Bicyclic compound and application thereof

Abstract

The invention relates to a compound shown in a formula (I). The invention also provides compositions and formulations comprising such compounds, as well as methods of using and making such compounds. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to bicyclic compounds, compositions and formulations comprising such compounds, and methods of using and preparing such compounds. Background Art

[0002] HIFs (Hypoxia inducible factors) belong to the transcription factor family. They are a pathway for the body to sense oxygen changes. They are also called hypoxia inducible factors. They mediate cellular hypoxia responses by controlling more than 40 hypoxia adaptation genes downstream. It is mainly composed of HIFα (HIF-1α, HIF-2α, HIF-3α) and HIF-1β. HIF-1β is always in the cell nucleus, while HIFα is located in the cytoplasm. Under conditions of sufficient oxygen, HIFα will be degraded by proteasomes through pathways such as hydroxylation by PHD prolyl hydroxylase and ubiquitination by VHL (Von Hippel-Lindau Syndrome) ubiquitinase. However, when hypoxia or metabolic pathways are abnormal, HIFα cannot be degraded, so it accumulates in the nucleus and combines with HIF-1β to form heterodimers, activating the hypoxia response element (HRE) in the promoter of downstream genes, thereby 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, etc. Among them, HIF-2α mediates chronic hypoxia and can be continuously activated under physiological hypoxia conditions, playing a more critical role in the occurrence and development of tumors.

[0003] Current studies have shown that the mechanisms by which HIF-2α mediates the occurrence and development of tumors mainly include: 1. Under conditions such as hypoxia or VHL mutation, the HIF-2α metabolic pathway is blocked, and it accumulates into the cell nucleus, forming a heterodimer with HIF-1β, thereby activating the hypoxia response element (HRE), regulating the upregulation of downstream cancer-related genes such as VEGFA, CXCR4, and Cyclin D1, and promoting tumor angiogenesis; 2. HIF-2α also participates in the transmission of immunosuppressive signals by upregulating CD73 expression. Therefore, targeting HIF-2α can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells, and NK cells.

[0004] The activation of the HIF-2α pathway is closely related to the occurrence and development of renal cell carcinoma, glioma, neuroblastoma and pheochromocytoma. VHL protein is an important component of E3 ubiquitin ligase, mediating the degradation of proteins by proteasomes. The VHL gene has a high mutation rate of 57% or a heterozygous loss of 98% in renal cell carcinoma (RCC), leading to pseudohypoxia and inducing HIF-2α activation into the nucleus. Among them, clear cell renal cell carcinoma (ccRCC) accounts for 70%-75% of primary renal cell malignancies, and more than 90% of ccRCC patients have VHL protein defects. In the absence of vascularization, gliomas have unstable blood supply, leading to a hypoxic microenvironment, thereby inducing local high expression of HIF-2α and promoting tumor growth. In pheochromocytoma and paraganglioma, the AA mutation rate of HIF-2α at position 529-532 is as high as 81%, which directly affects the hydroxylation degradation of HIF-2α and causes HIF-2α to be continuously activated.

[0005] The activation of HIF-2α and the formation of heterodimers with HIF-1β are the key factors leading to downstream activation, and the PAS binding domains of the two are the binding sites for the formation of heterodimers. Based on this, Peloton's R&D team developed the HIF-2α small molecule inhibitor PT2977, which exerts an anti-tumor effect by inhibiting the binding of HIF-2α and HIF-1β.

[0006] Since the HIF-2α pathway has a very important close relationship with tumor occurrence and migration, it is very necessary to develop more efficient new molecular entities. Summary of the invention

[0007] The present invention first provides a compound represented by formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

[0008]

[0009] in,

[0010] represents a single bond or a double bond;

[0011] L is a bond, -O-, -NH-, -(CR d R e ) n -, -S-, -S(=O)-, -S(=O)2-, -C=C-, -C≡C- or C3-C5 cycloalkyl;

[0012] X1 and X2 are independently selected from C or N;

[0013] X3 for CR f or NR f ;

[0014] X4 for CR j or NR j ;

[0015] And at least one of X1, X2, X3 and X4 is N;

[0016] R1 is selected from C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 wherein the 5-18-membered heteroaryl and the 3-10-membered heterocyclic group arbitrarily contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 The cycloalkyl and 3-10 membered heterocyclic groups may be optionally substituted with one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, -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 Rb replaced by;

[0017] R2 is selected from H, deuterium, halogen, -CN, -OH, =N-OH, C1-C5 haloalkyl, amino, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl or -NR a R b ;

[0018] R3 is selected from H, deuterium, halogen, -CN, -OH, =N-OH, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C5 haloalkyl, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl or C2-C 10 Alkynyl, the C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C5 haloalkyl, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 The alkyl group may be optionally substituted by one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or R2 and R3 together form an oxo group;

[0019] R4 and R5 are independently selected from H, halogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclic group; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted by one or more halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl;

[0020] R6 is selected from H, -CN, halogen, -OH, -NO2, -NH2, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclic group; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted by one or more H, halogen, -CN, -OH, amino, oxo, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or two R6 together with the C atom to which they are attached form a substituted or unsubstituted C3-C5 cycloalkyl or 3-5 membered heterocyclyl;

[0021] or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl group;

[0022] R d and R e are independently selected from H, halogen, cyano, -NR a R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl; or R d and R e Together they form an oxo group;

[0023] R f Selected from Absent, H, -CN, Halogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, oxo, -NR a R b ; said C1-C 10 Alkyl, C1-C 10 Haloalkyl and C3-C 10 Cycloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl;

[0024] R j Selected from H, -NO2, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -C 1- C6 alkylene-OR c 、-OR c 、-SR c 、-NRa 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 5-10 membered heteroaryl and the 3-10 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 The aryl and 5-10 membered heteroaryl groups may be optionally substituted by one or more halogen, hydroxy, amino, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl, -S(=O)2-C3-C5 cycloalkyl, -S(=O)-C1-C3 alkyl, -S(=O)-C3-C5 cycloalkyl, cyano, C1-C6 alkyl, C1-C6 alkoxy and / or C1-C6 haloalkyl.

[0025] R a , R b and R c are independently selected from H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C 2- C 10 Alkenyl, C 2- C 10 Alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- C 10 Aryl or 5-10 membered heteroaryl;

[0026] n is 1, 2 or 3;

[0027] m is 0, 1, 2, 3 or 4.

[0028] In some embodiments, wherein

[0029] represents a single bond or a double bond;

[0030] L is a bond, -O-, -CR d R e -, -S-, -S(=O)-, -S(=O)2-, -C=C- or -C≡C-;

[0031] X1 and X2 are independently selected from C or N;

[0032] X3 for CR f or NR f ;

[0033] X4 for CR j or NR j ;

[0034] And at least one of X1, X2, X3 and X4 is N;

[0035] R1 is selected from substituted or unsubstituted C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 wherein the 5-18 membered heteroaryl and the 3-10 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the R1 may be optionally replaced by one or more halogen, hydroxyl, cyano, oxo, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-5 Cycloalkyl, C 2-6 Alkynyl or C 1-6 substituted with haloalkyl;

[0036] R2 is selected from H, -OH, amino, C1-C 10 Alkoxy, -O-C1-C3 alkyl acyl or -NR a R b ;

[0037] R3 is selected from H, -OH, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Alkoxy, -OC 1-3 Alkyl acyl or C2-C 10 Alkynyl; or R2 and R3 together form an oxo group;

[0038] R4 and R5 are independently selected from H, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl;

[0039] R6 is selected from H, -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl; or two R6 together with the C atom to which they are attached form a substituted or unsubstituted C3-C5 cycloalkyl or 3-5 membered heterocyclic group;

[0040] or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl group;

[0041] R d and R e are independently selected from H, halogen, cyano, -NR a R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl; or R d and R e Together they form an oxo group;

[0042] R f Selected from H, -CN, halogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, oxo, -NR a R b ;

[0043] R j Selected from H, -NO2, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -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 Rb or -S(=O)(=NR a )R b 、P(=O)R a R b 、P(=S)R a R b ; wherein the 5-10 membered heteroaryl and the 3-10 membered heterocyclic group arbitrarily contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the R j It may be optionally substituted with halogen, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-C 3-5 Cycloalkyl, -S(=O)-C 1-3 Alkyl, -S(=O)-C 3-5 Cycloalkyl, cyano, C 1-6 Alkyl or C 1-6 substituted with haloalkyl;

[0044] R a , R b and R c are independently selected from H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0045] m is 0, 1, 2, 3 or 4.

[0046] In some embodiments, wherein

[0047] L is a bond, -O-, NH-, -CR d R e -, -S-, -S(=O)-, -S(=O)2-, -C=C- or -C≡C-;

[0048] X1 and X2 are C or N;

[0049] X3 for CR f or NR f ;

[0050] X4 for CR j or NR j ;

[0051] And at least one of X1, X2 and X4 is N;

[0052] R1 is selected from C1-C 10Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, C5-C 18 Heteroaryl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group; wherein the C5-C 18 Heteroaryl and C3-C 10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, C5-C 18 Heteroaryl, C3-C 10 Cycloalkyl and C3-C 10 The heterocyclic group may be optionally substituted by H, halogen, hydroxy, cyano, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-5 Cycloalkyl, C 2-6 Alkynyl or C 1-6 substituted with haloalkyl;

[0053] R2 is selected from H, -OH, oxo, amino, C1-C 10 Alkoxy, -OC 1-3 Alkyl acyl or -NR a R b ;

[0054] R3 is selected from H, -OH, oxo, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl or -OC 1-3 Alkyl acyl;

[0055] R4 and R5 are independently selected from H, halogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and C3-C6 heterocyclyl; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl;

[0056] R6 is selected from H, -CN, halogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and C3-C6 heterocyclyl; or two R6 together with the C atom to which they are attached form a substituted or unsubstituted C3-C5 cycloalkyl or C3-C5 heterocyclyl;

[0057] or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl group;

[0058] R d and R e are independently selected from H, halogen, cyano, -NR a R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl; or R d and R e Together they form an oxo group;

[0059] R j Selected from H, -NO2, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, -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 C5-C 10 Heteroaryl and C3-C10 The heterocyclic group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group may be optionally substituted by H, halogen, hydroxy, cyano, oxo, amino, C 1- -C6 alkyl, C 1-6 Alkoxy, C 1- -C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 cycloalkyl, C3-C6 heterocyclyl, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-C 3-5 Cycloalkyl, -S(=O)-C 1-3 Alkyl or -S(=O)-C 3-5 substituted by cycloalkyl;

[0060] R f Selected from Absent, H, -CN, Halogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, oxo, -NR a R b ;

[0061] R a , R b and R c are independently selected from H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 10 heteroaryl;

[0062] m is 0, 1, 2, 3 or 4.

[0063] Preferably, in some embodiments, the compound is as shown in formula (II):

[0064]

[0065] Among them, only one of X1 and X2 is N and the other is C.

[0066] Preferably, in some embodiments, the compound is as shown in formula (III-1) or formula (III-2):

[0067]

[0068] Preferably, in some embodiments, the compound is as shown in formula (III-A-1), formula (III-A-2) or formula (III-A-3),

[0069]

[0070] Preferably, in some embodiments, R2 is halogen, -CN, -OH or =N-OH.

[0071] Preferably, in some embodiments, R2 is halogen, -CN or -OH.

[0072] Preferably, in some embodiments, R2 is F, -CN or -OH.

[0073] Preferably, in some embodiments, R2 is halogen.

[0074] Preferably, in some embodiments, R2 is -CN.

[0075] Preferably, in some embodiments, R2 is -OH.

[0076] Preferably, in some embodiments, R2 and R3 together form an oxo group.

[0077] Preferably, in some embodiments, R3 is selected from H, deuterium, C1-C 10 Alkyl, C2-C 10 Alkenyl, the C1-C 10 Alkyl and C2-C 10 The alkenyl group may be optionally substituted by H, halogen, -CN, -OH, amino, C1-C5 haloalkyl; or R2 and R3 together form an oxo group.

[0078] Preferably, in some embodiments, R3 is selected from H, deuterium, C1-C3 alkyl, C2-C5 alkenyl, and the C1-C3 alkyl and C2-C5 alkenyl may be optionally substituted by H, halogen, -CN, -OH, amino, C1-C5 haloalkyl.

[0079] Preferably, in some embodiments, R3 is selected from H, deuterium or C1-C3 alkyl, and the C1-C3 alkyl and C2-C5 alkenyl may be optionally substituted by H, halogen, -CN, -OH, amino, C1-C5 haloalkyl.

[0080] Preferably, in some embodiments, R3 is selected from H, deuterium or C1-C3 alkyl.

[0081] Preferably, in some embodiments, R3 is H or deuterium.

[0082] Preferably, in some embodiments, R3 is H.

[0083] Preferably, in some embodiments, R2 is -OH, -CN or halogen, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0084] Preferably, in some embodiments, R2 is -OH, -CN or -F, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0085] Preferably, in some embodiments, R2 is -OH, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0086] Preferably, in some embodiments, the compound is as shown in formula (IV-1) or formula (IV-2),

[0087]

[0088] Among them, only one of X1 and X2 is N and the other is C.

[0089] Preferably, in some embodiments, R4 and R5 are independently selected from H, halogen or C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted by H, halogen, -CN, -OH, amino or oxo.

[0090] Preferably, in some embodiments, R4 and R5 are each independently selected from H, halogen or C1-C6 alkyl.

[0091] Preferably, in some embodiments, R4 and R5 are each independently selected from H or halogen.

[0092] Preferably, in some embodiments, R4 and R5 are each independently selected from H or F.

[0093] Preferably, in some embodiments, X4 is CR j .

[0094] Preferably, in some embodiments, the compound is as shown in formula (V),

[0095]

[0096] Among them, only one of X1 and X2 is N and the other is C.

[0097] Preferably, in some embodiments, L is a bond, -CH2-, -S(=O)2-, -C=C-, -C=O-, -C≡C- or C3-C5 cycloalkyl.

[0098] Preferably, in some embodiments, L is a bond.

[0099] Preferably, in some embodiments, the compound is represented by formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4) or formula (VI-5):

[0100]

[0101]

[0102] Preferably, in some embodiments, X3 is CR f .

[0103] Preferably, in some embodiments, R f Selected from H, -CN, -NH2, halogen, C1-C3 alkyl, cyclopropyl or C1-C3 haloalkyl, and the C1-C3 alkyl, cyclopropyl or C1-C3 haloalkyl may be optionally substituted by H, halogen, -CN, -OH, amino, C1-C3 alkyl, C2-C4 alkenyl, C1-C3 haloalkyl.

[0104] Preferably, in some embodiments, X3 is CR f , the R f Selected from H, -CN, halogen, C1-C3 alkyl or cyclopropyl.

[0105] Preferably, in some embodiments, R f It is H, -CN, halogen, C1-C6 alkyl or C1-C3 haloalkyl.

[0106] Preferably, in some embodiments, R f It is H, -CN, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0107] Preferably, in some embodiments, R f is H, -CN or halogen.

[0108] Preferably, in some embodiments, R f is H or halogen.

[0109] Preferably, in some embodiments, R f It is H, -CN, -F, -Cl, -Br or -CF3.

[0110] Preferably, in some embodiments, R f For H.

[0111] Preferably, in some embodiments, R6 is H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, and the C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl may be optionally substituted by H, halogen, -CN, -OH, oxo or amino.

[0112] Preferably, in some embodiments, R6 is H, halogen or C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted by H, halogen, -CN, -OH, oxo, or amino.

[0113] Preferably, in some embodiments, R6 is H, halogen or C1-C6 alkyl.

[0114] Preferably, in some embodiments, R6 is H, halogen or C1-C3 alkyl.

[0115] Preferably, in some embodiments, R6 is H or halogen.

[0116] Preferably, in some embodiments, R6 is H, F, Cl or Br.

[0117] Preferably, in some embodiments, R6 is H or F.

[0118] Preferably, in some embodiments, two R6 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl group.

[0119] Preferably, in some embodiments, R1 is C6-C 10 Aryl, 5-18 membered heteroaryl or C3-C 10 The 5- to 18-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0120] Preferably, in some embodiments, R1 is C6-C 10 The 5- to 18-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0121] Preferably, in some embodiments, R1 is C6-C 10 aryl or 5-18 membered heteroaryl, wherein the 5-18 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the C6-C 10 The aryl or 5-18 membered heteroaryl may be optionally substituted with one or more H, halogen, hydroxy, cyano, amino, C 1-4 Alkyl, C 3-5 Cycloalkyl or C 1-6 Substituted with haloalkyl.

[0122] Preferably, in some embodiments, R1 is C6-C 10 aryl or 5-18 membered heteroaryl, wherein the 5-18 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the C6-C 10 The aryl or 5-18 membered heteroaryl may be optionally substituted with one or more halogen, cyano and / or C 1-6 Substituted with haloalkyl.

[0123] Preferably, in some embodiments, R1 is C6-C8 aryl, 5-8 membered heteroaryl or C3-C6 cycloalkyl, wherein the 5-8 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the C6-C8 aryl, 5-8 membered heteroaryl or C3-C6 cycloalkyl may be optionally substituted by one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c 、-C0-C6 alkylene-C=OR c 、-NO2、C(=O)OR c and / or -S(=O)2R c replaced.

[0124] Preferably, in some embodiments, R1 is a benzene ring, a 5-6 membered heteroaryl or a C3-C6 cycloalkyl, wherein the 5-6 membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the benzene ring, the 5-6 membered heteroaryl or the C3-C6 cycloalkyl may be optionally substituted by one or more halogen, -CN and / or C1-C4 haloalkyl.

[0125] Preferably, in some embodiments, R1 is a benzene ring or a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms selected from N, O or S.

[0126] Preferably, in some embodiments, R1 is a benzene ring or a 6-membered heteroaryl group, and the 6-membered heteroaryl group optionally contains 1, 2 or 3 N heteroatoms.

[0127] Preferably, in some embodiments, R1 is a benzene ring or a pyridine ring.

[0128] Preferably, in some embodiments, the R1 is a benzene ring, and the benzene ring may be optionally substituted by one or more halogens, -CN and / or C1-C4 haloalkyl.

[0129] Preferably, in some embodiments, R1 is a benzene ring, which may be optionally substituted by one or more halogens, -CN, -CHF2, -CF3, -CH2CHF2 and / or -CH2CF3.

[0130] Preferably, in some embodiments, the R1 is a benzene ring, and the benzene ring may be optionally substituted by one or more halogens and / or -CN.

[0131] Preferably, in some embodiments, the R1 is a pyridine ring, and the pyridine ring may be optionally substituted by one or more halogens, -CN and / or C1-C4 haloalkyl.

[0132] Preferably, in some embodiments, the R1 is a pyridine ring, and the pyridine ring may be optionally substituted by one or more halogen, cyano and / or trifluoromethyl groups.

[0133] Preferably, in some embodiments, the R j Selected from H, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -S(=O)R c 、-C1-C6 alkylene-OR c 、-S(=O)2R c or P(=O)R a R b The 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl may be optionally substituted by one or more halogen, hydroxy, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl, -S(=O)2-C3-C5 cycloalkyl, -S(=O)-C1-C3 alkyl, -S(=O)-C3-C5 cycloalkyl, cyano, C1-C6 alkyl and / or C1-C6 haloalkyl;

[0134] The R a , R b and R c Each is independently H or C1-C4 alkyl.

[0135] Preferably, in some embodiments, the R j is selected from H, halogen, -CN, C1-C4 haloalkyl, C3-C5 cycloalkyl, 5-membered heteroaryl, S(=O)R c 、-S(=O)2Rc 、-S(=O)(=NR a )R b or P(=O)Me2; the C3-C5 cycloalkyl and 5-membered heteroaryl may be optionally substituted by one or more halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy and / or C1-C3 haloalkyl; the 5-membered heteroaryl may arbitrarily contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0136] The R a and R b Each independently selected from H, C1-C4 alkyl;

[0137] The R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

[0138] Preferably, in some embodiments, R j is selected from halogen, cyano, C1-C4 haloalkyl, C3-C6 cycloalkyl, 5-membered heteroaryl, S(=O)R c 、-S(=O)2R c 、-S(=O)(=NR a )R b or P(=O)Me2; the C3-C6 cycloalkyl, 5-membered heteroaryl may be optionally substituted by H, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Substituted with haloalkyl.

[0139] Preferably, in some embodiments, the R j Selected from C1-C4 haloalkyl, cyano, -S(=O)2R c or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl group may be optionally substituted by one or more halogen C1-C3 alkyl groups and / or C1-C3 haloalkyl groups;

[0140] The R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

[0141] Preferably, in some embodiments, the R j is selected from C1-C4 haloalkyl, cyano or 5-membered heteroaryl, wherein the C5 heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C5 heteroaryl may be optionally substituted by H, halogen or C1-C3 alkyl.

[0142] Preferably, in some embodiments, the R j It is a C1-C4 haloalkyl group.

[0143] Preferably, in some embodiments, the R j It is a C1-C4 fluoroalkyl group.

[0144] Preferably, in some embodiments, the R j It is -CF3, -CHF2, -CH2F, -CH2CH2F, -CH2CHF2 or -CH2CF3.

[0145] Preferably, in some embodiments, the R j It is -CF3.

[0146] Preferably, in some embodiments, the R a and R b Each is independently selected from H, C1-C4 alkyl.

[0147] Preferably, in some embodiments, the R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

[0148] Preferably, in some embodiments, the R j Selected from

[0149] Preferably, in some embodiments, the compound is as shown in formula (VII):

[0150]

[0151] in,

[0152] represents a single bond or a double bond;

[0153] X1 and X2 have only one N and the other C;

[0154] R1 is selected from C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 Cycloalkyl, wherein the 5-18 membered heteroaryl and the 3-10 membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0155] The R1 is optionally replaced by one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, -C1-C6 alkylene-OR c 、-NO2、-OR c 、-SR c 、-NRa 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 replaced by;

[0156] R2 is -OH, -CN or halogen, and R3 is H or deuterium; or R2 and R3 together form an oxo group;

[0157] R4 and R5 are each independently H or halogen;

[0158] R6 is H, halogen or C1-C6 alkyl;

[0159] R f is H, -CN, halogen, C1-C6 alkyl or C1-C3 haloalkyl;

[0160] R j H, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -S(=O)R c 、-C1-C6 alkylene-OR c 、-S(=O)2R c or P(=O)R a R b The 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10Aryl, 5-10 membered heteroaryl may be optionally substituted by one or more halogen, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl, -S(=O)2-C3-C5 cycloalkyl, -S(=O)-C1-C3 alkyl, -S(=O)-C3-C5 cycloalkyl, cyano, C1-C6 alkyl and / or C1-C6 haloalkyl;

[0161] The R a and R b Each independently selected from H or C1-C4 alkyl;

[0162] The R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

[0163] The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0164] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one;

[0165] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0166] 5,5-Difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0167] 5,5-Difluoro-3-iodo-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0168] 5-(5,5-difluoro-4-hydroxy-3-iodo-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile);

[0169] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0170] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0171] 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0172] 5,5-Difluoro-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0173] 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0174] 5,5-Difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0175] 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;

[0176] 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0177] 5,5-difluoro-1-(4-fluoro-3-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0178] 1-(3-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0179] 5,5-Difluoro-1-(3-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0180] 1-(5-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0181] 5,5-Difluoro-1-(2-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0182] 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0183] 1-(3,5-dichlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0184] 1-(4-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0185] 1-(3-Bromo-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0186] 5,5-difluoro-1-(pyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0187] 5,5-difluoro-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0188] 5,5-difluoro-3-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0189] 5,5-difluoro-1-(p-methylphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0190] 5,5-difluoro-1-(3-fluoro-5-hydroxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0191] 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0192] 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0193] 5,5-Difluoro-1-phenyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-ol;

[0194] 1-((3,3-difluorocyclobutyl)methyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0195] (5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)(3,3-difluorocyclobutyl)methanone;

[0196] 1-(3,5-difluorophenyl)-5,5-difluoro-1,5,6,7-tetrahydro-4H-indol-4-one;

[0197] 1-(3,5-difluorophenyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0198] 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0199] 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0200] 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0201] 3-Fluoro-5-(3-(methylsulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0202] 3-Fluoro-5-(4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0203] 1-(3,5-difluorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-cyano;

[0204] 3-Fluoro-5-(4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0205] 1-(3-chloro-5-fluorophenyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0206] 3-Fluoro-5-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0207] 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0208] 1-(3,3-difluorocyclobutyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0209] 2-Fluoro-5-(4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0210] 1-(3,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0211] (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0212] 1-(4-Fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0213] 1-(3,5-difluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0214] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0215] 1-(3-Chloro-5-fluorophenyl)-3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0216] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0217] 5-(5,5-difluoro-4-hydroxy-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;

[0218] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0219] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(furan-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0220] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0221] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0222] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0223] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0224] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-methyl-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0225] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-4-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0226] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(thiazol-5-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0227] (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0228] 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0229] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0230] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0231] 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0232] 5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-(4-fluorobenzonitrile;

[0233] (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-2-(4-fluorobenzonitrile;

[0234] 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindol-8-ol;

[0235] 7-Fluoro-3-phenyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0236] 3-(3,5-difluorophenyl)-7-fluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0237] 7-Fluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0238] 2-Fluoro-5-(7-fluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)benzonitrile;

[0239] 3-(3,5-difluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0240] 3-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-3-yl)-5-(4-fluorobenzonitrile;

[0241] (E)-3-(2-cyclohexylvinyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0242] 3-(Cyclopropylethynyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0243] 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0244] 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0245] 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0246] 3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindole-8(5H)-one;

[0247] 7,7-difluoro-1-(trifluoromethyl)-3-(3,4,5-trifluorophenyl)-6,7-dihydroindole-8(5H)-one;

[0248] 7,7-difluoro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(trifluoromethyl)-6,7-dihydroindole-8(5H)-one;

[0249] 7,7-difluoro-3-(1-phenylcyclopropyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0250] 7,7-difluoro-3-(phenylethynyl)-1-(trifluoromethyl)-5,6,7,8-tetrahydroindolizin-8-ol;

[0251] (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide;

[0252] (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;

[0253] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile;

[0254] 1-(3-Chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0255] 5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0256] 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0257] 5-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0258] 5-(5,5-difluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0259] 2-Fluoro-5-(5-fluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0260] (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0261] (4R,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0262] (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0263] (4R,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0264] 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0265] (S)-2-Chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0266] 1-(3-(difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0267] 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0268] 3-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;

[0269] 3-(3-(Difluoromethyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;

[0270] 3-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;

[0271] 1-(3-Chloro-5-fluorophenyl)-3,5,5-trifluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0272] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-2-cyano;

[0273] (R)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0274] (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0275] 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0276] 1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0277] 3-(3-Chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol;

[0278] 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0279] 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;

[0280] 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;

[0281] 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0282] 2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0283] 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;

[0284] 2-Cyano-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid;

[0285] 2-Acetyl-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0286] 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0287] 1-(4-Chlorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0288] 2-Fluoro-5-((4S)-5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0289] 5,6-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0290] 5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0291] (S)-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;

[0292] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0293] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0294] 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0295] 1-(4-chloro-3-nitrophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0296] 3-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0297] 1-(3-amino-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0298] 1-(3-chloro-5-fluorophenyl)-5,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0299] 1-(3-Chloro-5-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0300] 1-(3-chloro-5-fluorophenyl)-5-fluoro-2-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0301] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one;

[0302] 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-phenyl-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0303] (S)-2-Bromo-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0304] 5,5-difluoro-1-(thiophen-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0305] 5,5-difluoro-3-(trifluoromethyl)-1-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0306] 1-(3,5-dichloro-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0307] 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroindol-8-ol;

[0308] 3-(3-chloro-5-fluorophenyl)-6,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol;

[0309] 3-(3-Chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-7-ol;

[0310] 3-(3-chloro-5-fluorophenyl)-5,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol;

[0311] 3-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0312] 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-methoxybenzonitrile;

[0313] 5,5-Difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0314] 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile;

[0315] 5,5-difluoro-1-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0316] 5,5-difluoro-1-(pyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0317] 5,5-Difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0318] 5,5-difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0319] 5,5-difluoro-1-(2-methoxypyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0320] 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)picolinonitrile;

[0321] 1-(3,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0322] 5,5-difluoro-1-(2-fluoropyridin-4-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0323] 1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile;

[0324] (S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;

[0325] 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0326] 5,5-difluoro-1-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0327] 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0328] 5,5-difluoro-1-(5-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0329] 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0330] (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0331] (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol

[0332] (R)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0333] 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4-vinyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(p-fluorobenzonitrile;

[0334] 5,5-Difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-4-carbonitrile;

[0335] (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)nicotinonitrile;

[0336] 5-(5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0337] 5-((4S)-5,5-difluoro-4-hydroxy-6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0338] (E)-5,5-difluoro-1-phenylvinyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0339] (E)-5,5-difluoro-1-phenylvinyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0340] 1-(phenylsulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0341] (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0342] 5,5-difluoro-1-(phenylsulfonyl)-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0343] 5,5-difluoro-1-(phenylsulfonyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0344] (E)-1-(2-cyclohexylvinyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0345] 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(4-fluorobenzonitrile;

[0346] 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzaldehyde;

[0347] 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0348] 2-Fluoro-5-(5-fluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzaldehyde;

[0349] 1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one;

[0350] 3-Fluoro-5-(5-fluoro-4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0351] 3-(3-chloro-5-fluorophenyl)-7,7-difluoro-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol;

[0352] 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-7-ol;

[0353] (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;

[0354] (S)-2-Fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0355] (R)-2-Fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;

[0356] (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-p-fluorobenzonitrile;

[0357] or

[0358] (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl-4-d)-2-p-fluorobenzonitrile.

[0359] The present invention also provides a method for preparing the compound. The compound described by formula (I) of the present invention or the compound described in the specific examples can be prepared using known organic synthesis techniques, for example, using a preparation method similar to that in the specific examples.

[0360] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds and a pharmaceutically acceptable excipient, such as hydroxypropyl methylcellulose. In some compositions, the weight ratio of the compound to the excipient is about 0.001 to 10.

[0361] In addition, the present invention also provides a method for treating a subject suffering from 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.

[0362] In some aspects, the disease or illness is selected from VHL syndrome, autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cardiovascular disorders, kidney disease, viral infection and obesity. In some aspects, the disease or illness is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), the acute rejection of transplanted organs. In some aspects, the disease or illness is cancer, including hematological cancer, lymphoma, multiple myeloma, digestive system tumor, reproductive system tumor, brain tumor, nervous system tumor neoplasm.

[0363] In certain aspects, the disease or disorder is a glioma, pheochromocytoma, paraganglioma, a tumor or cancer of the colon, rectum, prostate (e.g., castrate resistant prostate cancer), lung (e.g., non-small cell lung cancer and / or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (e.g., basal or basal-like breast cancer and / or triple negative breast cancer), skin (e.g., melanoma), nervous system (including brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma, and medulloblastoma).

[0364] In some aspects, the disease or condition is VHL syndrome. In some aspects, the disease or condition is renal cancer. In some aspects, the subject is a human.

[0365] In certain aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally or orally. In one aspect, the compound is administered orally.

[0366] The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by HIF-2α.

[0367] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treatment. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a subject suffering from a disease or condition mediated by HIF-2α.

[0368] The present invention can be implemented in other specific forms without departing from its spirit or basic attributes. The present invention encompasses all combinations of the preferred aspects of the present invention mentioned herein. It should be understood that the subject matter disclosed in "Summary of the Invention" does not exhaustively or completely disclose the full scope of the present invention technology or any embodiment thereof, and any and all embodiments of the present invention can be used in combination with any other one or more embodiments to describe other embodiments. It should also be understood that each individual element of the embodiment is an independent embodiment of itself. In addition, any element of the embodiment is intended to be combined with any and all other elements from any embodiment to describe other embodiments.

[0369] In the present invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.

[0370] In the present invention, unless otherwise specified, the term "alkyl" includes a linear or branched saturated monovalent hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, "C1-C6" in C1-C6 alkyl refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched form.

[0371] The term "alkoxy" refers to an oxygen ether formed from the above-mentioned straight chain, branched chain or cyclic alkyl groups.

[0372] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two CH bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, the "C1-C4" in C1-C4 alkylene refers to an alkylene containing 1, 2, 3, or 4 carbon atoms.

[0373] The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced by a halogen atom. The term "haloalkoxy" refers to the group -O-haloalkyl.

[0374] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom.

[0375] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0376] The term "aryl" is a substituted or unsubstituted stable aromatic hydrocarbon group of 6 to 10 ring carbon atoms, which may contain one aromatic ring or multiple aromatic rings (e.g., fused and bicyclic). The aromatic ring does not contain heteroatoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, indenyl, etc.

[0377] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member, wherein the heteroatom is selected from N, O and / or S. The "5-18 members" in the 5-18 membered heteroaryl refers to a heteroaryl group consisting of 5-18 carbon atoms or ring atoms of N, O or S. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl, and the like.

[0378] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 10 The "C3-C 10 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The cycloalkyl group may include a monocyclic ring and a polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, and cyclocyclic rings). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, the cycloalkyl group also includes a portion having one or more aromatic rings fused to the cyclized alkyl ring, such as benzo or thienyl derivatives of cyclohexane, etc.

[0379] The term "cycloalkenyl" refers to a ring system having at least one cyclized alkenyl group having one or more carbon-carbon double bonds. 10 The "C3-C 10 " means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The cycloalkenyl group may include a single ring and a multiple ring (e.g., having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkenyl group includes but is not limited to cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, the cycloalkenyl group also includes a portion having one or more aromatic rings fused to the cyclized alkenyl ring, such as a benzo or thienyl derivative of a cyclohexene ring, etc.

[0380] The term "heterocyclic group" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic ring, wherein the heteroatom is selected from N, O and / or S. The heterocyclic group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclic group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. The definition of the heterocyclic group also includes a portion having one or more aromatic rings fused to the cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. In some embodiments, heterocyclic groups include but are not limited to pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepane, dihydrobenzofuranyl, etc.

[0381] The term "composition" in the present invention is intended to include products containing a specific number of specific components, and also includes any product obtained directly or indirectly from a specific number of specific components. Therefore, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods for preparing the compounds are also contents of the present invention. Moreover, the crystal forms of some compounds can exist in polymorphic forms, which are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.

[0382] The "compound" of the present invention includes compounds of formula (I) and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, isotope-labeled compounds, tautomers, prodrugs, or any mixture of all of the above forms.

[0383] The "enantiomers" are a pair of non-superimposable, mirror-image stereoisomers, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture. When specifying the stereochemistry of the compounds of the present invention, the conventional RS system is used (e.g., (1S, 2S) specifies a single stereoisomer with known relative and absolute configurations of two chiral centers). Optically active (R)- and (S)-isomers can be prepared using optically active raw material synthesis or chiral reagents, or separated using conventional techniques (e.g., separation on a chiral SFC or HPLC column).

[0384] The "diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. When the compound is enantiomerically pure, the stereochemistry at each chiral carbon can be specified by R or S.

[0385] Resolved compounds of unknown absolute configuration can be named (+) or (-) according to the direction (right or left) that they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the corresponding retention times of the corresponding enantiomers / diastereomers by chiral HPLC.

[0386] Those skilled in the art will recognize that the compounds of the present invention may contain one or more chiral centers and may produce diastereomers and optical isomers. The above formula (I) does not precisely define the stereostructure of a certain position of the compound and therefore may exist in different isomeric forms. Unless otherwise indicated, the present invention includes all possible stereoisomers of the compounds shown in formula (I) and pharmaceutically acceptable salts thereof, such as racemic mixtures, optically pure forms, and mixtures of isomers in any proportion. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. In the synthetic process for preparing such compounds, or in the process using racemization or epimerization methods known to those of ordinary skill in the art, the obtained product may be a mixture of stereoisomers.

[0387] Prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the treatment methods provided by the present invention includes the administration of the compounds disclosed in the present invention, or although not explicitly disclosed, it can be converted into the prodrug compound disclosed in the present invention in vivo after administration to the subject. Conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs" (ed. H. Bundgaard, Elsevier, 1985).

[0388] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select substituents or substitution patterns of the compounds of the present invention by means of prior art means and the methods described in the present invention to provide chemically stable and easily synthesized compounds.

[0389] Obviously, the definition of any substituent or variable at a specific position in one molecule is independent of the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compounds in the present invention can select suitable substituents or substitution patterns according to the prior art of this subject to provide chemically stable and easy to prepare and synthesize using the prior art of this subject or the methods described in the present invention.

[0390] When compound shown in formula (I) and pharmaceutically acceptable salt thereof are in the form of solvate or polymorph, the present invention includes any possible solvate and polymorph. The solvent type forming solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, similar solvents such as water, ethanol, propanol, acetone can be adopted.

[0391] 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, its corresponding salt can be conveniently 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 valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. 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, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0392] When compound provided by the invention is alkali, can be from pharmaceutically acceptable nontoxic acid, including inorganic acid and organic acid, conveniently make its corresponding salt.Such acid includes, as, 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, embroic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc.Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.More preferably, formic acid and hydrochloric acid. Since the compound of formula (I) is to be used as a pharmaceutical, it is preferably used in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight).

[0393] The pharmaceutical composition provided by the present invention includes a compound shown in formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable mode of administration of the active ingredient depends on the specific subject, subject property and severity of the disease to be administered, the pharmaceutical composition of the present invention includes a pharmaceutical composition suitable for oral, rectal, local and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration. The pharmaceutical composition of the present invention can be conveniently prepared in unit dosage forms known in the art and any preparation method known in the pharmaceutical field.

[0394] In fact, according to conventional drug mixing technology, the compound shown in formula (I) of the present invention, or a drug precursor, or a metabolite, or a pharmaceutically acceptable salt, can be used as an active ingredient and mixed with a drug carrier to form a pharmaceutical composition. The drug carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention can be in the form of an independent unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, water-in-oil emulsion, or oil-in-water emulsion. In addition, in addition to the common dosage forms mentioned above, the compound shown in formula (I) or its pharmaceutically acceptable salt can also be administered by controlled release and / or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier constituting one or more essential components. Generally, the pharmaceutical composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. The product can then be conveniently prepared into the desired presentation.

[0395] Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active compounds are also included in the pharmaceutical composition of the present invention.

[0396] The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. Gas carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. can be used for oral solid preparations such as powders, capsules and tablets. Considering the ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Optionally, tablet coating can use standard aqueous preparation or non-aqueous preparation technology.

[0397] Tablets containing the compounds or pharmaceutical compositions of the present invention may be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, in a suitable machine. Molded tablets may be prepared by wetting the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine. 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 intended for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with an appropriate and conveniently metered auxiliary material, which auxiliary material accounts for about 5% to 95% of the total pharmaceutical composition. Dosage unit forms generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0398] The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared into an aqueous solution or suspension by adding the active ingredient into water. Suitable surfactants such as hydroxypropylcellulose can be included. In glycerol, liquid polyethylene glycol, and mixtures thereof in oil, dispersions can also be prepared. Further, preservatives can also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

[0399] The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared into the form of sterile powders that can be used for instant preparation of sterile injections or dispersions. In any case, the final injection form must be sterile, and in order to be easy to inject, must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferred to preserve against microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0400] The pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, an aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use with a transdermal drug delivery device. These preparations can be prepared using the compound shown in formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. As an example, the preparation of an emulsion or ointment is by adding a hydrophilic material and water to about 5wt% to 10wt% of the above-mentioned compound to obtain an emulsion or ointment with the desired consistency.

[0401] The pharmaceutical composition provided by the present invention can be prepared in a form suitable for rectal administration with a solid as a carrier. The preferred dosage form is a suppository in which the mixture forms a unit dose. Suitable adjuvants include cocoa butter and other materials commonly used in the art. Suppositories can be easily prepared by first mixing the pharmaceutical composition with a softened or melted adjuvant, and then cooling and molding the mixture into a mold.

[0402] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, where appropriate, one or more additional auxiliary components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants and preservatives (including antioxidants), etc. In addition, other adjuvants may also include osmotic agents that regulate the osmotic pressure of the drug and blood. The pharmaceutical composition comprising the compound shown in formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or a concentrated solution.

[0403] Generally, the dosage level of the drug for treating the above-mentioned conditions or discomforts is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. However, it is understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health status, sex, diet, administration time, administration route, excretion rate, drug combination and the severity of the specific disease being treated. Specific implementation plan

[0404] In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with embodiments, which are merely illustrative and are not intended to limit the scope of application of the present invention. The experimental methods in the present invention are conventional methods unless otherwise specified. The experimental materials used in the present invention are commercially available unless otherwise specified.

[0405] Unless otherwise indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius.

[0406] The following abbreviations are used in the examples:

[0407] CuI: cuprous iodide;

[0408] DAST: diethylaminosulfur trifluoride;

[0409] DCM: dichloromethane;

[0410] DMF: N,N-dimethylformamide;

[0411] DMSO: dimethyl sulfoxide;

[0412] EA: ethyl acetate;

[0413] ESI-MS: electrospray ionization mass spectrometry;

[0414] K2CO3: potassium carbonate;

[0415] NaH: sodium hydride;

[0416] LDA: lithium diisopropylamide;

[0417] LiHMDS: lithium bis(trimethylsilyl)amide;

[0418] m-CPBA: meta-chloroperbenzoic acid;

[0419] MtBE: methyl tert-butyl ether;

[0420] Na2SO4: sodium sulfate;

[0421] NaBH4: sodium borohydride;

[0422] NBS: N-bromosuccinimide;

[0423] NFSI: N-fluorobis(benzenesulfonamide);

[0424] NIS: N-iodosuccinimide;

[0425] NMP: N-methylpyrrolidone;

[0426] PE: petroleum ether;

[0427] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0428] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0429] Pd(PPh3)4: tetrakis(triphenylphosphine)palladium;

[0430] Prep-TLC: Preparative thin layer chromatography;

[0431] SelectFlour: 1-Chloromethyl-4-fluoro-1,4-nitrogen Bicyclo[2.2.2]octane bis(tetrafluoroborate);

[0432] TBAF: tetrabutylammonium fluoride;

[0433] TEA: triethylamine;

[0434] THF: tetrahydrofuran;

[0435] Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene;

[0436] TLC: thin layer chromatography;

[0437] ESI-MS: electrospray ionization mass spectrometry;

[0438] LCMS or LC-MS: liquid chromatography-mass spectrometry;

[0439] 1 H NMR: hydrogen nuclear magnetic resonance;

[0440] [(R,R)-Ts-DPEN]RuCl(p-cymene): Chloro{[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) chloride.

[0441] Synthesis of Intermediate M1 (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one)

[0442]

[0443] Step 1: Synthesis of Compound M1-1

[0444] Under nitrogen protection, 6,7-dihydro-1H-indol-4(5H)-one (13.5g) was dissolved in DMF (100mL), 60% NaH (4.4g) was slowly added under ice bath, and triisopropylsilyl chloride (21.2g) was added after stirring for half an hour. The reaction solution was stirred at zero degree for 3 hours, and the reaction solution was poured into a mixture of ice water (500mL), extracted with ethyl acetate (500mL*2), washed with saturated brine (500mL*2), dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1-1 (20.3g). ESI-MS m / z:292.10[M+H] + .

[0445] Step 2: Synthesis of Compound M1-2

[0446] Under nitrogen protection, compound M1-1 (13.5 g) was dissolved in DMF (100 mL), NIS (11.5 g) was added in batches, and the mixture was reacted at room temperature for 7 hours. The reaction solution was poured into a mixture of ice water (500 mL), extracted with ethyl acetate (500 mL*2), washed with saturated brine (500 mL*2), dried, and concentrated to obtain a 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] + .

[0447] Step 3: Synthesis of Compound M1-3

[0448] Compound M1-2 (5.5 g) was dissolved in THF (50 mL), cooled to -78 °C, and a 1.0 M LiHMDS tetrahydrofuran solution (35.6 mL) was slowly added dropwise. After stirring at room temperature for half an hour, a tetrahydrofuran solution (50 mL) of NFSI (8.72 g) was added dropwise. Stirring at room temperature for two hours, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a 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] + .

[0449] Step 4: Synthesis of Compound M1

[0450] Compound M1-3 (2.1 g) was dissolved in a mixed solvent of THF (20 mL) and water (20 mL), K2CO3 (1.27 g) was added at room temperature, and stirred at room temperature for three hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (100% DCM) to obtain 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).

[0451] Synthesis of Intermediate M2 (5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one)

[0452]

[0453] M1 (12 g), cuprous iodide (7.8 g), and methyl fluorosulfonyl difluoroacetate (24 g) were added to DMF (120 mL), and heated to 130 degrees under nitrogen replacement protection. The reaction was allowed to proceed overnight. TLC and LCMS showed that no raw material remained. The mixture was cooled, diluted with ethyl acetate, and the organic phase was washed with saturated brine, dried with sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:5) to obtain 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). Synthesis of Intermediate M3 (5-fluoro-3-(trifluoromethyl)-1,5,6,7- Tetrahydro-4H-indol-4-one)

[0454]

[0455] Step 1: Synthesis of compound M3-1

[0456] Compound M1-2 (834 mg), cuprous iodide (380 mg), NMP (20 mL) and methyl fluorosulfonyl difluoroacetate (1.15 g) were added to a 50 mL single-mouth bottle in sequence, and the temperature was raised to 120°C. The reaction mixture was reacted for 6 hours. The reaction mixture was diluted with EA, washed with water three times, washed with saturated brine once, 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] + .

[0457] Step 2: Synthesis of Compound M3

[0458] Under nitrogen protection, compound M3-1 (264 mg) was dissolved in ultra-dry tetrahydrofuran (20 mL), cooled to -78 ° C, and 1.0 M LDA tetrahydrofuran solution (2.5 mL) was slowly added dropwise. After stirring for half an hour, NFSI (491 mg) tetrahydrofuran solution (5 mL) was added dropwise, and continued to stir at -78 ° C for two hours. Saturated aqueous ammonium chloride was added to the reaction mixture to quench the reaction, extracted twice with ethyl acetate, washed twice 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 (147 mg). ESI-MS m / z: 222.12 [M + H] + .

[0459] Intermediate M4 (3-bromo-7-fluoro-1-(trifluoromethyl)-6,7-dihydroindole-8(5H)-one) and Intermediate M5 (3- Synthesis of bromo-7,7-difluoro-1-(trifluoromethyl)-6,7-dihydroindole-8(5H)-one

[0460]

[0461] Step 1: Synthesis of Compound M4-1

[0462] Under nitrogen protection, 3-bromo-1H-pyrrole-2-carboxylic acid methyl ester (20.4 g) and 4-bromobutyric acid methyl ester (19.8 g) were dissolved in DMF (100 mL), cesium carbonate (65.2 g) was added, and after stirring at room temperature for 4 hours, the reaction solution was poured into a mixture of ice water (500 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which 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] + .

[0463] Step 2: Synthesis of compound M4-2

[0464] 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 under ice bath, stirred at 0°C for 3 hours, cooled to -78°C, and NFSI (18.9 g) tetrahydrofuran solution (50 mL) was added, and the reaction was continued at -78°C for 1 hour. After adding saturated ammonium chloride aqueous solution to quench the reaction, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a 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] + .

[0465] Step 3: Synthesis of compound M4-3

[0466] 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 methyl fluorosulfonyl difluoroacetate (23 g) were added, stirred at 100°C for 3 hours, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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] + .

[0467] Step 4: Synthesis of Compound M4-4

[0468] Compound M4-3 (4.23 g) was dissolved in a mixed solvent of ethanol (20 mL) and 6M aqueous hydrochloric acid solution (20 mL), and the reaction was refluxed for 3 hours. The ethanol was concentrated under reduced pressure and the residue was extracted with ethyl acetate (100 mL*2), the organic layer was washed with brine (100 mL*2), dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:4) to obtain the target compound M4-4 (2.1 g). ESI-MS m / z: 221.20 [M+H] + .

[0469] Step 5: Synthesis of Compound M4

[0470] Compound M4-4 (2.1 g) was dissolved in acetonitrile (20 mL), NBS (1.8 g) was added at room temperature, the reaction solution was refluxed for 4 hours, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3) to obtain the target compound M4 (2.5 g). ESI-MS m / z: 300.10 [M+H] + .

[0471] Step 6: Synthesis of Compound M5

[0472] Compound M4 (1.3 g) was dissolved in THF (50 mL), cooled to -78 °C, and slowly dripped into 1.0 M LiHMDS tetrahydrofuran solution (6 mL). After stirring for half an hour, a tetrahydrofuran solution (10 mL) of NFSI (1.5 g) was dripped into the solution, and the stirring was continued for two hours. After adding a saturated aqueous solution of ammonium chloride to quench the reaction, the mixture was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound M5 (2.1 g). ESI-MS m / z: 318.14 [M+H] + .

[0473] Synthesis of Intermediate M6 (5,6-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indol-4-one)

[0474]

[0475] Step 1: Synthesis of Compound M6-11

[0476] Under nitrogen protection, 1,3-dimethoxy-5-fluorobenzene (15.6 g) was dissolved in tert-butanol (25 mL) and tetrahydrofuran (15 mL), added to liquid ammonia solution (650 mL), and metallic lithium (1.75 g) was added in batches. The blue solution was stirred below -65 degrees for 3 hours, and solid ammonium chloride was added until the blue color disappeared. The temperature was raised to allow the liquid ammonia to evaporate and remove. The residue was diluted with petroleum ether, washed with water, washed with saturated brine, and dried and concentrated to obtain the target product M6-11 (10 g).

[0477] Step 2: Synthesis of Compound M6-12

[0478] Compound M6-11 (10 g) was dissolved in tetrahydrofuran solution (100 mL), 1N hydrochloric acid (100 mL) was added, stirred at room temperature overnight, diluted with ethyl acetate, extracted 3 times, dried and concentrated to obtain the target product M6-12 (10 g). ESI-MS m / z: 129.10 [MH] - .

[0479] Step 3: Synthesis of Compound M6-21

[0480] 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, heated to 90 degrees and stirred for 5 days, cooled to room temperature, diluted with water and ether, the aqueous phase was extracted with ether 3 times, and dried and concentrated to obtain M6-21 (30 g).

[0481] Step 4: Synthesis of Compound M6-13

[0482] Compound M6-21 (5.73 g) was dissolved in THF (150 mL), and M6-12 (3.86 g) and triphenylphosphine (11.8 g) were added. The mixture was heated under reflux overnight, cooled to room temperature, concentrated, and subjected to column chromatography to obtain M6-13 (7.24 g).

[0483] Step 5: Synthesis of Compound M6-14

[0484] Compound M6-13 (7.24 g) was dissolved in dichloromethane (100 mL), cooled to zero degrees, trifluoroacetic acid (5 mL) was added, stirred at room temperature overnight, concentrated, and column chromatography was performed to obtain the target product M6-14 (5 g).

[0485] Step 6: Synthesis of Compound M6-15

[0486] Referring to the preparation method of compound M1-1, M6-15 was obtained.

[0487] Step 7: Synthesis of Compound M6-16

[0488] Referring to the preparation method of compound M1-2, M6-16 was obtained.

[0489] Step 8: Synthesis of Compound M6-17

[0490] Referring to the preparation method of compound M3, step 2, M6-17 was obtained.

[0491] Step 9: Synthesis of Compound M6-18

[0492] Referring to the preparation method of intermediate M2, M6-18 was obtained.

[0493] Step 10: Synthesis of Compound M6

[0494] Refer to the preparation method of intermediate M1 step 4 to obtain M6.

[0495] Example 1 and Example 2 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indole- 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 Synthesis of Compound A2)

[0496]

[0497] Step 1: Synthesis of Compound A13

[0498] Compound M1 (300 mg) was dissolved in DCM (20 mL), and copper acetate (90 mg), 3-chloro-5-fluorophenylboronic acid (350 mg) and TEA (404 mg) were added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound A13 (255 mg). ESI-MS m / z: 426.09 [M+H] + .

[0499] Step 1: Synthesis of Compound A2

[0500] Compound A13 (43 mg) was dissolved in methanol (2 mL), NaBH4 (8 mg) was added under ice bath, and stirred at 0°C for 1 hour. Ice water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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-H2O] + .

[0501] Using a method substantially similar to that of Example 1, for example Replace with etc., prepared the following examples.

[0502]

[0503] Examples 6 and 7 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indole Indole-4-one (Compound A18) and 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- Synthesis of indole-4-ol (Compound A1)

[0504]

[0505] Step 1: Synthesis of Compound A18

[0506] Under nitrogen protection, compound A13 (255 mg) was dissolved in DMF (5 mL), Pd2(dba)3 (165 mg), CuI (114 mg) and methyl fluorosulfonyl difluoroacetate (230 mg) were added, and the mixture was stirred at 100°C for 3 hours, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:5) to obtain the target compound A18 (176 mg). ESI-MS m / z: 368.20 [M+H] + .

[0507] Step 2: Synthesis of Compound A1

[0508] Compound A18 (147 mg) was dissolved in methanol (4 mL), and NaBH4 (30 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A1 (118 mg). ESI-MS m / z: 352.11 [M+H-H2O] + .

[0509] Using a method substantially similar to that of Examples 1 to 7, for example, Replace with, etc., prepared the following examples.

[0510]

[0511]

[0512]

[0513] Example 28 and Example 29_1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrafluoroethylene Hydrogen-4H-indol-4-one (Compound A19) and 1-(3-chloro-5-fluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7- Synthesis of Tetrahydro-1H-indol-4-ol (Compound A3)

[0514]

[0515] Step 1: Synthesis of compound 3-1

[0516] The intermediate M1 (300 mg) was dissolved in DMF (10 mL), K2CO3 (276 mg) and 3-chloro-5-fluorobenzyl bromide (245 mg) were added, and stirred at room temperature for two hours. The reaction mixture was poured into water, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:7) to obtain the target compound 3-1 (307 mg). ESI-MS m / z: 440.10 [M+H] + .

[0517] Step 2: Synthesis of Compound A19

[0518] Under nitrogen protection, compound 3-1 (307 mg) was dissolved in DMF (5 mL), Pd2(dba)3 (192 mg), CuI (133 mg) and methyl fluorosulfonyl difluoroacetate (265 mg) were added, and the mixture was stirred at 100°C for three hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:10) to obtain the target compound A19 (186 mg). ESI-MS m / z: 382.20 [M+H] + .

[0519] Step 3: Synthesis of Compound A3

[0520] Compound A19 (186 mg) was dissolved in methanol (4 mL), and NaBH4 (56 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A3 (158 mg). ESI-MS m / z: 366.22 [M+H-H2O] + .

[0521] Using a method substantially similar to that of Examples 1 to 28, for example Replace with, etc., prepared the following examples.

[0522]

[0523] Example 33 and Example 34 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) synthesis

[0524] Step 1: Synthesis of compound 4-1

[0525] Under nitrogen protection, compound M1-1 (2.91 g) was dissolved in THF (40 mL), cooled to -78 ° C, and 1.0 M LiHMDS tetrahydrofuran solution (28 mL) was slowly added dropwise. After stirring for half an hour, NFSI (6.6 g) tetrahydrofuran solution (40 mL) was added dropwise, and stirring was continued at -78 ° C for two hours. Saturated aqueous ammonium chloride was added to the reaction mixture to quench the reaction, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain crude compound 4-1 (2.8 g), which was directly used in the next step.

[0526] Step 2: Synthesis of compound 4-2

[0527] The crude compound 4-1 (2.8 g) was dissolved in a mixed solvent of THF (20 mL) / water (20 mL), K2CO3 (2.76 g) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (DCM = 100%) to obtain the target compound 4-2 (512 mg). ESI-MS m / z: 172.12 [M+H] + .

[0528] Step 3: Synthesis of Compound A12

[0529] Compound 4-2 (171 mg) was dissolved in DCM (50 mL), copper acetate (90 mg), 3,5-difluorophenylboronic acid (316 mg), TEA compound (404 mg) were added, stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound A12 (170 mg). ESI-MS m / z: 284.08 [M+H] + .

[0530] Step 4: Synthesis of Compound A4

[0531] Compound A12 (170 mg) was dissolved in methanol (4 mL), and NaBH4 (46 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A4 (137 mg). ESI-MS m / z: 268.13MS[M+H-H2O] +.

[0532] Example 35 and Example 36 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indole Indole-4-one (Compound A20) and 1-cyclohexyl-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol Synthesis of (Compound A5)

[0533]

[0534] Step 1: Synthesis of compound 5-1

[0535] Compound M1-2 (19 g), THF (150 mL) and TBAF (13.09 g) were added to a 500 ml single-mouth bottle in sequence and reacted at room temperature for 30 min. The mixture was concentrated under reduced pressure to obtain a residue, to which PE / EA (V:V=1:1, 100 ml) was added, stirred and filtered, and the filter cake was rinsed twice with EA to obtain compound 5-1 (5.2 g).

[0536] Step 2: Synthesis of compound 5-2

[0537] Compound 5-1 (500 mg), cesium carbonate (2.5 g), 4-methylbenzenesulfonic acid cyclohexyl ester (1.2 g) and DMF (10 mL) were added to a 50 ml single-mouth bottle, and the temperature was raised to 100 ° C. The reaction mixture was diluted with EA, washed with water 3 times and saturated sodium chloride solution once, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound 5-2 (230 mg).

[0538] Step 3: Synthesis of compound 5-3

[0539] The target compound 5-3 can be prepared by using a preparation method similar to compound A19 and replacing compound 3-1 with compound 5-2.

[0540] Step 4: Synthesis of Compound A20

[0541] The target compound A20 can be prepared by adopting a preparation method similar to step 3 of intermediate M1, replacing compound M1-2 with compound 5-3.

[0542] Step 5: Synthesis of Compound A5

[0543] The target compound A5 can be prepared by using a preparation method similar to compound A4, replacing compound A12 with compound A20. LCMS: 306.18 [M+H-H2O] + .

[0544] Example 37 1-(3,5-difluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol (compound Synthesis of Compound A6)

[0545]

[0546] Step 1: Synthesis of compound 6-1

[0547] Using a preparation method similar to intermediate M4, replacing M4-4 with M1-1, compound 6-1 can be prepared.

[0548] Step 2: Synthesis of compound 6-2

[0549] 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), stirred for 1 hour, the reaction solution was concentrated, diluted with water, extracted with EA, and concentrated to obtain a crude product. The crude product was purified by silica gel column (EA:PE = 70%) to obtain the target compound 6-2 (1.1 g).

[0550] Step 3: Synthesis of compound 6-3

[0551] At room temperature, potassium carbonate (968 mg) and 1,3,5-trifluorobenzene (617 mg) were added to a DMF (10 mL) solution of compound 6-2 (500 mg), and then the temperature was raised to 100 °C and stirred overnight. The reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA: PE = 17%) to obtain the target compound 6-3 (400 mg).

[0552] Step 4: Synthesis of compound 6-4

[0553] Compound 6-3 (100 mg), cuprous iodide (111.18 mg), NMP (3 mL) and methyl fluorosulfonyl difluoroacetate (112.15 mg) were added to a 25 ml single-mouth bottle in sequence, and the temperature was raised to 120°C. The reaction mixture was reacted for 6 hours. The reaction mixture was diluted with EA, washed with water three times, washed with saturated brine once, dried, and concentrated to obtain a 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] + .

[0554] Step 5: Synthesis of Compound A6

[0555] The compound A6 can be prepared by using a preparation method similar to that of M3, replacing compound M3-1 with compound 6-4. LCMS: [M+H-H2O] + :300.09.

[0556] Example 38 and Example 39 3-Fluoro-5-(3-(methylsulfonyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-1- 1H-indol-1-yl)-3-fluoro-5-(4-hydroxy-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl) Synthesis of benzonitrile (Compound A8)

[0557]

[0558] Step 1: Synthesis of compound 8-1

[0559] At room temperature, potassium carbonate (1000 mg) and 3,5-difluorobenzonitrile (700 mg) were added to a DMF (10 mL) solution of compound 5-1 (500 mg), and then the temperature was raised to 100 ° C and stirred overnight. The reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA: PE = 17%) to obtain the target compound 8-1 (350 mg).

[0560] Step 2: Synthesis of compound 8-2

[0561] Compound 8-1 (380 mg), methyl 3-sulfanylpropionate (240 mg), Xantphos (116 mg) and Pd2(dba)3 (89 mg) were added to toluene (10 mL), stirred at 70°C overnight, concentrated to obtain a residue, and the residue was purified by column chromatography to obtain the target compound 8-2 (232 mg).

[0562] Step 3: Synthesis of compound 8-3

[0563] At -78°C, potassium tert-butoxide (43 mg) was added to a solution of compound 8-2 (120 mg) in THF (10 mL), stirred until the starting material disappeared, iodomethane (92 mg) was added, stirred for 5 hours, 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).

[0564] Step 4: Synthesis of Compound A24

[0565] At room temperature, m-CPBA (223 mg) was added to compound 8-3 (130 mg) in dichloromethane (10 mL), and stirred at room temperature for 10 hours. The reaction mixture was extracted with sodium thiosulfate aqueous solution, diluted with dichloromethane, washed with sodium bicarbonate aqueous solution, washed with saturated brine, dried, and concentrated to obtain a 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] + .

[0566] Step 5: Synthesis of Compound A8

[0567] The compound 8 can be prepared by using a preparation method similar to that of compound A2, where compound A13 is replaced by compound 8-4. ESI-MS m / z: 317.11 [M+H-H2O] + .

[0568] Example 40 1-(3,5-difluorophenyl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile (Compound Synthesis of A25)

[0569]

[0570] Step 1: Synthesis of compound A25-1

[0571] At room temperature, potassium carbonate (900 mg) and 1,3,5-trifluorobenzene (600 mg) were added to a DMF (10 mL) solution of compound 5-1 (450 mg), and then the temperature was raised to 100 °C and stirred overnight. The reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA: PE = 17%) to obtain the target compound A25-1 (400 mg).

[0572] Step 2: Synthesis of Compound A25-2

[0573] Under nitrogen protection, compound A25-1 (200 mg) was dissolved in DMF (5 mL), and Zn(CN)2 (117 mg) and Pd(PPh3)4 (58 mg) were added. The mixture was stirred at 120°C for 2 hours, 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=1:3) to obtain the target compound A25-2 (120 mg).

[0574] Step 3: Synthesis of Compound A25

[0575] Compound A25-2 (100 mg) was dissolved in a mixed solvent of THF (2 mL) and H2O (1 mL), and NaBH4 (18 mg) was added under ice bath, and stirred at 0°C for 1 hour. Ice water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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-H2O] + .

[0576] The following compounds were obtained by a preparation method similar to that of Example 1 to Example 40.

[0577]

[0578] Example 47 1-(3,5-difluorophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indole Synthesis of Indole-4-ol (Compound A7)

[0579]

[0580] Step 1: Synthesis of compound 7-1

[0581] At room temperature, Pd(dppf)Cl2 (12.52 mg), K2CO3 (42.38 mg), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (38.28 mg) were added to a mixed solution of compound 6-3 (50 mg) in dioxane (2 mL) / H2O (0.5 mL), and the mixture was replaced with nitrogen three times. The mixture was reacted at 100°C in a microwave for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated to obtain the target compound 7-1 (40 mg).

[0582] Step 2: Synthesis of Compound A7

[0583] The compound A7 can be prepared by using a preparation method similar to that of compound A2, where compound A13 is replaced by compound 7-1. ESI-MS m / z: 312.14 [M+H] + .

[0584] Example 48 (S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H- Synthesis of indole-4-ol (Compound A65)

[0585]

[0586] Step 1: Synthesis of compound A65-1

[0587] Compound A13 (100 mg), 2-thiophene boronic acid (36 mg), Pd(PPh3)4 (30 mg), potassium carbonate (97 mg) were added to dioxane (5 mL) and water (1 mL), and reacted at 90 degrees overnight under nitrogen protection, diluted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, concentrated, and Prep-TLC prepared the target product A65-1 (60 mg). ESI-MS m / z: [M+H] + :382.05.

[0588] Step 2: Synthesis of Compound A65

[0589] 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 dried by spin drying. The target product A65 (23 mg) was prepared by Prep-TLC. ESI-MS m / z: [M+H-H2O] + :366.11. 1H 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).

[0590] Example 49 1-(4-Fluorobenzyl)-3-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-1H-indole-4-yl Synthesis of alcohol (Compound A79)

[0591]

[0592] Step 1: Synthesis of compound A79-1

[0593] Compound M1-2 (19 g), THF (150 mL) and TBAF (13.09 g) were added to a 500 ml single-mouth bottle in sequence and reacted at room temperature for 30 min. The mixture was concentrated under reduced pressure to obtain a residue, to which PE / EA (V:V=1:1, 100 ml) was added, stirred and filtered, and the filter cake was rinsed twice with EA to obtain compound A79-1 (5.2 g).

[0594] Step 2: Synthesis of Compound A79-2

[0595] Compound A79-1 (300 mg) was dissolved in DMF (10 mL), K2CO3 (276 mg) and 4-fluorobenzyl bromide (260 mg) were added, and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into water, extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:7) to obtain the target compound A79-2 (200 mg).

[0596] Step 3: Synthesis of Compound A79-3

[0597] At room temperature, Pd(dppf)Cl2 (44 mg), K2CO3 (112 mg), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (112 mg) were added to a mixed solution of compound A79-2 (100 mg) in dioxane (2 mL) / H2O (0.5 mL), and the mixture was replaced with nitrogen three times. The mixture was 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).

[0598] Step 4: Synthesis of Compound A79

[0599] The compound can be prepared by reduction with sodium borohydride using a similar preparation method as compound A2. LCMS: 308.21 [M+H-H2O] + .

[0600] Using a preparation method similar to that of Example 1-49, for example Replace with etc., and obtained the following compound.

[0601]

[0602]

[0603]

[0604] Example 64 (S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole Synthesis of Indole-4-ol (Compound A9)

[0605]

[0606] Step 1: Synthesis of compound 9-1

[0607] Compound M1 (300 mg) was dissolved in DCM (20 mL), and copper acetate (90 mg), 3,5-difluorophenylboronic acid (350 mg) and TEA (404 mg) were added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound 9-1 (230 mg). ESI-MS m / z: 409.11 [M+H] + .

[0608] Step 2: Synthesis of compound 9-2

[0609] Under nitrogen protection, compound 9-1 (230 mg) was dissolved in DMF (5 mL), Pd2(dba)3 (165 mg), CuI (114 mg) and methyl fluorosulfonyl difluoroacetate (230 mg) were added, and the mixture was stirred at 100°C for 3 hours, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound 9-2 (150 mg). ESI-MS m / z: 352.20 [M+H] + .

[0610] Step 3: Synthesis of Compound A9

[0611] Compound 9-2 (150 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, the reaction mixture was bubbled with nitrogen, [(R,R)-Ts-DPEN]RuCl(p-cymene)] (12 mg) was added, and the mixture was stirred overnight at room temperature under nitrogen protection, and concentrated. 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-H2O] + .

[0612] Example 65 1-(3-chloro-5-fluorophenyl)-3-(difluoromethyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indole- Synthesis of 4-ol (Compound A29)

[0613]

[0614] Step 1: Synthesis of compound A29-1

[0615] Under nitrogen protection, compound A13 (400 mg) was dissolved in a mixed solvent of dioxane (5 mL) and H2O (5 mL), and Pd(PPh3)4 (109 mg), K2CO3 (390 mg) and vinylboronic acid pinacol ester (217 mg) were added. The mixture was reacted overnight at 90°C, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:5) to obtain the target compound A29-1 (210 mg). ESI-MS m / z: 326.03 [M+H] + .

[0616] Step 2: Synthesis of Compound A29-2

[0617] Compound A29-1 (210 mg) was dissolved in a mixed solvent of THF (5 mL) and H2O (5 mL), and NaIO4 (414 mg) and potassium osmate (20 mg) were added. The mixture was reacted at room temperature for 2 hours, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a 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] + .

[0618] Step 3: Synthesis of Compound A29-3

[0619] 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 addition was complete, the mixture was returned 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 obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:4) to obtain the target compound A29-3 (45 mg). ESI-MS m / z: 350.05 [M+H] + .

[0620] Step 4: Synthesis of Compound A29

[0621] Compound A29-3 (45 mg) was dissolved in a mixed solvent of THF (5 mL) and H2O (5 mL), and NaBH4 (20 mg) was added under ice bath, and the mixture was reacted at 90°C for half an hour, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound A29 (30 mg). ESI-MS m / z: 334.04 [M+H-H2O] + .

[0622] Example 66 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-vinyl-4,5,6,7-tetrahydro-1H-indol-4-ol Synthesis of (Compound D12)

[0623]

[0624] Using a similar preparation method to compound A2, A29-1 was reduced with sodium borohydride to obtain compound D12. ESI-MS m / z: [M+H-H2O] + :310.17.

[0625] Example 67 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(hydroxymethyl)-4,5,6,7-tetrahydro-1H-indole-4-yl Synthesis of alcohol (compound D20)

[0626]

[0627] Compound D20 can be prepared by reducing A29-2 with sodium borohydride using a similar preparation method as compound A2. ESI-MS m / z: [M+H-H2O] + :314.00.

[0628] Example 68 3-(3-chloro-5-fluorophenyl)-7-fluoro-1-(trifluoromethyl)-6,7-dihydroindole-8(5H)-one Synthesis of (Compound D70)

[0629]

[0630] Step 1: Synthesis of compound D70-1

[0631] 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, and the reaction mixture was stirred in an oil bath at 90°C for 0.5 hours. The reaction solution was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:2) to obtain the target compound D70-1 (185 mg). ESI-MS m / z: 350.09 [M+H] + .

[0632] Step 2: Synthesis of compound D70

[0633] Compound D70-1 (120 mg) was dissolved in methanol (4 mL), and NaBH4 (76 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a 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] + .

[0634] Example 69 and Example 70 5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydroindole- 3-yl)-2-fluorobenzonitrile (Compound D79) and (S)-5-(7,7-difluoro-8-hydroxy-1-(trifluoromethyl)-5,6,7,8-tetrahydro Synthesis of (indolizin-3-yl)-2-fluorobenzonitrile (Compound D76)

[0635]

[0636] Step 1: Synthesis of compound D76-1

[0637] 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, and the reaction mixture was stirred in an oil bath at 90°C for 0.5 hours. The reaction solution was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE = 1:2) to obtain the target compound D76-1 (215 mg). ESI-MS m / z: 358.45 [M+H] + .

[0638] Step 2: Synthesis of compound D79

[0639] Compound D76-1 (100 mg) was dissolved in methanol (4 mL), NaBH4 (38 mg) was added under ice bath, and after stirring at 0°C for 1 hour, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:3) to obtain compound D79 (72 mg). ESI-MS m / z: 343.11 [M+H-H2O] + .

[0640] Step 3: Synthesis of compound D76

[0641] Compound D76-1 (100 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, the reaction mixture was bubbled with nitrogen, [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was added, and the mixture was stirred overnight at room temperature under nitrogen protection, and concentrated. 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-H2O] + .

[0642] Using a preparation method similar to that of Example 1 to Example 70, for example Replace with Etc., and obtained the following embodiments.

[0643]

[0644]

[0645]

[0646] Example 88 1-(3,5-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole- Synthesis of 4-ol (Compound D80)

[0647]

[0648] Step 1: Synthesis of compound D80-1

[0649] Under nitrogen protection, carbonyldiimidazole (32.4 g) was dissolved in 100 mL of chloroform, and a chloroform solution (50 mL) of trifluoroacetic anhydride (32.4 g) was slowly added dropwise under ice bath, and the mixture was heated to room temperature, and a chloroform solution (50 mL) of a mixture of cyclohexane-1,3-dione (11.2 g) and imidazole (6.8 g) was added, and stirring was continued for 2 hours, and the mixture was washed with 1M dilute hydrochloric acid solution and saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:4) to obtain the target compound D80-1 (13.3 g). ESI-MS m / z: 209.15 [M+H] + .

[0650] Step 2: Synthesis of compound D80-2

[0651] 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 after reflux for 3 hours, the reaction solution 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] + .

[0652] Step 3: Synthesis of compound D80-3

[0653] Under nitrogen protection, compound D80-2 (316 mg), 3-methoxypropylamine (534 mg) and pivalic acid (21 mg) were dissolved in a mixed solution of toluene (20 mL) and cyclohexane (10 mL), refluxed overnight, and the reaction solution was spin-dried to obtain a crude target compound D80-3 (326 mg), which was directly used in the next step without purification. ESI-MS m / z: 388.41 [M+H] + .

[0654] Step 4: Synthesis of compound D80-4

[0655] Compound D80-3 (326 mg) was dissolved in acetonitrile (20 mL), SelectFlour (656 mg) was added, and the reaction was refluxed for 6 hours, cooled to room temperature, and the reaction mixture was treated with 1M dilute hydrochloric acid (20 mL), and stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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] + .

[0656] Step 5: Synthesis of compound D80

[0657] Compound D80-4 (100 mg) was dissolved in methanol (4 mL), NaBH4 (42 mg) was added under ice bath, and after stirring at 0°C for 1 hour, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound 1 (81 mg). ESI-MS m / z: 337.23 [M+H-H2O] + .

[0658] Using a preparation method similar to Example 88, replacing different aromatic hydrazines, the following example was obtained.

[0659]

[0660] Example 94 (1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indol-3-yl) Synthesis of dimethylphosphine oxide (Compound A50)

[0661]

[0662] Step 1: Synthesis of compound A50-1

[0663] Compound A13 (864 mg), dimethylphosphine oxide (200 mg), K3PO4 (520 mg), Xantphos (118 mg) and palladium acetate (46 mg) were added to DMF (15 mL). The reaction mixture was heated and stirred at 150 degrees under nitrogen protection overnight. After the reaction was completed, it was cooled and added to water. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, concentrated, and the target product A50-1 (300 mg) was obtained by column chromatography.

[0664] Step 2: Synthesis of Compound A50

[0665] The compound can be prepared by reduction with sodium borohydride using a similar preparation method as compound A2. ESI-MS m / z: 360.05

[0666] [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).

[0667] Example 95 (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-1- Synthesis of 2-fluorobenzonitrile (A61)

[0668]

[0669] Step 1: Synthesis of compound A61-1

[0670] Compound M2 (214 mg) was dissolved in DCM (10 mL), and copper acetate (108 mg), 4-fluoro-3-cyanophenylboronic acid (100 mg), and TEA (0.25 mL) were added. The mixture was stirred overnight under an oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product. The target compound A61-1 (120 mg) was obtained by column chromatography (EA / PE=1:3). ESI-MS m / z: 359.05 [M+H] + .

[0671] Step 2: Synthesis of Compound A61

[0672] Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), formic acid (0.04 mL) and triethylamine (0.1 mL) were added, nitrogen was bubbled through the reaction mixture, [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added, and the mixture was stirred overnight at room temperature under nitrogen protection, and concentrated. 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-H2O] + .

[0673] Example 96 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-3-carboxylate Synthesis of Nitrile (Compound A73)

[0674]

[0675] Step 1: Synthesis of Compound A73-1

[0676] Under nitrogen protection, compound A13 (212 mg) was dissolved in DMF (5 mL), Zn(CN)2 (117 mg) and Pd(PPh3)4 (58 mg) were added, and the mixture was stirred at 120°C for 2 hours, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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] + .

[0677] Step 2: Synthesis of Compound A73

[0678] Compound A73-1 (100 mg) was dissolved in a mixed solvent of THF (2 mL) and H2O (1 mL), and NaBH4 (18 mg) was added under ice bath, and stirred at 0°C for 1 hour. Ice water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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-H2O] + .

[0679] Example 97 1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole Synthesis of Indole-4-ol (A90)

[0680]

[0681] Step 1: Synthesis of Compound A90-1

[0682] Compound M6 (214 mg) was dissolved in DCM (10 mL), copper acetate (108 mg), 3-chloro-5-fluorophenylboronic acid (105 mg), TEA (0.25 mL) were added, stirred overnight under an oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3) to obtain the target compound A90-1 (83 mg). ESI-MS m / z: 368.07 [M+H] + .

[0683] Step 2: Synthesis of Compound A90

[0684] Compound A90-1 (104 mg) was dissolved in methanol (4 mL), and NaBH4 (42 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a 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-H2O] + .

[0685] Example 98 (5,5-difluoro-1-(4-fluoro-3-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro- Synthesis of 1H-indol-4-ol (Compound D37)

[0686]

[0687] Step 1: Synthesis of compound D37-1

[0688] Compound M2 (2.14 g) was dissolved in DCM (20 mL), copper acetate (1.08 g), 4-fluoro-3-formaldehyde phenylboronic acid (1.0 g), TEA (2.48 mL) were added, stirred at room temperature overnight under an oxygen atmosphere, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3) to obtain the target compound D37-1 (1.1 g). ESI-MS m / z: 362.08 [M+H] + .

[0689] Step 2: Synthesis of compound D37

[0690] Compound D37-1 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 g) was added in batches, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by LC-MS and TLC. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, dried and spin-dried, and the crude product was chromatographed to obtain D37 (100 mg). ESI-MS m / z: 348.05 [M+H-H2O] + .

[0691] Example 99 5,5-difluoro-1-(6-fluoropyridin-2-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole Synthesis of Indole-4-ol (Compound D40)

[0692]

[0693] Step 1: Synthesis of compound D40-1

[0694] Potassium carbonate (866 mg) and 2,6-difluoropyridine (481 mg) were added to a DMF (10 mL) solution of compound M2 (500 mg) at room temperature, and then the temperature was raised to 100°C and stirred overnight. The reaction mixture was quenched with water, diluted with ethyl acetate, and concentrated to obtain a 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] + .

[0695] Step 2: Synthesis of compound D40

[0696] The compound can be prepared by reduction with sodium borohydride using a similar preparation method as compound A2. ESI-MS m / z: 319.25 [M+H-H2O] + .

[0697] Example 100 5-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole Synthesis of (1-indole-1-yl)-2-fluorobenzonitrile (Compound D46)

[0698]

[0699] Step 1: Synthesis of compound D46

[0700] Under nitrogen protection, compound A61-1 (36 mg) was dissolved in tetrahydrofuran (5 mL), 3.0 M methylmagnesium chloride (0.3 mL) was added dropwise under ice bath, stirred at 0°C for 3 hours, quenched with 1 M dilute hydrochloric acid, the reaction solution was extracted twice with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column Pre-TLC (EA / PE=1:3) to obtain the target compound D46 (13 mg). ESI-MS m / z: 357.18 [M+H-H2O] + . 1 H 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).

[0701] Example 101 5-(5,5-difluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- Synthesis of (indol-1-yl)-2-(p-fluorobenzonitrile) (Compound D49)

[0702]

[0703] Step 1: Synthesis of compound D49-1

[0704] Ethyl trifluoroacetoacetate (25.02 g) was dissolved in glacial acetic acid (38 mL) under ice bath, and an aqueous solution (25 mL) of sodium nitrite (9.37 g) was added in batches. After addition, the mixture was reacted at 20°C for 2 hours, and then concentrated under reduced pressure. Water and ethyl acetate were added, and the layers were separated. 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] - .

[0705] Step 2: Synthesis of compound D49-2

[0706] Dissolve 5,5-dimethyl-1,3-cyclohexanedione (6.0 g) in glacial acetic acid (30 mL), heat to 60°C, add an aqueous solution (20 mL) of compound D49-1 (9.12 g), then slowly add zinc powder (5.59 g) in batches, heat to 90°C and react for 16 hours, add water and ethyl acetate to the reaction system, separate the liquids, extract the aqueous phase twice with ethyl acetate, wash the combined organic phases twice with saturated sodium bicarbonate aqueous solution, dry over Na2SO4, and concentrate to obtain a crude product, which is purified by column chromatography (EA / PE=1:3), the target compound D49-2 (2.2 g, 22.2%). ESI-MS m / z: 232.10 [M+H] + .

[0707] Step 3: Synthesis of compound D49-3

[0708] Under nitrogen protection, compound D49-2 (2.2 g) was dissolved in tetrahydrofuran (30 mL), sodium hydride (0.457 g) was added in batches under ice bath, and the mixture was reacted at 0°C for 0.5 hours, and then a tetrahydrofuran solution (5 mL) of triisopropylsilyl chloride (2.75 g) was added, and the reaction was continued for 1 hour. The reaction solution was poured into ice water to quench the reaction, extracted with ethyl acetate, washed with water, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3), the target compound D49-3 (2.93 g, 79.5%). ESI-MS m / z: 388.10 [M+H] + .

[0709] Step 4: Synthesis of compound D49-4

[0710] Under nitrogen protection, compound D49-3 (1.05 g) was dissolved in tetrahydrofuran (20 mL), cooled to -78 ° C, and 1.0 M LiHMDS tetrahydrofuran solution (7.33 mL) was slowly added dropwise. After stirring for half an hour, a tetrahydrofuran solution (10 mL) of NFSI (1.79 g) was added dropwise, and the mixture was stirred at -78 ° C for two hours. Saturated aqueous ammonium chloride was added to the reaction mixture to quench the reaction, extracted twice with ethyl acetate, washed twice 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 D49-4 (0.73 g, 55.2%). ESI-MS m / z: 424.05 [M + H] + .

[0711] Step 5: Synthesis of compound D49-5

[0712] The crude compound D49-4 (0.73 g) was dissolved in a mixed solvent of THF (20 mL) / water (20 mL), K2CO3 (0.48 g) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (DCM = 100%) to obtain the target compound D49-5 (402 mg). ESI-MS m / z: 268.12 [M+H] + .

[0713] Step 6: Synthesis of compound D49-6

[0714] Compound D49-5 (402 mg) was dissolved in DCM (20 mL), copper acetate (275 mg), 3,5-difluorophenylboronic acid (494 mg), TEA compound (304 mg) were added, stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, and column chromatography (EA / PE=1:3) was used to obtain the target compound D49-6 (512 mg). ESI-MS m / z: 387.08 [M+H] + .

[0715] Step 7: Synthesis of compound D49

[0716] Compound D49-6 (50 mg) was dissolved in methanol (4 mL), and NaBH4 (15 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:4) to obtain the target compound D49 (37 mg, 73.7%). ESI-MS m / z: 371.10 [M+H-H2O] + .

[0717] Example 102 2-Fluoro-5-(5-fluoro-4-hydroxy-6,6-dimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro- Synthesis of 1H-indol-1-yl)benzonitrile (Compound D50)

[0718]

[0719] Step 1: Synthesis of compound D50-1

[0720] Under nitrogen protection, compound D49-3 (1.0 g) was dissolved in tetrahydrofuran (20 mL), cooled to -78 ° C, and 1.0 M LDA tetrahydrofuran solution (3.9 mL) was slowly added dropwise. After stirring for half an hour, NFSI (895 mg) tetrahydrofuran solution (10 mL) was added dropwise, and stirring was continued at -78 ° C for two hours. Saturated aqueous ammonium chloride was added to the reaction mixture to quench the reaction, extracted twice with ethyl acetate, washed twice 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 D50-1 (550 mg). ESI-MS m / z: 406.12 [M + H] + .

[0721] Step 2: Synthesis of compound D50-2

[0722] The crude compound D50-1 (550 mg) was dissolved in a mixed solvent of THF (10 mL) / water (10 mL), K2CO3 (375 mg) was added at room temperature, and stirring was continued for three hours. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (DCM = 100%) to obtain the target compound D50-2 (208 mg). ESI-MS m / z: 250.06 [M+H] + .

[0723] Step 3: Synthesis of compound D50-3

[0724] Compound D50-2 (208 mg) was dissolved in DCM (15 mL), copper acetate (150 mg), 3,5-difluorophenylboronic acid (206 mg), TEA compound (168 mg) were added, stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, and column chromatography (EA / PE=1:3) was used to obtain the target compound D50-3 (217 mg). ESI-MS m / z: 369.10 [M+H] + .

[0725] Step 4: Synthesis of compound D50

[0726] Compound D50-3 (100 mg) was dissolved in methanol (4 mL), NaBH4 (21 mg) was added under ice bath, and after stirring at 0°C for 1 hour, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:4) to obtain the target compound D50 (82 mg). ESI-MS m / z: 353.12 [M+H-H2O] + .

[0727] Example 103 (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, Synthesis of a mixture of 7-tetrahydro-1H-indol-4-ols (compound D51-A, assumed structure)

[0728] Example 104 (4S, 5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7- Synthesis of Tetrahydro-1H-indol-4-ol (Compound D51-B, assumed structure)

[0729] Example 105 (4R, 5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-(trifluoromethyl)-4,5,6,7- Synthesis of Tetrahydro-1H-indol-4-ol (Compound D51-C, assumed structure)

[0730]

[0731] Step 1: Synthesis of compound D51-1

[0732] Compound M3 (147 mg) was dissolved in DCM (15 mL), and copper acetate (120 mg), 4-fluoro-3-formaldehyde phenylboronic acid (167 mg), and TEA (136 mg) were added. The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product. The target compound D51-1 (152 mg) was obtained by column chromatography (EA / PE=1:3). ESI-MS m / z: 344.08 [M+H] + .

[0733] Step 2: Synthesis of compound D51-2

[0734] Compound D51-1 (152 mg) was dissolved in DCM (10 mL), and DAST (214 mg) was added under ice bath, and stirred at 0°C for 3 hours, diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:3) to obtain the target compound D51-2 (129 mg). ESI-MS m / z: 344.08 [M+H] + .

[0735] Step 3: Synthesis of compound D51

[0736] Compound D51-2 (350 mg) was dissolved in MeOH (5 mL), sodium borohydride (0.15 g) was added in batches, and stirred at room temperature for 6 hours. LC-MS and TLC were used for monitoring. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, dried and spin-dried, and the crude product was chromatographed to obtain D51 (300 mg). D51 was separated by chiral preparative separation (column model: Daicel IF 250*20mm, 5μm; mobile phase A: n-hexane, mobile phase B: ethanol; mobile phase A: mobile phase B = 90:10 (V / V); detection wavelength: 254nM; flow rate: 15mL / min; column temperature: RT; running time: 25min; column pressure: 35Bar) to obtain three elution peaks.

[0737] D51-A (10 mg) is the first eluting peak, Rt = 7.5 min, ESI-MS m / z: 350.12 [M+H-H2O] + , 1HNMR (500MHz, DMSO) δ7.77–7.67 (m, 2H), 7.53-7.59 (m, 2H), 7.23 (t, J = 53.9 Hz, 1H), 5.44 (d, J = 6.7 Hz, 1H), 4.80 (d, J = 47.3 Hz, 1H), 4.64 (s, 1H), 2.64–2.54 (m, 1H), 2.48–2.51 (m, 1H), 2.18–1.94 (m, 2H). D51-B (70 mg) is the second eluting peak, Rt = 11 min, ESI-MS m / z: 350.12 [M+H-H2O] + , 1 H NMR (500MHz, DMSO) δ7.71 (dd, J = 5.7, 2.8 Hz, 2H), 7.62-7.49 (m, 2H), 7.23 (t, J = 53.9 Hz, 1H), 5.19 (d, J = 6.1 Hz, 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). D51-C (80 mg) is the third eluting peak, Rt = 14.5 min, ESI-MS m / z: 350.12 [M+H-H2O] + , 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).

[0738] Example 106 1-(3-chloro-5-fluorophenyl)-2,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- Synthesis of indole-4-ol (Compound A41)

[0739]

[0740] Step 1: Synthesis of Compound A41-1

[0741] 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 Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound A41-1 (79 mg).

[0742] Step 2: Synthesis of Compound A41

[0743] Compound A41-1 (79 mg) was dissolved in a mixed solvent of THF (2 mL) and H2O (1 mL), and NaBH4 (16 mg) was added under ice bath, and stirred at 0°C for 1 hour. Ice water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which 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-H2O] + . 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).

[0744] Example 107 (S)-2-Chloro-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrafluoroethylene Synthesis of Hydrogen-1H-Indol-4-ol (Compound A75)

[0745]

[0746] Step 1: Synthesis of compound A75-1

[0747] 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, extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a 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

[0748] [M+H] + .

[0749] Step 2: Synthesis of Compound A75

[0750] Compound A75-1 (40 mg) was dissolved in dichloromethane (3 mL), formic acid (0.01 mL) and triethylamine (0.03 mL) were added, nitrogen was bubbled through the reaction mixture, [(R,R)-Ts-DPEN]RuCl(p-cymene) (12 mg) was added, and the mixture was stirred overnight at room temperature under nitrogen protection, and concentrated. 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-H2O]+ .

[0751] Example 108 1-(3-(difluoromethyl)-4-fluorophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole Synthesis of Indole-4-ol (Compound D95)

[0752]

[0753] Step 1: Synthesis of compound D95-1

[0754] (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) respectively, and stirred at room temperature overnight under an oxygen atmosphere. After the reaction was completed, the mixture was diluted with dichloromethane, washed twice with saturated brine, dried, filtered, and concentrated to obtain a crude product. The target compound D95-1 (2.1 g) was obtained by column chromatography (EA / PE=1:3). ESI-MS m / z: 326.10 [M+H] + .

[0755] Step 2: Synthesis of compound D95-2

[0756] Compound D95-1 (500 mg) was added to dichloromethane (10 mL), and DAST (520 mg) was added. The mixture was stirred at room temperature. After the reaction was completed, the mixture was diluted with dichloromethane and quenched with saturated sodium bicarbonate. The organic phase was washed with water, dried, filtered, and concentrated to obtain a crude product. The target compound D95-2 (163 mg) was obtained by column chromatography (EA / PE=1:3). ESI-MS m / z: 348.05 [M+H] + .

[0757] Step 3: Synthesis of compound D95

[0758] Compound D95-2 (100 mg) was added to a mixed solution of tetrahydrofuran (2 mL) and water (1 mL), placed in an ice-water bath, sodium borohydride (80 mg) was added, stirred at room temperature overnight, diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried and purified by HPLC to obtain the target product D95 (50 mg). ESI-MS m / z: 350.10 [M+H] + .

[0759] The following examples were obtained by using different raw materials and / or intermediates and a preparation method similar to that of Example 1 to Example 108.

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771] Example 196 and Example 197 (S)-2-Fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1H-indol-1-yl)benzonitrile (compound D54, assumed) and (R)-2-fluoro-5-(4,5,5-trifluoro-3-(trifluoromethyl)-4,5, Synthesis of 6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Compound D55, hypothetical)

[0772]

[0773] Step 1: Synthesis of compound D54-1

[0774] Under nitrogen protection, A58 (360 mg) was dissolved in 20 mL of dichloromethane, and DAST (412 mg) was slowly added dropwise under ice bath, and the mixture was reacted at 0°C for 2 hours, and ice water was added to quench the mixture. The organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a 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] + .

[0775] Step 2: Synthesis of compounds D54 and D55

[0776] Compound D54-1 was separated by chiral preparative column (column model Daicel IF250*20mm,5μm, mobile phase A: n-hexane, mobile phase B: ethanol; mobile phase A: mobile phase B = 85:15 (V / V), detection wavelength 254nm; flow rate: 15mL / min; column temperature: RT; running time: 28min) separation and purification, Example D54 was obtained as the first elution peak, Rt = 16.5min, ESI-MS m / z: 325.00 [M+H-H2O] + ; 1HNMR (500MHz, DMSO) δ8.14–8.16 (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 is the second eluting peak, Rt=20 min, ESI-MS m / z: 325.00 [M+H-H2O] + .

[0777] Example 198 (Z)-5-(5,5-difluoro-4-(hydroxyimino)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- Synthesis of (indol-1-yl)-2-fluorobenzonitrile (Compound D56)

[0778]

[0779] Step 1: Synthesis of compound D56

[0780] Compound A58 (36 mg) and hydroxylamine hydrochloride (14 mg) were dissolved in 10 mL of ethanol, refluxed for 5 hours, and concentrated to obtain a crude product. The crude product was purified by Pre-TLC (EA / PE=1:3) to obtain the target compound D56 (16 mg). ESI-MS m / z: 392.08M+H-H2O] + .

[0781] Example 199 2-Fluoro-5-(5-fluoro-4-hydroxy-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl) Synthesis of Benzonitrile (D58)

[0782]

[0783] Step 1: Synthesis of compound D58-1

[0784] Under ice bath, 1,3-cyclohexanedione (1.10 g) was dissolved in an aqueous solution (4 mL) of potassium hydroxide (0.57 g), 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 methanol was dried by spin-drying, and water (5 mL) and 2-fluoro-5-aminobenzonitrile (1.2 g) were added to adjust the pH to 0 and refluxed for 14 hours. The reaction solution was dried by spin-drying and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound D58-1 (254 mg, 8%). ESI-MS m / z: 323.07 [M+H] + . 1HNMR (500MHz, CDCl3) δ7.66 (dd, J=14.2, 11.6Hz, 1H), 7.61 (dd, J=8.4, 4.0Hz, 1H), 7.41 (t, J = 8.4Hz, 1H), 7.10 (s, 1H), 2.57-2.44 (m, 4H), 2.22-2.12 (m, 2H).

[0785] Step 2: Synthesis of compound D58-2

[0786] Under nitrogen protection, compound D58-1 (60 mg) and NFSI (90 mg) were dissolved in tetrahydrofuran (2.00 mL), cooled to -78 °C, lithium diisopropylamide (0.20 mL, 2.00 mol / L) was added and stirred for 2 hours. Saturated ammonium chloride was used for quenching, ethyl acetate was used for extraction, and the crude product was concentrated to obtain a crude product, which 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] + .

[0787] Step 3: Synthesis of compound D58

[0788] Compound D58-2 (40 mg) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), sodium borohydride (10 mg) was added under ice bath, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added, and the organic phase was concentrated to obtain a crude product, which 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-H2O] + .

[0789] Example 200 (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indole-1- Synthesis of 4-(4-d)-2-(4-fluorobenzonitrile) (Compound D74)

[0790]

[0791] Step 1: Synthesis of compound D74

[0792] Compound A61-1 (120 mg) was dissolved in dichloromethane (3 mL), deuterated formic acid (0.04 mL) and triethylamine (0.1 mL) were added, the reaction mixture was nitrogen bubbled, [(R,R)-Ts-DPEN]RuCl(p-cymene) (22 mg) was added, and the mixture was stirred overnight at room temperature under nitrogen protection, and concentrated. 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] - . 1H 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).

[0793] Example 201 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-5,6-dihydro-4H-isoxazolo[5,4-e] Synthesis of Indole (Compound D100)

[0794]

[0795] Step 1: Synthesis of compound D100-1

[0796] Compound M3-1 (203 mg) was dissolved in DCM (20 mL), copper acetate (180 mg), 3-chloro-5-fluorophenylboronic acid (261 mg) and TEA (202 mg) were added, and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by Pre-TLC (EA / PE=1:3) to obtain the target compound D100-1 (275 mg). ESI-MS m / z: 332.05 [M+H] + .

[0797] Step 2: Synthesis of compound D100-2

[0798] Under nitrogen protection, compound D100-1 (100 mg) was dissolved in ethanol (5 mL), cooled to 0 ° C, sodium ethoxide (20 mg) was added, stirred for 10 minutes, and ethyl formate (23 mg) was added dropwise, and the ice bath was removed and stirred overnight at room temperature. The reaction solution was spin-dried and diluted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound D100-2 (35 mg). ESI-MS m / z: 360.17 [M+H] + .

[0799] Step 3: Synthesis of compound D100

[0800] Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), and hydroxylamine hydrochloride (23 mg) was added and stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which 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] + . 1H 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).

[0801] Example 202 6-(3-chloro-5-fluorophenyl)-8-(trifluoromethyl)-1,4,5,6-tetrahydropyrrolo[2,3-g]indazole Synthesis of (Compound D101)

[0802]

[0803] Step 1: Synthesis of compound D101

[0804] Compound D100-2 (100 mg) was dissolved in acetic acid (5 mL), hydrazine hydrate (30 uL) was added and stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which 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] + .

[0805] Some exemplary compounds 1 The H NMR data are shown below:

[0806] 1 H NMR (500 MHz, DMSO-d6) δ 8.13-8.11 (m, 1H), 7.88-7.85 (m, 1H), 7.74-7.62 (m, 1H), 7.26 (s, 1H), 5.89 (d, J=6.4 Hz, 1H), 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).

[0807] 1 H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 1H), 7.13 (s, 2H), 6.96 (d, J = 8.6 Hz, 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).

[0808] 1H NMR (500 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.42–7.30 (m, 3H), 6.07 (d, J=6.7 Hz, 1H), 4.59 (q, J=6.6 Hz, 1H), 2.91–2.69 (m, 2H), 2.44–2.23 (m, 1H), 2.17–2.12 (m, 1H) (Example 8).

[0809] 1 H NMR (500 MHz, 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).

[0810] 1 H NMR (500 MHz, 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).

[0811] 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.62-7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J=6.0 Hz, 2H), 2.69-2.58 (m, 2H) (Example 15).

[0812] 1 H NMR (500 MHz, 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).

[0813] 1H NMR (500 MHz, 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).

[0814] 1 H NMR (500 MHz, 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).

[0815] 1 H NMR (500 MHz, 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).

[0816] 1 H NMR (500 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.43–7.36 (m, 3H), 6.07 (d, J=6.7 Hz, 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).

[0817] 1H NMR (500 MHz, 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).

[0818] 1 H NMR (500 MHz, DMSO) δ 7.75-7.58 (m, 3H), 6.22 (d, J=6.4 Hz, 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).

[0819] 1 H NMR (500 MHz, 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).

[0820] 1 H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J = 1.6 Hz, 1H), 7.60–7.40 (m, 3H), 6.07 (d, J = 6.6 Hz, 1H), 4.59 (q, J = 6.8 Hz, 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).

[0821] 1 H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.62-7.47 (m, 3H), 3.36 (s, 3H), 3.09 (t, J=6.0 Hz, 2H), 2.69-2.58 (m, 2H) (Example 118).

[0822] 1H NMR (500 MHz, DMSO) δ 7.88–7.84 (m, 1H), 7.67–7.48 (m, 3H), 6.03 (d, J=7.0 Hz, 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).

[0823] 1 H NMR (500 MHz, DMSO) δ 7.88–7.84 (m, 1H), 7.67–7.48 (m, 3H), 6.03 (d, J=7.0 Hz, 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).

[0824] 1 H NMR (500 MHz, 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).

[0825] 1 H NMR (500 MHz, 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).

[0826] 1 H NMR (500 MHz, 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).

[0827] 1H NMR (500 MHz, 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 = 1.4 Hz, 1H), 7.04-6.82 (m, 1H), 4.93 (q, J = 5.4 Hz, 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).

[0828] 1 H NMR (500 MHz, DMSO-d6) δ9.10 (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 177).

[0829] 1 H NMR (500 MHz, 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).

[0830] 1 H NMR (500 MHz, 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).

[0831] 1H NMR (500 MHz, DMSO-d6) δ 8.30-8.28 (m, 1H), 8.04-8.02 (m, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.74 (t, J = 9.0 Hz, 1H), 5.71-5.61 (m, 1H), 2.92-2.76 (m, 2H), 2.43-2.36 (m, 2H) (Example 196).

[0832] Pharmacological experiments

[0833] VEGFA ELISA test (IC 50 )

[0834] 786-O cells in logarithmic phase were inoculated in 96-well plates, with a cell concentration of 65,000 cells per ml of culture medium, 180ul per well. The compound was diluted to the corresponding concentration, and 20ul of compound solution of different concentrations was added to the corresponding cell wells, so that the final concentrations of the compound were (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After 24h of culture, the cell culture supernatant was taken, and the VEGFA concentration was determined using an ELISA kit (purchased from abcam). Finally, the reaction was terminated, and the light absorbance of each well was measured at a wavelength of 450nm using an ELISA reader, and the IC was calculated using GraphPadPrism. 50 Meanwhile, CellTiter-Glo reagent was used to determine cell viability.

[0835] IC of the exemplary embodiment 50 The data are provided in Table 1, where A represents IC 50 ≤0.5μM; B means 0.5μM<IC 50 ≤1.5μM; C means 1.5μM<IC 50 ≤10μM, D represents IC 50 >1.5μM.

[0836] Table 1

[0837]

[0838]

[0839] Luciferase assay

[0840] The luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2α reporter gene cells (786-O-HIF2α-Luc cells). The experiment was carried out when the 786-O-HIF2α-Luc cells were in the logarithmic growth phase, the culture medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, and PBS was rinsed three times; trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells, and the cells were washed with culture medium, 10% fetal bovine serum, 1% penicillin, and streptomycin to terminate the digestion. The cells were collected by centrifugation, washed twice with PBS to remove the phenol red in the culture medium, and the cells were resuspended to an appropriate concentration. The cell density and viability were detected to ensure that the cell viability was above 90% before it could be used for the experiment.

[0841] Use Echo550 (non-contact sonic liquid transfer system, purchased from Labcyte) to transfer the gradient concentration compound to 384 wells, 25nl / well; seed the cells in 384 well plates, 4500 cells / well, 25μl culture medium, so that the final concentration of the compound is 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM. Incubate the cells at 37℃, 5% CO2 for 18-20h; add Steady-Glo TM Luciferase assay system (purchased from Promega) was added to a 384-well plate, 25 μl / well; Envision was used to detect the luminescence value. The inhibition rate was calculated based on the RLU (Record Luminescence) signal value of each well, and then the IC of the corresponding compound was calculated by fitting using Graphpad 8.0. 50 .

[0842] IC of the exemplary embodiment 50 The data are provided in Table 2, where A represents IC 50 ≤0.5μM; B means 0.5μM<IC 50 ≤1.5μM; C means 1.5μM<IC 50 ≤10μM, D represents IC 50 >1.5μM.

[0843] Table 2

[0844]

[0845]

[0846] In vivo PK

[0847] The compound was prepared with 5% DMSO, 5% Solutol and 90% NaCl. Animals were selected from SD rats and Balb / c mice for administration, with an intravenous dose of 1 mg / kg and an oral dose of 5 mg / kg. Blood was collected from the eye sockets at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. After blood collection, the mixture was centrifuged at 4000 rpm for 10 min, the supernatant was taken, 200 μL of internal standard solution was added to 30 μL of supernatant for precipitation, vortexed and centrifuged at 12000 rpm for 10 min, and 100 μL of supernatant solution was mixed with purified water in a 1:1 ratio for injection. The concentration of the compound in plasma was detected by HPLC-MS, and the concentration of the compound in the plasma sample was quantitatively analyzed by internal standard quantitative method. After the compound concentration was measured, the pharmacokinetic parameters including Cmax, AUC, etc. were calculated by Winnonln software. It was found through experiments that the exemplary compounds of the present invention have good in vivo PK properties.

Claims

1. A compound represented by formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, in, 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 C3-C5 cycloalkyl; X1 and X2 are independently selected from C or N; X3 for CR f or NR f ; X4 for CR j or NR j ; And at least one of X1, X2, X3 and X4 is N; R1 is selected from C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 wherein the 5-18-membered heteroaryl and the 3-10-membered heterocyclic group arbitrarily contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 The cycloalkyl and 3-10 membered heterocyclic groups may be optionally substituted with one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, -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 replaced by; R2 is selected from H, deuterium, halogen, -CN, -OH, =N-OH, C1-C5 haloalkyl, amino, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl or -NR a R b ; R3 is selected from H, deuterium, halogen, -CN, -OH, =N-OH, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C5 haloalkyl, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 Alkyl or C2-C 10 Alkynyl, the C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C5 haloalkyl, C1-C 10 Alkoxy, -OC(=O)-C 1-3 Alkyl, -C(=O)-OC 1-3 The alkyl group may be optionally substituted by one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or R2 and R3 together form an oxo group; R4 and R5 are independently selected from H, halogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclic group; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted by one or more halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted cyclopropyl; R6 is selected from H, -CN, halogen, -OH, -NO2, -NH2, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclic group; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted by one or more H, halogen, -CN, -OH, amino, oxo, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; or two R6 together with the C atom to which they are attached form a substituted or unsubstituted C3-C5 cycloalkyl or 3-5 membered heterocyclyl; or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl group; R d and R e are independently selected from H, halogen, cyano, -NR a R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl; or R d and R e Together they form an oxo group; R f Selected from Absent, H, -CN, Halogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, oxo, -NR a R b ; said C1-C 10 Alkyl, C1-C 10 Haloalkyl and C3-C 10 Cycloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl and / or C1-C5 haloalkyl; R j Selected from H, -NO2, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -C 1- 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 5-10 membered heteroaryl and the 3-10 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 The aryl and 5-10 membered heteroaryl groups may be optionally substituted by one or more halogen, hydroxy, amino, P(=O)Me2, P(=S)Me2, -S(=O)2-C1-C3 alkyl, -S(=O)2-C3-C5 cycloalkyl, -S(=O)-C1-C3 alkyl, -S(=O)-C3-C5 cycloalkyl, cyano, C1-C6 alkyl, C1-C6 alkoxy and / or C1-C6 haloalkyl. R a , R b and R c are independently selected from H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C 2- C 10 Alkenyl, C 2- C 10 Alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- C 10 Aryl or 5-10 membered heteroaryl; n is 1, 2 or 3; m is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, characterized in that: The compound is represented by formula (IV-1), formula (IV-2) or formula (V), Among them, only one of X1 and X2 is N and the other is C.

3. The compound according to claim 1, or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, characterized in that: The R2 is selected from halogen, -CN, -OH, =N-OH; and / or the R3 is selected from H, deuterium or C1-C3 alkyl, and the C1-C3 alkyl and C2-C5 alkenyl may be optionally substituted by H, halogen, -CN, -OH, amino, C1-C5 haloalkyl; or R2 and R3 together form an oxo group.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: R4 and R5 are independently selected from H, halogen or C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted by H, halogen, -CN, -OH, amino or oxo; preferably, R4 and R5 are independently selected from H or halogen.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: X3 for CR f Preferably, the R f is selected from H, -CN, halogen, -NH2, C1-C3 alkyl, cyclopropyl or C1-C3 haloalkyl, wherein the C1-C3 alkyl, cyclopropyl or C1-C3 haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C3 alkyl, C2-C4 alkenyl and / or C1-C3 haloalkyl; preferably, R f Selected from H, -CN, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: R6 is H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, and the C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo and / or amino; preferably, R6 is H, halogen or C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo and / or amino.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: The R1 is C6-C 10 Aryl, 5-18 membered heteroaryl or C3-C 10 cycloalkyl; the 5-18 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, R1 is C6-C8 aryl, 5-8 membered heteroaryl or C3-C6 cycloalkyl, 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, 5-8 membered heteroaryl group or C3-C6 cycloalkyl group may be optionally substituted by one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c 、-C0-C6 alkylene-C=OR c 、-NO2、C(=O)OR c and / or -S(=O)2R c further preferably, R1 is a benzene ring, a 5-6 membered heteroaryl or a C3-C6 cycloalkyl, wherein the 5-6 membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the benzene ring, the 5-6 membered heteroaryl or the C3-C6 cycloalkyl may be optionally substituted by one or more halogen, -CN and / or C1-C4 haloalkyl.

8. The compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that: The R j Selected from C1-C4 haloalkyl, cyano, -S(=O)2R c or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl group may be optionally substituted by one or more halogen C1-C3 alkyl groups and / or C1-C3 haloalkyl groups; The R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

9. A compound, characterized in that The compound is selected from:

10. A luciferase experimental method, characterized in that: The method comprises, (1) The luciferase LUC gene was stably transferred into 786-O cells using Lipofectamine 3000 transfection reagent to construct HIF2α reporter gene cells; (2) The 786-O-HIF2α-Luc cells were tested when they were in the logarithmic growth phase to ensure that the cell viability was above 90%; (3) After culturing the cells for 18-20 hours, add Steady-Glo TM Luciferase assay system to detect luminescence value.

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