Bicyclic compounds and uses thereof

Abstract

The present invention relates to compounds of formula (I). Additionally, compositions and formulations containing such compounds, as well as methods of using and making such compounds, are provided. [Formula 1] JPEG2023529471000099.jpg60167

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] HIF (Hypoxia inducible factor), also known as hypoxia-inducible factor, is a member of a family of transcription factors that mediate the cellular hypoxic response by controlling over 40 downstream hypoxia-adaptive genes. It mainly consists of two types of HIF: HIFα (HIF-1α, HIF-2α, and HIF-3α) and HIF-1β. HIF-1β is primarily located in the nucleus, whereas HIFα is located in the cytoplasm. Under oxygen-sufficient conditions, HIFα is hydroxylated by prolyl hydroxylase PHD and ubiquitinated by VHL (Von Hippel-Lindau Syndrome) ubiquitin-conjugating enzyme, ultimately leading to proteasomal degradation. However, under hypoxic or metabolic conditions, HIFα cannot be degraded and accumulates in the nucleus. It binds to HIF-1β to form heterodimers, activating hypoxia response elements (HREs) in downstream gene promoters and regulating the transcription of related genes, allowing cells to survive under hypoxic conditions. These genes are involved in tumor angiogenesis, cell proliferation, survival, metabolism, invasion and metastasis, drug resistance, inflammation, and immunity. HIF-2α, which mediates chronic hypoxia and can be continuously activated under physiological hypoxic conditions, plays a more important role in tumor development and progression.

[0003] Previous studies have revealed that the main mechanisms by which HIF-2α mediates tumor initiation and progression are as follows: 1. Under conditions such as hypoxia or VHL mutation, the HIF-2α metabolic pathway is disrupted, resulting in its accumulation in the cell nucleus and its heterodimerization with HIF-1β, which then activates the hypoxia response element (HRE). This in turn upregulates downstream cancer-related genes, such as VEGFA, CXCR4, and cyclin D1, promoting tumor angiogenesis. 2. Because HIF-2α is also involved in the transmission of immunosuppressive signals by upregulating CD73 expression, targeting HIF-2α can restore or enhance the antitumor immune function of mature DCs, 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 essential component of the E3 ubiquitin ligase, mediating proteasomal degradation of proteins. The VHL gene has a high mutation rate of 57% or loss of heterozygosity of 98% in renal cell carcinoma (RCC), causing pseudohypoxia and activating HIF-2α, which is then transported into the nucleus. Clear cell renal cell carcinoma (ccRCC) accounts for 70-75% of primary renal cell malignancies, and VHL protein is deficient in more than 90% of ccRCC patients. When gliomas lack blood vessels, an unstable blood supply creates a hypoxic microenvironment, which induces localized high expression of HIF-2α and promotes 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 continuous activation of HIF-2α.

[0005] Activation of HIF-2α and the formation of heterodimers between HIF-1β are important factors in activating downstream pathways, and the PAS-binding domains of the two HIF-2α proteins are the binding sites for forming heterodimers. Based on this, Peloton's research and development team has developed PT2977, a small molecule inhibitor of HIF-2α that exerts anti-tumor effects by inhibiting the binding of HIF-2α and HIF-1β. Summary of the Invention [Problem to be solved by the invention]

[0006] As the HIF-2α pathway is closely related to tumor development and migration, there is a particular need to develop many more novel and more effective molecular entities. [Means for solving the problem]

[0007] The present invention provides, for the first time, a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof: [ka] During the ceremony, [ka] represents a single bond or a double bond, L is a bond, -O-, -NH-, -(CR d R e ) n -, -S-, -S(=O)-, -S(=O)2-, -C=C-, -C≡C- or a C3 to C5 cycloalkyl group, X1 and X2 are each independently selected from C or N; X3 is CR f or NR f and X4 is CR j or NR j and and at least one of X1, X2, X3, and X4 is N; R1 is C1~C10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy group, C6-C 10 Aryl group, 5-18 membered heteroaryl group, C3-C 10 cycloalkyl groups, and 3- to 10-membered heterocyclyl groups, provided that the 5- to 18-membered heteroaryl groups and 3- to 10-membered heterocyclyl groups each optionally 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 10 Alkoxy group, C6-C 10 Aryl group, 5-18 membered heteroaryl group, C3-C 10 The cycloalkyl group and the 3- to 10-membered heterocyclyl group may optionally be one or more of halogen, —OH, —CN, an oxo group, an amino group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C3-C5 cycloalkyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, —C1-C6 alkylene-OR c , -C0-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 and / or -P(=S)R a R b may be replaced by R2 is H, deuterium, halogen, -CN, -OH, =N-OH, C1-C5 haloalkyl group, amino group, C1-C 10 Alkoxy group, -OC(=O)-C 1~3 Alkyl group, -C(=O)-OC 1~3 Alkyl group or -NR a R b Selected from R3 is H, deuterium, halogen, -CN, -OH, =N-OH, C1 to C 10 Alkyl groups, C2-C 10 Alkenyl group, C1-C5 haloalkyl group, 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, and the C1 to C 10 Alkyl groups, C2-C 10 Alkenyl group, C1-C5 haloalkyl group, C1-C 10 Alkoxy group, -OC(=O)-C 1~3 Alkyl group, -C(=O)-OC 1~3 the alkyl group may be optionally substituted by one or more H, halogen, —CN, —OH, amino group, C1-C5 alkyl group, C2-C6 alkenyl group and / or C1-C5 haloalkyl group, or R2 and R3 form an oxo group; R4 and R5 are each H, halogen, -OH, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C2-C 10 Alkenyl groups, C2-C 10 alkynyl groups, C3-C5 cycloalkyl groups and 3- to 6-membered heterocyclyl groups, and 10 Alkenyl groups, C2-C 10The alkynyl group, the C3-C5 cycloalkyl group and the 3-6 membered heterocyclyl group may be optionally substituted by one or more halogens, -CN, -OH, amino groups, C1-C5 alkyl groups, C2-C6 alkenyl groups and / or C1-C5 haloalkyl groups, or R4, R5 and the C atoms connected thereto form a substituted or unsubstituted cyclopropyl group; R6 is H, -CN, halogen, -OH, -NO2, -NH2, oxo group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C2-C 10 Alkenyl groups, C2-C 10 alkynyl groups, C3-C5 cycloalkyl groups and 3- to 6-membered heterocyclyl groups, and the C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C2-C 10 Alkenyl groups, C2-C 10 The alkynyl group, the C3-C5 cycloalkyl group and the 3- to 6-membered heterocyclyl group may be optionally substituted by one or more H, halogen, -CN, -OH, amino group, oxo group, C1-C5 alkyl group, C2-C6 alkenyl group and / or C1-C5 haloalkyl group, or two R6 and the C atom connected thereto form a substituted or unsubstituted C3-C5 cycloalkyl group or a 3- to 5-membered heterocyclyl group; or R6, R5 and the C atom connected thereto form a substituted or unsubstituted C3-C4 cycloalkyl group; R d , R e are H, halogen, cyano group, and -NR a R b , C1~C 10 Alkyl group or C3-C 10 independently selected from cycloalkyl groups, or R d and R e forms an oxo group, R f None, H, -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl group, oxo group, -NR a R band C1 to C 10 Alkyl groups, C1-C 10 Haloalkyl groups and C3-C 10 the cycloalkyl group may be optionally substituted by one or more H, halogen, —CN, —OH, amino group, C1-C5 alkyl group, C2-C6 alkenyl group and / or C1-C5 haloalkyl group; R j H, -NO2, -CN, halogens, C1 to C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, -C1-C6 alkylene-OR c , -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 or -S(=O)(=NR a )R b , P(=O)R a R b , P(=S)R a R b wherein the 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocyclyl group each optionally 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 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C6-C10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with one or more halogen, hydroxy group, amino group, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl group, -S(=O)2-C3-C5 cycloalkyl group, -S(=O)-C1-C3 alkyl group, -S(=O)-C3-C5 cycloalkyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group and / or C1-C6 haloalkyl group.

[0008] R a , R b , R c are H, C1 to C, respectively. 10 Alkyl groups, C1-C 10 Haloalkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C6-C 10 independently selected from an aryl group or a 5- to 10-membered heteroaryl group; n is 1, 2 or 3; m is 0, 1, 2, 3 or 4.

[0009] In certain embodiments, [ka] represents a single bond or a double bond, L is a bond, -O-, -CR d R e -, -S-, -S(=O)-, -S(=O)2-, -C=C- or -C≡C-; X1 and X2 are each independently selected from C or N; X3 is CR f or NR f and X4 is CR j or NR j and and at least one of X1, X2, X3, and X4 is N; R1 is a substituted or unsubstituted C1-C 10Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy group, C6-C 10 Aryl group, 5-18 membered heteroaryl group, C3-C 10 cycloalkyl groups, and 3- to 10-membered heterocyclyl groups, wherein the 5- to 18-membered heteroaryl groups and the 3- to 10-membered heterocyclyl groups each optionally contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; and wherein R1 is optionally one or more of a halogen atom, a hydroxy group, a cyano group, an oxo group, an amino group, C 1~6 Alkyl group, C 2~6 Alkenyl group, C 3~5 Cycloalkyl groups, C 2~6 Alkynyl group or C 1~6 optionally substituted with haloalkyl groups; R2 is H, -OH, amino group, C1 to C 10 Alkoxy group, -O-C1-C3 alkyl acyl group or -NR a R b Selected from R3 is H, -OH, C1 to C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C 10 Alkoxy group, -OC 1~3 Alkyl acyl group or C2-C 10 alkynyl groups, or R2 and R3 together form an oxo group; R4 and R5 are each independently selected from H, halogen, —OH, a C1-C6 alkyl group or a C1-C6 haloalkyl group, or R4, R5 and the C atom connected thereto form a substituted or unsubstituted cyclopropyl group; R6 is selected from H, -CN, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or two R6 and a C atom connected thereto form a substituted or unsubstituted C3-C5 cycloalkyl group or a 3-5 membered heterocyclyl group; or R6, R5 and the C atom connected thereto form a substituted or unsubstituted C3-C4 cycloalkyl group; R d , Re are H, halogen, cyano group, and -NR a R b , C1~C 10 Alkyl group or C3-C 10 independently selected from cycloalkyl groups, or R d and R e forms an oxo group, R f H, -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, oxo, -NR a R b Selected from R j H, -NO2, -CN, halogens, C1 to C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C6-C 10 Aryl group, 5- to 10-membered heteroaryl group, -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 or -S(=O)(=NR a )R b , P(=O)R a R b , P(=S)R a R b wherein the 5- to 10-membered heteroaryl group and the 3- to 10-membered heterocyclyl group each optionally contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; jis optionally a halogen, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1~3 Alkyl group, -S(=O)2-C 3~5 Cycloalkyl group, -S(=O)-C 1~3 Alkyl group, -S(=O)-C 3~5 Cycloalkyl group, cyano group, C 1~6 Alkyl group or C 1~6 optionally substituted with haloalkyl groups; R a , R b , R c are H, C1 to C, respectively. 10 Alkyl groups, C1-C 10 Haloalkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, C6-C 10 independently selected from an aryl group or a 5- to 10-membered heteroaryl group; m is 0, 1, 2, 3 or 4.

[0010] In certain embodiments, L is a bond, -O-, NH-, -CR d R e -, -S-, -S(=O)-, -S(=O)2-, -C=C- or -C≡C-; X1 and X2 are C or N, X3 is CR f or NR f and X4 is CR j or NR j and and at least one of X1, X2 and X4 is N; R1 is C1~C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy group, C6-C 10 Aryl groups, C5-C 18 Heteroaryl groups, C3-C 10 Cycloalkyl groups, C3-C10 heterocyclyl groups, provided that the C5-C 18 Heteroaryl groups, C3-C 10 Heterocyclyl groups optionally contain one, two or three heteroatoms, each independently selected from N, O and S, and are selected from the C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy group, C6-C 10 Aryl groups, C5-C 18 Heteroaryl groups, C3-C 10 Cycloalkyl groups and C3-C 10 The heterocyclyl group may optionally be H, a halogen, a hydroxy group, a cyano group, an oxo group, an amino group, a C 1~6 Alkyl group, C 1~6 Alkoxy group, C 2~6 Alkenyl group, C 3~5 Cycloalkyl groups, C 2~6 Alkynyl group or C 1~6 optionally substituted with haloalkyl groups; R2 is H, -OH, oxo group, amino group, C1-C 10 Alkoxy group, -OC 1~3 Alkyl acyl group or -NR a R b Selected from R3 is H, -OH, oxo group, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Alkoxy groups, C1-C 10 Haloalkyl group or -OC 1~3 alkyl acyl groups, R4 and R5 are each H, halogen, -OH, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C2-C 10 Alkenyl groups, C2-C 10are independently selected from an alkynyl group, a C3-C5 cycloalkyl group and a C3-C6 heterocyclyl group, or R4, R5 and the C atom connected thereto form a substituted or unsubstituted cyclopropyl group; R6 is H, -CN, halogen, -OH, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, C2-C 10 Alkenyl groups, C2-C 10 selected from an alkynyl group, a C3-C5 cycloalkyl group, and a C3-C6 heterocyclyl group, or two R6s and a C atom connected thereto form a substituted or unsubstituted C3-C5 cycloalkyl group or a C3-C5 heterocyclyl group; or R6, R5 and the C atom connected thereto form a substituted or unsubstituted C3-C4 cycloalkyl group; R d , R e are H, halogen, cyano group, and -NR a R b , C1~C 10 Alkyl group or C3-C 10 independently selected from cycloalkyl groups, or R d and R e forms an oxo group, R j H, -NO2, -CN, halogens, C1 to C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl groups, C5-C 10 Heteroaryl group, -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)2Rc , -S(=O)2NR a R b or -S(=O)(=NR a )R b , P(=O)R a R b , P(=S)R a R b Selected from the above, provided that the C5 to C 10 Heteroaryl groups, C3-C 10 Heterocyclyl groups optionally contain one, two or three heteroatoms, each independently selected from N, O and S, and are selected from the C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl groups and C5-C 10 The heteroaryl group may optionally be substituted with H, halogen, hydroxy, cyano, oxo, amino, C1-C6 alkyl, C 1~6 Alkoxy group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C5 cycloalkyl group, C3-C6 heterocyclyl group, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1~3 Alkyl group, -S(=O)2-C 3~5 Cycloalkyl group, -S(=O)-C 1~3 Alkyl group or -S(=O)-C 3~5 optionally substituted by a cycloalkyl group; R f None, H, -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, oxo, -NR a R b Selected from R a , R b , R c are H, C1 to C, respectively. 10 Alkyl groups, C1-C10 Haloalkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C3-C 10 Cycloalkyl groups, C3-C 10 Heterocyclyl groups, C6-C 10 Aryl group or C5-C 10 heteroaryl groups, m is 0, 1, 2, 3 or 4.

[0011] Preferably, in certain embodiments, the compound is as shown in formula (II): [ka] In the formula, only one of X1 and X2 is N, and the other is C.

[0012] Preferably, in certain embodiments, the compound is as shown in formula (III-1) or formula (III-2). [ka]

[0013] Preferably, in certain embodiments, the compound is as shown in formula (III-A-1), formula (III-A-2) or formula (III-A-3). [ka]

[0014] Preferably, in certain embodiments, R2 is halogen, -CN, -OH, or =N-OH. Preferably, in certain embodiments, R2 is halogen, -CN or -OH. Preferably, in certain embodiments, R2 is F, -CN, or -OH. Preferably, in certain embodiments, R2 is halogen. Preferably, in certain embodiments, R2 is -CN. Preferably, in certain embodiments, R2 is -OH. Preferably, in certain embodiments, R2 and R3 form an oxo group.

[0015] Preferably, in certain embodiments, R3 is H, deuterium, C1-C 10 Alkyl groups, C2-C 10 alkenyl groups, and 10 Alkyl groups and C2-C 10 The alkenyl group may be optionally substituted with H, halogen, -CN, -OH, an amino group, a C1-C5 haloalkyl group, or R2 and R3 together form an oxo group.

[0016] Preferably, in certain 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 H, halogen, —CN, —OH, an amino group, or a C1-C5 haloalkyl group.

[0017] Preferably, in certain embodiments, R3 is selected from H, deuterium, or a C1-C3 alkyl group, and the C1-C3 alkyl group and the C2-C5 alkenyl group may be optionally substituted with H, halogen, —CN, —OH, an amino group, or a C1-C5 haloalkyl group. Preferably, in certain embodiments, R3 is selected from H, deuterium, or a C1-C3 alkyl group. Preferably, in certain embodiments, R3 is H or deuterium. Preferably, in certain embodiments, R3 is H. Preferably, in certain embodiments, R2 is -OH, -CN or halogen and R3 is H or deuterium, or R2 and R3 form an oxo group. Preferably, in certain embodiments, R2 is -OH, -CN, or -F, and R3 is H or deuterium, or R2 and R3 form an oxo group. Preferably, in certain embodiments, R2 is -OH and R3 is H or deuterium, or R2 and R3 form an oxo group.

[0018] Preferably, in certain embodiments, the compound is as shown in formula (IV-1) or formula (IV-2). [ka] In the formula, only one of X1 and X2 is N, and the other is C.

[0019] Preferably, in certain embodiments, R4 and R5 are each independently selected from H, halogen, or a C1-C6 alkyl group, and the C1-C6 alkyl group may be optionally substituted with H, halogen, -CN, -OH, an amino group, or an oxo group. Preferably, in certain embodiments, R4, R5 are each independently selected from H, halogen, or a C1-C6 alkyl group. Preferably, in certain embodiments, R4, R5 are each independently selected from H or halogen. Preferably, in certain embodiments, R4, R5 are each independently selected from H or F. Preferably, in certain embodiments, X4 is CR j is.

[0020] Preferably, in certain embodiments, the compound is as shown in formula (V): [ka] In the formula, only one of X1 and X2 is N, and the other is C. Preferably, in certain embodiments, L is a bond, -CH2-, -S(=O)2-, -C=C-, -C=O-, -C≡C-, or a C3-C5 cycloalkyl group. Preferably, in certain embodiments, L is a bond.

[0021] Preferably, in certain embodiments, the compound is as shown in formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4) or formula (VI-5). [ka] Preferably, in certain embodiments, X3 is CR f is.

[0022] Preferably, in certain embodiments, R f is selected from H, —CN, —NH2, halogen, a C1-C3 alkyl group, a cyclopropyl group, or a C1-C3 haloalkyl group, and the C1-C3 alkyl group, cyclopropyl group, or C1-C3 haloalkyl group may be optionally substituted with H, halogen, —CN, —OH, an amino group, a C1-C3 alkyl group, a C2-C4 alkenyl group, or a C1-C3 haloalkyl group. Preferably, in certain embodiments, X3 is CR f and R f is selected from H, —CN, halogen, a C1-C3 alkyl group, or a cyclopropyl group. Preferably, in certain embodiments, R f is H, —CN, halogen, a C1-C6 alkyl group or a C1-C3 haloalkyl group. Preferably, in certain embodiments, R f is H, —CN, halogen, a C1-C3 alkyl group or a C1-C3 haloalkyl group. Preferably, in certain embodiments, R f is H, —CN or halogen. Preferably, in certain embodiments, R f is H or a halogen. Preferably, in certain embodiments, R f is H, —CN, —F, —Cl, —Br or —CF3. Preferably, in certain embodiments, R f is H.

[0023] Preferably, in certain embodiments, R6 is H, -CN, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkyl group, and the C1-C6 alkyl group, C1-C6 alkoxy group, or C1-C6 haloalkyl group may be optionally substituted with H, halogen, -CN, -OH, an oxo group, or an amino group.

[0024] Preferably, in certain embodiments, R6 is H, halogen, or a C1-C6 alkyl group, and the C1-C6 alkyl group may be optionally substituted with H, halogen, —CN, —OH, an oxo group, or an amino group. Preferably, in certain embodiments, R6 is H, halogen, or a C1-C6 alkyl group. Preferably, in certain embodiments, R6 is H, halogen, or a C1-C3 alkyl group. Preferably, in certain embodiments, R6 is H or halogen. Preferably, in certain embodiments, R6 is H, F, Cl or Br. Preferably, in certain embodiments, R6 is H or F. Preferably, in certain embodiments, two R6 and the C atom connected thereto form a substituted or unsubstituted cyclopropyl group.

[0025] Preferably, in certain embodiments, R1 is C6-C 10 Aryl group, 5-18 membered heteroaryl group or C3-C 10 cycloalkyl groups, and said 5-18 membered heteroaryl groups optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S, respectively.

[0026] Preferably, in certain embodiments, R1 is C6-C 10 an aryl group or a 5- to 18-membered heteroaryl group, each of which optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0027] Preferably, in certain embodiments, R1 is C6-C10 an aryl group or a 5- to 18-membered heteroaryl group, each of which optionally contains one, two, or three heteroatoms independently selected from N, O, and S; 10 The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more H, halogen, hydroxyl, cyano, amino, C 1~4 Alkyl group, C 3~5 Cycloalkyl group or C 1~6 It may be substituted with a haloalkyl group.

[0028] Preferably, in certain embodiments, R1 is C6-C 10 an aryl group or a 5- to 18-membered heteroaryl group, each of which optionally contains one, two, or three heteroatoms independently selected from N, O, and S; 10 The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more halogens, cyano groups and / or C 1~6 It may be substituted with a haloalkyl group.

[0029] Preferably, in certain embodiments, R1 is a C6-C8 aryl group, a 5-8 membered heteroaryl group, or a C3-C6 cycloalkyl group, wherein the 5-8 membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the C6-C8 aryl group, the 5-8 membered heteroaryl group, or the C3-C6 cycloalkyl group optionally contains one or more of halogen, -OH, -CN, oxo group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, -C1-C6 alkylene-OR c , -C0-C6 alkylene -C=OR c , -NO2, C(=O)OR c and / or -S(=O)R c may be replaced by

[0030] Preferably, in certain embodiments, R1 is a benzene ring, a 5- to 6-membered heteroaryl group, or a C3-C6 cycloalkyl group, wherein the 5- to 6-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the benzene ring, the 5- to 6-membered heteroaryl group, or the C3-C6 cycloalkyl group may optionally be substituted with one or more halogens, —CN, and / or C1-C4 haloalkyl groups.

[0031] Preferably, in certain embodiments, R1 is a benzene ring or a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0032] Preferably, in certain embodiments, R1 is a benzene ring or a six-membered heteroaryl group, said six-membered heteroaryl group optionally containing one, two or three N heteroatoms. Preferably, in certain embodiments, R1 is a benzene ring or a pyridine ring.

[0033] Preferably, in certain embodiments, R1 is a benzene ring, which may be optionally substituted with one or more halogens, -CN and / or C1-C4 haloalkyl groups.

[0034] Preferably, in certain embodiments, said R1 is a benzene ring, which may optionally be substituted with one or more halogens, -CN, -CHF2, -CF3, -CH2CHF2 and / or -CH2CF3.

[0035] Preferably, in certain embodiments, R1 is a benzene ring, which may optionally be substituted with one or more halogens and / or -CN.

[0036] Preferably, in certain embodiments, R1 is a pyridine ring, which may be optionally substituted with one or more halogens, -CN and / or C1-C4 haloalkyl groups.

[0037] Preferably, in certain embodiments, R1 is a pyridine ring, which may optionally be substituted with one or more halogens, cyano groups, and / or trifluoromethyl groups.

[0038] Preferably, in certain embodiments, the R j H, -CN, halogen, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, -S(=O)R c , -C1 to C6 alkylene-OR c , -S(=O)2R c or P(=O)R a R b wherein the 5- to 10-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S; and the C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted by one or more halogen atoms, hydroxy groups, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl groups, -S(=O)2-C3-C5 cycloalkyl groups, -S(=O)-C1-C3 alkyl groups, -S(=O)-C3-C5 cycloalkyl groups, cyano groups, C1-C6 alkyl groups and / or C1-C6 haloalkyl groups; R a , R b , R c are each independently H or a C1 to C4 alkyl group.

[0039] Preferably, in certain embodiments, the R j is H, halogen, -CN, C1-C4 haloalkyl group, C3-C5 cycloalkyl group, 5-membered heteroaryl group, S(=O)R c , -S(=O)2R c , -S(=O)(=NR a )R b or P(=O)Me2, wherein the C3-C5 cycloalkyl group, the 5-membered heteroaryl group may be optionally substituted by one or more halogens, hydroxy groups, C1-C3 alkyl groups, C1-C3 alkoxy groups and / or C1-C3 haloalkyl groups, and the 5-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; R a , R b are each independently selected from H and a C1-C4 alkyl group; R c is selected from H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

[0040] Preferably, in certain embodiments, R j is a halogen, a cyano group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a 5-membered heteroaryl group, S(=O)R c , -S(=O)2R c , -S(=O)(=NR a )R b or P(=O)Me2, and the C3-C6 cycloalkyl group and the 5-membered heteroaryl group are optionally selected from H, halogen, hydroxyl group, C 1~3 Alkyl group, C 1~3 Alkoxy group or C 1~3 It may be substituted with a haloalkyl group.

[0041] Preferably, in certain embodiments, the R j represents a C1-C4 haloalkyl group, a cyano group, -S(=O)2R cor a 5-membered heteroaryl group, said 5-membered heteroaryl group optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, said 5-membered heteroaryl group optionally being substituted by one or more halogen C1-C3 alkyl groups and / or C1-C3 haloalkyl groups; R c is selected from H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

[0042] Preferably, in certain embodiments, the R j is selected from a C1-C4 haloalkyl group, a cyano group, or a 5-membered heteroaryl group, wherein the C5 heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S, and the C5 heteroaryl group may be optionally substituted by H, halogen, or a C1-C3 alkyl group. Preferably, in certain embodiments, the R j is a C1-C4 haloalkyl group. Preferably, in certain embodiments, the R j is a C1-C4 fluoroalkyl group. Preferably, in certain embodiments, the R j is -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2 or -CH2CF3. Preferably, in certain embodiments, the R j is -CF3. Preferably, in certain embodiments, the R a , R b are each independently selected from H and a C1-C4 alkyl group. Preferably, in certain embodiments, the R c is selected from H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group. Preferably, in certain embodiments, the R j teeth, [ka] Selected from.

[0043] Preferably, in certain embodiments, the compound is as shown in formula (VII). [ka] During the ceremony, [ka] represents a single bond or a double bond, Only one of X1 and X2 is N and the other is C, R1 is C6~C 10 Aryl group, 5-18 membered heteroaryl group, C3-C 10 cycloalkyl groups, with the proviso that said 5- to 18-membered heteroaryl groups and 3- to 10-membered heterocyclyl groups each optionally contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; The R1 may optionally be one or more of halogen, -OH, -CN, oxo group, amino group, C1 to C6 alkyl group, C1 to C6 alkoxy group, C2 to C6 alkenyl group, C3 to C5 cycloalkyl group, C2 to C6 alkynyl group, C1 to C6 haloalkyl group, -C1 to C6 alkylene-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 or -S(=O)(=NR a )R b , P(=O)R a R b and / or P(=S)R a R b is replaced by R2 is -OH, -CN or halogen, and R3 is H or deuterium, or R2 and R3 together form an oxo group; R4 and R5 are each independently H or halogen; R6 is H, halogen or a C1-C6 alkyl group; R f is H, —CN, halogen, a C1-C6 alkyl group or a C1-C3 haloalkyl group, R j H, -CN, halogen, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C6-C 10 Aryl group, 5-10 membered heteroaryl group, -S(=O)R c , -C1 to C6 alkylene-OR c , -S(=O)2R c or P(=O)R a R b wherein the 5- to 10-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C1-C 10 Haloalkyl groups, C3-C 10 Cycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted by one or more halogens, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl group, -S(=O)2-C3-C5 cycloalkyl group, -S(=O)-C1-C3 alkyl group, -S(=O)-C3-C5 cycloalkyl group, cyano group, C1-C6 alkyl group and / or C1-C6 haloalkyl group; R a , R b are each independently selected from H or a C1-C4 alkyl group; R c is selected from H, a C1-C3 alkyl group, or a C1-C3 haloalkyl group.

[0044] The present invention further provides a compound or a pharmaceutically acceptable salt thereof, said compound being as follows: 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-iodo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 5,5-difluoro-1-(4-fluoro-3-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chlorobenzene)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(5-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3,5-dichlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-bromo-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(pyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(p-tolyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluoro-5-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-ol, 1-((3,3-difluorocyclobutyl)methyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)(3,3-difluorocyclobutyl) ketone, 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-fluoro-5-(3-(methanesulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 3-fluoro-5-(4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3,5-difluorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-cyano, 3-fluoro-5-(4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-chloro-5-fluorophenyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-fluoro-5-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-fluoro-5-(4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(4-fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methyl-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-4-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-p-fluorobenzonitrile, (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-p-fluorobenzonitrile, 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolyl-8-ol, 7-fluoro-3-phenyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3,5-difluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7-fluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 2-fluoro-5-(7-fluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)benzonitrile, 3-(3,5-difluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-5-p-fluorobenzonitrile, (E)-3-(2-cyclohexylvinyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(cyclopropylethynyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-3-(1-phenylcyclopropyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-3-(phenylethynyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethyloxyphosphine, (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-nitrile, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 2-fluoro-5-(5-fluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-(difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 3-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-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-chloro-5-fluorophenyl)-3,5,5-trifluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-2-cyano, (R)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol, 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-cyano-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid, 2-acetyl-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(4-chlorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-fluoro-5-((4S)-5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 5,6-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-5-(5,5-difluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(4-chloro-3-nitrophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-amino-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5-fluoro-2-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-bromo-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(thiophen-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-dichloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolyl-8-ol, 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol, 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol, 3-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-methoxybenzonitrile, 5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 5,5-difluoro-1-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-(methanesulfonyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-methoxypyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)pyridinecarbonitrile, 1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-nitrile, (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (R)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4-vinyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-4-carbonitrile, (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)nicotinonitrile, 5-(5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-((4S)-5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(benzenesulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-(benzenesulfonyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-(benzenesulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzaldehyde, 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 2-fluoro-5-(5-fluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzaldehyde, 1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-fluoro-5-(5-fluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol, (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, or (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-p-fluorobenzonitrile.

[0045] The present invention further provides a method for preparing the compounds, and the compounds of formula (I) according to the present invention or the compounds described in the specific examples can be prepared by known organic synthesis techniques, for example, by employing a preparation method similar to that of the specific examples.

[0046] The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one of the compounds and a pharmaceutically acceptable excipient (e.g., hydroxypropylmethylcellulose). In certain compositions, the weight ratio of the compound to the excipient is about 0.001-10.

[0047] Furthermore, the present invention provides a method for treating a subject having a disease or condition mediated by HIF-2α, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In certain embodiments, the disease or condition is selected from VHL syndrome, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, nephropathy, viral infections, and obesity. In certain embodiments, the disease or condition is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type 1 diabetes), and acute transplant rejection. In certain embodiments, the disease or condition is cancer, including blood cancers, lymphoma, multiple myeloma, gastrointestinal tumors, reproductive system tumors, brain tumors, and nervous system tumors and neoplasms.

[0049] In certain embodiments, the disease or condition is a glioma, a pheochromocytoma, a paraganglioma, a colon tumor or cancer, a rectal tumor or cancer, a prostate tumor or cancer (e.g., castrate-resistant prostate cancer), a lung cancer (e.g., non-small cell lung cancer and / or small cell lung cancer), a pancreatic tumor or cancer, a liver tumor or cancer, a kidney tumor or cancer, a cervical tumor or cancer, a uterine tumor or cancer, a gastric tumor or cancer, an ovarian tumor or cancer, a breast tumor or cancer (e.g., basal or basal-like breast cancer and / or triple-negative breast cancer), a skin tumor or cancer (e.g., melanoma), a tumor or cancer of the nervous system (including the brain, meninges, and central nervous system) (including neuroblastoma, glioblastoma, meningioma, medulloblastoma).

[0050] In certain embodiments, the disease or condition is VHL syndrome. In certain embodiments, the disease or condition is renal cancer. In certain embodiments, the subject is a human. In certain embodiments, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one embodiment, the compound is administered orally. The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by HIF-2α.

[0051] The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, and further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject having a disease or condition mediated by HIF-2α.

[0052] The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The present invention includes all combinations of the preferred aspects of the present invention as set forth herein. It should be understood that the subject matter disclosed in the "Summary of the Invention" does not exhaustively or completely disclose the technology of the present invention or any embodiment thereof, and that any and all embodiments of the present invention may be combined with any other embodiment or embodiments to describe separate embodiments. It should also be understood that each individual element of an embodiment is its own independent embodiment. Furthermore, any element of an embodiment is intended to be combined with any or all other elements of any embodiment to describe separate embodiments.

[0053] In the present invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halo groups refer to fluorine, chlorine and bromine.

[0054] In the present invention, unless otherwise specified, the term "alkyl group" includes straight-chain or branched-chain saturated monovalent hydrocarbon groups. 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 groups. Similarly, in a C1-C6 alkyl group, "C1-C6" refers to a group containing 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight-chain or branched-chain configuration.

[0055] The term "alkoxy group" refers to an ether formed by a straight, branched, or cyclic alkyl group as defined above.

[0056] The term "alkylene group" refers to a divalent alkyl-linked group. An alkylene group geometrically refers to a hydrocarbon in which two C—H bonds replace the alkylene group's points of attachment 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.

[0057] The term "haloalkyl group" refers to an alkyl group in which one or more H is replaced by a halogen atom. The term "haloalkoxy group" refers to the group -O-haloalkyl group.

[0058] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a dimethyl substituent, which when attached to a C forms a carbonyl group, and when attached to a heteroatom forms a sulfinyl or sulfonyl group or an N-oxide group.

[0059] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a carbocycle or heterocycle as a polyunsaturated ring having aromaticity (having (4n+2) delocalized π electrons, where n is an integer).

[0060] The term "aryl group" refers to a substituted or unsubstituted stable aromatic hydrocarbon group having 6 to 10 ring 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.

[0061] The term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S. The term "5-18-membered" in a 5-18-membered heteroaryl group refers to a heteroaryl group containing 5-18 carbon atoms or N, O, or S as ring atoms. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuryl, and the like.

[0062] The term "cycloalkyl group" refers to a ring system having at least one cyclic alkyl group. 10 Cycloalkyl group" and "C3~C 10 " refers to the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Cycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused, spiro, paracyclic, etc.) rings. In certain embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like, and in certain embodiments, cycloalkyl groups further include moieties having one or more aromatic rings fused to the cyclic alkyl group, such as, for example, benzo or thienyl derivatives of cyclohexane.

[0063] The term "cycloalkenyl group" refers to a ring system having at least one cyclic alkenyl group, said cycloalkenyl group having one or more carbon-carbon double bonds. 10Cycloalkenyl group" and "C3-C 10 " refers to the fact that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Cycloalkenyl groups may include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused, spiro, bridged, etc.) rings. In certain embodiments, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, and the like; in certain embodiments, cycloalkenyl groups further include moieties having one or more aromatic rings fused to the cyclic alkenyl ring, such as benzo or thienyl derivatives of a cyclohexene ring.

[0064] The term "heterocyclyl group" refers to a ring system having at least one cycloalkyl or cyclic alkenyl group containing a heteroatom, where the heteroatom is selected from N, O, and / or S. The heterocyclyl group may contain a single ring or multiple rings (e.g., two, three, or four fused, spiro, bridged, etc. rings). The heterocyclyl group may be connected 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 cyclic alkyl or cyclic alkenyl ring, e.g., benzo or thienyl derivatives such as piperidine, morpholine, etc. In certain embodiments, heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuryl, piperidinyl, morpholinyl, azepane, dihydrobenzofuryl, and the like.

[0065] As used herein, the term "composition" includes a product containing a specified number of specified components, and is intended to include any product obtained directly or indirectly from the specified number of specified components. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for producing the compounds are also within the scope of the present invention. Furthermore, crystalline forms of certain compounds may exist in the form of crystalline polymorphs, which are also included in the present invention. Furthermore, certain compounds form solvates with water (e.g., hydrates) or common organic solvents, and these solvates are also included in the present invention.

[0066] As used herein, "compound" includes compounds of formula (I) and all of their pharmaceutically acceptable forms, including salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, isotopically labeled compounds, tautomers, prodrugs, or any mixture of all of the foregoing forms.

[0067] The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable and mirror images of each other; 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 conventional RS system is used (e.g., (1S,2S) to specify a single stereoisomer having two chiral centers of known relative and absolute configuration). Optically active (R)- and (S)-isomers may be synthesized from optically active starting materials, prepared with chiral reagents, or resolved by conventional techniques (e.g., separation on chiral SFC or HPLC columns).

[0068] The "diastereomers" are stereoisomers that have at least two asymmetric atoms and are not mirror images of each other. When compounds are pure enantiomers, the stereochemistry of each chiral carbon can be designated as R or S.

[0069] Resolved compounds of unknown absolute configuration can be named (+) or (-) for the direction (right-handed or left-handed) they rotate plane-polarized light at the wavelength of the sodium D line, or they can be defined by the corresponding retention times of the corresponding enantiomers / diastereomers on chiral HPLC.

[0070] Those skilled in the art will recognize that the compounds of the present invention may contain one or more chiral centers, resulting in the formation of diastereomers and optical isomers. Because the stereochemistry of the compounds at specific positions in Formula (I) is not clearly defined, they may exist in different isomeric forms. Unless otherwise specified, the present invention includes all possible stereoisomers of the compounds of Formula (I) and pharmaceutically acceptable salts thereof, including, for example, racemic mixtures, optically pure forms, and mixtures of isomers in any ratio. Furthermore, mixtures of stereoisomers and resolved specific stereoisomers are encompassed by the present invention. The products of synthetic processes for preparing such compounds, or processes using racemization or epimerization methods well known to those skilled in the art, may be mixtures of stereoisomers.

[0071] Drug precursors (prodrugs) of the compounds of the present invention are included within the scope of protection of the present invention. Generally, the drug precursor refers to a functional derivative that is easily converted into a predetermined compound under in vivo conditions. Therefore, the term "administration" in the treatment methods provided by the present invention includes administration of a compound disclosed in the present invention, or administration of a compound that is not explicitly disclosed but that is converted into a prodrug disclosed in the present invention under in vivo conditions after administration to a subject. Conventional methods for selecting and preparing suitable drug precursor derivatives are described in literature such as "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

[0072] It should be understood that the definition of any substituent or variable at a particular position in a particular molecule is independent of other positions in the molecule, and those skilled in the art will appreciate that the substituents or substitution patterns of the compounds of the present invention can be selected using techniques known in the art and methods described herein to provide compounds that are chemically stable and easy to synthesize.

[0073] It is understood that the definition of any substituent or variable at a particular position in a particular molecule is independent of the definition of any substituent or variable at a particular position in another molecule, and it is understood that by selecting appropriate substituents or substitution patterns based on the prior art in the field, the compounds of the present invention are chemically stable and can be prepared or synthesized by methods known in the art or described herein.

[0074] When the compound represented by formula (I) and its pharmaceutically acceptable salts are in the form of a solvate or crystalline polymorph, the present invention includes any possible solvate and crystalline polymorph. The type of solvent for forming the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, any solvent such as water, ethanol, propanol, or acetone can be used.

[0075] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be easily prepared from a pharmaceutically acceptable non-toxic base (including inorganic bases and organic bases). Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low), iron (III), iron (II), lithium, magnesium, manganese (high and low), potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Non-toxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines, and tertiary amines, as well as cyclic amines and amines containing substituents (e.g., naturally occurring amines and synthetic amines containing substituents). Other pharmaceutically acceptable, non-toxic organic bases which can be converted into 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 glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminotrimethylolmethane, and the like.

[0076] When the compound provided by the present invention is a base, the corresponding salt can be easily prepared from a pharmaceutically acceptable non-toxic acid (including inorganic and organic acids). Examples of such acids include 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, cyclohexylsulfamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, etc. Preferred are citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, it is formic acid or hydrochloric acid. Since the compound of formula (I) is used as a drug, it is preferable to use a substantially pure form, for example, at least 60% pure, preferably at least 75% pure, particularly at least 98% pure (% by weight).

[0077] The pharmaceutical compositions provided by the present invention comprise a compound represented by Formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and any other therapeutic ingredients or additives. In any case, the most appropriate administration mode of the active ingredient will be determined based on the recipient, the subject's attributes, and the severity of the condition, but the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous administration, intramuscular injection, and intravenous administration) administration. The pharmaceutical compositions of the present invention may be presented in a unit dosage form well known in the art, and may be prepared by any manufacturing method well known in the pharmaceutical arts.

[0078] In practice, according to conventional drug mixing techniques, the compound of formula (I) of the present invention, or a drug precursor, metabolite, or pharmaceutically acceptable salt thereof, can be mixed with a pharmaceutical carrier as an active ingredient to obtain a pharmaceutical composition. The pharmaceutical carrier can take a variety of forms depending on the desired mode of administration (e.g., oral or injection (including intravenous injection)). Accordingly, the pharmaceutical composition of the present invention can be in a discrete unit form suitable for oral administration, such as a capsule, cachet, or tablet containing a predetermined dose of the active ingredient. Furthermore, the pharmaceutical composition of the present invention can be in the form of a powder, granules, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms described above, the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a controlled-release manner and / or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of combining the active ingredient with a carrier comprising one or more necessary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers, or finely divided solid carriers, or a mixture of both, and then easily giving the product the desired appearance.

[0079] Thus, pharmaceutical compositions according to the present invention comprise a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the present invention also include a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more other compounds having therapeutic activity.

[0080] Pharmaceutical carriers used in the present invention may be, for example, solid carriers, liquid carriers, or gaseous carriers. Solid carriers include lactose, algae powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, and water. Gaseous carriers include carbon dioxide and nitrogen. Any suitable pharmaceutically acceptable medium can be used to prepare pharmaceutically acceptable oral preparations. For example, water, ethylene glycol, oils, alcohols, sweeteners, preservatives, coloring agents, and the like can be used for oral liquid preparations (e.g., suspensions, elixirs, and solutions), while carriers (e.g., starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, and the like) can be used for oral solid preparations (e.g., powders, capsules, and tablets). Considering ease of administration, tablets and capsules are preferred oral preparations, and solid pharmaceutical carriers are used in these preparations. Optionally, tablet coating may utilize standard aqueous or nonaqueous formulation techniques.

[0081] Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compression or molding, optionally with 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. The powdered compound or pharmaceutical composition can be moistened with an inert liquid diluent and then molded in a suitable machine to produce tablets. Preferably, each tablet contains about 0.05 mg to 5 g of the active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of the active ingredient. For example, a dosage form for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with suitable excipients for easy measurement, which excipients 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.

[0082] The pharmaceutical compositions suitable for parenteral administration provided by the present invention may be prepared by adding the active ingredient to water to form an aqueous solution or suspension. A suitable surfactant such as hydroxypropyl cellulose may be included. Dispersions can also be prepared from glycerin, liquid polyethylene glycols, and mixtures thereof in oils. In addition, preservatives may be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

[0083] The pharmaceutical compositions suitable for injection according to the present invention include sterile aqueous solutions or dispersions. Furthermore, the pharmaceutical compositions can be manufactured in the form of sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In any case, the final injectable product must be sterile and fluid for easy injection. Furthermore, the pharmaceutical composition must be stable during manufacture and storage. Therefore, it is preferably preserved so as to be protected from the contamination of microorganisms (e.g., bacteria and fungi). The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0084] The pharmaceutical compositions provided by the present invention may be in a form suitable for topical administration, such as an aerosol, emulsion, ointment, lotion, powder, or other dosage form. Furthermore, the pharmaceutical compositions provided by the present invention may be in a form suitable for use in transdermal administration devices. The compounds of formula (I) according to the present invention, or pharmaceutically acceptable salts thereof, can be prepared by conventional processing methods. For example, emulsions or ointments can be prepared by adding a hydrophilic material and water to about 5 wt% to 10 wt% of the compound to produce an emulsion or ointment with the desired properties.

[0085] The pharmaceutical composition provided by the present invention may be prepared using a solid carrier so as to be in a form suitable for rectal administration. A preferred dosage form is a unit-dose suppository formed from a mixture. Suitable additives include cocoa butter and other materials commonly used in the art. Suppositories can be easily prepared by first mixing the pharmaceutical composition with softened or melted additives, followed by cooling and shaping in a mold.

[0086] In addition to the above-mentioned carrier components, the pharmaceutical formulation may contain one or more suitable additional additive components, such as, for example, diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants include penetration enhancers that adjust the blood osmotic pressure of the drug. Pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared in the form of a powder or a liquid concentrate.

[0087] Generally, the dosage level of a drug for treating the above-mentioned conditions or disorders is about 0.01 mg / kg to 150 mg / kg of body weight per day, or 0.5 mg to 7 g per patient per day. However, it will be understood that the specific dosage level for a particular patient will depend on various factors, such as age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concurrent drug use, and the severity of the disease being treated. DETAILED DESCRIPTION OF THE INVENTION

[0088] In order to facilitate understanding of the present invention, the present invention will be described in detail below in conjunction with examples. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Unless otherwise specified, all experimental methods used in the present invention are conventional methods. Unless otherwise specified, all experimental materials used in the present invention are commercially available products. All parts and percentages are calculated by weight and all temperatures are in degrees Celsius unless otherwise stated.

[0089] The following abbreviations are used in the examples: CuI: cuprous iodide; DAST: diethylaminosulfur trifluoride; DCM: dichloromethane, 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 hexamethyldisilazane; m-CPBA: m-chloroperbenzoic acid; MtBE: tert-butyl methyl 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: tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0), Prep-TLC: preparative thin layer chromatography; Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), TBAF: tetrabutylammonium fluoride; TEA: triethylamine; THF: tetrahydrofuran; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TLC: thin layer chromatography; ESI-MS: electrospray mass spectrometry; LCMS or LC-MS: Liquid Chromatography Mass Spectrometry; 1 H NMR: hydrogen nuclear magnetic resonance spectrum; [(R,R)-Ts-DPEN]RuCl(p-cymene): chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide}(p-cymene)ruthenium(II).

[0090] Intermediate M1: Synthesis of (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0091] Step 1: Synthesis of compound M1-1 Under nitrogen protection, 6,7-dihydro-1H-indol-4(5H)-one (13.5 g) was dissolved in DMF (100 mL), and 60% NaH (4.4 g) was slowly added in an ice bath. After stirring for 30 minutes, triisopropylsilyl chloride (21.2 g) was added. The reaction mixture was stirred at 0 °C for 3 hours, poured into ice-water (500 mL), extracted with ethyl acetate (500 mL x 2), washed with saturated brine (500 mL x 2), dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:10) to obtain the target compound M1-1 (20.3 g). ESI-MS m / z: 292.10 [M+H] + .

[0092] Step 2: Synthesis of compound M1-2 Under nitrogen protection, compound M1-1 (13.5 g) was dissolved in DMF (100 mL), NIS (11.5 g) was added in several portions, and the mixture was allowed to react at room temperature for 7 hours. The reaction mixture was poured into ice-water (500 mL) and extracted with ethyl acetate (500 mL x 2), washed with saturated brine (500 mL x 2), dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:10) to obtain the target compound M1-2 (8.7 g). ESI-MS m / z: 418.10 [M+H] + .

[0093] Step 3: Synthesis of compounds M1-3 Compound M1-2 (5.5 g) was dissolved in THF (50 mL) and cooled to -78 ° C. A 1.0 M LiHMDS solution in tetrahydrofuran (35.6 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. After that, a tetrahydrofuran solution (50 mL) of NFSI (8.72 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:10) to obtain the target compound M1-3 (2.1 g). ESI-MS m / z: 454.10 [M + H] + .

[0094] Step 4: Synthesis of compound M1 Compound M1-3 (2.1 g) was dissolved in a mixture of THF (20 mL) and water (20 mL), and K2CO3 (1.27 g) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (DCM 100%) to give the target compound M1 (0.5 g). ESI-MS m / z: 297.99 [M+H] + . 1 H NMR (500MHz, DMSO-d6): δ12.05 (s, 1H), 7.12 (d, J = 2.3Hz, 1H), 2.98 (t, J = 6.2Hz, 2H), 2.60-2.53 (m, 2H).

[0095] Intermediate M2: Synthesis of (5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0096] M1 (12 g), cuprous iodide (7.8 g), and methyl fluorosulfonyldifluoroacetate (24 g) were added to DMF (120 mL) and heated to 130 °C under nitrogen protection overnight. After TLC and LCMS confirmed that no starting material remained, the mixture was cooled and diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (EA:PE = 1:5) to give the target compound M2 (8.4 g). ESI-MS m / z: 238.00 [MH] - . 1 H NMR (500MHz, DMSO) δ12.37 (s, 1H), 7.56 (s, 1H), 3.03 (t, J = 6.1Hz, 2H), 2.68-2.55 (m, 2H).

[0097] Intermediate M3: Synthesis of (5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0098] 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 added to a 50 mL single-neck flask in this order, and the temperature was raised to 120 ° C. and the reaction was continued for 6 hours. The reaction mixture was diluted with EA, washed three times with water, washed once with saturated brine, 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). ESI-MS m / z: 204.08 [M + H]+ .

[0099] Step 2: Synthesis of compound M3 Under nitrogen protection, compound M3-1 (264 mg) was dissolved in ultra-dehydrated tetrahydrofuran (20 mL), cooled to -78 °C, and 1.0 M LDA tetrahydrofuran solution (2.5 mL) was slowly added dropwise. After stirring for 30 minutes, NFSI (491 mg) in tetrahydrofuran solution (5 mL) was added dropwise. The reaction mixture was then stirred for 2 hours at -78 °C. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM 100%) to obtain the target compound M3 (147 mg). ESI-MS m / z: 222.12 [M+H] + .

[0100] 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]

[0101] Step 1: Synthesis of compound M4-1 Under nitrogen protection, methyl 3-bromo-1H-pyrrole-2-carboxylate (20.4 g) and methyl 4-bromobutyrate (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 mixture was poured into ice-water (500 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:10) to obtain the target compound M4-1 (28.3 g). ESI-MS m / z: 304.10 [M+H] + .

[0102] Step 2: Synthesis of compound M4-2 Under nitrogen protection, 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 in an ice bath. After stirring at 0 ° C for 3 hours, the mixture was cooled to -78 ° C, and NFSI (18.9 g) in tetrahydrofuran solution (50 mL) was added dropwise. The mixture was then reacted at -78 ° C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to obtain the target compound M4-2 (9.1 g). ESI-MS m / z: 277.15 [M + H] + .

[0103] Step 3: Synthesis of compound M4-3 Under nitrogen protection, 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 over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:4) to obtain the target compound M4-3 (4.23 g). ESI-MS m / z: 279.20 [M+H] + .

[0104] Step 4: Synthesis of compound M4-4 Compound M4-3 (4.23 g) was dissolved in a mixture of ethanol (20 mL) and 6 M aqueous hydrochloric acid (20 mL) and refluxed for 3 hours. The ethanol was removed by concentration under reduced pressure, and the residue was extracted with ethyl acetate (100 mL x 2). The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:4) to give the target compound M4-4 (2.1 g). ESI-MS m / z: 221.20 [M+H] + .

[0105] 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, and the reaction mixture was refluxed for 4 hours. The mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound M4 (2.5 g). ESI-MS m / z: 300.10 [M+H] + .

[0106] Step 6: Synthesis of compound M5 Compound M4 (1.3 g) was dissolved in THF (50 mL), cooled to -78 ° C, and 1.0 M LiHMDS in tetrahydrofuran (6 mL) was slowly added dropwise. After stirring for 30 minutes, NFSI (1.5 g) in tetrahydrofuran (10 mL) was added dropwise. After stirring for 2 hours, saturated aqueous ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate twice, washing with saturated brine twice, drying, and concentration to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound M5 (2.1 g). ESI-MS m / z: 318.14 [M + H] + .

[0107] Intermediate M6: Synthesis of (5,6-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one) [ka]

[0108] Step 1: Synthesis of compound M6-11 Under nitrogen protection, 1,3-dimethoxy-5-fluorobenzene (15.6 g) was dissolved in tert-butanol (25 mL) and tetrahydrofuran (15 mL) and added to liquefied ammonia solution (650 mL). Metallic lithium (1.75 g) was added in several portions, and the blue solution was stirred at -65°C or below for 3 hours. Solid ammonium chloride was added, and when the blue color disappeared, the temperature was raised to volatilize and remove the liquefied ammonia. The residue was diluted with petroleum ether, washed with water, washed with saturated brine, dried, and concentrated to obtain the desired product M6-11 (10 g).

[0109] Step 2: Synthesis of compound M6-12 Compound M6-11 (10 g) was dissolved in tetrahydrofuran (100 mL), 1N hydrochloric acid (100 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, extracted three times, and then dried and concentrated to give the desired product M6-12 (10 g). ESI-MS m / z: 129.10 [M−H] - .

[0110] Step 3: Synthesis of compound M6-21 The compound 2-bromo-1,1-dimethoxyethane (82.4 mL) was dissolved in DMSO (14 mL), sodium azide (1.95 g) and potassium iodide (0.33 g) were added, the mixture was heated to 90°C and stirred for 5 days, cooled to room temperature, diluted with water and diethyl ether, and the aqueous phase was extracted three times with diethyl ether, dried, and concentrated to obtain M6-21 (30 g).

[0111] Step 4: Synthesis of compound M6-13 Compound M6-21 (5.73 g) was dissolved in THF (150 mL), M6-12 (3.86 g) was added, triphenylphosphine (11.8 g) was added, and the mixture was heated to reflux overnight, cooled to room temperature, concentrated, and subjected to column chromatography to give M6-13 (7.24 g).

[0112] Step 5: Synthesis of compound M6-14 Compound M6-13 (7.24 g) was dissolved in dichloromethane (100 mL), cooled to 0° C., trifluoroacetic acid (5 mL) was added, stirred at room temperature overnight, concentrated, and subjected to column chromatography to give the desired product M6-14 (5 g).

[0113] Step 6: Synthesis of compound M6-15 M6-15 was obtained by referring to the preparation method of compound M1-1. Step 7: Synthesis of compound M6-16 M6-16 was obtained by referring to the preparation method of compound M1-2. Step 8: Synthesis of compound M6-17 M6-17 was obtained by referring to the preparation method of Step 2 of compound M3. Step 9: Synthesis of compound M6-18 M6-18 was obtained by referring to the preparation method of intermediate M2. Step 10: Synthesis of compound M6 M6 was obtained by following the procedure for preparing Intermediate M1, Step 4.

[0114] Examples 1 and 2: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A13) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A2) [ka]

[0115] Step 1: Synthesis of compound A13 Compound M1 (300 mg) was dissolved in DCM (20 mL), copper acetate (90 mg), 3-chloro-5-fluorophenylboronic acid (350 mg), and TEA (404 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to give the target compound A13 (255 mg). ESI-MS m / z: 426.09 [M+H] + .

[0116] Step 1: Synthesis of compound A2 Compound A13 (43 mg) was dissolved in methanol (2 mL), NaBH4 (8 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:5) to obtain the target compound A2 (34 mg). ESI-MS m / z: 409.90 [M + H-HO] + . Substantially the same method as in Example 1 was adopted, [ka] The following examples are prepared:

[0117] [ka]

[0118] Examples 6 and 7: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A18) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A1) [ka]

[0119] Step 1: Synthesis of compound A18 Under nitrogen protection, compound A13 (255 mg) was dissolved in DMF (5 mL), Pd2(dba)3 (165 mg), CuI (114 mg), and methyl fluorosulfonyldifluoroacetate (230 mg) 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 over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to give the target compound A18 (176 mg). ESI-MS m / z: 368.20 [M+H] + .

[0120] Step 2: Synthesis of compound A1 Compound A18 (147 mg) was dissolved in methanol (4 mL), NaBH4 (30 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:5) to give the target compound A1 (118 mg). ESI-MS m / z: 352.11 [M + H-HO] + . Substantially the same method as in Examples 1 to 7 was adopted. [ka] The following examples are prepared:

[0121] [ka] [ka] [ka]

[0122] Example 28 and Example 29: Synthesis of 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A19) and 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A3) [ka]

[0123] Step 1: Synthesis of compound 3-1 Intermediate M1 (300 mg) was dissolved in DMF (10 mL), K2CO3 (276 mg) and 3-chloro-5-fluorobenzyl bromide (245 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:7) to give the target compound 3-1 (307 mg). ESI-MS m / z: 440.10 [M+H] + .

[0124] Step 2: Synthesis of compound A19 Under nitrogen protection, compound 3-1 (307 mg) was dissolved in DMF (5 mL), Pd(dba) (192 mg), CuI (133 mg), and methyl fluorosulfonyldifluoroacetate (265 mg) were added, and the mixture was stirred at 100 °C for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:10) to give the target compound A19 (186 mg). ESI-MS m / z: 382.20 [M+H] + .

[0125] Step 3: Synthesis of compound A3 Compound A19 (186 mg) was dissolved in methanol (4 mL), NaBH4 (56 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:5) to give the target compound A3 (158 mg). ESI-MS m / z: 366.22 [M + H-HO]. + . Substantially the same method as in Examples 1 to 28 was used, [ka] The following examples are prepared:

[0126] [ka]

[0127] Example 33 and Example 34: Synthesis of 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A12) and 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A4) [ka]

[0128] Step 1: Synthesis of compound 4-1 Under nitrogen protection, compound M1-1 (2.91 g) was dissolved in THF (40 mL) and cooled to -78 °C. A 1.0 M solution of LiHMDS in tetrahydrofuran (28 mL) was slowly added dropwise and stirred for 30 minutes. After that, a solution of NFSI (6.6 g) in tetrahydrofuran (40 mL) was added dropwise and stirred for 2 hours while maintaining the temperature at -78 °C. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain crude compound 4-1 (2.8 g), which was used directly in the next step.

[0129] Step 2: Synthesis of compound 4-2 Crude compound 4-1 (2.8 g) was dissolved in a mixed solvent of THF (20 mL) and water (20 mL), and K2CO3 (2.76 g) was added at room temperature. The mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (DCM 100%) to give the target compound 4-2 (512 mg). ESI-MS m / z: 172.12 [M+H] + .

[0130] Step 3: Synthesis of compound A12 Compound 4-2 (171 mg) was dissolved in DCM (50 mL), copper acetate (90 mg), 3,5-difluorophenylboronic acid (316 mg), and TEA (404 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to give the crude product, which was then subjected to column chromatography (EA:PE = 1:5) to give the target compound A12 (170 mg). ESI-MS m / z: 284.08 [M+H] + .

[0131] Step 4: Synthesis of compound A4 Compound A12 (170 mg) was dissolved in methanol (4 mL), NaBH4 (46 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:5) to give the target compound A4 (137 mg). ESI-MS m / z: 268.13 MS [M + H-HO] + .

[0132] Example 35 and Example 36: Synthesis of 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one (Compound A20) and 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A5) [ka]

[0133] Step 1: Synthesis of compound 5-1 Compound M1-2 (19 g), THF (150 mL), and TBAF (13.09 g) were added to a 500 mL single-neck flask in this order and allowed to react at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give a residue. PE / EA (V:V = 1:1, 100 mL) was added to the residue, stirred, and filtered under suction. The filter cake was eluted twice with EA to give compound 5-1 (5.2 g).

[0134] Step 2: Synthesis of compound 5-2 Compound 5-1 (500 mg), cesium carbonate (2.5 g), cyclohexyl 4-methylbenzenesulfonate (1.2 g), and DMF (10 mL) were added to a 50 mL single-neck flask in this order, and the mixture was heated to 100°C and reacted overnight. The reaction mixture was diluted with EA, washed three times with water and once with saturated sodium chloride solution, dried, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound 5-2 (230 mg).

[0135] Step 3: Synthesis of compound 5-3 The target compound 5-3 can be prepared by employing a similar synthesis method to compound A19, substituting compound 5-2 for compound 3-1.

[0136] Step 4: Synthesis of compound A20 Using a similar synthesis method to Step 3 of intermediate M1, and substituting compound 5-3 for compound M1-2, target compound A20 can be prepared.

[0137] Step 5: Synthesis of compound A5 Using the same synthesis method as compound A4, compound A12 can be replaced with compound A20 to prepare target compound A5. LCMS: 306.18 [M+H-H2O] + .

[0138] Example 37: Synthesis of 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A6) [ka]

[0139] Step 1: Synthesis of compound 6-1 Using a similar procedure to intermediate M4, compound 6-1 can be prepared by replacing M4-4 with M1-1.

[0140] Step 2: Synthesis of compound 6-2 At room temperature, TBAF (21 mL, 1 M in THF) was added to a solution of compound 6-1 (2.6 g) in THF (30 mL), and the mixture was stirred for 1 h. The reaction mixture was concentrated, diluted with water, extracted with EA, and concentrated to give the crude product. The crude product was purified on a silica gel column (EA:PE=70%) to give the target compound 6-2 (1.1 g).

[0141] Step 3: Synthesis of compound 6-3 At room temperature, potassium carbonate (968 mg) and 1,3,5-trifluorobenzene (617 mg) were added to a solution of compound 6-2 (500 mg) in DMF (10 mL), and the temperature was then raised to 100°C and stirred overnight. The reaction mixture was quenched by adding water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA:PE=17%) to obtain the target compound 6-3 (400 mg).

[0142] Step 4: Synthesis of compound 6-4 Compound 6-3 (100 mg), cuprous iodide (111.18 mg), NMP (3 mL), and methyl fluorosulfonyldifluoroacetate (112.15 mg) were added to a 25 mL single-neck flask in this order, and the mixture was heated to 120 ° C. and reacted for 6 hours. The reaction mixture was diluted with EA, washed three times with water, washed once with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (DCM:PE = 2:1) to obtain the target compound 6-4 (9.8 mg). ESI-MS m / z: 332.06 [M + H] + .

[0143] Step 5: Synthesis of Compound A6 Using the same synthesis method as M3, compound A6 can be prepared by replacing compound M3-1 with compound 6-4. LCMS: [M+H-H2O] + :300.09.

[0144] Example 38 and Example 39: Synthesis of 3-fluoro-5-(3-(methanesulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound A24) and 3-fluoro-5-(4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound A8) [ka]

[0145] Step 1: Synthesis of compound 8-1 At room temperature, potassium carbonate (1000 mg) and 3,5-difluorobenzonitrile (700 mg) were added to a solution of compound 5-1 (500 mg) in DMF (10 mL), and the temperature was then raised to 100°C and stirred overnight. The reaction mixture was quenched by adding water, diluted with ethyl acetate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE=17%) to obtain the target compound 8-1 (350 mg).

[0146] Step 2: Synthesis of compound 8-2 Compound 8-1 (380 mg), methyl 3-mercaptopropionate (240 mg), Xantphos (116 mg), and Pd2(dba)3 (89 mg) were added to toluene (10 mL), stirred at 70 °C overnight, and concentrated to give a residue. The residue was purified by column chromatography to give the target compound 8-2 (232 mg).

[0147] Step 3: Synthesis of compound 8-3 At -78 °C, potassium tert-butoxide (43 mg) was added to a solution of compound 8-2 (120 mg) in THF (10 mL). After stirring until the raw materials disappeared, iodomethane (92 mg) was added and the mixture was stirred for 5 hours. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound 8-3 (71 mg).

[0148] Step 4: Synthesis of compound A24 At room temperature, m-CPBA (223 mg) was added to compound 8-3 (130 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 10 hours. The reaction mixture was extracted with aqueous sodium thiosulfate, diluted with dichloromethane, washed with aqueous sodium bicarbonate, washed with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound A24 (71 mg). ESI-MS m / z: 333.20 [M+H] + .

[0149] Step 5: Synthesis of compound A8 Compound 8 can be prepared by using the same synthesis method as compound A2, replacing compound A13 with compound 8-4. ESI-MS m / z: 317.11 [M+H-HO] + .

[0150] Example 40: Synthesis of 1-(3,5-difluorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile (Compound A25) [ka]

[0151] Step 1: Synthesis of compound A25-1 At room temperature, potassium carbonate (900 mg) and 1,3,5-trifluorobenzene (600 mg) were added to a solution of compound 5-1 (450 mg) in DMF (10 mL), and the temperature was then raised to 100°C and stirred overnight. The reaction mixture was quenched by adding water, diluted with ethyl acetate, and concentrated to obtain the crude product, which was purified by column chromatography (EA:PE=17%) to obtain the target compound A25-1 (400 mg).

[0152] Step 2: Synthesis of compound A25-2 Under nitrogen protection, compound A25-1 (200 mg) was dissolved in DMF (5 mL), Zn(CN) (117 mg) and Pd(PPh) (58 mg) were added, and the mixture was stirred at 120 °C for 2 h. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to give the target compound A25-2 (120 mg).

[0153] Step 3: Synthesis of compound A25 Compound A25-2 (100 mg) was dissolved in a mixed solvent of THF (2 mL) and HO (1 mL), and NaBH (18 mg) was added in an ice bath. The mixture was stirred at 0 °C for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A25 (15 mg). ESI-MS m / z: 257.10 [M + H-HO] + . The following compounds are obtained by employing the same preparation methods as in Examples 1 to 40.

[0154] [ka]

[0155] Example 47: Synthesis of 1-(3,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A7) [ka]

[0156] Step 1: Synthesis of compound 7-1 At room temperature, Pd(dppf)Cl (12.52 mg), KCO (42.38 mg), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (38.28 mg) were added to a solution of compound 6-3 (50 mg) in dioxane (2 mL) and H2O (0.5 mL). The mixture was purged with nitrogen three times and reacted in a microwave at 100 °C for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated to give the target compound 7-1 (40 mg).

[0157] Step 2: Synthesis of compound A7 Compound A7 can be prepared by using the same preparation method as compound A2, replacing compound A13 with compound 7-1. ESI-MS m / z: 312.14 [M+H] + .

[0158] Example 48: Synthesis of (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A65) [ka]

[0159] Step 1: Synthesis of compound A65-1 Compound A13 (100 mg), 2-thiopheneboronic acid (36 mg), Pd(PPh3)4 (30 mg), and potassium carbonate (97 mg) were added to dioxane (5 mL) and water (1 mL). The mixture was reacted overnight at 90 °C under nitrogen protection, diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to prep-TLC to obtain the desired product A65-1 (60 mg). ESI-MS m / z: [M+H] + :382.05.

[0160] Step 2: Synthesis of compound A65 Compound A65-1 (60 mg) was dissolved in dichloromethane (2 mL), cooled in an ice-water bath, and [(R,R)-Ts-DPEN]RuCl(p-cymene) (10 mg), TEA (32 mg), and formic acid (23 mg) were added. The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with saturated brine, and the organic phase was concentrated to dryness. Prep-TLC was used to obtain the desired product A65 (23 mg). ESI-MS m / z: [M+H-HO] + :366.11. 1 H NMR(500MHz,DMSO-d6)δ7.53-7.45(m,3H),7.43-7.36(m,2H),7.33(d,J=3.5Hz,1H),7.08(dd,J=5.1,3.5Hz,1H),6.01(d,J=6.5H) z,1H),5.75(s,1H),4.60(d,J=6.2Hz,1H),2.90(ddd,J=17.0,11.3,6.3Hz,1H),2.80(dd,J=16.2,6.4Hz,1H),2.19-2.11(m,1H).

[0161] Example 49: Synthesis of 1-(4-fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A79) [ka]

[0162] Step 1: Synthesis of compound A79-1 Compound M1-2 (19 g), THF (150 mL), and TBAF (13.09 g) were added to a 500 mL single-neck flask in this order and allowed to react at room temperature for 30 minutes. The residue was concentrated under reduced pressure, and PE / EA (V:V = 1:1, 100 mL) was added to the residue, stirred, and filtered under suction. The filter cake was eluted twice with EA to give compound A79-1 (5.2 g).

[0163] Step 2: Synthesis of compound A79-2 Compound A79-1 (300 mg) was dissolved in DMF (10 mL), KCO (276 mg) and 4-fluorobenzyl bromide (260 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:7) to give the target compound A79-2 (200 mg).

[0164] Step 3: Synthesis of compound A79-3 At room temperature, Pd(dppf)Cl (44 mg), KCO (112 mg), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (112 mg) were added to a solution of compound A79-2 (100 mg) in dioxane (2 mL) and HO (0.5 mL). The mixture was purged with nitrogen three times and reacted at 100°C for 6 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated to obtain the target compound A79-3 (40 mg).

[0165] Step 4: Synthesis of compound A79 This compound was prepared in the same manner as compound A2, and was obtained by reduction with sodium borohydride. LCMS: 308.21 [M+H-H2O] + . The same manufacturing method as in Examples 1 to 49 was used. [ka] The following compounds are obtained:

[0166] [ka] [ka]

[0167] Example 64: Synthesis of (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A9) [ka]

[0168] Step 1: Synthesis of compound 9-1 Compound M1 (300 mg) was dissolved in DCM (20 mL), copper acetate (90 mg), 3,5-difluorophenylboronic acid (350 mg), and TEA (404 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to give the target compound 9-1 (230 mg). ESI-MS m / z: 409.11 [M+H] + .

[0169] Step 2: Synthesis of compound 9-2 Under nitrogen protection, compound 9-1 (230 mg) was dissolved in DMF (5 mL), Pd(dba) (165 mg), CuI (114 mg), and methyl fluorosulfonyldifluoroacetate (230 mg) were added, and the mixture was stirred at 100 °C for 3 hours. The mixture was extracted with ethyl acetate, washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to give the target compound 9-2 (150 mg). ESI-MS m / z: 352.20 [M+H] + .

[0170] Step 3: Synthesis of compound A9 Compound 9-2 (150 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, and the reaction mixture was purged with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene)] (12 mg) was added and stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the crude product was purified by prep-TLC (EA:PE = 1:5) to obtain the target compound A9 (100 mg). LC-MS: 336.20 [M + H - HO] + .

[0171] Example 65: Synthesis of 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A29) [ka]

[0172] Step 1: Synthesis of compound A29-1 Under nitrogen protection, compound A13 (400 mg) was dissolved in a mixture of dioxane (5 mL) and HO (5 mL), and Pd(PPh) (109 mg), KCO (390 mg), and vinylboronic acid pinacol ester (217 mg) were added. The mixture was incubated overnight at 90 °C, extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:5) to give the target compound A29-1 (210 mg). ESI-MS m / z: 326.03 [M+H]. + .

[0173] Step 2: Synthesis of compound A29-2 Compound A29-1 (210 mg) was dissolved in a mixed solvent of THF (5 mL) and HO (5 mL), and NaIO (414 mg) and potassium osmate (20 mg) were added. The mixture was allowed to react at room temperature for 2 hours, extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:4) to obtain the target compound A29-2 (45 mg). ESI-MS m / z: 328.10 [M+H] + .

[0174] Step 3: Synthesis of compound A29-3 Under nitrogen protection, compound A29-2 (80 mg) was dissolved in dichloromethane (4 mL), and DAST (98 mg) was added under ice bath. After the dropwise addition was completed, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:4) to give the target compound A29-3 (45 mg). ESI-MS m / z: 350.05 [M+H] + .

[0175] Step 4: Synthesis of compound A29 Compound A29-3 (45 mg) was dissolved in a mixed solvent of THF (5 mL) and HO (5 mL), and NaBH (20 mg) was added in an ice bath. The mixture was then incubated at 90 °C for 30 minutes, extracted with ethyl acetate, washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to give the target compound A29 (30 mg). ESI-MS m / z: 334.04 [M + H-HO] + .

[0176] Example 66: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D12) [ka]

[0177] Using a similar preparation method to compound A2, compound D12 was obtained by reducing A29-1 with sodium borohydride. ESI-MS m / z: [M+H-HO] + :310.17.

[0178] Example 67: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D20) [ka]

[0179] Using a similar preparation method to compound A2, A29-2 was reduced with sodium borohydride to give compound D20. ESI-MS m / z: [M+H-H2O] + :314.00.

[0180] Example 68: Synthesis of 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one (Compound D70) [ka]

[0181] Step 1: Synthesis of compound D70-1 Under nitrogen protection, compound M4 (300 mg) and (3-chloro-5-fluorophenyl)boronic acid (260 mg) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). Pd(PPh3)4 (110 mg) and potassium carbonate (276 mg) were added. The reaction mixture was stirred in an oil bath at 90 °C for 30 minutes. The reaction mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:2) to give the target compound D70-1 (185 mg). ESI-MS m / z: 350.09 [M+H] + .

[0182] Step 2: Synthesis of compound D70 Compound D70-1 (120 mg) was dissolved in methanol (4 mL), NaBH (76 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na SO , and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:2) to obtain the target compound D70 (96 mg). ESI-MS m / z: 334.01 [M+H] + .

[0183] Example 69 and Example 70: Synthesis of 5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-fluorobenzonitrile (Compound D79) and (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-fluorobenzonitrile (Compound D76) [ka]

[0184] Step 1: Synthesis of compound D76-1 Under nitrogen protection, compound M5 (317 mg) and (3-cyano-4-fluorophenyl)boronic acid (248 mg) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL). Pd(PPh3)4 (110 mg) and potassium carbonate (276 mg) were added. The reaction mixture was stirred in an oil bath at 90 °C for 30 minutes. The reaction mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:2) to give the target compound D76-1 (215 mg). ESI-MS m / z: 358.45 [M+H] + .

[0185] Step 2: Synthesis of compound D79 Compound D76-1 (100 mg) was dissolved in methanol (4 mL), NaBH (38 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na SO , and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to obtain compound D79 (72 mg). ESI-MS m / z: 343.11 [M + H - HO] + .

[0186] Step 3: Synthesis of compound D76 Compound D76-1 (100 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, and the reaction mixture was bubbled with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was added and stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound D76 (68 mg). LC-MS m / z: 343.09 [M + H - HO] + . The same manufacturing method as in Examples 1 to 70 was used. [ka] The following examples were obtained:

[0187] [ka] [ka] [ka]

[0188] Example 88: Synthesis of 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ol (Compound D80) [ka]

[0189] Step 1: Synthesis of compound D80-1 Under nitrogen protection, carbonyldiimidazole (32.4 g) was dissolved in 100 mL of chloroform. A solution of trifluoroacetic anhydride (32.4 g) in chloroform (50 mL) was slowly added dropwise in an ice bath. The mixture was then warmed to room temperature, and a solution of cyclohexane-1,3-dione (11.2 g) and imidazole (6.8 g) in chloroform (50 mL) was added. The mixture was stirred for 2 hours, washed with 1 M diluted hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:4) to give the target compound D80-1 (13.3 g). ESI-MS m / z: 209.15 [M+H] + .

[0190] Step 2: Synthesis of compound D80-2 Under nitrogen protection, compound D80-1 (2.08 g) was dissolved in ethanol (100 mL), (3,5-difluorophenyl)hydrazine (1.44 g) was added, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D80-2 (1.9 g). ESI-MS m / z: 317.45 [M+H] + .

[0191] Step 3: Synthesis of compound D80-3 Under nitrogen protection, compound D80-2 (316 mg), 3-methoxypropylamine (534 mg), and pivalic acid (21 mg) were dissolved in a mixture of toluene (20 mL) and cyclohexane (10 mL), refluxed overnight, and the reaction mixture was concentrated to dryness to obtain the crude product of target compound D80-3 (326 mg), which was used directly in the next step without further purification. ESI-MS m / z: 388.41 [M+H] + .

[0192] Step 4: Synthesis of compound D80-4 Compound D80-3 (326 mg) was dissolved in acetonitrile (20 mL), Selectfluor (656 mg) was added, and the mixture was refluxed for 6 hours. After cooling to room temperature, the reaction mixture was treated with 1 M dilute hydrochloric acid (20 mL), stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D80-4 (213 mg). ESI-MS m / z: 353.10 [M+H] + .

[0193] Step 5: Synthesis of compound D80 Compound D80-4 (100 mg) was dissolved in methanol (4 mL), NaBH (42 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na SO , and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to give target compound 1 (81 mg). ESI-MS m / z: 337.23 [M + H-HO] + . Using the same preparation method as in Example 88, but substituting different aromatic hydrazines, the following examples were obtained.

[0194] [ka]

[0195] Example 94: Synthesis of (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethyloxyphosphine (Compound A50) [ka]

[0196] Step 1: Synthesis of compound A50-1 Compound A13 (864 mg), dimethyloxyphosphine (200 mg), K3PO4 (520 mg), Xantphos (118 mg), and palladium acetate (46 mg) were added to DMF (15 mL). Under nitrogen protection, the reaction mixture was heated at 150 °C and stirred overnight. Upon completion of the reaction, the mixture was cooled, poured into water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography to obtain the desired product A50-1 (300 mg).

[0197] Step 2: Synthesis of compound A50 This compound was prepared in the same manner as compound A2, and was obtained by reduction with sodium borohydride. ESI-MS m / z: 360.05 [M+H-H2O] + . 1 H NMR (500MHz, DMSO-d6) δ7.57-7.43(m,4H),6.21(d,J=4.8Hz,1H),4.84(q,J=7.1Hz,1H),2.87-2.73(m,2H),2.34-2.14(m,2H),1.68(d,J=13.6Hz,6H).

[0198] Example 95: Synthesis of (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (A61) [ka]

[0199] Step 1: Synthesis of compound A61-1 Compound M2 (214 mg) was dissolved in DCM (10 mL), copper acetate (108 mg), 4-fluoro-3-cyanophenylboronic acid (100 mg), and TEA (0.25 mL) were added, and the mixture was stirred overnight under an oxygen atmosphere. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE = 1:3) to obtain the target compound A61-1 (120 mg). ESI-MS m / z: 359.05 [M+H] +.

[0200] Step 2: Synthesis of compound A61 Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), formic acid (0.04 mL) and triethylamine (0.1 mL) were added, and the reaction mixture was sparged with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added and stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A61 (90 mg, ee > 96%). ESI-MS m / z: 343.05 [M + H - HO] + .

[0201] Example 96: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile (Compound A73) [ka]

[0202] Step 1: Synthesis of compound A73-1 Under nitrogen protection, compound A13 (212 mg) was dissolved in DMF (5 mL), Zn(CN) (117 mg) and Pd(PPh) (58 mg) were added, and the mixture was stirred at 120 °C for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound A73-1 (137 mg). ESI-MS m / z: 325.08 [M+H] + .

[0203] Step 2: Synthesis of compound A73 Compound A73-1 (100 mg) was dissolved in a mixture of THF (2 mL) and HO (1 mL), and NaBH (18 mg) was added in an ice bath. The mixture was stirred at 0 °C for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A73 (13 mg). ESI-MS m / z: 309.12 [M + H-HO] + .

[0204] Example 97: Synthesis of 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (A90) [ka]

[0205] Step 1: Synthesis of compound A90-1 Compound M6 (214 mg) was dissolved in DCM (10 mL), copper acetate (108 mg), 3-chloro-5-fluorophenylboronic acid (105 mg), and TEA (0.25 mL) were added, and the mixture was stirred overnight under an oxygen atmosphere. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound A90-1 (83 mg). ESI-MS m / z: 368.07 [M+H] + .

[0206] Step 2: Synthesis of compound A90 Compound A90-1 (104 mg) was dissolved in methanol (4 mL), NaBH4 (42 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A90 (63 mg). ESI-MS m / z: 352.07 [M + H-HO] + .

[0207] Example 98: Synthesis of (5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D37) [ka]

[0208] Step 1: Synthesis of compound D37-1 Compound M2 (2.14 g) was dissolved in DCM (20 mL), copper acetate (1.08 g), 4-fluoro-3-formylphenylboronic acid (1.0 g), and TEA (2.48 mL) were added, and the mixture was stirred overnight at room temperature under an oxygen atmosphere. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound D37-1 (1.1 g). ESI-MS m / z: 362.08 [M+H] + .

[0209] Step 2: Synthesis of compound D37 Compound D37-1 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 g) was added in portions, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction was confirmed by LC-MS and TLC, the reaction mixture was poured into water, extracted with ethyl acetate, concentrated to dryness, and the crude product was chromatographed to give D37 (100 mg). ESI-MS m / z: 348.05 [M+H-HO]. + .

[0210] Example 99: Synthesis of 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D40) [ka]

[0211] Step 1: Synthesis of compound D40-1 At room temperature, potassium carbonate (866 mg) and 2,6-difluoropyridine (481 mg) were added to a solution of compound M2 (500 mg) in DMF (10 mL), and the temperature was then raised to 100 °C and stirred overnight. The reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE=17%) to obtain the target compound D40-1 (400 mg). ESI-MS m / z: 335.05 [M+H] + .

[0212] Step 2: Synthesis of compound D40 This compound was prepared in the same manner as compound A2, and was obtained by reduction with sodium borohydride. ESI-MS m / z: 319.25 [M+H-H2O] + .

[0213] Example 100: Synthesis of 5-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound D46) [ka]

[0214] Step 1: Synthesis of compound D46 Under nitrogen protection, compound A61-1 (36 mg) was dissolved in tetrahydrofuran (5 mL), 3.0 M methylchloromagnesium (0.3 mL) was added dropwise in an ice bath, and the mixture was stirred at 0 °C for 3 hours. After that, the mixture was quenched with 1 M dilute hydrochloric acid. The reaction mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography and pre-TLC (EA:PE = 1:3) to obtain the target compound D46 (13 mg). ESI-MS m / z: 357.18 [M + H - HO] + . 1H NMR(500MHz,DMSO-d6)δ8.20-8.17(m,1H),7.94-7.91(m,1H),7.69(t,J=9 .0Hz,1H),7.61(s,1H),2.83-2.59(m,2H),2.45-2.16(m,2H),1.53(s,3H).

[0215] Example 101: Synthesis of 5-(5,5-difluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile (Compound D49) [ka]

[0216] Step 1: Synthesis of compound D49-1 Ethyl trifluoroacetoacetate (25.02 g) was dissolved in glacial acetic acid (38 mL) in an ice bath, and an aqueous solution (25 mL) of sodium nitrite (9.37 g) was added in several portions. After completion, the mixture was allowed to react at 20 °C for 2 hours, concentrated under reduced pressure, and then water and ethyl acetate were added. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the target compound D49-1 (22 g). ESI-MS m / z: 212.03 [MH] - .

[0217] Step 2: Synthesis of compound D49-2 5,5-Dimethyl-1,3-cyclohexanedione (6.0 g) was dissolved in glacial acetic acid (30 mL) and heated to 60 ° C., followed by the addition of an aqueous solution (20 mL) of compound D49-1 (9.12 g). Zinc powder (5.59 g) was then slowly added in portions. Upon completion, the temperature was raised to 90 ° C. and the reaction was continued for 16 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed twice with saturated aqueous sodium bicarbonate, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D49-2 (2.2 g, 22.2%). ESI-MS m / z: 232.10 [M+H] + .

[0218] Step 3: Synthesis of compound D49-3 Under nitrogen protection, compound D49-2 (2.2 g) was dissolved in tetrahydrofuran (30 mL), and sodium hydride (0.457 g) was added in several portions in an ice bath. The reaction was continued at 0 °C for 30 minutes. Then, a solution of triisopropylsilyl chloride (2.75 g) in tetrahydrofuran (5 mL) was added, and the reaction continued for 1 hour. The reaction mixture was poured into ice water to quench the reaction, extracted with ethyl acetate, washed with water, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D49-3 (2.93 g, 79.5%). ESI-MS m / z: 388.10 [M+H] + .

[0219] Step 4: Synthesis of compound D49-4 Under nitrogen protection, compound D49-3 (1.05 g) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 °C. A 1.0 M LiHMDS solution in tetrahydrofuran (7.33 mL) was slowly added dropwise and stirred for 30 minutes. Then, a tetrahydrofuran solution (10 mL) of NFSI (1.79 g) was added dropwise and stirred for 2 hours at -78 °C. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM 100%) to obtain the target compound D49-4 (0.73 g, 55.2%). ESI-MS m / z: 424.05 [M+H] + .

[0220] Step 5: Synthesis of compound D49-5 Crude compound D49-4 (0.73 g) was dissolved in a THF (20 mL) / water (20 mL) mixed solvent, and K2CO3 (0.48 g) was added at room temperature. The mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (DCM 100%) to give the target compound D49-5 (402 mg). ESI-MS m / z: 268.12 [M+H] + .

[0221] Step 6: Synthesis of compound D49-6 Compound D49-5 (402 mg) was dissolved in DCM (20 mL), copper acetate (275 mg), 3,5-difluorophenylboronic acid (494 mg), and TEA (304 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product. The crude product was subjected to column chromatography (EA:PE=1:3) to obtain the target compound D49-6 (512 mg). ESI-MS m / z: 387.08 [M+H] + .

[0222] Step 7: Synthesis of compound D49 Compound D49-6 (50 mg) was dissolved in methanol (4 mL), NaBH (15 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na SO , and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:4) to give the target compound D49 (37 mg, 73.7%). ESI-MS m / z: 371.10 [M + H - HO] + .

[0223] Example 102: Synthesis of 2-fluoro-5-(5-fluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D50) [ka]

[0224] Step 1: Synthesis of compound D50-1 Under nitrogen protection, compound D49-3 (1.0 g) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 ° C. 1.0 M LDA tetrahydrofuran solution (3.9 mL) was slowly added dropwise and stirred for 30 minutes. After that, NFSI (895 mg) tetrahydrofuran solution (10 mL) was added dropwise and stirred for 2 hours while maintaining the temperature at -78 ° C. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM 100%) to obtain the target compound D50-1 (550 mg). ESI-MS m / z: 406.12 [M+H] + .

[0225] Step 2: Synthesis of compound D50-2 Crude compound D50-1 (550 mg) was dissolved in a THF (10 mL) / water (10 mL) mixed solvent, and K2CO3 (375 mg) was added at room temperature. The mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (DCM 100%) to give the target compound D50-2 (208 mg). ESI-MS m / z: 250.06 [M+H] + .

[0226] Step 3: Synthesis of compound D50-3 Compound D50-2 (208 mg) was dissolved in DCM (15 mL), copper acetate (150 mg), 3,5-difluorophenylboronic acid (206 mg), and TEA (168 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound D50-3 (217 mg). ESI-MS m / z: 369.10 [M+H] + .

[0227] Step 4: Synthesis of compound D50 Compound D50-3 (100 mg) was dissolved in methanol (4 mL), NaBH (21 mg) was added in an ice bath, and the mixture was stirred at 0 °C for 1 hour. After adding ice water, the mixture was extracted with ethyl acetate, washed with brine, dried over Na SO , and concentrated to give the crude product, which was purified by prep-TLC (EA:PE = 1:4) to give the target compound D50 (82 mg). ESI-MS m / z: 353.12 [M + H - HO] + .

[0228] Example 103: Synthesis of a mixture of (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol and (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-A, tentative structure) Example 104: Synthesis of (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-B, tentative structure) Example 105: Synthesis of (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D51-C, tentative structure) [ka]

[0229] Step 1: Synthesis of compound D51-1 Compound M3 (147 mg) was dissolved in DCM (15 mL), copper acetate (120 mg), 4-fluoro-3-formylphenylboronic acid (167 mg), and TEA (136 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound D51-1 (152 mg). ESI-MS m / z: 344.08 [M+H] + .

[0230] Step 2: Synthesis of compound D51-2 Compound D51-1 (152 mg) was dissolved in DCM (10 mL), DAST (214 mg) was added in an ice bath, and the mixture was stirred at 0 ° C for 3 hours. The mixture was then diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE = 1:3) to obtain the target compound D51-2 (129 mg). ESI-MS m / z: 344.08 [M + H] + .

[0231] Step 3: Synthesis of compound D51 Compound D51-2 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 g) was added in portions, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction as confirmed by LC-MS and TLC, the reaction mixture was poured into water, extracted with ethyl acetate, and concentrated to dryness. The crude product was chromatographed to give D51 (300 mg). D51 was separated by chiral preparative chromatography (column model: Daicel CHIR ALPAK® IF 250 × 20 mm, 5 μm, mobile phase A: n-hexane, mobile phase B: ethanol, mobile phase A: mobile phase B = 90:10 (V / V), detection wavelength: 254 nm, flow rate: 15 mL / min, column temperature: RT, run time: 25 min, column pressure: 35 Bar) to give three elution peaks.

[0232] D51-A (10 mg) was the first eluting peak, Rt = 7.5 min. ESI-MS m / z: 350.12 [M + H - HO] + . 1H NMR(500MHz,DMSO)δ7.77-7.67(m,2H),7.53-7.59(m,2H),7.23(t,J=53.9Hz,1H),5.44(d,J=6.7Hz ,1H),4.80(d,J=47.3Hz,1H),4.64(s,1H),2.64-2.54(m,1H),2.48-2.51(m,1H),2.18-1.94(m,2H).

[0233] D51-B (70 mg) was the second eluting peak, Rt = 11 min. ESI-MS m / z: 350.12 [M+H-HO] + . 1 H NMR(500MHz,DMSO)δ7.71(dd,J=5.7,2.8Hz,2H),7.62-7.49(m,2H),7.23(t,J=53.9Hz,1H),5.19(d,J=6. 1Hz,1H),4.92-4.69(m,2H),2.77-2.60(m,1H),2.60-2.51(m,1H),2.26-2.07(m,1H),1.85-1.90(m,1H).

[0234] D51-C (80 mg) was the third eluting peak, Rt = 14.5 min. ESI-MS m / z: 350.12 [M + H - HO] + . 1 H NMR(500MHz,DMSO)δ7.71(dd,J=5.7,2.8Hz,2H),7.62-7.49(m,2H),7.23(t,J=53.9Hz,1H),5.19(d,J=6. 1Hz,1H),4.92-4.69(m,2H),2.77-2.60(m,1H),2.60-2.51(m,1H),2.26-2.07(m,1H),1.85-1.90(m,1H).

[0235] Example 106: Synthesis of 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A41) [ka]

[0236] Step 1: Synthesis of compound A41-1 Under nitrogen protection, compound 1-2 (106 mg) was dissolved in acetonitrile (5 mL), Selectfluor (133 mg) was added, and the mixture was stirred at 80°C for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over NaSO, and concentrated to give the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to give the target compound A41-1 (79 mg).

[0237] Step 2: Synthesis of compound A41 Compound A41-1 (79 mg) was dissolved in a mixed solvent of THF (2 mL) and HO (1 mL), and NaBH (16 mg) was added in an ice bath. The mixture was stirred at 0 °C for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over NaSO, and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A41 (45 mg). ESI-MS m / z: 370.02 [M + H-HO] + . 1 H NMR(500MHz,DMSO-d6)δ7.72-7.67(m,2H),7.66-7.62(m,1H),6.22(d,J=6.4Hz,1H ),4.55(q,J=6.6Hz,1H),2.61-2.57(m,2H),2.41-2.24(m,1H),2.19-2.10(m,1H).

[0238] Example 107: Synthesis of (S)-2-chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound A75) [ka]

[0239] Step 1: Synthesis of compound A75-1 Under nitrogen protection, compound 1-2 (106 mg) was dissolved in acetonitrile (5 mL), NCS (50 mg) was added, and the mixture was stirred at 80 °C for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na SO , and concentrated to obtain the crude product. The crude product was purified by prep-TLC (EA:PE=1:3) to obtain the target compound A75-1 (81 mg). ESI-MS m / z: 401.9 [M+H] + .

[0240] Step 2: Synthesis of compound A75 Compound A75-1 (40 mg) was dissolved in dichloromethane (3 mL), formic acid (0.01 mL) and triethylamine (0.03 mL) were added, and the reaction mixture was purged with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was added and stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound A75 (15 mg). ESI-MS m / z: 387.85 [M + H - HO] + .

[0241] Example 108: Synthesis of 1-(3-(difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (Compound D95) [ka]

[0242] Step 1: Synthesis of compound D95-1 (4-Fluoro-3-formylphenyl)boronic acid (2.0 g), compound M3-1 (3.63 g), copper acetate (2.16 g), and triethylamine (4.97 mL) were added to dichloromethane (40 mL) and stirred overnight at room temperature under an oxygen atmosphere. Upon completion of the reaction, the mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound D95-1 (2.1 g). ESI-MS m / z: 326.10 [M+H] +.

[0243] Step 2: Synthesis of compound D95-2 Compound D95-1 (500 mg) was added to dichloromethane (10 mL), DAST (520 mg) was added, and the mixture was stirred at room temperature. When the reaction was complete, the mixture was diluted with dichloromethane, quenched with saturated sodium bicarbonate, washed with water, dried, filtered, and concentrated to obtain the crude product, which was then subjected to column chromatography (EA:PE=1:3) to obtain the target compound D95-2 (163 mg). ESI-MS m / z: 348.05 [M+H] + .

[0244] Step 3: Synthesis of compound D95 Compound D95-2 (100 mg) was added to a mixture of tetrahydrofuran (2 mL) and water (1 mL), and sodium borohydride (80 mg) was added in an ice-water bath. The mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried and purified by preparative HPLC to obtain the target product D95 (50 mg). ESI-MS m / z: 350.10 [M+H] + . The following examples were obtained by using different raw materials and / or intermediates and employing the same preparation methods as in Examples 1 to 108.

[0245] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0246] Example 196 and Example 197: Synthesis of (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D54, tentative) and (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D55, tentative) [ka]

[0247] Step 1: Synthesis of compound D54-1 Under nitrogen protection, A58 (360 mg) was dissolved in 20 mL of dichloromethane, and DAST (412 mg) was slowly added dropwise in an ice bath. The reaction was allowed to proceed at 0 °C for 2 hours. The mixture was quenched by adding ice water, and the organic phase was washed with saturated aqueous sodium bicarbonate and then saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D54-1 (285 mg). ESI-MS m / z: 362.30 [M+H] + .

[0248] Step 2: Synthesis of compounds D54 and D55 Compound D54-1 was separated and purified by chiral preparative column chromatography (column model Daicel CHIRALPAK® IF 250 × 20 mm, 5 μm, mobile phase A: n-hexane, mobile phase B: ethanol, mobile phase A: mobile phase B = 85:15 (V / V), detection wavelength 254 nm, flow rate: 15 mL / min, column temperature: RT, run time: 28 min). Example D54 was obtained as the first eluting peak, Rt = 16.5 min. ESI-MS m / z: 325.00 [M + H - HO] + . 1 H NMR (500 MHz, DMSO) δ 8.14-8.16 (m, 1H), 7.89-7.92 (m, 1H), 7.73-7.67 (m, 1H), 7.59 (s, 1H), 5.23 (d, J = 6.0 Hz, 1H), 4.88-4.70 (m, 2H), 2.56-2.76 (m, 2H), 2.23-2.13 (m, 1H), 1.85-1.92 (m, 1H). Example D55 was obtained as the second eluting peak, Rt = 20 min. ESI-MS m / z: 325.00 [M + H - HO] + .

[0249] Example 198: Synthesis of (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile (Compound D56) [ka]

[0250] Step 1: Synthesis of compound D56 Compound A58 (36 mg) and hydroxylamine hydrochloride (14 mg) were dissolved in 10 mL of ethanol, refluxed for 5 hours, and then concentrated to give the crude product. The crude product was purified by pre-TLC (EA:PE = 1:3) to give the target compound D56 (16 mg). ESI-MS m / z: 392.08M + H - HO. + .

[0251] Example 199: Synthesis of 2-fluoro-5-(5-fluoro-4-hydroxy-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (D58) [ka]

[0252] Step 1: Synthesis of compound D58-1 1,3-Cyclohexanedione (1.10 g) was dissolved in an aqueous solution (4 mL) of potassium hydroxide (0.57 g) in an ice bath, and a solution of 3-bromo-1,1,1-trifluoroacetone (1.84 g) in methanol (10 mL) was added dropwise. After stirring for 2 hours, the mixture was concentrated to dryness to remove the methanol. Water (5 mL) and 2-fluoro-5-aminobenzonitrile (1.2 g) were added, the pH was adjusted to 0, and the mixture was refluxed for 14 hours. The reaction mixture was concentrated to dryness and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to give the target compound D58-1 (254 mg, 8%). ESI-MS m / z: 323.07 [M+H] + . 1 H NMR(500MHz,CDCl3)δ7.66(dd,J=14.2,11.6Hz,1H),7.61(dd,J=8.4,4.0Hz,1 H),7.41(t,J=8.4Hz,1H),7.10(s,1H),2.57-2.44(m,4H),2.22-2.12(m,2H).

[0253] Step 2: Synthesis of compound D58-2 Under nitrogen protection, compound D58-1 (60 mg) and NFSI (90 mg) were dissolved in tetrahydrofuran (2.00 mL), cooled to -78 °C, and lithium diisopropylamide (0.20 mL, 2.00 mol / L) was added and stirred for 2 hours. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA:PE = 1:2) to obtain the target compound D58-2 (40 mg, 59%). ESI-MS m / z: 341.06 [M+H] + .

[0254] Step 3: Synthesis of compound D58 Compound D58-2 (40 mg) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), and sodium borohydride (10 mg) was added in an ice bath. The mixture was then stirred at room temperature for 2 hours. Water and ethyl acetate were added, and the organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:2) to obtain the target compound D58 (20 mg). ESI-MS m / z: 336.20 [M + H-HO] + .

[0255] Example 200: Synthesis of (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-p-fluorobenzonitrile (Compound D74) [ka]

[0256] Step 1: Synthesis of compound D74 Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), deuterated formic acid (0.04 mL) and triethylamine (0.1 mL) were added, and the reaction mixture was sparged with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added and stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the crude product was purified by prep-TLC (EA:PE = 1:3) to obtain the target compound D74 (70 mg, ee > 96%). ESI-MS m / z: 406.07 [M+HCOOH-H] - . 1 H NMR(500MHz,DMSO)δ8.22(dd,J=5.4,2.7Hz,1H),8.02-7.85(m,1H),7.80-7.49(m ,2H),6.16-5.82(m,1H),2.86-2.60(m,2H),2.42-2.26(m,1H),2.26-2.06(m,1H).

[0257] Example 201: Synthesis of 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-5,6-dihydro-4H-isoxazolo[5,4-e]indole (Compound D100) [ka]

[0258] Step 1: Synthesis of compound D100-1 Compound M3-1 (203 mg) was dissolved in DCM (20 mL), and copper acetate (180 mg), 3-chloro-5-fluorophenylboronic acid (261 mg), and TEA (202 mg) were added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to give the crude product. The crude product was purified by pre-TLC (EA:PE = 1:3) to give the target compound D100-1 (275 mg). ESI-MS m / z: 332.05 [M+H] + .

[0259] Step 2: Synthesis of compound D100-2 Under nitrogen protection, compound D100-1 (100 mg) was dissolved in ethanol (5 mL), cooled to 0 °C, and sodium ethoxide (20 mg) was added. After stirring for 10 minutes, ethyl formate (23 mg) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 1:3) to obtain the target compound D100-2 (35 mg). ESI-MS m / z: 360.17 [M+H] + .

[0260] Step 3: Synthesis of compound D100 Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), hydroxylamine hydrochloride (23 mg) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by pre-TLC (EA:PE = 1:3) to obtain the target compound D100 (42 mg). ESI-MS m / z: 357.12 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.49(s,1H),7.82(s,1H),7.67-7.56(m,3H),2.96(t,J=8.5Hz,2H),2.83(t,J=8.5Hz,2H).

[0261] Example 202: Synthesis of 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-1,4,5,6-tetrahydropyrrole[2,3-g]indazole (Compound D101) [ka]

[0262] Step 1: Synthesis of compound D101 Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), hydrazine hydrate (30 μL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by pre-TLC (EA:PE = 1:3) to obtain the target compound D101 (30 mg). ESI-MS m / z: 356.12 [M+H] + .

[0263] Some exemplary compounds 1 The 1 H NMR data is as follows:

[0264] 1 H NMR(500MHz,DMSO-d6)δ8.13-8.11(m,1H),7.88-7.85(m,1H),7.74-7.62(m,1H),7.26(s,1H),5.89(d,J=6.4Hz,1 H), 5.76 (s, 2H), 4.31-4.27 (m, 1H), 2.84-2.77 (m, 1H), 2.80-2.74 (m, 1H), 2.39-2.32 (m, 1H), 2.12 (s, 1H) (Example 5).

[0265] 1 H NMR(500MHz,CDCl3)δ7.18(d,J=8.6Hz,1H),7.13(s,2H),6.96(d,J=8.6Hz,1H),4.94-4.88 (m, 1H), 2.85-2.78 (m, 1H), 2.74-2.67 (m, 1H), 2.63-2.40 (m, 2H), 2.26-2.16 (m, 1H) (Example 7).

[0266] 1 H NMR(500MHz,DMSO-d6)δ7.67(s,1H),7.42-7.30(m,3H),6.07(d,J=6.7Hz,1H),4.5 9(q, J=6.6Hz, 1H), 2.91-2.69(m, 2H), 2.44-2.23(m, 1H), 2.17-2.12(m, 1H) (Example 8).

[0267] 1¹H NMR (500MHz, DMSO-d⁶) δ 7.59–7.42 (m, 6H), 6.01 (d, J = 6.8 Hz, 1H), 4.59 (q, J = 6.9 Hz, 1H), 2.81–2.60 (m, 2H), 2.46–2.29 (m, 1H), 2.16–2.09 (m, 1H) (Example 9).

[0268] 1 ¹H NMR (500MHz, CDCl₃) δ 7.41–7.34 (m, 2H), 7.25 (dt, J = 8.6, 2.1 Hz, 1H), 7.09 (s, 1H), 4.88–4.82 (m, 1H), 2.80–2.70 (m, 1H), 2.66–2.59 (m, 1H), 2.55 (d, J = 2.5 Hz, 1H), 2.51–2.12 (m, 2H) (Example 12).

[0269] 1 ¹H NMR (500MHz, DMSO-d6) δ 7.96 (s, 1H), 7.62–7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J = 6.0Hz, 2H), 2.69–2.58 (m, 2H) (Example 15).

[0270] 1 ¹H NMR (500MHz, DMSO) δ 7.33–7.17 (m, 3H), 7.07 (d, J = 2.9 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 5.69 (d, J = 6.6 Hz, 1H), 4.61–4.53 (m, 1H), 2.92–2.75 (m, 2H), 2.41–2.24 (m, 1H), 2.20–2.08 (m, 1H) (Example 34).

[0271] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.14–8.13 (m, 1H), 7.91–7.89 (m, 1H), 7.69 (t, J = 9.0 Hz, 1H), 7.52 (s, 1H), 4.78 (d, J = 6.3 Hz, 1H), 4.70–4.68 (m, 1H), 2.50–2.38 (m, 1H), 1.92–1.85 (m, 1H), 1.82–1.68 (m, 2H), 1.71–1.63 (m, 1H) (Example 46).

[0272] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.53–7.45 (m, 3H), 7.43–7.36 (m, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.08 (dd, J = 5.1, 3.5 Hz, 1H), 6.01 (d, J = 6.5 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J = 6.2 Hz, 1H), 2.90 (ddd, J = 17.0, 11.3, 6.3 Hz, 1H), 2.80 (dd, J = 16.2, 6.4 Hz, 1H), 2.19–2.11 (m, 1H) (Example 48).

[0273] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.53–7.45 (m, 3H), 7.43–7.36 (m, 2H), 7.33 (d, J = 3.5 Hz, 1H), 7.08 (dd, J = 5.1, 3.5 Hz, 1H), 6.01 (d, J = 6.5 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J = 6.2 Hz, 1H), 2.90 (ddd, J = 17.0, 11.3, 6.3 Hz, 1H), 2.80 (dd, J = 16.2, 6.4 Hz, 1H), 2.19–2.11 (m, 1H) (Example 59).

[0274] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.67 (s, 1H), 7.43–7.36 (m, 3H), 6.07 (d, J = 6.7Hz, 1H), 4.67–4.52 (m, 1H), 2.93–2.69 (m, 2H), 2.44–2.27 (m, 1H), 2.19–2.10 (m, 1H) (Example 64).

[0275] 1 ¹H NMR (500MHz, DMSO) δ 8.30–8.24 (m, 1H), 8.04–7.98 (m, 1H), 7.81–7.68 (m, 2H), 6.13 (d, J = 6.6 Hz, 1H), 4.70–4.60 (m, 1H), 2.89–2.70 (m, 2H), 2.50–2.31 (m, 1H), 2.25–2.13 (m, 1H) (Example 95).

[0276] 1¹H NMR (500MHz, DMSO) δ 7.75–7.58 (m, 3H), 6.22 (d, J = 6.4Hz, 1H), 4.58–4.50 (m, 1H), 2.70–2.52 (m, 2H), 2.43–2.24 (m, 1H), 2.20–2.10 (m, 1H) (Example 106).

[0277] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.69 (s, 1H), 7.62–7.54 (m, 3H), 6.37 (d, J = 6.1 Hz, 1H), 4.82 (q, J = 6.5 Hz, 1H), 3.24 (s, 3H), 2.85–2.79 (m, 1H), 2.75–2.70 (m, 1H), 2.29 (d, J = 8.9 Hz, 1H), 2.16 (s, 1H) (Example 109).

[0278] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.68 (d, J = 1.6Hz, 1H), 7.60–7.40 (m, 3H), 6.07 (d, J = 6.6Hz, 1H), 4.59 (q, J = 6.8Hz, 1H), 2.88–2.81 (m, 1H), 2.84–2.70 (m, 2H), 2.42–2.38 (m, 1H), 2.17–2.12 (m, 1H) (Example 115).

[0279] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.96 (s, 1H), 7.62–7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J = 6.0Hz, 2H), 2.69–2.58 (m, 2H) (Example 118).

[0280] 1 ¹H NMR (500MHz, DMSO) δ 7.88-7.84 (m, 1H), 7.67-7.48 (m, 3H), 6.03 (d, J = 7.0Hz, 1H), 4.62-4.55 (m, 1H), 2.84-2.62 (m, 2H), 2.44-2.26 (m, 1H), 2.20-2.10 (m, 1H) (Example 120).

[0281] 1¹H NMR (500MHz, DMSO) δ 7.88-7.84 (m, 1H), 7.67-7.48 (m, 3H), 6.03 (d, J = 7.0Hz, 1H), 4.62-4.55 (m, 1H), 2.84-2.62 (m, 2H), 2.44-2.26 (m, 1H), 2.20-2.10 (m, 1H) (Example 124).

[0282] 1 ¹H NMR (500MHz, DMSO) δ 7.83–7.70 (m, 1H), 7.65–7.55 (m, 2H), 7.36–7.42 (m, 1H), 6.05 (d, J = 6.6 Hz, 1H), 4.52–4.55 (m, 1H), 2.80–2.60 (m, 2H), 2.45–2.26 (m, 1H), 2.20–2.05 (m, 1H) (Example 137).

[0283] 1 ¹H NMR (500MHz, DMSO) δ 7.59–7.49 (m, 3H), 7.37 (t, J = 8.7 Hz, 2H), 6.01 (d, J = 6.8 Hz, 1H), 4.62–4.53 (m, 1H), 2.76–2.59 (m, 2H), 2.44–2.27 (m, 1H), 2.18–2.08 (m, 1H) (Example 160).

[0284] 1 ¹H NMR (500MHz, DMSO) δ 7.83–7.70 (m, 1H), 7.65–7.55 (m, 2H), 7.36–7.42 (m, 1H), 6.05 (d, J = 6.6 Hz, 1H), 4.52–4.55 (m, 1H), 2.80–2.60 (m, 2H), 2.45–2.26 (m, 1H), 2.20–2.05 (m, 1H) (Example 164).

[0285] 1¹H NMR (500MHz, CDCl₃) δ 7.55 (m, 7.56-7.54, 1H), 7.43-7.40 (m, 1H), 7.30-7.28 (m, 1H), 7.12 (d, J=1.4Hz, 1H), 7.04-6.82 (m, 1H), 4.93 (q, J=5.4Hz, 1H), 2.78-2.72 (m, 1H), 2.66-2.61 (m, 1H), 2.55-2.42 (m, 2H), 2.25-2.17 (m, 1H) (Example 168).

[0286] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.10 (d, J = 1.8 Hz, 1H), 9.05 (d, J = 2.5 Hz, 1H), 8.63 (t, J = 2.2 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 6.11 (d, J = 6.7 Hz, 1H), 4.60 (q, J = 6.7 Hz, 1H), 2.86–2.72 (m, 2H), 2.16 (s, 1H) (Example 1cc77).

[0287] 1 ¹H NMR (500MHz, CDCl₃) δ 7.53–7.45 (m, 2H), 7.32 (t, J = 8.4 Hz, 1H), 7.04 (d, J = 1.4 Hz, 1H), 4.92 (q, J = 9.8 Hz, 1H), 2.55–2.43 (m, 2H), 2.38–2.28 (m, 1H), 2.24 (dd, J = 8.4, 2.3 Hz, 1H), 0.02 (d, J = 34.9 Hz, 3H) (Example 179).

[0288] 1 ¹H NMR (500MHz, CDCl₃) δ 7.42–7.35 (m, 5H), 7.34–7.29 (m, 1H), 7.13 (d, J = 14.4 Hz, 1H), 6.69 (d, J = 14.4 Hz, 1H), 4.88 (t, J = 6.6 Hz, 1H), 2.96–2.80 (m, 2H), 2.63–2.46 (m, 1H), 2.45–2.41 (m, 1H), 2.32–2.24 (m, 1H) (Example 181).

[0289] 1H NMR(500MHz,DMSO-d6)δ8.30-8.28(m,1H),8.04-8.02(m,1H),7.82(d,J=1.6Hz,1H),7. 74(t, J=9.0Hz, 1H), 5.71-5.61(m, 1H), 2.92-2.76(m, 2H), 2.43-2.36(m, 2H) (Example 196).

[0290] Pharmacological experiments:

[0291] VEGFA ELISA detection (IC 50 ) Logarithmic growth phase 786-O cells were seeded into 96-well plates at a cell concentration of 65,000 cells per mL of culture medium (180 μL per well). Compounds were diluted to the corresponding concentrations, and 20 μL of each compound solution was added to the corresponding cell wells to achieve final compound concentrations of 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, and 10,000 nM. After 24 hours of culture, cell culture supernatants were collected and VEGFA concentrations were measured using an ELISA kit (purchased from Abcam). Finally, the reaction was stopped, and the absorbance of each well was measured at 450 nm using a microplate reader. IC values ​​were calculated using GraphPad Prism. 50 The cell viability was measured using CellTiter-Glo reagent.

[0292] Table 1 shows the IC of an exemplary embodiment. 50 In the table, A stands for IC 50 ≦0.5 μM, B represents 0.5 μM <IC 50 ≦1.5 μM, C is 1.5 μM <IC 50 ≤ 10 μM, D represents IC 50 represents >1.5 μM.

[0293] [Table 1]

[0294] Luciferase experiments: HIF2α reporter cells (786-O-HIF2α-Luc cells) were constructed by stable transfection of 786-O cells (purchased from ATCC) with the luciferase LUC gene using Lipofectamine 3000 transfection reagent (purchased from Invitrogen). Experiments were performed when 786-O-HIF2α-Luc cells were in logarithmic growth phase. The medium (RPMI Medium 1640, purchased from Invitrogen) was discarded, washed three times with PBS, and cells were digested with trypsin (TrypLE, purchased from Invitrogen). The digestion was stopped by washing the cells with medium, 10% fetal bovine serum, 1% penicillin, and streptomycin. Cells were collected by centrifugation, purged twice with PBS to remove phenol red, and resuspended to an appropriate concentration. Cell density and viability were monitored, confirming that cell viability was above 90% before proceeding with the experiment.

[0295] Using an Echo550 (a non-contact ultrasonic dispenser, purchased from Labcyte), gradient concentrations of compounds were transferred to 384-well wells at 25 nL / well. Cells were seeded into a 384-well plate at 4500 cells / well with 25 μL of medium, with final compound concentrations of 10,000, 3,333, 1,111, 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 hours. Steady-Glo™ Luciferase Assay System (purchased from Promega) was added to the 384-well plate at 25 μL / well. Luminescence was detected using Envision. The RLU (Record Luminescence) signal values ​​of each well were used to calculate the % inhibition, and the IC values ​​of the corresponding compounds were then fitted in Graphpad 8.0. 50 was calculated.

[0296] Table 2 shows the IC of an exemplary embodiment. 50 In the table, A stands for IC 50 ≦0.5 μM, B represents 0.5 μM <IC 50 ≦1.5 μM, C is 1.5 μM <IC50 ≤ 10 μM, D represents IC 50 represents >1.5 μM.

[0297] [Table 2]

[0298] In vivo PK: The compounds were formulated in 5% DMSO, 5% Solutol, and 90% NaCl. SD rats and Balb / c mice were used as treatment animals. The intravenous dose was 1 mg / kg, and the oral dose was 5 mg / kg. Blood was collected via the orbit at 5, 15, 30, 1, 2, 4, 7, and 24 hours, respectively. After blood collection, the samples were centrifuged at 4000 rpm for 10 minutes to collect the supernatant. 30 μL of the supernatant was added to 200 μL of internal standard solution to precipitate the mixture. After vortexing, the mixture was centrifuged at 12000 rpm for 10 minutes to obtain 100 μL of the supernatant solution. This was mixed with purified water at a 1:1 ratio and loaded onto the tube. Plasma compound concentrations were detected using a high-performance liquid chromatography mass spectrometer, and the compound concentrations in the plasma samples were quantitatively analyzed using the internal standard quantification method. After measuring the compound concentrations, the C NMR spectrum was analyzed using the Winnonln software. max Relevant pharmacokinetic parameters such as AUC, etc. were calculated. Exemplary compounds of the present invention were experimentally found to have good in vivo PK properties.

Claims

1. Formula (V) 【Chemistry 1-1】 (In the formula, [Chemistry 1-2] represents a single bond or a double bond, L is a bond, —CH ２ -, -S(=O) ２ -, -C=C-, -C(=O)-, -C≡C- or C ３ ~C ５ is a cycloalkyl group, X １ , X ２ are each independently selected from C or N, and X １ and X ２ is N on one side and C on the other side, X ３ is CR ｆ or NR ｆ and R １ is C ６ ~C １０ an aryl group, a 5- to 18-membered heteroaryl group, or C ３ ~C １０ cycloalkyl groups, wherein said 5- to 18-membered heteroaryl groups optionally contain 1, 2, or 3 heteroatoms each independently selected from N, O, and S; ６ ~C １０ aryl groups, 5- to 18-membered heteroaryl groups, and C ３ ~C １０ The cycloalkyl group may optionally contain one or more halogens, —OH, —CN, oxo groups, amino groups, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ haloalkyl group, —C １ ~C ６ Alkylene-OR ｃ , -C ０ ~C ６ Alkylene -C(=O)-R ｃ , -NO ２ , C(=O)OR ｃ and / or -S(=O) ２ R ｃ may be replaced by R ２ is selected from halogen, —CN, or —OH; R ３ is H, deuterium, halogen, -OH, C １ ~C １０ Alkyl group, C ２ ~C １０ alkenyl groups, １ ~C １０ Alkyl group, C ２ ~C １０ The alkenyl group may optionally contain one or more of H, halogen, —CN, —OH, amino group, C １ ~C ５ Alkyl group, C ２ ~C ６ Alkenyl group and / or C １ ~C ５ may be substituted by haloalkyl groups, or R ２ and R ３ forms an oxo group, R ５ is H, halogen, —OH or C １ ~C ６ alkyl group, １ ~C ６ The alkyl group may optionally contain one or more halogens, —CN, —OH, amino groups, C １ ~C ５ Alkyl group, C ２ ~C ６ Alkenyl group and / or C １ ~C ５ optionally substituted with haloalkyl groups; R ６ -CN, halogen, -OH, -NO ２ , -NH ２ , C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Haloalkyl group, C ２ ~C １０ Alkenyl group and C ２ ~C １０ alkynyl groups, １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Haloalkyl group, C ２ ~C １０ Alkenyl group and C ２ ~C １０ The alkynyl group may optionally contain one or more of H, halogen, —CN, —OH, amino, oxo, C １ ~C ５ Alkyl group, C ２ ~C ６ Alkenyl group and / or C １ ~C ５ optionally substituted with haloalkyl groups; R ｆ , none, H, -CN, halogen, C １ ~C １０ Alkyl group or C １ ~C １０ haloalkyl groups, １ ~C １０ Alkyl group and C １ ~C １０ The haloalkyl group may optionally include one or more of H, halogen, —CN, —OH, amino, C １ ~C ５ Alkyl group, C ２ ~C ６ Alkenyl group and / or C １ ~C ５ optionally substituted with haloalkyl groups; R ｊ is H, -NO ２ , -CN, halogen, C １ ~C １０ Alkyl group, C ２ ~C １０ Alkenyl group, C ２ ~C １０ Alkynyl group, C １ ~C １０ Haloalkyl group, C ３ ~C １０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６ ~C １０ an aryl group, a 5- to 10-membered heteroaryl group, —C １ ~C ６ Alkylene-OR ｃ , -OR ｃ , -SR ｃ , -NR ａ R ｂ , -NC(=O)R ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ , -S(=O) ２ NR ａ R ｂ or -S(=O)(=NR ａ ) R ｂ , P(=O)R ａ R ｂ , P(=S)R ａ R ｂ wherein said 5- to 10-membered heteroaryl group and said 3- to 10-membered heterocyclyl group each optionally contain 1, 2, or 3 heteroatoms independently selected from N, O, and S; and wherein said C １ ~C １０ Alkyl group, C ２ ~C １０ Alkenyl group, C ２ ~C １０ Alkynyl group, C １ ~C １０ Haloalkyl group, C ３ ~C １０ Cycloalkyl group, 3- to 10-membered heterocyclyl group, C ６ ~C １０ The aryl and 5- to 10-membered heteroaryl groups may optionally contain one or more halogens, hydroxy groups, amino groups, P(═O)Me ２ , P(=S)Me ２ , -S(=O) ２ -C １ ~C ３ Alkyl group, —S(═O) ２ -C ３ ~C ５ Cycloalkyl group, —S(═O)—C １ ~C ３ Alkyl group, —S(═O)—C ３ ~C ５ Cycloalkyl group, cyano group, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group and / or C １ ~C ６ optionally substituted with haloalkyl groups; R ａ , R ｂ , R ｃ are H and C, respectively. １ ~C １０ Alkyl group, C １ ~C １０ Haloalkyl 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 independently selected from an aryl group or a 5- to 10-membered heteroaryl group; m is 0, 1, 2, 3 or 4. or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

2. The R ３ is H, deuterium or C １ ~C ３ alkyl group, １ ~C ３ The alkyl group may optionally be H, a halogen, —CN, —OH, an amino group, C １ ~C ５ may be substituted by haloalkyl groups, or R ２ and R ３ and R are together formed an oxo group, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

3. The R ３ 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein is selected from H or deuterium.

4. R ５ 3. The compound according to claim 1, wherein is selected from H or halogen, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

5. The compound has the formula (III-1) or the formula (III-2): 【Chemistry 2】 【Transformation 3】 (In the formula, R ４ is F) 4. The compound according to claim 1, wherein the compound is a compound represented by the formula:

6. X ３ is CR ｆ 6. The compound according to any one of claims 1 to 5, wherein:

7. 5. The compound according to any one of claims 1 to 4, wherein L is a bond, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

8. The compound is represented by formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4), or formula (VI-5): 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 8. The compound according to any one of claims 1 to 7, which is a compound represented by the formula:

9. R ６ is -CN, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group or C １ ~C ６ is a haloalkyl group, １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group or C １ ~C ６ 9. The compound of any one of claims 1 to 8, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the haloalkyl group is optionally substituted by one or more H, halogen, -CN, -OH, oxo and / or amino groups.

10. R ６ is a halogen or C １ ~C ６ 10. The compound according to any one of claims 1 to 9, wherein the compound is an alkyl group, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

11. The R ｆ is H, -CN, halogen, C １ ~C ３ Alkyl group or C １ ~C ３ 11. The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from haloalkyl groups.

12. R １ is C ６ ~C ８ an aryl group, a 5- to 8-membered heteroaryl group, or C ３ ~C ６ a cycloalkyl group, wherein the 5- to 8-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S; ６ ~C ８ an aryl group, a 5- to 8-membered heteroaryl group, or C ３ ~C ６ The cycloalkyl group may optionally contain one or more halogens, —OH, —CN, oxo groups, amino groups, C １ ~C ６ Alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ haloalkyl group, —C １ ~C ６ Alkylene-OR ｃ , -C ０ ~C ６ Alkylene -C(=O)-R ｃ , -NO ２ , C(=O)OR ｃ and / or -S(=O) ２ R ｃ 12. The compound according to any one of claims 1 to 11, wherein the compound is optionally substituted by:

13. R １ is a benzene ring, a 5- to 6-membered heteroaryl group, or C ３ ~C ６ a cycloalkyl group, wherein the 5- to 6-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S; and wherein the benzene ring, the 5- to 6-membered heteroaryl group, or C ３ ~C ６ The cycloalkyl group may optionally contain one or more halogens, —CN and / or —C １ ~C ４ 13. The compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, optionally substituted by a haloalkyl group.

14. The R ｊ is H, -CN, halogen, C １ ~C １０ Alkyl group, C ２ ~C １０ Alkenyl group, C １ ~C １０ Haloalkyl group, C ３ ~C １０ Cycloalkyl group, C ６ ~C １０ Aryl group, 5- to 10-membered heteroaryl group, —S(═O)R ｃ , -C １ ~C ６ Alkylene-OR ｃ , -S(=O) ２ R ｃ or P(=O)R ａ R ｂ wherein said 5- to 10-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S; １ ~C １０ Alkyl group, C ２ ~C １０ Alkenyl group, C １ ~C １０ Haloalkyl group, C ３ ~C １０ Cycloalkyl group, C ６ ~C １０ The aryl group, the 5- to 10-membered heteroaryl group, optionally contains one or more halogens, hydroxy groups, P(═O)Me ２ , P(=S)Me ２ , -S(=O) ２ -C １ ~C ３ Alkyl group, —S(═O) ２ -C ３ ~C ５ Cycloalkyl group, —S(═O)—C １ ~C ３ Alkyl group, —S(═O)—C ３ ~C ５ Cycloalkyl group, cyano group, C １ ~C ６ Alkyl group and / or C １ ~C ６ optionally substituted with haloalkyl groups; The R ａ , R ｂ are H and C, respectively. １ ~C ４ independently selected from alkyl groups, The R ｃ is H, C １ ~C ３ Alkyl group or C １ ~C ３ 14. The compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from haloalkyl groups.

15. The R ｊ is H, halogen, -CN, C １ ~C ４ Haloalkyl group, C ３ ~C ５ Cycloalkyl groups, 5-membered heteroaryl groups, S(=O)R ｃ , -S(=O) ２ R ｃ , -S(=O)(=NR ａ ) R ｂ or P(=O)Me ２ wherein the 5-membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms each independently selected from N, O, and S; ３ ~C ５ The cycloalkyl group, the 5-membered heteroaryl group may optionally contain one or more halogen atoms, hydroxy groups, C １ ~C ３ Alkyl group, C １ ~C ３ Alkoxy group and / or C １ ~C ３ optionally substituted with haloalkyl groups; The R ａ , R ｂ are H and C, respectively. １ ~C ４ independently selected from alkyl groups, The R ｃ is H, C １ ~C ３ Alkyl group or C １ ~C ３ 15. The compound according to any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from haloalkyl groups.

16. The R ｊ is C １ ~C ４ Haloalkyl group, cyano group, —S(═O) ２ R ｃ or a 5-membered heteroaryl group, said 5-membered heteroaryl group optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, said 5-membered heteroaryl group optionally containing one or more halogens C １ ~C ３ Alkyl group and / or C １ ~C ３ optionally substituted with haloalkyl groups; The R ｃ is H, C １ ~C ３ Alkyl group or C １ ~C ３ 16. The compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from haloalkyl groups.

17. The compound is 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-iodo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 5,5-difluoro-1-(4-fluoro-3-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chlorobenzene)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(5-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3,5-dichlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-bromo-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(pyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(p-tolyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-fluoro-5-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-ol, 1-((3,3-difluorocyclobutyl)methyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)(3,3-difluorocyclobutyl)ketone, 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methyl-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-4-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-p-fluorobenzonitrile, (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-p-fluorobenzonitrile, 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolyl-8-ol, 7-fluoro-3-phenyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3,5-difluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7-fluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 2-fluoro-5-(7-fluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)benzonitrile, 3-(3,5-difluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-5-p-fluorobenzonitrile, (E)-3-(2-cyclohexylvinyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(cyclopropylethynyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-6,7-dihydroindolizin-8(5H)-one, 7,7-difluoro-3-(1-phenylcyclopropyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, 7,7-difluoro-3-(phenylethynyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol, (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethyloxyphosphine, (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-nitrile, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 2-fluoro-5-(5-fluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(5,5-difluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile, 3-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-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-chloro-5-fluorophenyl)-3,5,5-trifluoro-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-2-cyano, (R)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-cyano-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid, 2-acetyl-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(4-chlorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-fluoro-5-((4S)-5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 5,6-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-5-(5,5-difluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(4-chloro-3-nitrophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 1-(3-amino-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5-fluoro-2-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one, 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-bromo-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(thiophen-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3,5-dichloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolyl-8-ol, 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, 3-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-methoxybenzonitrile, 5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile, 5,5-difluoro-1-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(3-(methanesulfonyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-methoxypyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)pyridinecarbonitrile, 1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-nitrile, (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile, 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5,5-difluoro-1-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (R)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4-vinyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)nicotinonitrile, 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-4-carbonitrile, 5-(5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-((4S)-5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (E)-5,5-difluoro-1-styryl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-(benzenesulfonyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 5,5-difluoro-1-(benzenesulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzaldehyde, 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 2-fluoro-5-(5-fluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzaldehyde, 1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one, 3-fluoro-5-(5-fluoro-4-hydroxy-3-(methanesulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol, (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methanesulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol, (S)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile, (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile, or (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-p-fluorobenzonitrile 2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, selected from:

18. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 17 and at least one pharmaceutically acceptable excipient.

19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for treating a disease mediated by HIF-2α.

20. 20. The use according to claim 19, wherein the disease is VHL syndrome, an autoimmune disease, an inflammatory disease and / or cancer.

21. 21. The use according to claim 20, wherein the cancer is selected from the group consisting of blood cancer, lymphoma, multiple myeloma, gastrointestinal tumors, reproductive system tumors, brain tumors, and nervous system tumors and neoplasms.

22. 22. The use according to claim 21, wherein the cancer is selected from glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, gastric cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neuroblastoma, meningioma and medulloblastoma.

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