presence of an oxidizing agent (e.g., iodobenzene diacetate) to produce a compound represented by formula (B-4), and the compound represented by formula (B-4) is introduced with Ra by alkylation (e.g., methyl iodide, ethyl iodide, etc.) or introduced with Ra by coupling reaction (e.g., coupling with cuprous cyanide) to obtain a compound represented by formula (A-1). In some other embodiments, the compound represented by formula (A-2) can be prepared by the following method, [ka] Here, R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, and further, R1 is [ka] and R x , R z is as defined in the previous embodiment.

[0078] The compound represented by formula (B-1) can be subjected to an oxidation reaction to obtain the compound represented by formula (A-2), where the oxidizing agent includes metachloroperbenzoic acid, potassium peroxymonosulfonate, ruthenium trichloride / sodium periodate system, ruthenium trichloride / sodium hypochlorite system, etc.

[0079] In some other embodiments, the compound of formula (A-2) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, and X is a halogen; [ka]

[0080] The compound represented by formula (C-1) can be prepared by coupling with a corresponding sulfinic acid salt (e.g., methanesulfinic acid sodium salt, etc.) in the presence of a metal catalyst (e.g., cuprous salt) to obtain the compound represented by formula (A-2).

[0081] In some other embodiments, the compound of formula (A-2) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, and X is a halogen; [ka]

[0082] The compound represented by formula (C-1) can be converted into a compound represented by formula (D-1) by introducing a sulfinic acid group by a coupling reaction, or can be converted into a compound represented by formula (D-1) by converting its halogen atom X into a negative ion and reacting it with a sulfur dioxide equivalent that generates sulfur dioxide in situ (e.g., potassium metabisulfite, 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinic acid, etc.) to introduce a sulfinic acid group, and the compound represented by formula (D-1) can be produced by a nucleophilic reaction with an electrophile (e.g., Togni's reagent, methyl iodide, methyl trifluoroiodide, etc.), where M + is any monovalent positive ion that can be salified, e.g., Na + , K + , MgBr + And so on.

[0083] In some alternative embodiments, the compound of formula (B-1) can be prepared by the following method: [ka] Here, R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, X is halogen, and R 101 is C 1-10 is an alkyl group, and R1 is [ka] and R x , R z is as defined in the previous embodiment.

[0084] The compound represented by formula (C-1) can be subjected to a coupling reaction with an alkyl mercaptopropionate (e.g., methyl mercaptopropionate, ethyl mercaptopropionate, tert-butyl mercaptopropionate, etc.) to obtain a compound represented by formula (C-2). The compound represented by formula (C-2) can be subjected to an alkaline condition (potassium carbonate, cesium carbonate, potassium phosphate, etc.). The corresponding Rc group is introduced to the sulfur atom by a corresponding alkylating or electrophilic agent (e.g., methyl iodide, methyl fluoroiodide, methyl trifluoroiodide, bromoacetonitrile, bromofluoromethyl diethyl phosphate, etc.) to produce the compound represented by formula (B-1).

[0085] In some other embodiments, the compound of formula (B-1) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, and X is a halogen; [ka]

[0086] Nucleophilic Sulfur Reagents - The compound represented by formula (B-1) can be obtained by coupling reaction of SRc (eg, silver triflate, copper triflate, etc.) with the compound represented by formula (C-1).

[0087] In some other embodiments, the compound of formula (C-1) can be prepared by the following method, wherein R1, R4, R5, R6, R f , m is as defined in the previous embodiment, X is a halogen, X1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 an alkyl group or two R 102 together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C 1-3 may be substituted with an alkyl group, [ka]

[0088] The compound represented by formula (F-0) is commercially available (e.g., 1,5,6,7-tetrahydro-4H-indol-4-one), and the compound represented by formula (F-1) is obtained by carrying out an N-atom protection reaction on the compound represented by formula (F-0) under alkaline conditions. The compound represented by formula (F-1) is obtained by introducing a halogen atom to the 3-position of pyrrole using an electrophilic halogenation reagent (e.g., NIS) to obtain a compound represented by formula (F-2), and the compound represented by formula (F-2) is obtained by removing the proton at the ortho-position of the carbonyl group under alkaline conditions (e.g., LiHDMS, LDA, etc.), reacting with an electrophilic agent (e.g., NFSI, Selectfluor, etc.) to introduce R4 and R5 groups to obtain a compound represented by formula (F-4), which is deprotected to obtain a compound represented by formula (F-5), and then a coupling reaction is carried out to obtain a compound represented by formula (C-1).

[0089] First, under alkaline conditions, R4 and R5 groups can be introduced at the ortho-position of the carbonyl group of compound of formula (F-1) using an electrophilic agent to obtain compound of formula (F-3), and then a halogen atom can be introduced at the 3-position of the pyrrole of compound of formula (F-3) using a corresponding electrophilic halogenating reagent to obtain compound of formula (F-4).

[0090] In some other embodiments, the compound of formula (B-1) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, X1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 an alkyl group or two R 102 together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C 1-3 may be substituted with an alkyl group, [ka]

[0091] The compound represented by formula (F-1) is reacted with an electrophilic agent (e.g., a precipitating agent, N-(trifluoromethylthio)phthalimide, etc.) to carry out electrophilic substitution at the 3-position of pyrrole to produce the compound represented by formula (E-1), and then under alkaline conditions, the ortho-position of the carbonyl group is deprotonated to introduce R4 and R5 groups to obtain the compound represented by formula (E-3), the compound represented by formula (E-3) is deprotected to obtain the compound represented by formula (E-4), and then a coupling reaction is carried out to produce the compound represented by formula (B-1).

[0092] First, under alkaline conditions, compound (F-1) can be deprotonated at the ortho position of the carbonyl group to introduce R4 and R5 groups to obtain compound (F-3), and then compound (F-3) can be subjected to electrophilic substitution under alkaline conditions to obtain compound (E-3).

[0093] In some other embodiments, the compound of formula (A-2) can be prepared by the following method, wherein R1, R4, R5, R6, R f , R c , m is as defined in the previous embodiment, X1 is -TIPS, -Trt or -TBDPS, R 102 is H, C 1-3 an alkyl group or two R 102 together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C 1-3 may be substituted with an alkyl group, [ka]

[0094] The compound represented by formula (F-1) is subjected to electrophilic substitution with a sulfonylating agent (e.g., trifluoromethanesulfonic anhydride, etc.) to introduce a sulfonyl group to obtain a compound represented by formula (G-2), and then, under alkaline conditions, deprotonation is performed at the ortho position of the carbonyl group to introduce R4 and R5 groups to obtain a compound represented by formula (G-4), which is deprotected to obtain a compound represented by formula (G-5), and then a coupling reaction is performed to obtain a compound represented by formula (A-2).

[0095] First, under alkaline conditions, the compound represented by formula (F-1) is protonated at the ortho position of the carbonyl group to introduce R4 and R5 groups to obtain a compound represented by formula (F-3), and then, under alkaline conditions, the compound represented by formula (F-3) is subjected to electrophilic substitution with a sulfonylating reagent (e.g., trifluoromethanesulfonic anhydride, etc.) to introduce a sulfonyl to obtain a compound represented by formula (G-4).

[0096] In some other embodiments, the compound of formula (G-5) can be prepared by the following method, wherein R4, R5, R6, R f , R cm is as defined in the previous embodiment, X is a halogen, and X2 is -Boc or a phenylsulfonyl group; [ka]

[0097] The compound represented by formula (H-1) is prepared by protecting the N atom with the compound represented by formula (F-0); and The compound of formula (H-1) can be obtained by carrying out a halogenation reaction, and the compound of formula (H-2) can be obtained by carrying out a coupling reaction with a nucleophilic sulfur reagent. - The compound represented by formula (H-2) is obtained by reacting with SRc (e.g., silver triflate, copper triflate, etc.), and the compound represented by formula (H-2) is subjected to an oxidation reaction to obtain a compound represented by formula (H-3), and then a deprotection reaction is performed to finally obtain a compound represented by formula (G-5).

[0098] In another aspect of the present invention, there is further provided an intermediate for preparing the compounds of formula (IX-1) and formula (IX-2), which comprises [ka] The structure is selected from Here, R1, R4, R5, R6, R f , R c , R a , m is as described in the above embodiment. X is a halogen, X1 is selected from -TIPS, -Trt or -TBDPS, X2 is -Boc or a phenylsulfonyl group, R 101 is C 1-3 It is an alkyl group.

[0099] Furthermore, the present invention further provides intermediates for preparing the compounds represented by formula (XI-1) and formula (XI-2), which are [ka] The structure is selected from Here, R1, R4, R5, R6, R f , R c , R a , R x , R z , m is the above embodiment As described above, X is a halogen, X1 is selected from TIPS-, Trt-, X2 is -Boc, and R 101 is C 1-10 It is an alkyl group.

[0100] The present invention further provides a pharmaceutical composition, which comprises a therapeutically effective amount of at least one of the compounds described above and a pharma- ceutically acceptable excipient, such as hydroxypropylmethylcellulose. In some compositions, the weight ratio of the compound to the excipient is about 0.001-10.

[0101] Furthermore, the present invention further provides a method of treating a subject suffering from a HIF-2α mediated disease or condition, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the disease or condition is selected from VHL syndrome, an autoimmune disease, cancer, an inflammatory disease, a neurodegenerative disease, a cardiovascular disorder, a renal disorder, a viral infection, and obesity.

[0103] In some embodiments, the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), and acute rejection of transplanted organs.

[0104] In some aspects, the disease or condition is cancer, and the cancer is selected from malignant solid tumors and hematological tumors.

[0105] In some aspects, the cancer includes, but is not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, uterine cancer, cervical cancer, endometrial cancer, lymphoma, esophageal cancer, colon cancer, rectal cancer, thyroid cancer, prostate cancer, sarcoma, leukemia, bladder cancer, kidney cancer, glioma, cystadenoma, squamous cell carcinoma, pheochromocytoma, lung cancer, pancreatic cancer, liver cancer, renal cancer, breast cancer, meningioma, neurocytoma, paraganglioma, blastoma, endocrine tumors, meningioma, and meloblastoma.

[0106] In some embodiments, the disease or condition is VHL syndrome.

[0107] In some aspects, the disease or condition is renal cancer, further, the disease is renal cell carcinoma, and the disease is clear cell renal carcinoma.

[0108] In some embodiments, the subject is a human.

[0109] In some embodiments, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one embodiment, the compound is administered orally.

[0110] The invention further provides the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a HIF-2α mediated disease or condition.

[0111] The present invention further provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for treating a subject suffering from a HIF-2α mediated disease or condition.

[0112] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes all combinations of the preferred aspects of the invention referred to herein. It should be understood that the subject matter disclosed in the description of the invention is not intended to be limiting unless otherwise specified by the present invention. or the entire scope of any other embodiment, and any and all embodiments of the present invention may be used in combination with any other embodiment or embodiments to describe other embodiments. It should be further understood that each element of an embodiment is its own independent embodiment. However, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe another embodiment.

[0113] In the present invention, unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.

[0114] In the present invention, unless otherwise stated, the term "alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, "C1-C6" in C1-C6 alkyl group refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched form.

[0115] The term "alkoxy group" refers to oxygen ethers of straight, branched, or cyclic alkyl groups as defined above.

[0116] The term "alkylene group" refers to a divalent alkyl linking group. An alkylene group formally refers to an alkane in which two C-H bonds are replaced by points of attachment of the alkylene group to the rest of the compound. Similarly, the "C-C" in a C-C alkylene group refers to an alkylene group containing 1, 2, 3, or 4 carbon atoms.

[0117] The term "halogenated alkyl group" refers to an alkyl group in which one or more H has been replaced with a halogen atom. The term "halogenated alkoxy group" refers to the group -O-halogenated alkyl group.

[0118] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when connected to C, and a sulfoxide or sulfone group or N-oxide group when connected to a heteroatom.

[0119] In the present invention, unless otherwise stated, the terms "aromatic ring", "aromatic ring" or "heteroaromatic ring" refer to a carbocyclic or heterocyclic ring that is a polyunsaturated ring having aromatic character (having (4n+2) delocalized π electrons, where n is an integer).

[0120] An "aryl group" is a substituted or unsubstituted stable aromatic hydrocarbon group having 6 to 10 ring-forming carbon atoms, which may contain one aromatic ring or multiple aromatic rings (e.g., fused bicyclic rings). The aromatic rings do not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.

[0121] The term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member, said heteroatom being selected from N, O and / or S. The "5-18 members" in a 5-18 membered heteroaryl group refers to a heteroaryl group containing 5-18 carbon atoms or consisting of N, O or S ring-forming atoms. Examples of such heteroaryl groups are pyridyl, pyrimidinyl, pyrrole, and the like. These include, but are not limited to, imidazolyl groups, thiazole groups, thiophenyl groups, benzimidazole groups, benzothiophenyl groups, benzofuranyl groups, and the like.

[0122] The term "cycloalkyl group" refers to a ring system having at least one cyclized alkyl group. 10Cycloalkyl groups: C3-C 10 The term "cycloalkyl" refers to cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming atoms. Cycloalkyl groups can include single and multiple rings (e.g., having 2, 3, or 4 fused, spiro, parallel, etc. rings). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like. In some embodiments, cycloalkyl groups further include moieties having one or more aromatic rings fused to the cyclized alkyl group, such as, for example, benzo or thiophenyl derivatives of cyclohexane.

[0123] The term "cycloalkenyl group" refers to a ring system having at least one cyclized alkenyl group, said cycloalkenyl group having one or more carbon-carbon double bonds. 10 Cycloalkenyl group: C3-C 10 The term "cycloalkenyl" refers to a cycloalkenyl group that can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming atoms. Cycloalkenyl groups can include single and multiple rings (e.g., having 2, 3, or 4 fused, spiro, bridged, etc. rings). In some embodiments, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like. In some embodiments, cycloalkenyl groups further include moieties that have one or more aromatic rings fused to the cyclized alkenyl group, such as benzo or thiophenyl derivatives of a cyclohexene ring.

[0124] The term "heterocyclyl group" refers to a ring system having at least one cyclized alkyl or alkenyl group containing a heterocyclic atom, the heteroatom being selected from N, O and / or S. The heterocyclyl group may contain a single ring or multiple rings (e.g., having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group may be linked to other moieties of the compound through a ring-forming carbon atom or a ring-forming heteroatom. The definition of the heterocyclyl group further includes moieties having one or more aromatic rings fused to the cyclized alkyl or alkenyl group ring, for example, benzo or thiophenyl derivatives such as piperidine, morpholine, etc. In some embodiments, heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, etc.

[0125] In the present invention, the term "composition" includes a product containing a specific number of specific ingredients, and is intended to include a product obtained directly or indirectly from a specific number of specific ingredients. Therefore, the present invention also includes a pharmaceutical composition containing the compound of the present invention as an active ingredient and a method for producing the compound. In addition, the crystalline form of some compounds may exist in the form of crystalline polymorphs, which are also included in the present invention. In addition, some compounds and water (e.g., hydrates) or common organic solvents form solvates, and these solvates are also included in the present invention.

[0126] "Compounds according to the invention" include compounds of formula (I) and all pharma- ceutically acceptable forms thereof, including salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, isotopically labeled compounds, tautomers, drug precursors, or any mixture of all of the above forms.

[0127] The "enantiomers" are a pair of stereoisomers that are non-superimposable and mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture. When specifying the stereochemistry of the compounds of the present invention, the common RS system is used (e.g., (1S,2S) specifies a single stereoisomer with two chiral centers and known relative and absolute configuration). Optically active (R)- and (S)-isomers can be prepared by synthesis from optically active starting materials or by using chiral reagents, or resolved using conventional techniques (e.g., separation by chiral SFC or HPLC chromatography columns).

[0128] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. When compounds are pure enantiomers, the stereochemistry at each chiral carbon can be specified by R or S.

[0129] Resolved compounds of unknown absolute configuration may be named (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line, or resolved compounds may be defined by the corresponding retention times of the corresponding enantiomers / diastereomers on chiral HPLC.

[0130] Those skilled in the art will recognize that the compounds of the present invention may contain one or more chiral centers, which may produce diastereomers and optical isomers. The compounds may exist in different isomeric forms, since the stereochemistry at certain positions in formula (I) above is not clearly defined. Unless otherwise stated, the present invention includes all possible stereoisomers of the compounds shown in formula (I) and their pharma- ceutically acceptable salts, including racemic mixtures, optically pure forms, and mixtures of isomers in any ratio. In addition, mixtures of stereoisomers and separated specific stereoisomers are also included in the present invention. In the synthetic process for producing such compounds, or in the process using racemization or epimerization methods well known to those skilled in the art, the product produced may be a mixture of stereoisomers.

[0131] Drug precursors (prodrugs) of the compounds of the present invention are included in the scope of protection of the present invention. Generally, the drug precursor refers to a functional derivative that can be easily converted into the required compound in the body. Therefore, the term "administration" in the treatment method according to the present invention includes administration of a compound disclosed in the present invention, or a compound that is not explicitly disclosed but can be converted into a prodrug disclosed in the present invention in the body after being administered to a subject. General methods for the selection and preparation of suitable drug precursor derivatives are described in books such as, for example, "Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985".

[0132] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. As can be easily understood, one skilled in the art can provide chemically stable and easily synthesized compounds by selecting the substituents or substitution patterns of the compounds of the present invention according to conventional technical means and the methods described in the present invention.

[0133] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of the definition of any substituent or variable at a particular position in another molecule. As can be easily understood, the compounds in the present invention can be provided that are chemically stable and can be easily produced and synthesized by the methods described in the prior art of the present invention or the methods described in the present invention by selecting appropriate substituents or substitution patterns based on the prior art of the present invention.

[0134] When the compound represented by formula (I) and its pharma- ceutically acceptable salts are in the form of a solvate or crystalline polymorphism, the present invention includes any possible solvate and crystalline polymorphism. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water Similar solvents such as ethanol, propanol, acetone, etc. can be used.

[0135] The term "pharmaceutical acceptable salt" refers to salts prepared from pharmaceutical acceptable non-toxic bases or acids. When the compound according to the present invention is an acid, its corresponding salts can be easily prepared from pharmaceutical acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low valent), ferric, ferrous, lithium, magnesium, manganese (high and low valent), potassium, sodium, zinc, and the like salts. In particular, ammonium, calcium, magnesium, potassium, and sodium salts are preferred. Non-toxic organic bases that can be derivatized into pharmaceutical acceptable salts include primary amines, secondary amines, and tertiary amines, including cyclic amines and substituted aminos, such as naturally occurring and synthetic substituted aminos. Other pharma- ceutically acceptable organic non-toxic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometamol, and the like.

[0136] When the compound according to the present invention is a base, its corresponding salt can be easily prepared from pharma- ceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. Preferred are citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferred are formic acid and hydrochloric acid. For use as a pharmaceutical, the compounds of formula (I) are preferably used in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (percentages are by weight).

[0137] The pharmaceutical compositions according to the present invention comprise a compound of formula (I) (or a pharma- ceutically acceptable salt thereof) as an active ingredient, a pharma- ceutically acceptable excipient, and other optional therapeutic ingredients or additives. Although the optimal mode of administration of the active ingredient in any particular case will depend on the particular subject to be administered, the nature of the subject, and the severity of the condition, the pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions of the present invention are readily available in unit dosage forms well known in the art and can be readily prepared by any of the manufacturing methods well known in the pharmaceutical arts.

[0138] In practice, according to common drug mixing techniques, the compound of formula (I) of the present invention, or a drug precursor, or a metabolite, or a pharma- ceutically acceptable salt, as an active ingredient, can be mixed with a drug carrier to form a pharmaceutical composition. The drug carrier may be in various forms, depending on the desired mode of administration, for example, oral administration or injection (including intravenous injection). Thus, the pharmaceutical composition of the present invention may be in the form of a separate unit suitable for oral administration, for example, a capsule, cachet, or tablet containing a predetermined dose of the active ingredient. Furthermore, the pharmaceutical composition of the present invention may be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, Or the form of a water-in-oil emulsion may be used. In addition to the common dosage forms mentioned above, the compound of formula (I) or its pharma- ceutical acceptable salt may also be administered by controlled release methods and / or delivery devices. The pharmaceutical compositions of the present invention may be prepared by any pharmaceutical method. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or a mixture of both. The product can then be easily manufactured into the required appearance.

[0139] Thus, the pharmaceutical compositions of the present invention comprise a pharma- ceutically acceptable carrier and a compound of formula (I) or a pharma- ceutically acceptable salt thereof. The pharmaceutical compositions of the present invention also include a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and one or more other therapeutically active compounds.

[0140] The drug carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Liquid carriers include syrup, peanut oil, olive oil, and water. Gas carriers include carbon dioxide and nitrogen gas. When preparing oral formulations of drugs, any convenient pharmaceutical medium can be used. For example, water, glycols, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used in oral liquid formulations, such as suspensions, elixirs, and solutions, and carriers, such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used in oral solid formulations, such as powders, capsules, and tablets. Considering ease of administration, oral formulations are preferably tablets and capsules, in which solid pharmaceutical carriers are used. Optionally, tablet coating may be performed using standard aqueous or nonaqueous formulation techniques.

[0141] Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compression or molding with any one or more accessory ingredients or adjuvants. The active ingredient can be mixed in a free-flowing form, e.g., powder or granules, with a binder, lubricant, inert diluent, surfactant or dispersant, and compressed in a suitable machine to produce compressed tablets. Molded tablets can be prepared by moistening the powdered compound or pharmaceutical composition with an inert liquid diluent and molding in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, combined with suitable and easily measurable accessory materials, which accessory materials comprise about 5% to 95% of the total weight of the pharmaceutical composition. Dosage unit forms generally contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0142] Pharmaceutical compositions suitable for parenteral administration according to the present invention can be prepared as aqueous solutions or suspensions by adding active ingredients to water.Appropriate surfactants such as hydroxypropylcellulose may be included.Glycerol, liquid polyethylene glycols, and mixtures thereof in oils can also be prepared as dispersions.In addition, preservatives may be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

[0143] The pharmaceutical compositions suitable for injection according to the present invention include sterile aqueous solutions or dispersions. Moreover, the pharmaceutical compositions may be prepared in the form of sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In any case, the final injectable form must be sterile and easily flowable to facilitate injection. Moreover, the pharmaceutical compositions must be stable during manufacture and storage. Therefore, they are suitable for use in treating the diseases caused by microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0144] The pharmaceutical composition according to the present invention may be in a form suitable for topical administration, such as an aerosol, emulsion, ointment, lotion, dusting powder, or other similar dosage form. In addition, the pharmaceutical composition according to the present invention may be in a form suitable for use in a transdermal administration device. These preparations can be prepared by a general processing method using the compound of formula (I) of the present invention, or a pharma-ceutically acceptable salt thereof. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the above compound to prepare an emulsion or ointment having the desired uniformity.

[0145] The pharmaceutical composition according to the present invention can be prepared in a form suitable for rectal administration by using a solid as a carrier.The preferred dosage form is a unit dose suppository that forms a mixture.Suitable additives include cocoa butter and other materials that are commonly used in the art.Suppositories can be easily prepared by first mixing the pharmaceutical composition with softened or melted additives, then cooling and molding.

[0146] In addition to the above-mentioned carrier components, the pharmaceutical preparation may further include one or more additional additive components, such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants), if necessary. Other adjuvants may further include penetration enhancers that adjust the isotonicity of the drug with blood. The pharmaceutical composition containing the compound of formula (I) or a pharma-ceutically acceptable salt thereof may be prepared in the form of a powder or a concentrated liquid.

[0147] In general, when treating the above-mentioned conditions or discomforts, the dosage level of the drug is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. However, as can be appreciated, the specific dosage level for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, administration time, administration route, excretion rate, concurrent drug use, and the severity of the particular disease being treated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0148] In order to facilitate understanding of the present invention, the present invention will be described below with reference to examples, which are merely for illustrative purposes and are not intended to limit the scope of application of the present invention. Unless otherwise specified, all experimental methods in the present invention are general methods. Unless otherwise specified, all experimental materials used in the present invention are commercially available.

[0149] Unless otherwise stated, all parts and percentages are by weight and all temperatures are in degrees Celsius.

[0150] In the examples, the following abbreviations are used: CuI: cuprous iodide; DAST: diethylaminotrifluoride; DCM: dichloromethane, DIEA: N,N-diisopropylethylamine, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide; EA: ethyl acetate, ESI-MS: electrospray ionization mass spectrometry; K2CO3: Potassium carbonate, NaH: sodium hydride; LDA: lithium diisopropylamide; LiHMDS: lithium bis(trimethylsilyl)amide; m-CPBA: metachloroperbenzoic acid; MtBE: methyl tert-butyl ether; Na2SO4: sodium sulfate, NaBH4: sodium borohydride; NBS: N-bromosuccinimide, NFSI: N-fluorobenzenesulfonimide; NIS: N-iodosuccinimide, NMP: N-methylpyrrolidone, PE: petroleum ether; Pd2(dba)3: tri(dibenzylideneacetone)dipalladium, Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, Prep-TLC: Thin-layer chromatography preparative; TMSC2F5: (pentafluoroethyl)trimethylsilane, TBAF: Tetrabutylammonium fluoride; TEA: triethylamine; THF: tetrahydrofuran; Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, TLC: thin layer chromatography; ESI-MS: electrospray mass spectrometry; LCMS or LC-MS: Liquid Chromatography Mass Spectrometry; 1 H NMR: proton nuclear magnetic resonance; [(R,R)-Ts-DPEN]RuCl(p-cymene): chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II).

[0151] Synthesis of intermediate M1 (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0152] Step 1: Synthesis of compound M1-1 Under the protection of nitrogen gas, 6,7-dihydro-1H-indol-4(5H)-one (13.5 g) was suspended in THF (100 mL), and DBU (33.44 g) and triisopropylsilyl chloride (21.2 g) were slowly added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours, and MTBE (100 mL) and 10% aqueous citric acid solution (100 mL) were added to the reaction mixture, followed by separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound M1- 1 (20.3 g) was obtained and used directly in the next step.

[0153] ESI-MS m / z: 292.10 [M+H] + .

[0154] Step 2: Synthesis of compound M1-2 Under the protection of nitrogen gas, compound M1-1 (13.5 g) was dissolved in acetonitrile (100 mL), NIS (11.5 g) was added little by little, and the mixture was reacted at room temperature for 5 hours. The reaction was cooled, and the precipitated solid was filtered, rinsed with methanol (50 mL * 2), and dried to obtain the target compound M1-2 (15.4 g).

[0155] ESI-MS m / z: 418.10 [M+H]+.

[0156] Step 3: Synthesis of compound M1 Compound M1-2 (4.2 g) and NFSI (7.9 g) were suspended in THF (100 mL), cooled to -78°C, and 1.0 M LiHMDS tetrahydrofuran solution (28.2 mL) was slowly added dropwise to the suspension. o After stirring at C for 2 hours, a saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction solution, which was then extracted twice with ethyl acetate, washed twice with saturated saline, dried and concentrated to obtain a crude product. The crude product was rinsed with methanol to obtain the target compound M1 (2.1 g).

[0157] ESI-MS m / z: 297.99 [M+H] + .

[0158] 1 H NMR (500MHz, DMSO-d6): δ 12.05 (s, 1H), 7.12 (d, J = 2.3Hz, 1H), 2.98 (t, J = 6.2Hz, 2H), 2.60-2.53 (m, 2H).

[0159] Synthesis of intermediate M2 (5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0160] M1 (12 g), cuprous iodide (7.8 g), fluorosulfonyldifluoromethyl acetate (24 g) were added to NMP (120 mL), heated to 120° C. under nitrogen gas replacement and protection, and reacted overnight. TLC and LCMS showed no remaining raw material, cooled by lowering the temperature, diluted with ethyl acetate, washed the organic phase with saturated saline, dried over sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound M2 (8.4 g).

[0161] ESI-MS m / z: 238.00 [MH] - .

[0162] 1 H NMR(500MHz,DMSO) δ 12.37(s,1H),7.56(s,1H),3.03(t,J=6.1Hz,2H),2.68 - 2.55(m,2H).

[0163] Synthesis of intermediate M3 (5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0164] Step 1: Synthesis of compound M3-1 Compound M1-2 (834 mg), cuprous iodide (380 mg), NMP (20 mL) and methyl fluorosulfonyldifluoroacetate (1.15 g) were sequentially added to a 50 mL single-neck flask, the temperature was raised to 120° C., and the reaction was carried out for 6 h. The reaction mixture was diluted with EA, washed three times with water, washed once with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM=100%) to obtain the target compound M3-1 (264 mg).

[0165] ESI-MS m / z: 204.08 [M+H + ] + .

[0166] Step 2: Synthesis of compound M3 Method 1: Under the protection of nitrogen gas, compound M3-1 (264 mg) was dissolved in ultra-dehydrated tetrahydrofuran (20 mL), cooled to -78 ° C., 1.0 M LDA tetrahydrofuran solution (2.5 mL) was slowly added dropwise, and after stirring for 30 minutes, NFSI (491 mg) tetrahydrofuran solution (5 mL) was added dropwise and stirred for 2 hours while maintaining at -78 ° C. The reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated saline, dried and concentrated to obtain a crude product, which was purified by column chromatography (DCM = 100%) to obtain the target compound M3 (147 mg).

[0167] Method 2: Under the protection of nitrogen gas, compound M3-1 (200 mg) was dissolved in methanol (3 mL), NFSI (465 mg) was added, and the mixture was refluxed at 70° C. overnight. After the reaction was completed, the mixture was concentrated and purified by column chromatography (DCM=100%) to obtain the target compound M3 (173 mg).

[0168] ESI-MS m / z: 222.12 [M+H + ] + .

[0169] Synthesis of intermediate M4 (3-bromo-7-fluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one) and intermediate M5 (3-bromo-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one) [ka]

[0170] Step 1: Synthesis of compound M4-1 Under the protection of nitrogen gas, 3-bromo-1H-pyrrole-2-carboxylate methyl (20.4 g) and 4-bromobutyrate methyl (19.8 g) were dissolved in DMF (100 mL), cesium carbonate (65.2 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was then poured into an ice-water (500 mL) mixture, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:10) to obtain the target compound M4-1 (28.3 g).

[0171] ESI-MS m / z: 304.10 [M+H] + .

[0172] Step 2: Synthesis of compound M4-2 Under the protection of nitrogen gas, compound M4-1 (15.2 g) was dissolved in THF (100 mL), and 1.0 M potassium tert-butoxide tetrahydrofuran solution (60 mL) was slowly added dropwise under ice bath, and after stirring at 0 ° C for 3 hours, it was cooled to -78 ° C, and NFSI (18.9 g) in tetrahydrofuran solution (50 mL) was added dropwise, and the reaction was continued at -78 ° C for 1 hour, and the reaction was quenched by adding an aqueous solution of saturated ammonium chloride, and then extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 1:5) to obtain the target compound M4-2 (9.1 g).

[0173] ESI-MS m / z: 277.15 [M+H] + .

[0174] Step 3: Synthesis of compound M4-3 Under the protection of nitrogen gas, compound M4-2 (8.3 g) was dissolved in DMF (100 mL), palladium acetate (3.3 g), CuI (11.4 g) and fluorosulfonyldifluoromethyl acetate (23 g) were added, and the mixture was stirred at 100° C. for 3 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried with Na2SO4 and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:4) to obtain the target compound M4-3 (4.23 g).

[0175] ESI-MS m / z: 279.20 [M+H] + .

[0176] Step 4: Synthesis of compound M4-4 Compound M4-3 (4.23 g) was dissolved in a mixed solvent of ethanol (20 mL) and 6M aqueous hydrochloric acid (20 mL), and the mixture was refluxed for 3 hours. The mixture was concentrated under reduced pressure, and the ethanol was removed by centrifugation. The residue was extracted with ethyl acetate (100 mL * 2). The organic layer was washed with brine (100 mL * 2), dried with Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE = 1: 4) to obtain the target compound M4-4 (2.1 g).

[0177] ESI-MS m / z: 221.20 [M+H] + .

[0178] Step 5: Synthesis of compound M4 Compound M4-4 (2.1 g) was dissolved in acetonitrile (20 mL), NBS (1.8 g) was added at room temperature, the reaction solution was refluxed for 4 hours, quenched by adding water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3) to obtain the target compound M4 (2.5 g).

[0179] ESI-MS m / z: 300.10 [M+H] + .

[0180] Step 6: Synthesis of compound M5 Compound M4 (1.3 g) was dissolved in THF (50 mL), cooled to -78 ° C., 1.0 M LiHMDS tetrahydrofuran solution (6 mL) was slowly added dropwise, and after stirring for 30 minutes, NFSI (1.5 g) tetrahydrofuran solution (10 mL) was added dropwise, and stirring was continued for 2 hours. The reaction was quenched by adding an aqueous solution of saturated ammonium chloride, and then the mixture was extracted twice with ethyl acetate, washed twice with saturated saline, dried and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 1:3) to obtain the target compound M5 (0.8 g).

[0181] Example 1 Synthesis of 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzonitrile (Compound B1) [ka]

[0182] Step 1: Synthesis of compound B1-1 Potassium acetate (0.76 g), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.21 g), bis(pinacolato)diboron (1.31 g), 5-bromo-2,3-difluorobenzonitrile (0.56 g) were dissolved in dioxane (6 mL) and dimethyl sulfoxide (0.05 mL), purged with nitrogen gas, and stirred at 95 ° C overnight. After the reaction was completed, ethyl acetate and water were added, the mixture was separated, washed with saturated saline, dried, and concentrated to obtain crude product B1-1 (0.7 g), which was used directly in the next step.

[0183] Step 2: Synthesis of compound B1-2 Copper acetate (0.31 g), 4A molecular sieves (0.5 g), compound M2 (0.47 g) and compound B1-1 (0.7 g) were placed in a reaction flask, DMF (1 mL) and triethylamine (0.71 mL) were added, the mixture was purged with oxygen gas, stirred at 80° C. overnight, cooled to room temperature, filtered, diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated and purified by column chromatography to obtain the target compound B1-2 (0.07 g).

[0184] Step 3: Synthesis of compound B1 Compound B1-2 (0.07 g) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), cooled in an ice-water bath, sodium borohydride (0.02 g) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, ethyl acetate and water were added to the reaction solution, which was washed with saturated saline, dried, and concentrated to obtain the target compound B1 (0.07 g) by prep-TLC.

[0185] ESI-MS m / z: 423.21 [M+HCOO - ] - .

[0186] Example 2 Synthesis of 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound B2) [ka]

[0187] 5,5-Difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (100 mg) was dissolved in dichloromethane (2 mL), cooled in an ice-water bath, DAST (48 mg) was added, and the mixture was stirred in an ice-water bath for 1 hour. Saturated sodium bicarbonate was then added to the reaction mixture, which was diluted with dichloromethane and separated. The organic phase was washed with saturated saline, dried, concentrated, and the target compound B2 (10 mg) was obtained by prep-TLC separation.

[0188] ESI-MS m / z: 350.10 [M+HO-H + ] + .

[0189] Example 3 Synthesis of (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile (Compound B3) [ka]

[0190] Step 1: Synthesis of compound B3-1 Potassium acetate (224 mg), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (42 mg), bis(pinacolato)diboron (305 mg), and 4-bromo-2-(difluoromethyl)benzonitrile (265 mg) were dissolved in dioxane (6 mL) and stirred overnight at 80°C under nitrogen gas protection. After the reaction was completed, ethyl acetate and water were added to the reaction solution, which was separated, washed with saturated saline, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound B3-1 (165 mg).

[0191] Step 2: Synthesis of compound B3-2 To a mixture of copper acetate (92 mg), 4A molecular sieves (100 mg), compound M2 (61 mg) and compound B3-1 (50 mg), DCM (5 mL) and diisopropylethylamine (0.13 mL) were added, the mixture was purged with oxygen gas, stirred at room temperature overnight, filtered, concentrated and purified by column chromatography to obtain the target compound B3-2 (64 mg).

[0192] Step 3: Synthesis of compound B3 A solution of compound B3-2 (64 mg) in dichloromethane was added with triethylamine (0.05 mL) and chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4 -toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg) and formic acid (23 mg) were added, and the mixture was stirred at room temperature overnight, concentrated, and purified by column chromatography to obtain the target compound B3 (35 mg).

[0193] ESI-MS m / z: 437.24 [M+HCOO - ] - .

[0194] Example 4 Synthesis of (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound A3) [ka]

[0195] Step 1: Synthesis of compound A3-1 To a solution of compound M2 (0.9 g) in DCM (50 mL), copper acetate (0.55 g), 3-cyano-4-fluorophenylboronic acid (1.0 g) and TEA (1.2 g) were added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated saline, dried and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound A3-1 (0.92 g).

[0196] Step 2: Synthesis of compound A3-2 A mixture of compound A3-1 (1.26 g), methyl 3-mercaptopropionate (0.73 g), xantphos (0.35 g), tri(dibenzylideneacetone)dipalladium (0.28 g), DIEA (1.5 mL) and toluene (40 mL) was stirred at 70° C. overnight. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound A3-2 (1.10 g).

[0197] Step 3: Synthesis of compound A3-3 Under the condition of -78 ° C., a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.5 mL) was added to a solution of compound A3-2 (0.40 g) in tetrahydrofuran (10 mL), and after stirring for 10 minutes, diethyl bromofluoromethylphosphonate (0.40 g) was added. After stirring for 2 hours, water was added to quench the reaction. The reaction solution was warmed to room temperature and stirred overnight. Water and ethyl acetate were added to the reaction solution to dilute it. The organic phase was washed with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE = 1:3) to obtain the target compound A3-3 (0.18 g).

[0198] Step 4: Synthesis of compound A3-4

[0199] To a mixture of compound A3-3 (0.15 g), acetonitrile (1 mL), dichloromethane (1 mL) and water (2 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.5 g) were added and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A3-4 (0.1 g).

[0200] Step 5: Synthesis of compound A3 To a dichloromethane solution of compound A3-4 (0.12 g), triethylamine (0.08 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (0.04 g) and formic acid (0.04 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A3 (0.09 g).

[0201] ESI-MS m / z: 451.16 [M+HCOO - ] - .

[0202] Example 5 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A4) [ka]

[0203] Step 1: Synthesis of compound A4-1 (4-Fluoro-3-formylphenyl)boronic acid (2.0 g), compound M2 (3.5 g), copper acetate (2.5 g) and triethylamine (5.0 mL) were added to dichloromethane (40 mL), and the mixture was stirred overnight at room temperature under an oxygen gas atmosphere. After the reaction was completed, the reaction mixture was diluted with dichloromethane, washed twice with saturated saline, dried, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A4-1 (1.8 g).

[0204] ESI-MS m / z: 420.0 [M+H] + .

[0205] Step 2: Synthesis of compound A4-2 DAST (700 mg) was added to a solution of compound A4-1 (500 mg) in dichloromethane (10 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with dichloromethane and quenched with saturated sodium bicarbonate. The organic phase was washed with water, dried, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A4-2 (150 mg).

[0206] ESI-MS m / z: 442.0 [M+H] + .

[0207] Step 3: Synthesis of compound A4-3 A mixture of compound A4-2 (0.88 g), methyl 3-mercaptopropionate (0.36 g), xantphos (0.23 g), tri(dibenzylideneacetone)dipalladium (0.18 g), DIEA (0.66 mL) and toluene (5 mL) was stirred at 70° C. overnight. After the reaction was completed, the mixture was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound A4-3 (0.8 g).

[0208] ESI-MS m / z: 434.0 [M+H] + .

[0209] Step 4: Synthesis of compound A4-4 Compound A4-3 (0.30 g) was dissolved in tetrahydrofuran (10 mL), the temperature was lowered to -78 ° C, and the mixture was stirred for 30 minutes. Then, 1.0 M potassium tert-butoxide in tetrahydrofuran solution (1.0 mL) was added, and after stirring for 10 minutes, methyl iodide (0.09 mL) was added and the mixture was stirred at -78 ° C for 2 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE = 1:3) to obtain the target compound A4-4 (0.20 g).

[0210] ESI-MS m / z: 362.0 [M+H] + .

[0211] Step 5: Synthesis of compound A4-5 To a mixture of compound A4-4 (0.2 g), acetonitrile (10 mL) and water (2 mL), potassium peroxymonosulfonate (0.71 g) was added and stirred at 60° C. for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A4-5 (0.18 g).

[0212] ESI-MS m / z: 394.0 [M+H] + .

[0213] Step 6: Synthesis of compound A4 A solution of A4-5 (0.06 g) in dichloromethane (3 mL) was added with triethylamine (0.03 g), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl] (4-Toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (0.01 g) and formic acid (0.02 g) were added and stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water and saturated saline, dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound A4 (0.03 g).

[0214] ESI-MS m / z: 451.16 [M+H + -H2O] + .

[0215] Example 6 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A5) [ka]

[0216] Step 1: Synthesis of compound A5-1 Compound A4-3 (0.20 g) was dissolved in tetrahydrofuran (10 mL), the temperature was lowered to -78 ° C and stirred for 30 minutes, 1.0 M potassium tert-butoxide tetrahydrofuran solution (0.7 mL) was added, and after stirring for 10 minutes, diethyl bromofluoromethylphosphonate (0.20 g) was added and stirred at -78 ° C for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated and purified by column chromatography to obtain the target compound A5-1 (0.15 g).

[0217] ESI-MS m / z: 398.0 [M+H] + .

[0218] Step 2: Synthesis of compound A5-2 To a mixture of compound A5-1 (0.15 g), acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.24 g) were added and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried, concentrated and purified by column chromatography to obtain the target compound A5-2 (0.08 g).

[0219] Step 3: Synthesis of compound A5 To a solution of compound A5-2 (0.08 g) in dichloromethane (3 mL), triethylamine (0.05 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (0.01 g) and formic acid (0.03 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography to obtain the target compound A5 (0.03 g).

[0220] ESI-MS m / z: 414.05 [M+H + -H2O] + .

[0221] Example 7 and Example 8 Synthesis of (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A13, hypothetical) and (S)-3-((R)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A14, hypothetical) [ka]

[0222] Step 1: Synthesis of compound A13-11 By substituting 3-trifluoromethyl-4-fluorophenylboronic acid for 3-cyano-4-fluorophenylboronic acid and following the procedure of Example 4, Step 1, compound A13-11 can be obtained.

[0223] Step 2: Synthesis of compound A13-12 By replacing compound A3-1 with compound A13-11 and following the method of Example 4, step 2, compound 13-12 can be obtained.

[0224] Step 3: Synthesis of compound 13-1 By replacing compound A3-2 with compound 13-11 and following the method of Example 4, step 3, compound 13-1 can be obtained.

[0225] Step 4: Synthesis of compound A13-2 To a mixed solution of compound A13-1 (120 mg) in acetonitrile (2 mL) and water (2 mL), potassium peroxymonosulfonate (210 mg) was added and stirred at 65° C. overnight. After the reaction was completed, the mixture was cooled, diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography to obtain the target compound A13-2 (90 mg).

[0226] ESI-MS m / z: 430.0 [MH + ] - .

[0227] Step 5: Synthesis of Compounds A13 and A14 A13-2 (100 mg) in dichloromethane (5 mL) was added with chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg), triethylamine (0.06 mL) and formic acid (0.03 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water, washed with saturated saline, dried and concentrated, and the crude product was purified by HPLC (Luna PREP C18, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile (35% to 70%), flow rate: 40 mL / min, detection wavelength: 254 nm, temperature: room temperature). The pre-peak was collected as the target compound A13 (20 mg), and the post-peak was collected as the target compound A14 (20 mg).

[0228] ESI-MS m / z: 416.07 [M+H + -H2O] + .

[0229] Example 9 Synthesis of 5-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound A10) [ka]

[0230] Step 1: Synthesis of compound A10-1 A mixture of A3-1 (130 mg), cuprous iodide (0.12 g), silver fluoride (0.08 g) and dimethyl sulfoxide (2 mL) was added with TMSC2F5 (0.11 mL) and pyridine (0.12 mL), stirred at 80°C overnight, and diluted with ethyl acetate. The extract was washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography to obtain the target compound A10-1 (100 mg).

[0231] Step 2: Synthesis of compound A10 Compound A10-1 (100 mg) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), cooled to 0° C. in an ice-water bath, sodium borohydride (30 mg) was added, and the mixture was reacted at room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A10 (90 mg).

[0232] ESI-MS m / z: 455.17 [M+HCOO - ] - .

[0233] Example 10 Synthesis of (S)-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound A11) [ka]

[0234] Step 1: Synthesis of compound A11-1 To a mixture of copper(I) thiophene-2-carboxylate (270 mg), compound A3-1 (400 mg) and silver trifluoromethanethiol (300 mg), N,N-dimethylacetamide (2 mL) was added, stirred at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated and purified by column chromatography (EA / PE=1:3) to obtain the target compound A11-1 (210 mg).

[0235] ESI-MS m / z: 389.0 [MH + ] - .

[0236] Step 2: Synthesis of compound A11-2 To a mixture of compound A11-1 (100 mg) in acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.22 g) were added and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A11-2 (70 mg).

[0237] ESI-MS m / z: 421.0 [MH + ] - .

[0238] Step 3: Synthesis of compound A11 To a solution of compound A11-2 (50 mg) in dichloromethane (5 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg), triethylamine (0.03 mL) and formic acid (30 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A11 (10 mg).

[0239] ESI-MS m / z: 469.10 [M+HCOO - ] - .

[0240] Example 11 Synthesis of (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound A16) [ka]

[0241] Step 1: Synthesis of compound A16-1 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.44 mL) was added to a solution of compound A3-2 (120 mg) in tetrahydrofuran (10 mL), and the mixture was stirred for 10 minutes. Then, fluoromethyl iodide (70 mg) was added and the mixture was stirred for 2 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A16-1 (80 mg).

[0242] ESI-MS m / z: 353.0 [MH + ] - .

[0243] Step 2: Synthesis of compound A16-2 To a mixed solution of compound A16-1 (60 mg) in acetonitrile (3 mL) and water (3 mL), potassium peroxymonosulfonate (0.63 g) was added and stirred at 60° C. overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A16-2 (50 mg).

[0244] ESI-MS m / z: 385.0 [MH + ] - .

[0245] Step 3: Synthesis of compound A16 Compound A16-2 (70 mg) in dichloromethane (5 mL) was dissolved in triethylamine ( 0.05 mL) was added, chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg) and formic acid (20 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water and saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A16 (30 mg).

[0246] ESI-MS m / z: 433.16 [M+HCOO - ] - .

[0247] Example 12 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A17) [ka]

[0248] Step 1: Synthesis of compound A17-1 To a mixture of copper(I) thiophene-2-carboxylate (140 mg), compound A4-2 (220 mg) and silver trifluoromethanethiol (160 mg), N,N-dimethylacetamide (5 mL) was added, stirred at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated and purified by column chromatography to obtain the target compound A17-1 (160 mg).

[0249] ESI-MS m / z: 416.0 [M+H + ] + .

[0250] Step 2: Synthesis of compound A17-2 To a mixture of compound A17-1 (0.17 g) in acetonitrile (3 mL), dichloromethane (3 mL) and water (6 mL), ruthenium trichloride (0.01 g) and sodium periodate (0.44 g) were added and stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A17-2 (0.07 g).

[0251] ESI-MS m / z: 446.0 [MH + ] - .

[0252] Step 3: Synthesis of compound A17 A solution of A17-2 (70 mg) in dichloromethane (5 mL) was treated with chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg), triethylamine ( The reaction mixture was diluted with dichloromethane, washed with water and saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A17 (60 mg).

[0253] ESI-MS m / z: 494.12 [M+HCOO - ] - .

[0254] Example 13 Synthesis of (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile (Compound A18) [ka]

[0255] Step 1: Synthesis of compound A18-2 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.5 mL) was added to a solution of A18-1 (160 mg) in tetrahydrofuran (10 mL), and the mixture was stirred for 10 minutes. After that, bromoacetonitrile (60 mg) was added and the mixture was stirred for 2 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A18-2 (120 mg).

[0256] ESI-MS m / z: 405 [M+H + ] + .

[0257] Step 2: Synthesis of compound A18-3 To a mixture of compound A18-2 (120 mg) in acetonitrile (3 mL) and water (3 mL), potassium peroxymonosulfonate (457 mg) was added and stirred at 60° C. for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A18-3 (100 mg).

[0258] ESI-MS m / z: 435[MH + ] - .

[0259] Step 3: Synthesis of compound A18 To a solution of compound A18-3 (100 mg) in dichloromethane (5 mL), triethylamine (0.06 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg) and formic acid (30 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with chloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to give the target compound A18 (50 mg).

[0260] ESI-MS m / z: 437.12 [MH - ] - .

[0261] Example 14 Synthesis of (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A19) [ka]

[0262] Step 1: Synthesis of compound A19-1 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (10 mL) was added to a solution of compound A4-3 (270 mg), and the mixture was stirred for 10 minutes. After that, fluoromethyl iodide (0.15 g) was added, and the mixture was stirred for 2 hours while maintaining the temperature. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A19-1 (180 mg).

[0263] ESI-MS m / z: 380 [M+H + ] + .

[0264] Step 2: Synthesis of compound A19-2 To a solution of compound A19-1 (190 mg) in acetonitrile (4 mL) / water (4 mL), potassium peroxymonosulfonate (1.85 g) was added and stirred at 60° C. for 3 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A19-2 (150 mg).

[0265] ESI-MS m / z: 412 [M+H + ] + .

[0266] Step 3: Synthesis of compound A19 To a solution of compound A19-2 (150 mg) in dichloromethane (5 mL), triethylamine (0.11 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (20 mg) and formic acid (50 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A19 (90 mg). obtained.

[0267] ESI-MS m / z: 458.11 [M+HCOO - ] - .

[0268] Example 15 Synthesis of 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide (Compound A20) [ka]

[0269] Step 1: Synthesis of compound A20-1 To a solution of ethyl bromodifluoroacetate (100 mg) in dimethyl sulfoxide (1 mL), copper powder (30 mg) and compound A3-1 (100 mg) were added, stirred at 95° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography to obtain the target compound A20-1 (70 mg).

[0270] Step 2: Synthesis of compound A20-2 To a solution of compound A20-1 (70 mg) in methanol (1 mL), 7 mol / L aminomethanol solution (0.49 mL) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated to give the target compound A20-2, which was used directly in the next step without further purification.

[0271] ESI-MS m / z: 384.1 [M+H + ] + .

[0272] Step 3: Synthesis of compound A20 A20-2 (70 mg) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL) and cooled in an ice-water bath, and then sodium borohydride (20 mg) was added and reacted at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A20 (40 mg).

[0273] ESI-MS m / z: 430.0 [M+HCOO - ] - .

[0274] Example 16 Synthesis of (S)-3-(ethylsulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A21) [ka]

[0275] Step 1: Synthesis of compound A21-1 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.6 mL) was added to a solution of compound A18-1 (180 mg) in tetrahydrofuran (10 mL), and the mixture was stirred for 10 minutes. After that, ethyl iodide (90 mg) was added and the reaction solution was stirred for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A21-1 (150 mg).

[0276] ESI-MS m / z: 394 [M+H + ] + .

[0277] Step 2: Synthesis of compound A21-2 To a mixture of compound A21-1 (150 mg), acetonitrile (5 mL) and water (5 mL), potassium peroxymonosulfonate (0.7 g) was added and stirred at 60° C. for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A21-2 (150 mg).

[0278] ESI-MS m / z: 424[MH + ] - .

[0279] Step 3: Synthesis of compound A21 To a solution of compound A21-2 (150 mg) in dichloromethane (5 mL), triethylamine (0.10 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (20 mg) and formic acid (50 mg) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A21 (60 mg).

[0280] ESI-MS m / z: 472.15 [M+HCOO - ] - .

[0281] Example 17 Synthesis of 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound A22) [ka]

[0282] Step 1: Synthesis of compound A22-1 A solution of compound A20-2 (0.7 g) in dichloromethane (2 mL) was cooled to 0° C., and triethylamine (0.07 mL) and trifluoroacetic anhydride (0.07 mL) were added, stirred at 50° C. overnight, and concentrated to give the target compound A22-1, which was used directly in the next step without further purification.

[0283] Step 2: Synthesis of compound A22 Sodium borohydride (20 mg) was added to a solution of compound A22-1 (60 mg) dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and the mixture was reacted at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A22 (20 mg).

[0284] ESI-MS m / z: 412.0 [M+HCOO - ] - .

[0285] Example 18 Synthesis of N-(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide (Compound A23) [ka]

[0286] Step 1: Synthesis of compound A23-1 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.7 mL) was added to a solution of compound A3-2 (180 mg) in tetrahydrofuran (10 mL), and the mixture was stirred for 10 minutes. After that, methyl iodide (90 mg) was added and the reaction solution was stirred for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A23-1 (116 mg).

[0287] ESI-MS m / z: 337 [M+H + ] + .

[0288] Step 2: Synthesis of compound A23-2 To a solution of compound A23-1 (200 mg) in acetonitrile (5 mL), cyanamide (40 mg) and iodobenzene diacetate (250 mg) were added, stirred at room temperature overnight, concentrated, and the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A23-2 (120 mg).

[0289] ESI-MS m / z: 377 [M+H + ] + .

[0290] Step 3: Synthesis of compound A23-3 Compound A23-2 (120 mg) was dissolved in acetonitrile (2 mL), dichloromethane (2 mL) and water (4 mL), to which ruthenium trichloride (10 mg) and sodium periodate (370 mg) were added and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated and purified by column chromatography (EA / PE=1:3) to obtain the target compound A23-3 (40 mg).

[0291] ESI-MS m / z: 393.0 [M+H + ] + .

[0292] Step 4: Synthesis of compound A23 To a solution of compound A23-3 (40 mg) in dichloromethane (5 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (10 mg), triethylamine (0.03 mL) and formic acid (14 mg) were added and stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated and purified by column chromatography to obtain the target compound A23 (10 mg).

[0293] ESI-MS m / z: 395.11 [M+H + ] + .

[0294] Example 19 Synthesis of (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile (Compound A24) [ka]

[0295] Step 1: Synthesis of compound A24-1 Under the condition of -78°C, a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (3.0 mL) was added to a solution of A4-3 (0.86 g) in tetrahydrofuran (20 mL), and the mixture was stirred for 10 minutes. After that, bromoacetonitrile (0.36 g) was added, and the reaction solution was stirred for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic phase was washed with saturated saline, dried, concentrated, and purified by column chromatography to obtain the target compound A24-1 (0.38 g).

[0296] ESI-MS m / z: 387 [M+H + ] + .

[0297] Step 2: Synthesis of compound A24-2 To a mixture of compound A24-1 (0.38 g) dissolved in acetonitrile (6 mL) and water (6 mL), potassium peroxymonosulfonate (3.6 g) was added and stirred at 60° C. overnight. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A24-2 (0.34 g).

[0298] ESI-MS m / z: 417[MH + ] - .

[0299] Step 3: Synthesis of compound A24 To a solution of compound A24-2 (0.34 g) in dichloromethane (10 mL), triethylamine (0.23 mL), chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) (0.08 g) and formic acid (0.11 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated saline, dried, concentrated, and purified by column chromatography (EA / PE=1:3) to obtain the target compound A24 (0.18 g).

[0300] ESI-MS m / z: 419[MH - ] - .

[0301] The following examples were prepared using methods substantially similar to Examples 1-19.

[0302] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0303] Some exemplary compounds 1 The H NMR data is as follows: 1H NMR (500MHz,CDCl3)δ7.91(d,J=8.3Hz,1H),7.71(s,1H),7.56(d,J=8.2Hz,1H),7.21(s,1H),7.00(dd,J=70.0,38.6Hz,1H),4.93(t,J=6.2Hz,1H),2.92 - 2.81(m,1H),2.74 - 2.64(m,1H),2.60 - 2.45(m,1H),2.30 - 2.20(m,1H). (Example 3) 1 H NMR(500MHz, CDCl3)δ 7.67(dd,J=5.2,2.7Hz,1H),7.62(ddd,J=8.9,4.4,2.8Hz,1H),7.50(s,1H),7.46 - 7.40(m,1H),6.39(t,J=54.0Hz,1H),5.06(t,J=6.3Hz,1H),3.11(s,1H),2.83 - 2.70(m,1H),2.62(ddd,J=16.3,6.3,2.3Hz,1H),2.55-2.38(m,1H),2.31-2.19(m,1H). (Example 4) 1 H NMR (500MHz, DMSO) δ 7.85 - 7.75 (m, 2H), 7.65 (s, 1H), 7.57 (t, J = 9.2Hz, 1H), 7.23 (t, J = 53.9Hz, 1H), 6.35 (d, J = 6.0Hz, 1H), 4.85 - 4.80 (m, 1H), 3.24 (s, 3H), 2.80 - 2.70 (m, 1H), 2.70 - 2.59 (m, 1H), 2.35 - 2.25 (m, 1H), 2.20 - 2.10 (m, 1H). (Example 5) 1 H NMR (500MHz,CDCl3)δ7.62(dd,J=5.7,2.7Hz,1H),7.58(d,J=9.2Hz,1H),7.52 - 7.44(m,1H),7.35(t,J=8.9Hz,1H),7.08 - 6.78(m,1H),5.03(dt,J=7.5,3.7Hz,1H),3.02(d,J=7.4Hz,1H),2.85 - 2.73(m,1H),2.67 - 2.43(m,2H),2.35 - 2.18(m,1H). (Example 12) 11H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 5.8, 2.7 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.32 (t, J = 8.9 Hz, 1H), 6.94 (dd, J = 59.6, 49.5 Hz, 1H), 5.47 (dd, J = 47.2, 9.8 Hz, 1H), 5.25 - 5.07 (m, 2H), 3.00 (d, J = 3.4 Hz, 1H), 2.76 (ddd, J = 16.5, 10.5, 6.1 Hz, 1H), 2.64 (ddd, J = 16.3, 6.2, 2.7 Hz, 1H), 2.55 - 2.37 (m, 1H), 2.31 - 2.16 (m, 1H). (Example 14)

[0304] 1 1H NMR (500 MHz, CDCl3) δ 7.63 - 7.58 (m, 1H), 7.56 (s, 1H), 7.51 - 7.42 (m, 1H), 7.33 (t, J = 8.9 Hz, 1H), 6.94 (t, J = 54.5 Hz, 1H), 5.15 (s, 1H), 4.63 (d, J = 16.4 Hz, 1H), 4.17 (d, J = 16.4 Hz, 1H), 2.90 (s, 1H), 2.83 - 2.61 (m, 2H), 2.53 - 2.16 (m, 2H). (Example 19) 1 1H NMR (500 MHz, CDCl3) δ 7.52 (s, J = 6.3 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.19 (d, J = 0.9 Hz, 1H), 7.02 (dt, J = 8.3, 2.1 Hz, 1H), 6.39 (t, J = 54.0 Hz, 1H), 5.05 (t, J = 6.4 Hz, 1H), 3.08 (s, 1H), 2.85 - 2.75 (m, 1H), 2.70 (ddd, J = 16.4, 6.3, 2.4 Hz, 1H), 2.56 - 2.38 (m, 1H), 2.32 - 2.17 (m, 1H). (Example 23) 1 1H NMR (500 MHz, CDCl3) δ 7.41 (dd, J = 6.2, 2.6 Hz, 1H), 7.36 (s, 1H), 7.29 (t, J = 8.5 Hz, 1H), 7.21 (ddd, J = 8.7, 4.0, 2.7 Hz, 1H), 5.14 (t, J = 6.4 Hz, 1H), 3.25 (s, 3H), 3.21 (d, J = 2.2 Hz, 1H), 2.80 - 2.59(m,2H),2.55-2.35(m,1H),2.28-2.19(m,1H). (Example 24) 1 H NMR(500MHz, CDCl3)δ 7.74 - 7.67(m,2H),7.55(dd,J=8.6,2.6Hz,1H),7.51(s,1H),6.38(t,J=54.0,1H),5.10 - 5.02(m,1H),3.11(d,J=3.4Hz,1H),2.85 - 2.75(m,1H),2.64(ddd,J=16.3,6.2,2.4Hz,1H),2.57 - 2.36(m,1H),2.33 - 2.20(m,1H). (Example 28) 1 H NMR(500MHz, CDCl3)δ 7.96(d,J=8.3Hz,1H),7.76(s,1H),7.61(dd,J=8.3,2.1Hz,1H),7.47(s,1H),7.03(t,J=67.7Hz,1H),5.22 - 5.15(m,1H),3.21(d,J=3.0Hz,1H),2.92 - 2.82(m,1H),2.73(ddd,J=16.2,6.0,2.9Hz,1H),2.56 - 2.40(m,1H),2.34 - 2.24(m,1H). (Example 29) 1 H NMR(500MHz, CDCl3)δ 8.00(d,J=8.3,1H),7.81(d,J=9.4,1H),7.79 - 7.68(m,1H),7.53(s,1H),5.51(dd,J=47.2,9.9Hz,1H),5.25 - 5.05(m,2H),3.00(s,1H),2.94 - 2.79(m,1H),2.75 - 2. 65(m,1H),2.56 - 2.38(m,1H),2.31 - 2.22(m,1H). (Example 45) 1 H NMR(500MHz, CDCl3)δ 7.97(d,J=8.4Hz,1H),7.78(d,J=2.1Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.14(s,1H),4.89(t,J=5.9Hz,1H),2.92 - 2.83(m,1H),2.69(dd,J=16.1,6.4Hz,1H),2.63 - 2.42(m,2H),2.34 - 2.17(m,1H). (Example 46)

[0305] Pharmacological experiments VEGFA ELISA detection (IC 50 ) 786-O cells growing in log phase were taken and inoculated into 96-well plates at 180ul per well, the cell concentration was 65000 cells / ml culture medium. The compounds were diluted to the corresponding concentrations, and 20ul of compound solutions with different concentrations were added to the corresponding cell wells, the compound concentrations were (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000, respectively. After 24h culture, the cell culture supernatant was taken and the VEGFA concentration was measured by ELISA kit (purchased from abcam), and finally the reaction was stopped and the light absorption value of each well was measured at a wavelength of 450nm using a microplate reader, and the IC was calculated by GraphPadPrism. 50 was calculated. At the same time, cell viability was measured using CellTiter-Glo reagent.

[0306] Example embodiment IC 50 The data are shown in Table 2, where A is the IC 50 ≦0.5 μM, B represents 0.5 μM <IC 50 ≦1.5 μM, C is 1.5 μM <IC 50 ≦10 μM, and D represents IC 50 >10μM.

[0307] [Table 2]

[0308] Luciferase experiments The luciferase (LUC) gene was transfected into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen). The cells were stably transformed and constructed as HIF2α reporter gene cells (786-O-HIF2α-Luc cells). The test was performed when the 786-O-HIF2α-Luc cells were in the logarithmic growth phase, the medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, rinsed three times with PBS, trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells, and digestion was stopped with medium, 10% fetal bovine serum, 1% penicillin, and streptomycin. The cells were collected by centrifugation, purged twice with PBS to remove phenolsulfonphthalein in the medium, and the cells were resuspended to an appropriate concentration, and the cell density and viability were detected, and the cell viability was 90% or more before it could be used in the experiment.

[0309] Using an Echo550 (non-contact sonic pipetting system, purchased from Labcyte), gradient concentrations of compounds were transferred to 384-well plates at 25 nl / well, and cells were seeded into 384-well plates at 4500 cells / well, with 25 μl of medium, and the final concentrations of compounds were 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, and 0.5 nM, respectively. Cells were cultured at 37°C in a 5% CO2 environment for 18-20 h, and then analyzed by Steady-Glo. TM Luciferase assay system (purchased from Promega) was added to the 384-well plate at 25 μl / well, and the luminescence value was detected by Envision. The inhibition rate % was calculated based on the RLU (Record Luminescence) signal value of each well, and the IC of the corresponding compound was calculated by fitting with Graphpad 8.0. 50 was calculated.

[0310] Example embodiment IC 50 The data are shown in Table 3, where A is the IC 50 ≦0.1 μM, B is 0.1 μM <IC 50 ≦0.5 μM, C represents IC 50 >0.5μM.

[0311] [Table 3]

[0312] In vivo PK Compounds were prepared with 5% DMSO, 5% Solutol and 90% NaCl. SD rats and Balb / c mice were selected as the animals to be administered, and the intravenous dose was 1 mg / kg, and the oral dose was 5 mg / kg. Blood was collected from the orbit at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h and 24 h, respectively. After blood collection, the samples were centrifuged at 4000 rpm for 10 min, the supernatant was taken, and 200 μL of internal standard solution was added to 30 μL of the supernatant to precipitate, and after vortexing and shaking, the samples were centrifuged at 12000 rpm for 10 min, and 100 μL of the supernatant solution was taken and mixed with purified water in a 1:1 ratio for sampling. The compound concentration in plasma was detected by a high-performance liquid chromatography mass spectrometer, and the compound concentration in the plasma sample was quantitatively analyzed using the internal standard quantitative method. After the compound concentration was measured, the relevant pharmacokinetic parameters including Cmax, AUC, etc. were calculated by Winnonln software. Experiments have shown that exemplary compounds of the present invention have good in vivo PK properties.

Claims

1. A compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, 【Chemistry 1】 【Chemistry 2】 represents a single bond or a double bond, X １ , X ２ , X ３ , X ４ are each independently selected from C or N, and X １ , X ２ , X ３ and X ４ at least one of is N; W is selected from C, N, O or S; R １ is C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C １ -C １０ Alkoxy group, C ６ -C １０ aryl group, 5- to 18-membered heteroaryl group, C ５ -C １０ cycloalkyl groups, and 5- to 10-membered heterocyclyl groups, wherein the 5- to 18-membered heteroaryl groups and the 5- to 10-membered heterocyclyl groups each contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; and the C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C １ -C １０ Alkoxy group, C ６ -C １０ aryl group, 5- to 18-membered heteroaryl group, C ５ -C １０ The cycloalkyl and 5- to 10-membered heterocyclyl groups are optionally substituted with H, halogen, —OH, —CN, oxo, amino, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyl group, C ３ -C ５ Cycloalkyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Halogenated alkyl groups, cyano-substituted C １ -C ６ Alkyl group, cyano-substituted C １ -C ６ Haloge C alkyl group １ -C ６ Halogenated alkoxy group, —C １ -C ６ Alkylene-OR ｃ , -C １ -C ６ Alkylene -C=O-R ｃ , -NO ２ , -OR ｃ , -SR ｃ , -NR ａ R ｂ , -C(=O)R ｃ , -C(=O)OR ｃ , —C(═O)NR ａ R ｂ , -NC(=O)R ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ , -S(=O) ２ NR ａ R ｂ , -S(=O)(=NR ａ ) R ｂ , -P(=O)R ａ R ｂ or -P(=S)R ａ R ｂ and optionally substituted with one or more substituents selected from R ３ is H, deuterium, halogen, -NO ２ , -NR ａ R ｂ , -CN, -OH,C １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C １ -C ５ Halogenated alkyl group, C １ -C １０ Alkoxy group, —O—C(═O)—C １－３ Alkyl group, —C(═O)—O—C １－３ Alkyl group or C ２ -C １０ alkynyl groups, １ -C １０ Alkyl group, C ２ -C １０ Alkenyl group, C １ -C ５ Halogenated alkyl group, C １ -C １０ Alkoxy group, —O—C(═O)—C １－３ Alkyl group, —C(═O)—O—C １－３ Alkyl group, C ２ -C １０ The alkynyl group may optionally be substituted with H, a halogen, —CN, —OH, an amino group, C １ -C ５ Alkyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyl group or C １ -C ５ may be substituted with one or more substituents selected from halogenated alkyl groups; R ４ and R ５ are each independently H, a halogen, or —NO ２ , -OH, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Halogenated alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C ５ cycloalkyl groups and 3- to 6-membered heterocyclyl groups, １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Halogenated alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C ５ The cycloalkyl and 3- to 6-membered heterocyclyl groups may optionally be substituted with H, halogen, —CN, —OH, amino, oxo, C １ -C ５ Alkyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyl group or C １ -C ５ may be substituted with one or more substituents selected from halogenated alkyl groups, or R ４ and R ５ together form an oxo group, or R ４ and R ５ form together with the C atom to which they are attached a substituted or unsubstituted cyclopropyl group, R ６ is H, -CN, halogen, -NO ２ , —OH, —NO ２ , -NR ａ R ｂ , oxo group, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Halogenated alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C ５ cycloalkyl groups and 3- to 6-membered heterocyclyl groups, １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Halogenated alkyl group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C ５ The cycloalkyl group and the 3- to 6-membered heterocyclyl group may optionally be selected from the group consisting of H, halogen, —CN, —OH, amino, oxo, C １ -C ５ Alkyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyl group or C １ -C ５ or two R ６ are substituted or unsubstituted C atoms together with the C atoms to which they are attached. ３ -C ５ forming a cycloalkyl group or a 3- to 5-membered heterocyclyl group, or R ６ and R ５ are substituted or unsubstituted C atoms together with the C atoms to which they are attached. ３ -C ４ forming a cycloalkyl group, R ｆ is absent or is H, —CN, halogen, C １ -C １０ Alkyl group, C １ -C １０ Halogenated alkyl group, C ３ -C １０ Cycloalkyl group, oxo group, —NR ａ R ｂ and C is selected from １ -C １０ Alkyl group, C １ -C １０ Halogenated alkyl group and C ３ -C １０ The cycloalkyl group may optionally be selected from the group consisting of H, halogen, —CN, —OH, amino, C １ -C ５ Alkyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyl group or C １ -C ５ may be substituted with one or more substituents selected from halogenated alkyl groups; R ｊ is -C １ -C ６ Alkylene -C(=O)R ｃ , -C １ -C ６ Alkylene -C(=O)OR ｃ , -C ２ F ５ , -C(=O)R ｃ , -C(=O)OR ｃ , -SR ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ or -S(=O)(=NR ａ ) R ｃ wherein said C １ -C ６ The alkylene group may optionally be selected from the group consisting of H, halogen, cyano, C １ -C ４ Alkyl group, C ２ -C ４ Alkenyl group, C ２ -C ４ Alkynyl group, C １ -C ４ Halogenated alkyl group, C １ -C ４ Alkoxy group and C １ -C ４ and optionally substituted with one or more substituents selected from halogenated alkoxy groups; R ａ and R ｂ are each independently H, CN, or C １ -C １０ Alkyl group, C １ -C １０ Halogenated alkyl group, C １ -C １０ Alkoxy group, C ２ -C １０ Alkenyl group, C ２ -C １０ Alkynyl group, C ３ -C １０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６ -C １０ selected from an aryl group or a 5- to 10-membered heteroaryl group; R ｃ is C １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C ６ Cycloalkyl groups and -NR ａ R ｂ and C is selected from １ -C １０ Alkyl group, C １ -C １０ Alkoxy group and C ３ -C ６ The cycloalkyl group is optionally selected from H, halogen, CN, -NH ２ , oxo group, C １ -C ４ Halogenated alkyl group, C １ -C ４ Halogenated alkoxy group, C ３ -C ６ optionally substituted with one or more substituents selected from cycloalkyl groups; n is 0 or 1; m is 0, 1, 2, 3 or 4; The condition is that the compound is 3-fluoro-5-(4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 3-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfoxy)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxy)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-fluoro-5-(5-fluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile, and A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, that is not 1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol.

2. The compound has formula (II-1) or formula (II-2): 【Transformation 3】 2. The compound of claim 1, wherein:

3. The compound is represented by formula (III-1), formula (III-2), formula (III-3) or formula (III-4): 【Chemistry 4】 2. The compound of claim 1, wherein:

4. The R ３ is H, deuterium, C １ -C ３ Alkyl group, C ２ -C ５ alkenyl groups, １ -C ３ Alkyl group and C ２ -C ５ The alkenyl group may optionally be substituted with H, a halogen, —CN, —OH, an amino group, C １ -C ５ 10. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from halogenated alkyl groups.

5. The R ３ is H, deuterium or C １ -C ３ 5. The compound of claim 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of alkyl groups.

6. The R ３ is H or deuterium, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof.

7. R ４ and R ５ are each independently H, halogen or C １ -C ６ alkyl group, １ -C ６ The alkyl group may optionally be substituted with H, halogen, —CN, —OH, amino, 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, noncovalent complex or solvate thereof, optionally substituted with one or more substituents selected from a methyl group, ...

8. R ４ and R ５ are each independently H, halogen or C １ -C ６ 8. The compound of claim 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of alkyl groups.

9. R ４ and R ５ are each independently selected from H or halogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, noncovalent complex, or solvate thereof.

10. R ６ is H, -CN, halogen, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group or C １ -C ６ halogenated alkyl groups, １ -C ６ Alkyl group, C １ -C ６ Alkoxy group or C １ -C ６ 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein the halogenated alkyl group is optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, oxo, and amino.

11. R ６ is H, halogen or C １ -C ６ is an alkyl group, １ -C ６ 11. The compound of claim 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the alkyl group is optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, oxo, and amino.

12. R ６ is H or a halogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof.

13. The R ｆ is H, -CN, -NH ２ , halogen, C １ -C ３ an alkyl group, a cyclopropyl group, or C １ -C ３ halogenated alkyl groups, １ -C ３ an alkyl group, a cyclopropyl group, or C １ -C ３ The halogenated alkyl group may optionally be H, a halogen, —CN, —OH, an amino group, C １ -C ３ Alkyl group, C ２ -C ４ Alkenyl group, C １ -C ３ 10. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from halogenated alkyl groups.

14. The R ｆ is H, -CN, halogen, C １ -C ３ Alkyl group or C １ -C ３ 14. The compound of claim 13, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of halogenated alkyl groups.

15. The R ｆ is selected from H, —CN or halogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof.

16. 2. The compound of claim 1, wherein W is C or O, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, noncovalent complex, or solvate thereof.

17. The R １ is C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ a cycloalkyl group or a 5- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group and the 5- to 10-membered heterocyclyl group each independently contain 1, 2, or 3 heteroatoms selected from N, O, and S; ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ The cycloalkyl group or the 5- to 10-membered heterocyclyl group may optionally be substituted with a halogen, —OH, —CN, an oxo group, an amino group, a C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Halogenated alkyl groups, cyano-substituted C １ -C ６ Alkyl group, cyano-substituted C １ -C ６ Halogenated alkyl group, —C １ -C ６ Alkylene-OR ｃ , -C １ -C ６ Alkylene -C=O-R ｃ , -NO ２ , C(=O)OR ｃ Or -S(=O) ２ R ｃ or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from:

18. The R １ is C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ a cycloalkyl group or a 5- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group and the 5- to 10-membered heterocyclyl group contain 1 or 2 N heteroatoms, and the C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ The cycloalkyl group or the 5- to 10-membered heterocyclyl group may optionally be selected from the group consisting of halogen, hydroxy, cyano, amino, C １ -C ６ Alkyl group, C ３－５ Cycloalkyl group, C １ -C ６ Halogenated alkyl groups, cyano-substituted C １ -C ６ Alkyl group, cyano-substituted C １ -C ６ Halogenated alkyl group or C １ -C ６ 18. The compound of claim 17, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from halogenated alkoxy groups.

19. The R １ is C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ a cycloalkyl group or a 5- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group and the 5- to 10-membered heterocyclyl group contain 1 or 2 N heteroatoms, and the C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ５ -C １０ The cycloalkyl group or the 5- to 10-membered heterocyclyl group may optionally be selected from the group consisting of halogen, cyano, cyano-substituted C １ -C ６ Halogenated alkyl groups, cyano-substituted C １ -C ６ Alkyl group or C １ -C ６ 20. The compound of claim 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from halogenated alkyl groups.

20. The R １ represents a phenyl group, a pyridyl group, a naphthyl group, a 10-membered heteroaryl group, C ８ -C １０ a cycloalkyl group or an 8- to 10-membered heterocyclyl group, wherein the 10-membered heteroaryl group and the 8- to 10-membered heterocyclyl group optionally contain 1 or 2 N heteroatoms; and the phenyl group, pyridyl group, naphthyl group, 10-membered heteroaryl group, C ８ -C １０ The cycloalkyl group or the 8- to 10-membered heterocyclyl group may optionally be selected from the group consisting of halogen, cyano, or C １ -C ６ 20. The compound of claim 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from halogenated alkyl groups.

21. The R ｊ is -C １ -C ６ Alkylene -C(=O)R ｃ , -C １ -C ６ Halogenated alkylene -C(=O)R ｃ , -C １ -C ６ Halogenated alkylene -C(=O)OR ｃ , -C ２ F ５ , -C １ -C ６ Cyano-substituted alkylene -C(=O)R ｃ , -C(=O)R ｃ , -C(=O)OR ｃ , -SR ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ or -S(=O)(=NR ａ ) R ｃ The compound according to claim 1, or its derivatives, isomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates.

22. The R ｊ is -C ２ F ５ , -C １ -C ６ Halogenated alkylene -C(=O)R ｃ , -C １ -C ６ Halogenated alkylene -C(=O)OR ｃ , -C(=O)OR ｃ , -C(=O)R ｃ , -SR ｃ , -S(=O) ２ R ｃ or -S(=O)(=NR ａ ) R ｃ 22. The compound of claim 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, selected from:

23. The R ｃ is C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, C ３ -C ６ Cycloalkyl groups and -NH ２ and C is selected from １ -C ６ Alkyl group, C １ -C ６ Alkoxy group and C ３ -C ６ The cycloalkyl group is optionally selected from H, halogen, CN, -NH ２ , C １ -C ４ Halogenated alkyl group, C ３ -C ６ 23. The compound of claim 22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, optionally substituted with one or more substituents selected from cycloalkyl groups.

24. The R ｃ is C １ -C ６ alkyl group, １ -C ６ 24. The compound of claim 23, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the alkyl group may be optionally substituted with one or more substituents selected from H, halogen, CN.

25. The R ａ is H, CN or C １ -C ４ 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of alkyl groups.

26. The R ｂ is H, CN or C １ -C ４ 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of alkyl groups.

27. The R ｊ teeth, 【Transformation 5】 2. The compound of claim 1, wherein the compound is selected from:

28. The compound is represented by formula (IX-1) or formula (IX-2): 【Transformation 6】 2. The compound of claim 1, wherein:

29. 1. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein said compound is 1) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzyl Zonitrile, 2) 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 4) (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 5) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 6) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 7) (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 8) (S)-3-((R)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 9) 5-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 10) (S)-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 11) (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 12) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 13) (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile, 14) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 15) 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide, 16) (S)-3-(ethylsulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 17) 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 18) N-(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro (fluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide, 19) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile, 20) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 21) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 22) (S)-5-(3-((difluoromethyl)sulfonyl)-2,5,5-trifluoroether-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 23) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 24) 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 25) 1-(3-chloro-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 26) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 27) (S)-2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 28) (S)-2-chloro-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 29) (S)-4-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 30) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 31) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 32) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 33) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 34) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 35) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoro) methyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 36) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 37) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 38) (S)-4-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 39) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 40) (S)-2-chloro-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 41) 4-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 42) (S)-4-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 43) (S)-2-(difluoromethyl)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 44) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile, 45) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 46) (S)-4-(5,5-difluoro-4-hydroxy-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 47) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile, 48) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroethyl acetate, 49) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetonitrile, 50) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide, 51) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(thiazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 52) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-( (trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 53) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(oxazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 54) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2,2-difluoroacetonitrile, 55) 2-(((S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile, 56) (S)-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide methyl 57) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)propionitrile, 58) (S)-1-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)cyclopropane-1-nitrile, 59) N-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide, 60) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carboxylate ethyl 61) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 62) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-formamide, 63) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 64) (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 65) (R)-2-(difluoromethyl)-4-(4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 66) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-3-fluorobenzonitrile, 67) (4S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 68) (S)-1-((R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 69) (S)-1-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 70) (S)-1-(2,4-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 71) (S)-2-((5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl)-5-fluorobenzonitrile, 72) (S)-1-(2,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 73) N-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxy)(trifluoromethyl)-16-sulfino)cyanamide, 74) N-((difluoromethyl)((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxo)-16-sulfino)cyanamide, 75) (S)-2-(5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorophenyl)acetonitrile, 76) (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(fluoromethyl)benzonitrile, 77) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 78) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 79) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 80) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol, 81) (S)-5-(5,5-difluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-5,6-dihydrocyclopentadiene[b]pyrrol-1(4H)-yl)-yl 2-fluorobenzonitrile, 82) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindol-8-ol, 83) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, 84) (7R,8S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7-fluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindolizin-8-ol, 85) 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,7-tetrahydropyridine pyrrol-4-ol, 86) 2-(difluoromethyl)-4-((4S,5R)-3-((difluoromethyl)sulfonyl)-5-fluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 87) 2-(difluoromethyl)-4-((4S,5R)-5-fluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 88) (S)-5,5-difluoro-1-(imidazo[1,2-a]pyridin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 89) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 90) (S)-8-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluoro-1-naphthonitrile, 91) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 92) (S)-5,5-difluoro-1-(quinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 93) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 94) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 95) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 96) 1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((fluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 97) (4S)-1-(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 98) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 99) (4S)-5,5-difluoro-3-(methylsulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 100) 5,5-difluoro-3-((fluoromethyl)sulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 101) (4S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 102) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinoline phosphon-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 103) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-((trifluoromethyl)thio)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 104) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 105) 2-fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,7-dihydropyran[3,4-b]pyrrol-1(5H)-yl)benzonitrile, 106) 2-fluoro-5-(2,5,5-trifluoro-4-hydroxy-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, or 107) A compound selected from 2-(difluoromethyl)-4-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, noncovalent complex, or solvate thereof.

30. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 29 and at least one pharmaceutically acceptable excipient.

31. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for treating a HIF-2α mediated disease.

32. Use of the pharmaceutical composition described in claim 30 in the manufacture of a medicine for treating a HIF-2α mediated disease.

33. 32. The application according to claim 31, wherein the disease is VHL syndrome, an autoimmune disease, an inflammatory disease and / or cancer.

34. 34. The application of claim 33, wherein the cancer is selected from bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, cervical cancer, endometrial cancer, lymphoma, esophageal cancer, colon cancer, thyroid cancer, prostate cancer, sarcoma, leukemia, bladder cancer, kidney cancer, glioma, cystadenoma, squamous cell carcinoma, pheochromocytoma, lung cancer, liver cancer, breast cancer, meningioma, neurocytoma, paraganglioma, blastoma, endocrine tumors, meningioma and meloblastoma.

35. A method for producing the compound according to claim 28, comprising oxidizing an intermediate compound represented by formula (A-1) or formula (A-2) to form a compound represented by formula (IX-1) or formula (IX-2), 【Transformation 7】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , R ａ , m is as defined in any one of claims 1 to 27, More preferably, the method comprises producing a compound represented by formula (A-1) by the method of Scheme 1 or Scheme 2, Scheme 1 【Transformation 8】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , R ａ , m is as defined in any one of claims 1 to 27, Scheme 2 【Chemistry 9】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , R ａ , m is as defined in any one of claims 1 to 27, More preferably, the method comprises producing a compound represented by formula (A-2) by the method of Scheme 3, Scheme 4, Scheme 5 or Scheme 6, Scheme 3 【Chemistry 10】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, Scheme 4 【Chemistry 11】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , m is as defined in any one of claims 1 to 27, and X is a halogen; Scheme 5 【Chemistry 12】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, and X is a halogen; Scheme 6 【Chemistry 13】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, and X １ is -TIPS, -Trt or -TBDPS, R １０２ is H, C １－３ alkyl group or two R １０２ together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C １－３ may be substituted with an alkyl group, More preferably, the method comprises preparing a compound of formula (C-1) by the method of Scheme 7: Scheme 7 【Chemistry 14】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , m is as defined in any one of claims 1 to 27, X is a halogen, and X １ is -TIPS, -Trt or -TBDPS, R １０２ is H, C １－３ alkyl group or two R １０２ together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C １－３ may be substituted with an alkyl group, More preferably, the method comprises producing a compound represented by formula (B-1) by the method of Scheme 8, Scheme 9 or Scheme 10, Scheme 8 【Chemistry 15】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, X is halogen, and R １０１ is C １－１０ Scheme 9 【Chemistry 16】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is any one of claims 1 to 27 wherein X is a halogen; Scheme 10 【Chemistry 17】 Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, and R １０２ is H, C １－３ alkyl group or two R １０２ together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C １－３ may be substituted with an alkyl group, More preferably, the method comprises producing a compound represented by formula (G-5) by the method of Scheme 11: Scheme 11 [Chemistry 18] Here, R ４ , R ５ , R ６ , R ｆ , R ｃ , m is as defined in any one of claims 1 to 27, X is a halogen, and X ２ is -Boc or a phenylsulfonyl group.

36. 1. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein said compound is 【Chemistry 19】 It is selected from the structure Here, R １ , R ４ , R ５ , R ６ , R ｆ , R ｃ , R ａ , m is as defined in any one of claims 1 to 27, X is a halogen, and X １ is -TIPS, -Trt or -TBDPS, and X ２ is -Boc or a phenylsulfonyl group, and R １０１ is C １－１０ is an alkyl group, and R １０２ is H, C １－３ alkyl group or two R １０２ together with the O atom to which they are attached form a 5-membered heterocycle containing two oxygen atoms and one boron atom, said 5-membered heterocycle optionally containing one or more C １－３ 1. A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein:

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