WO2022063115A1 - Bicyclic compounds and application thereof - Google Patents

Abstract

The present invention relates to compounds represented by formula (I). Further provided are a composition that comprises said type of compound and a preparation, and a method for using and preparing such compounds.

Description

Bicyclic compounds and their applications technical field

The present invention relates to a bicyclic compound, compositions and formulations containing the compound, and methods of using and preparing the compound.

Background technique

HIFs (Hypoxia inducible factors) are members of the transcription factor family and are a pathway for the body to sense changes in oxygen, also known as hypoxia-inducible factors. It is mainly composed of HIFα (HIF-1α, HIF-2α, HIF-3α) and HIF-1β, among which HIF-1β is always in the nucleus, and HIFα is located in the cytoplasm. Under sufficient oxygen conditions, HIFα will undergo PHD prolyl hydroxylase hydroxylation, VHL (Von Hippel-Lindau Syndrome) ubiquitinase ubiquitination labeling and other pathways, and finally be degraded by the proteasome. learning role. However, when the metabolic pathway is abnormal, HIFα cannot be degraded, so it accumulates in the nucleus, combines with HIF-1β to form a heterodimer, activates the hypoxia response element (HRE) in the downstream gene promoter, and then regulates related genes Transcription that allows cells to survive in hypoxic conditions. These genes are involved in tumor angiogenesis, cell proliferation, survival, metabolism, invasion and metastasis, drug resistance, inflammation and immunity. Among them, HIF-2α is mediated by chronic hypoxia, which can be continuously activated under physiological hypoxic conditions and plays a more critical role in the occurrence and development of tumors.

Current research shows that the mechanism of HIF-2α-mediated tumor development and development mainly includes: 1. Under conditions such as hypoxia or VHL mutation, HIF-2α metabolic pathway is blocked, accumulates into the nucleus, and forms heterodimer with HIF-1β, Then activate the hypoxia response element (HRE), regulate the up-regulation of downstream cancer-related genes such as VEGFA, CXCR4, Cyclin D1, etc., and promote tumor angiogenesis; 2. HIF-2α also participates in the transduction of immunosuppressive signals by up-regulating the expression of CD73, so targeting HIF-2α can restore or enhance the anti-tumor immune function of mature DC cells, activated B cells and NK cells.

The activation of 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, which mediates protein degradation by proteasome. The VHL gene has a 57% high mutation rate or 98% loss of heterozygosity in renal cell carcinoma (RCC) cells, leading to pseudohypoxia and induction of 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 deficiency. In the absence of vascularization in gliomas, the unstable blood supply leads to a hypoxic microenvironment, which induces local high expression of HIF-2α and promotes tumor growth. In pheochromocytoma and paraganglioma, the mutation rate of AA at positions 529-532 of HIF-2α is as high as 81%, which directly affects the hydroxylation and degradation of HIF-2α and makes HIF-2α continue to activate.

The activation of HIF-2α and the formation of heterodimers of HIF-1β are the key factors leading to downstream activation, and the PAS binding domain of the two is the binding site for the formation of heterodimers. Based on this, the R&D team of Peloton Company developed a generation of Two small-molecule HIF-2α inhibitors, PT2385 and second-generation PT2977, exert anti-tumor effects by inhibiting the binding of HIF-2α and HIF-1β.

Based on the close relationship between HIF-2α pathway and tumorigenesis and migration, it is very necessary to develop more efficient new molecular entities.

SUMMARY OF THE INVENTION

The present invention first provides the compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate,

in,

L is a bond, -O-, NH-, -CR _{d Re} -, -S-, -S(=O)-, -S(=O) ₂ -, -C=C- or -C≡C- ;

X ₁ and X ₂ are each independently selected from C or N;

X ₃ is CR ₈ or NR ₈ ;

X ₄ is CR ₇ or NR ₇ ;

and at least one of X ₁ , X ₂ and X ₄ is N;

R ₁ is selected from C ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkenyl group, C ₂ -C ₁₀ alkynyl group, C ₁ -C ₁₀ alkoxy group, C ₆ -C ₁₀ aryl group, 5-18-membered hetero group Aryl, C ₃ -C ₁₀ cycloalkyl, 3-10-membered heterocyclic group; wherein, the 5-18-membered heteroaryl and 3-10-membered heterocyclic group optionally contain 1, 2 or 3 respectively independently Heteroatoms selected from N, O and S; the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkoxy, C ₆ - C ₁₀ aryl, 5-18 membered heteroaryl, C ₃ -C ₁₀ membered cycloalkyl and 3-10 membered heterocyclyl may be optionally replaced by one or more H, halogen, hydroxy, cyano, oxo , amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₃ -C ₅ cycloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ haloalkoxy, -C ₁ -C ₆ alkylene-OR _c , -C ₁ -C ₆ alkylene-C=OR _c , -NO ₂ , -SR _c , -NR _a R _b , -C(=O)R _c , -OC(=O)R _c , -C(=O)OR _c , -C(=O)NR _a R _b , -NC(=O)R _c , -S(=O)R _c , -S(=O) ₂ R _c , -S(=O) ₂ NR _a R _b , -S(=O)(=NR _a )R _b , -P(= O) R _a R _b or -P(=S) R _a R _b replaced;

R ₂ is selected from H, -OH, amino, C ₁ -C ₁₀ alkoxy, -OC(=O)-C _1-3 alkyl, -NR _a R _b , deuterium, halogen, -CN, =N- OH, C ₁ -C ₅ haloalkyl or -C(=O)-OC _1-3 alkyl;

R ₃ is selected from H, -OH, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, -OC(=O)-C _1-3 alkyl, deuterium, halogen, -CN, =N-OH, -C(=O)-OC _1-3 alkyl, -OC(=O)-C _{1- 3} haloalkyl or -C(=O)-OC _1-3 haloalkyl, wherein the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, -C(=O)-OC _1-3 alkyl, -C(=O)-OC _1-3 alkyl, -OC(=O)-C _{1 -3} haloalkyl and -C(=O)-OC _1-3 haloalkyl may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, _{C1 -} C5alkyl, _C2- C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted;

or R ₂ and R ₃ together form an oxo group on the C atom to which it is attached;

R ₄ and R ₅ are each independently selected from H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl; wherein, the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 independently selected from Heteroatoms of N, O and S; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkyne radicals, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl may be optionally replaced by one or more of H, halogen, -CN, -OH, oxo, amino, C ₁ -C ₅ alkyl , C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted; or R ₄ and R ₅ together with the C atom to which they are attached together form substituted or unsubstituted C ₃ -C ₄ cycloalkyl or C ₃ -C ₅ heterocyclyl;

R ₆ is selected from H, -CN, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ - C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl, 3-6 membered heterocyclyl, -NO ₂ , -NH ₂ or oxo; wherein, the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ Alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, oxo substituted with C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl; or two R ₆ together with the C atom to which they are attached together form a substituted or unsubstituted C ₃ - C ₅ cycloalkyl or 3-5 membered heterocyclyl;

Or R ₆ and R ₅ together with the C atom to which they are attached together form a substituted or unsubstituted C ₃ -C ₄ cycloalkyl or 3-5 membered heterocyclic group;

R _d and R _e are each independently selected from H, halogen, cyano, -NR _a R _b , C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl; or R _d and R _e are taken together at their attachment An oxo group is formed on the C atom of ;

R ₇ is selected from H, -NO ₂ , -CN, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ - C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -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) ₂ R _c , -S(=O) ₂ NR _a R _b , -S(=O)(=NR _a )R _b , -P(=O)R _a R _b , -P(=S)R _a R _b ,- OC(=O)R _c or -C ₁ -C ₆ alkylene-OR _c ; wherein, the 5-10-membered heteroaryl group and the 3-10-membered heterocyclic group optionally contain 1, 2 or 3 respectively Heteroatoms independently selected from N, O and S; the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ - _C10 cycloalkyl, 3-10 membered heterocyclyl, _C6 - _C10 membered aryl and 5-10 membered heteroaryl may be optionally replaced by one or more H, halogen, hydroxy, cyano, oxo , amino, C ₁ -C ₆ alkyl, C _1-6 alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₅ cycloalkane base, 3-6 membered heterocyclic group, P(=O)Me ₂ , P(=S)Me ₂ , -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, -S(=O) ₂ -C _1-3 haloalkyl Or -S(=O)-C _1-3 haloalkyl substituted;

R ₈ is selected from absent, H, -CN, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, oxo and -NR _a R _b ; The C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl and C ₃ -C ₁₀ cycloalkyl groups may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted;

R _a , R _b and R _c are each independently selected from H, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ - C ₁₀ -membered cycloalkyl, 3-10-membered heterocyclic group, C ₆ -C ₁₀ -membered aryl group or 5-10-membered heteroaryl group; wherein, the 3-10-membered heterocyclic group and 5-10-membered heteroaryl group are any contains 1, 2 or 3 heteroatoms independently selected from N, O and S;

m is 0, 1 or 2.

In some embodiments, the X ₁ is N.

In some embodiments, the X ₂ is N.

In some embodiments, the X ₃ is CR ₈ .

In some embodiments, the X ₄ is CR ₇ .

In some embodiments, the X ₄ is NR ₇ .

In some embodiments, L is a bond, _-CH2- , -S(=O) _2- , -C=C-, -C=O-, -C≡C- or C3 _{- C5cycloalkyl} .

In some embodiments, L is a bond or _{-CRdRe- .}

In some embodiments, L is a bond.

_In some embodiments, the R ₄ and R ₅ are each independently optionally selected from H, halogen, and C ₁ -C ₆ alkyl, which may be optionally replaced by _one or more of H, substituted by halogen, -CN, -OH, amino or oxo.

In some embodiments, R ₄ and R ₅ are each independently optionally selected from H, halogen, and C ₁ -C ₆ alkyl.

In some embodiments, R ₄ and R ₅ are each independently H or halo.

In some embodiments, R ₄ and R ₅ are each independently H or F.

_In some embodiments, R4 is F.

_In some embodiments, R5 is F.

In some embodiments, R ₂ is halo, -CN, -OH, or =N-OH.

In some embodiments, R ₂ is halo, -CN or -OH.

In some embodiments, R ₂ is F, -CN or -OH.

In some embodiments, R ₂ is halogen.

In some embodiments, R ₂ is hydroxy.

In some embodiments, R ₂ and R ₃ together form oxo.

In some embodiments, R ₃ is H, deuterium, C ₁ -C ₁₀ alkyl or C ₂ -C ₁₀ alkenyl; wherein, the C ₁ -C ₁₀ alkyl and C ₂ -C ₁₀ alkenyl may be optional is substituted with one or more H, halogen, -CN, -OH, amino or _C1 - _C5 haloalkyl.

In some embodiments, R ₃ is H, deuterium or C ₁ -C ₃ alkyl, C ₂ -C ₅ alkenyl, wherein the C ₁ -C ₃ alkyl and C ₂ -C ₅ alkenyl are optional is substituted with one or more of H, halogen, -CN, -OH, amino, _C1 - _C5 haloalkyl.

In some embodiments, _{R 3} is H, deuterium, or C ₁ -C ₃ alkyl, which may optionally be replaced by _one or more of H, halogen, -CN, -OH, amino, or C ₁ -C ₅ haloalkyl substituted.

In some embodiments, R ₃ is selected from H, deuterium, or C ₁ -C ₃ alkyl.

Preferably, in some embodiments, _R3 is H or deuterium.

Preferably, in some embodiments, _R3 is H.

In some embodiments, R ₂ is -OH, -CN or halogen, and R ₃ is H or deuterium; or R ₂ and R ₃ together form oxo.

In some embodiments, R ₂ is -OH, -CN or -F, and R ₃ is H or deuterium; or R ₂ and R ₃ together form oxo.

In some embodiments, R ₂ is -OH and R ₃ is H or deuterium; or R ₂ and R ₃ together form oxo.

In some embodiments, R ₁ is C ₆ -C ₁₀ aryl, 5-18 membered heteroaryl, or C ₃ -C ₁₀ cycloalkyl, said 5-18 membered heteroaryl optionally containing 1, 2, or 3 heteroatoms each independently selected from N, O, and S.

In some embodiments, the R ₁ is a C ₆ -C ₁₀ aryl group or a 5-18-membered heteroaryl group, and the 5-18-membered heteroaryl group optionally contains 1, 2 or 3 independently selected from N , O and S heteroatoms.

In some embodiments, the R ₁ is phenyl or a 5-6 membered heteroaryl; the 5-6 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

In some embodiments, the R ₁ is phenyl or 6-membered heteroaryl; the 6-membered heteroaryl optionally contains 1, 2 or 3 N heteroatoms.

In some embodiments, R ₁ is a C ₆ -C ₈ aryl group or a 5-8 membered heteroaryl group optionally containing 1, 2 or 3 atoms independently selected from N, O and the heteroatom of S; wherein, the C ₆ -C ₈ aryl and 5-8 membered heteroaryl may be optionally replaced by one or more H, halogen, -OH, -CN, oxo, amino , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene-OR _c , -C ₀ -C ₆ alkylene-C Substituted with = _ORc , _-NO2 , -C(=O) _ORc or -S(=O _{) 2Rc} .

In some embodiments, R ₁ is phenyl or a 5-6 membered heteroaryl optionally containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, respectively , the phenyl and 5-6 membered heteroaryl groups can be optionally replaced by one or more H, halogen, -OH, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene -OR _c or -CN substituted.

In some embodiments, R ₁ is phenyl or a 5-6 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, respectively , the phenyl or 5-6 membered heteroaryl may be optionally substituted with one or more halogen, cyano and/or C ₁ -C ₆ haloalkyl.

In some embodiments, R ₁ is phenyl or a 5-6 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, respectively , the phenyl or 5-6 membered heteroaryl may be optionally substituted with one or more halogen, cyano and/or trifluoromethyl.

In some embodiments, the R1 may be optionally substituted with _one or more halogen and/or cyano groups.

In some embodiments, the R ₁ is phenyl.

In some embodiments, the R ₁ is pyridyl.

In some embodiments, the R ₁ is pyrimidinyl, pyrazinyl, or pyridazinyl.

In some embodiments, the R ₁ is phenyl or pyridyl, which phenyl or pyridyl may be optionally replaced by one or more halogen, -OH, amino, C ₁ -C ₆ alkyl, C ₁ - Substituted with C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene-OR _c or -CN.

In some embodiments, the R ₁ is phenyl or pyridyl, which may be optionally substituted with one or more halogen, -CN, or C ₁ -C ₆ haloalkyl.

In some embodiments, the R ₁ is phenyl or pyridyl, which phenyl or pyridyl can optionally be replaced by one or more halogen, -CN, -CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ and/or -CH ₂ CF ₃ substituted.

In some embodiments, the R ₆ is H, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ haloalkyl, wherein the C ₁ -C _6Alkyl , _{C1 - C6alkoxy} or _C1 -C6haloalkyl may be optionally substituted with one or more of H, halogen, -CN, -OH, oxo, amino.

_In some embodiments, R ₆ is H, halo, or C ₁ -C ₆ alkyl, which may optionally be replaced by _one or more of H, halo, -CN, -OH, oxo base, amino substituted.

In some embodiments, R ₆ is H, halogen, or C ₁ -C ₆ alkyl.

In some embodiments, R ₆ is H and/or halogen.

In some embodiments, R ₆ is H, F, Cl or Br.

In some embodiments, R ₆ is H or F.

In some embodiments, R ₆ is H.

In some embodiments, the two R ₆ together with the C atom to which they are attached form a cyclopropyl group.

In some embodiments, R ₈ is H, -CN, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, _R8 is H, -CN or halogen.

In some embodiments, R ₈ is selected from H, -CN, -NH ₂ , halogen, C ₁ -C ₃ alkyl, and cyclopropyl.

In some embodiments, _R8 is H or halo.

In some embodiments, _R8 is H, -CN, -F, -Cl, -Br, or _-CF3 .

In some embodiments, _R8 is H.

In some embodiments, the R ₇ is selected from H, -CN, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl , C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -S(=O)R _c , -C ₁ -C ₆ alkylene-OR _c , -S(=O) ₂ R _c or P (=O)R _a R _b ; the 5-10 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the C ₁ -C ₁₀ Alkyl, C ₂ -C ₁₀ alkenyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl may be optionally replaced by one or Multiple halogens, hydroxyl, P(=O)Me ₂ , P(=S)Me ₂ , -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -C _3-5 ring Alkyl, -S(=O)-C _1-3 alkyl, -S(=O)-C _1-3 haloalkyl, -S(=O)-C _3-5 cycloalkyl, cyano, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl substituted;

Said R _a and R _b are independently selected from H, C ₁ -C ₆ alkyl;

Said R _c is selected from H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, R ₇ is selected from halogen, cyano, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 5-membered heteroaryl, S(=O)R _c , -S(=O ) ₂ R _c , -S(=O)(=NR _a )R _b or P(=O)Me ₂ ; wherein, the 5-membered heteroaryl optionally contains 1, 2 or 3 independently selected from Heteroatoms of N, O and S; the C3 _{- C6} cycloalkyl, 5-membered heteroaryl can be optionally replaced by H, halogen, hydroxy, _{C1 -} C3 alkyl, _{C1 -} C3 alkane substituted with oxy or C ₁ -C ₃ haloalkyl.

In some embodiments, the R ₇ is selected from halogen, cyano, C ₁ -C ₄ haloalkyl, C ₃ -C ₅ cycloalkyl, 5-membered heteroaryl, S(=O)R _c , -S( =O) ₂ R _c , -S(=O)(=NR _a )R _b or -P(=O)Me ₂ ; wherein, the 5-membered heteroaryl optionally contains 1, 2 or 3 independently Heteroatoms selected from N, O and S; the C ₃ -C ₅ cycloalkyl and 5-membered heteroaryl may be optionally replaced by H, halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ - C ₃ alkoxy or C ₁ -C ₃ haloalkyl substituted.

In some embodiments, the R ₇ is selected from C ₁ -C ₆ haloalkyl, cyano, -S(=O) ₂ R _c , -P(=O)Me ₂ or 5-membered heteroaryl, the 5 A membered heteroaryl group optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S _; C ₃ alkyl or C ₁ -C ₃ haloalkyl substituted.

In some embodiments, the R ₇ is selected from C ₁ -C ₆ haloalkyl, -S(=O) ₂ R _c or a 5-membered heteroaryl optionally containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; the 5-membered heteroaryl may be optionally substituted with one or more H, halogen, _{C1 -} C3 alkyl, or _{C1 -} C3 haloalkyl replaced.

In some embodiments, the R ₇ is selected from trifluoromethyl, difluoromethyl, cyano, -S(=O) ₂ -R _c or 5-membered heteroaryl, the 5-membered heteroaryl is optionally containing 1 , 2 or 3 heteroatoms independently selected from N, O and S; the R _c is selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the R ₇ is C ₁ -C ₄ haloalkyl.

In some embodiments, the R ₇ is -S(=O) ₂ -R _c , and the R _c is selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the R _a and R _b are each independently selected from H, C ₁ -C ₄ alkyl.

In some embodiments, the R _c is selected from H, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl.

In some embodiments, the R ₇ is selected from

In some embodiments, the R ₇ is selected from

In some embodiments, the compound is represented by formula (II-1), formula (II-2) or formula (II-3),

The R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , L and m are as described in the foregoing embodiments.

In some embodiments, the compound is represented by formula (III-1), formula (III-2) or formula (III-3),

The R ₁ , R ₆ , R ₇ , R ₈ and m are as described in the foregoing embodiments.

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, the compound refers to:

1) 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1-yl]-2-fluorobenzonitrile;

2) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopento[b]pyrrole-3-carbonitrile;

3) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

4) 2-Chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)- base) benzonitrile;

5) 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

6) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) benzonitrile;

7) 2-Chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

8) 2-Chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) benzonitrile;

9) 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile ;

10) 5-(5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro benzonitrile;

11) (S)-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H) )-yl)benzonitrile;

12) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)phthalate Nitrile;

13) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro benzonitrile;

14) 2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

15) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H) -ketone;

16) 3-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

17) 3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluoro benzonitrile

18) 5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalic acid Nitrile;

19) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

20) 2-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluoro benzonitrile

21) 5-Chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

22) 1-(4-Chloro-2-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

23) 1-(4-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

24) 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

25) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)benzonitrile;

26) 5-(5,5-Difluoro-4-hydroxy-3-(thiazol-4-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalene formonitrile;

27) 3-(5,5-Difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5- Fluorobenzonitrile;

28) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

29) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)benzonitrile;

30) 1-(3-Chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[ b] pyrrol-4-ol;

31) 5-(5,5-Difluoro-4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl) isophthalonitrile;

32) 2-Chloro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile ;

33) 2-Chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

34) 2-Chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)- base) benzonitrile;

35) 5-(3-Chloro-5-fluorophenyl)-2,2-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

36) 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

37) 1-(6-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

38) 1-(5-chloropyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

39) 1-(5-Aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

40) 5,5-Difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

41) 5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro - Cyanopyridine;

42) 1-(5-Chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

43) 1-(3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)- 5-Fluorophenyl)ethyl-1-one;

44) 4-(5,5-Difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl )-2-hydroxybenzonitrile;

45) 2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl- 4-deuterium) benzonitrile;

46) 3-5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorocyanide benzene;

47) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole -4-ol;

48) 5-(3-Chloro-5-fluorophenyl)-2,3-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

49) 3-(3-Chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-pyrrole[1,2-c]imidazole -7-ol;

50) 5-(3-chloro-5-fluorophenyl)-2-fluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolizin-1-ol;

51) (S)-2-Fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentoyl[b]pyrrole-1( 4H)-yl)benzonitrile;

52) 5,5-Difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b ] pyrrol-4-ol;

53) 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

54) 5-(5,5-Difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl)-2 - Fluorobenzonitrile;

55) 5-(5,5-Difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl)-2 - Fluorobenzonitrile;

56) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-methyl oxybenzonitrile;

57) 5,5-Difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole -4-ol;

58) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl )-2-fluorobenzonitrile;

59) (S)-5,5-difluoro-1-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro Cyclopenta[b]pyrrol-4-ol;

60) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -3-(difluoromethyl)-2-fluorobenzonitrile;

61) (S)-4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -2-(difluoromethyl)benzonitrile;

62) (S)-1-(3-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

63) (S)-3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

64) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetra Hydrocyclopenta[b]pyrrol-4-ol;

65) (S)-5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro Cyclopenta[b]pyrrol-4-ol;

66) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -2,3-Difluorobenzonitrile;

67) 5-((4S,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

68) 5-((4S,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile

69) 5-((4S,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

70) 5-((4S,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

71) 5-((4R,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

72) 5-((4R,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

73) 5-((4R,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile; or

74) 5-((4R,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-co- Valence complex or solvate and pharmaceutically acceptable excipients such as hydroxypropyl methylcellulose. In some compositions, the compound or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof and the excipient The weight ratio is about 0.001-10.

In addition, the present invention also provides a method of 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 stereoisomer, tautomer thereof Conforms, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates.

In certain aspects, the disease or disorder is selected from the group consisting of VHL syndrome, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, cardiovascular disorder, renal disorder, viral infection, and obesity. In certain aspects, the disease or disorder 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), Acute rejection of transplanted organs. In certain aspects, the disease or disorder is cancer, including hematological cancer, lymphoma, multiple myeloma, digestive system tumor, reproductive system tumor, brain tumor, nervous system tumor neoplasia.

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

In certain aspects, the disease or disorder is VHL syndrome. In certain aspects, the disease or disorder is kidney cancer. In certain aspects, the subject is a human.

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

The present invention also provides compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates thereof in the preparation of Use in a medicament for the treatment of a disease or disorder mediated by HIF-2α.

The present invention also provides compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates thereof for use in therapy thing. Further provided are compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs thereof for use in the treatment of subjects suffering from a disease or disorder mediated by HIF-2α , chelate, non-covalent complex or solvate. In the present invention, unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups refer to fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, the term "alkyl" includes linear, branched or cyclic saturated monovalent hydrocarbon groups. 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, "C _1-6 " in C _1-6 alkyl refers to groups containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain.

The term "alkoxy" refers to oxygen ethers formed from the above-mentioned straight chain, branched chain or cyclic alkyl groups.

The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound. Similarly, "C _1-4 " in a C _1-4 alkylene group refers to an alkylene group containing 1, 2, 3 or 4 carbon atoms.

The term "haloalkyl" refers to an alkyl group in which one or more Hs have been replaced by halogen atoms. The term "haloalkoxy" refers to the group -O-haloalkyl.

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

In the present invention, unless otherwise specified, the terms "aromatic ring", "aromatic ring" or "aromatic heterocycle" refer to those having aromatic characteristics (having (4n+2) delocalized π electrons, where n is carbocyclic or heterocyclic polyunsaturated ring of an integer).

The term "aryl" refers to a substituted or unsubstituted stable aromatic hydrocarbon group of 6 to 10 ring carbon atoms, which may contain 1 aromatic ring or multiple aromatic rings (eg, fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.

The term "heteroaryl" refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocycle having at least one heteroatom ring member selected from N, O and/or S. "3-10-membered" in the 3-10-membered heteroaryl group refers to a heteroaryl group consisting of 3-10 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.

The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. "C _3-10 " in the term C _3-10 cycloalkyl means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3, or 4 fused rings, spiro rings, paracyclic rings, etc.). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, cycloalkyl groups also include those having one or more aromatic rings fused to the cyclized alkyl ring. moieties, such as benzo- or thienyl derivatives of cyclohexane, etc.

The term "cycloalkenyl" refers to a ring system having at least one cycloalkenyl group having one or more carbon-carbon double bonds therein. "C _3-10 " in the term C _3-10 cycloalkenyl means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming atoms. Cycloalkenyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; Parts of aromatic rings, such as benzo or thienyl derivatives of cyclohexene rings, etc.

The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom selected from N, O and/or S. The heterocyclyl group may include monocyclic or polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). A heterocyclyl group can be attached to the rest of the compound via a ring carbon atom or a ring heteroatom. The "5-18-membered" in the 5-18-membered heterocyclic group refers to a heterocyclic group containing 5-18 carbon atoms or ring atoms of N, O or S. Also included in the definition of said heterocyclyl are moieties having one or more aromatic rings fused to a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. . In some embodiments, heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepanyl, dihydrobenzofuranyl, and the like .

The term "composition" in the present invention is intended to include products containing the specified components in the specified amounts, as well as any product that is directly or indirectly derived from the specified amounts of the specified components. Accordingly, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods of preparing the compounds are also within the scope of the present invention. Furthermore, some of the crystalline forms of the compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (eg, hydrates) or common organic solvents, and these solvates are also included in the present invention.

Prodrugs (prodrugs) of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Accordingly, the term "administering" in the methods of treatment provided herein includes administering a compound disclosed herein, or, although not explicitly disclosed, is administered to a subject capable of converting in vivo to a prodrug compound disclosed herein. Conventional methods for the selection and preparation of suitable prodrug derivatives are described in, for example, Design of Prodrugs (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

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 those of ordinary skill in the art can select the substituents or substitution forms of the compounds of the present invention by means of the prior art and the methods described in the present invention, so as to provide chemically stable and easily synthesized compounds.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

The above formula (I) does not exactly define the stereoscopic structure of the compound at a certain position. The present invention includes all stereoisomers of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. During synthetic procedures to prepare such compounds, or during the use of racemization or epimerization methods well known to those of ordinary skill in the art, the resulting product may be a mixture of stereoisomers.

When the compound represented by formula (I) exists as a tautomer, unless otherwise stated, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compounds of formula (I) and their pharmaceutically acceptable salts are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc, and the like. The ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Nontoxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable nontoxic organic bases capable of forming salts, including 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, Haramine, Isopropylamine , lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, ammonia Butanetriol, etc.

When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexamic 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 medicament, it is preferred to use a substantially pure form, eg, at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% is by weight ).

The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although the most suitable mode of administration of the active ingredient in any given situation will depend on the particular subject being administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.

In fact, according to conventional pharmaceutical mixing techniques, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component, mixed with a pharmaceutical carrier to form a pharmaceutical combination thing. The pharmaceutical carrier can take a wide variety of forms depending on the desired mode of administration, eg, oral or injection (including intravenous). Accordingly, the pharmaceutical compositions of the present invention may take the form of discrete units suitable for oral administration, such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical compositions of the present invention may take the form of powders, granules, solutions, aqueous suspensions, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition, in addition to the common dosage forms mentioned above, the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release manner and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. In general, the pharmaceutical compositions are prepared by homogeneous intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers, or a mixture of both. The product can then be conveniently prepared to the desired appearance.

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, together with one or more other compounds having therapeutic activity are also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier employed in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. Gas carriers, including carbon dioxide and nitrogen. In the preparation of pharmaceutical oral formulations, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used in oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used for oral solid preparations such as powders, capsules and tablets. For ease of administration, tablets and capsules are preferred for oral formulations, where solid pharmaceutical carriers are employed. Alternatively, the tablet coating can use standard aqueous or non-aqueous formulation techniques.

A tablet containing a compound or pharmaceutical composition of the present invention may be prepared by compressing or molding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by wetting the powdered compound or pharmaceutical composition with an inert liquid diluent and molding in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, dosage forms intended for oral administration to humans comprise from about 0.5 mg to about 5 g of the active ingredient in admixture with suitable and conveniently metered adjunct materials comprising from about 5% to 95% of the total pharmaceutical composition. A unit dosage form generally contains from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding the active ingredient to water. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared in the form of sterile powders that can be used for the extemporaneous preparation of sterile injectable solutions or dispersions. In any event, the final injectable form must be sterile and, for ease of injection, must be readily flowable. Furthermore, the pharmaceutical compositions must be stable during manufacture and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, an aerosol, cream, 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 in a transdermal drug delivery device. These formulations can be prepared by conventional processing methods using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof. As an example, a cream or ointment is prepared by adding a hydrophilic material and water to about 5% to 10% by weight of the above compound to produce a cream or ointment having the desired consistency.

The pharmaceutical composition provided by the present invention can be made into a form that is suitable for rectal administration by using a solid as a carrier. The preferred dosage form is admixture to form unit dose suppositories. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, then cooling and moulding.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, enhancers Thickeners, lubricants and preservatives (including antioxidants), etc. In addition, other adjuvants can also include osmotic enhancers that adjust the isotonic pressure of the drug and blood. The pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can also be prepared in the form of powder or concentrate.

In general, to treat the conditions or disorders indicated above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. It will be understood, however, that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concomitant use, and acceptance The severity of the specific disease being treated.

detailed description

In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with the examples. These examples are only illustrative and are not limited to the scope of application of the present invention. The specific experimental methods not mentioned in the following examples, It is usually carried out according to conventional experimental methods.

All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

The following abbreviations are used in the examples:

ACN: acetonitrile;

AcOH: acetic acid;

AIBN: azobisisobutyronitrile;

CuI: cuprous iodide;

DAST: diethylaminosulfur trifluoride;

DCM: dichloromethane;

DMSO: dimethyl sulfoxide;

DMF: N,N-dimethylformamide;

EA: ethyl acetate;

ESI-MS: Electrospray Ionization Mass Spectrometry;

m-CPBA: m-chloroperoxybenzoic acid;

NaH: sodium hydride;

LiHMDS: lithium bis(trimethylsilyl)amide;

PE: petroleum ether;

PBS: Phosphate Buffered Saline;

Na ₂ SO ₄ : sodium sulfate;

NaBH ₄ : sodium borohydride;

NBS: N-bromosuccinimide;

NFSI: N-fluorobisbenzenesulfonamide;

NIS: N-iodosuccinimide;

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium;

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium;

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;

Prep-TLC: preparative thin layer chromatography;

Selectfluor: 1-Chloromethyl-4-fluoro-1,4-azoniumbicyclo[2.2.2]octanebis(tetrafluoroborate);

TEA: triethylamine;

THF: tetrahydrofuran;

TFA: trifluoroacetic acid;

Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;

¹ H NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy

[(R,R)-Ts-DPEN]RuCl(p-cymene)]: Chlorine {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonic acid) Acyl)amino}(P-isopropyltoluene)ruthenium(II).

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

Step 1: Synthesis of Compound M1-1

Under nitrogen protection, 2-pyrrolecarbaldehyde (30 g) was dissolved in THF (300 mL), 60% NaH (19 g) was slowly added under ice bath, and after stirring for 1 hour, benzenesulfonyl chloride (66 g) was added. The reaction solution was stirred at 0 °C for 3 hours, poured into a mixture of ice water (1000 mL), extracted with EA (500 mL*3), washed with saturated brine (500 mL*2), dried over Na ₂ SO ₄ , and concentrated to obtain the crude product, The crude product was purified by column chromatography (EA/PE=1:10) to obtain the target compound M1-1 (68 g).

ESI-MS m/z: 236.06 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound M1-2

Under nitrogen protection, tert-butyl diethylphosphonoacetate (73 g) was dissolved in THF (700 mL), 60% NaH (17 g) was slowly added under an ice bath, and after stirring at room temperature for 1 hour, M1-1 ( 68g). The reaction solution was stirred for 3 hours, poured into a mixture of ice and water (1000mL), extracted with EA (1000mL*3), washed with saturated brine (1000mL*2), dried over Na ₂ SO ₄ , and concentrated to obtain the crude product M1- 2 (95g). The crude product was used directly in the next step.

ESI-MS m/z: 276.05 [Mt-Bu ⁺ ] ^- .

Step 3: Synthesis of Compound M1-3

At room temperature, M1-2 (95 g) was dissolved in MeOH (1000 mL), Pd/C (10%, 10 _g ) was added to the reaction system, stirred overnight under H atmosphere, the reaction solution was filtered and concentrated to obtain the target compound M1-3 (95g), used directly in the next step.

ESI-MS m/z: 278.06 [Mt-Bu ⁺ ] ^- .

Step 4: Synthesis of Compound M1-4

At room temperature, M1-3 (95 g) was dissolved in DCM (1000 mL), TFA (50 mL) was added to the reaction system under an ice bath, and stirred for 2 hours. The reaction solution was concentrated to dryness to obtain the target compound M1-4 (80 g). ), used directly in the next step.

Step 5: Synthesis of Compounds M1-5

Under ice bath, oxalyl chloride (48 mL) was added dropwise to a solution of M1-4 (80 g) and DMF (1 mL) in DCM (800 mL), then stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness. The residue was dissolved in DCM (800 mL) and cooled to 0°C, AlCl3 ₍ 95 g) was added in portions and stirring was continued at room temperature for 2 hours. The reaction solution was quenched by pouring into an ice-water mixture, extracted with EA, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (EA/PE=1:10) to obtain the target compound M1-5 (33 g).

ESI-MS m/z: 262.05 [M+H ⁺ ] ⁺ .

Step 6: Synthesis of Compounds M1-6

Under ice bath, NaOH (9.2 g) was added to M1-5 (33 g) in MeOH (300 mL), stirred at room temperature for 15 minutes, the reaction solution was decompressed to remove most of the solvent, diluted with water, extracted with EA, Na ₂ SO ₄ It was dried, filtered, concentrated, and the crude product was purified by column chromatography (EA/PE=1:5) to obtain the target compound M1-6 (15 g).

ESI-MS m/z: 122.09 [M+H ⁺ ] ⁺ .

Step 7: Synthesis of Compounds M1-7

Under nitrogen protection, M1-6 (15 g) was dissolved in THF (150 mL), 60% NaH (7.4 g) was slowly added under an ice bath, and after stirring for half an hour, triisopropyl chlorosilane (28.5 g) was added to react. The mixture was stirred at 0°C for 3 hours. The reaction solution was poured into a mixture of ice and water (500 mL), extracted with ethyl acetate (500 mL*2), washed with saturated brine (500 mL*2), dried over Na ₂ SO ₄ , and concentrated to obtain the crude product, which was subjected to column chromatography (EA/PE=1:10) purification to obtain the target compound M1-7 (28 g).

ESI-MS m/z: 278.23 [M+H ⁺ ] ⁺ .

Step 8: Synthesis of Compounds M1-8

Under nitrogen protection, compound M1-7 (28 g) was dissolved in ACN (100 mL), NIS (27 g) was added in portions, and the temperature was raised to 60° C. and stirred for 5 hours. Then the reaction solution was poured into an ice-water (500 mL) mixture, extracted with EA (500 mL*2), washed with saturated brine (500 mL*2), dried over Na ₂ SO ₄ , and concentrated to obtain a crude product, which was subjected to column chromatography ( EA/PE=1:10) was purified to obtain the target compound M1-8 (18 g).

Step 9: Synthesis of Compound M1

Compound M1-8 (2.5 g) was dissolved in THF (30 mL), cooled to -78°C, and slowly added dropwise to LiHMDS tetrahydrofuran solution (1.0 M, 17.5 mL), and after stirring for half an hour, NFSI (4.1 g) was added dropwise. Tetrahydrofuran solution (10 mL), and continued stirring at -78°C for two hours. After quenching the reaction with a saturated aqueous ammonium chloride solution, it was extracted twice with ethyl acetate, washed twice with saturated brine, dried over Na ₂ SO ₄ , and concentrated to obtain a crude product, which was subjected to column chromatography (EA/PE=1 : 10) was purified to obtain the target compound M1 (700 mg).

ESI-MS m/z: 283.97 [M+H ⁺ ] ⁺ .

Synthesis of Intermediate M2 (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one)

Step 1: Synthesis of Compound M2-1

Ethyl 4,4,4-trifluoro-3-oxobutyrate (50 g) was dissolved in AcOH (80 mL), cooled in an ice-water bath, and sodium nitrite (19 g) in water (50 mL) was added dropwise below 10°C The solution was warmed to room temperature after the addition, and after 2 hours, concentrated, diluted with EA, washed with water, combined the organic phases, dried and concentrated the target compound M2-1 (59 g).

Step 2: Synthesis of Compound M2

Cyclopentanedione (21g) was dissolved in acetic acid (125mL), heated to 60°C, then a solution of M2-1 in water (65mL) was added, stirred at 60°C for 10 minutes, and then zinc powder (28g) was added in batches , stirred at 60°C for 0.5 hours, then heated to 90°C for overnight reaction, concentrated, diluted with EA, adjusted pH to about 8 with saturated sodium bicarbonate, filtered, separated, the aqueous phase was extracted twice with EA, the organic phases were combined and dried , concentrated and purified by column chromatography to obtain the target compound M2 (12g).

Example 1 5-[5,5-Difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1-yl]-2-fluorobenzonitrile ( Synthesis of compound A1)

Step 1: Synthesis of Compound 1-1

Compound M1 (200 mg) was dissolved in DCM (20 mL), copper acetate (60 mg), 3-cyano-4-fluorophenylboronic acid (300 mg) and TEA (300 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed twice with saturated brine, dried and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA/PE=1:5) to obtain the target compound 1-1 (110 mg).

ESI-MS m/z: 403 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compounds 1-2

Under nitrogen protection, compound 1-1 (50 mg) was dissolved in DMF (5 mL), Pd ₂ (dba) ₃ (23 mg), CuI (28 mg) and methyl fluorosulfonyldifluoroacetate (71 mg) were added, 100 Stir overnight at °C, extract with EA, wash the organic layer with brine, dry over Na ₂ SO ₄ , and concentrate to obtain the crude product, which is purified by column chromatography (EA/PE=1:5) to obtain the target compound 1-2 (30 mg) .

ESI-MS m/z: 345 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound A1

Compound 1-2 (30 mg) was dissolved in THF (4 mL), NaBH ₄ (10 mg) was added, after stirring at room temperature for 3 hours, quenched by adding saturated ammonium chloride solution, extracted with EA, the organic layer was washed with brine, Na ₂ Dry over SO ₄ and concentrate to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A1 (10 mg).

ESI-MS m/z: 328.95 [M+H ⁺ -H ₂ O] ⁺ .

Example 2 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonitrile ( Compound A2)

Step 1: Synthesis of Compound 2-1

Substituting boronic acid with 3-chloro-5-fluorobenzeneboronic acid, and referring to the preparation method of compound 1-1, compound 2-1 can be obtained.

ESI-MS m/z: 411.9 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 2-2

Under nitrogen protection, compound 2-1 (212 mg) was dissolved in DMF (5 mL), Zn(CN) ₂ (150 mg) and Pd(PPh ₃ ) ₄ (80 mg) were added, stirred at 120°C overnight, extracted with EA, organic The layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to obtain the crude product, which was purified by column chromatography (EA/PE=1:3) to obtain the target compound 2-2 (120 mg).

ESI-MS m/z: 311.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound A2

Referring to the preparation method of compound 1, compound 2-2 was reduced by NaBH ₄ to obtain the target compound A2.

Example 3 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) Synthesis of benzonitrile (Compound A22)

Step 1: Synthesis of Compound 22-1

Substituting boronic acid with 4-chloro-3-cyanophenylboronic acid, and referring to the preparation method of compound 1-1, compound 22-1 can be obtained.

ESI-MS m/z: 418.9 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 22-2

Compound 22-1 (380 mg), methyl 3-sulfanyl propionate (300 mg), Xantphos (116 mg) and Pd ₂ (dba) ₃ (89 mg) were added to toluene (10 mL), stirred at 70° C. overnight, and concentrated to obtain The residue was purified by column chromatography to obtain the target compound 22-2 (200 mg).

ESI-MS m/z: 411.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound 22-3

At -78°C, potassium tert-butoxide (50 mg) was added to a solution of compound 22-2 (120 mg) in THF (10 mL), stirred at room temperature until the raw material disappeared, added iodomethane (100 mg), stirred at room temperature for 5 hours, and saturated with Quenched with ammonium chloride, extracted with EA, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound 22-3 (70 mg).

ESI-MS m/z: 339.0 [M+H ⁺ ] ⁺ .

Step 4: Synthesis of Compound 22-4

At room temperature, m-CPBA (300 mg) was added to a solution of compound 22-3 (130 mg) in dichloromethane (10 mL), stirred at room temperature for 10 h, the reaction mixture was extracted with aqueous sodium thiosulfate, diluted with DCM, and aqueous NaHCO ₃ Washed, washed with saturated brine, dried, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the target compound 22-4 (60 mg).

ESI-MS m/z: 371.0 [M+H ⁺ ] ⁺ .

Step 5: Synthesis of Compound A22

Referring to the preparation method of compound 1, compound 22-4 is reduced by NaBH ₄ to obtain the target compound A22.

LCMS: 355.01 [M ⁺ H ⁺ -H2O] ₊ .

Example 4 2-Chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)- Synthesis of phenyl)benzonitrile (Compound A24)

Step 1: Synthesis of Compound 24-1

Substitute 3-cyano-4-fluorobenzeneboronic acid with 3-cyano-4-chlorobenzeneboronic acid, and refer to the methods of step 1 and step 2 of Example 1 to prepare compound 24-1.

ESI-MS m/z: 361.0 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 24-2

Under nitrogen protection, compound 24-1 (100 mg) was dissolved in acetonitrile (5 mL), Selectfluor (150 mg) was added, stirred at 80 °C overnight, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to obtain The crude product was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound 24-2 (20 mg).

ESI-MS m/z: 379.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound A24

Compound 24-2 (20 mg) was dissolved in a mixed solvent of THF (2 mL) and H ₂ O (1 mL), NaBH ₄ (20 mg) was added under ice bath, and the mixture was stirred at 0° C. for 1 hour. Ice water was added to the reaction solution, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A24 ( 15mg).

ESI-MS m/z: 363.01 [M+H ⁺ -H ₂ O] ⁺ .

Example 5 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 - Synthesis of alcohol (compound A25)

Step 1: Synthesis of Compound 25-1

Intermediate M1 (300 mg) was dissolved in DMF (10 mL), K ₂ CO ₃ (300 mg) and 3,5-difluorobenzyl bromide (300 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted twice with EA, 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 25-1 (320 mg).

ESI-MS m/z: 410.0 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 25-2

Under nitrogen protection, compound 25-1 (320 mg) was dissolved in DMF (5 mL), Pd ₂ (dba) ₃ (192 mg), CuI (133 mg) and methyl fluorosulfonyldifluoroacetate (300 mg) were added, 100 Stir at °C for three hours, the reaction solution was extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA/PE=1:10) to obtain the target compound 25- 2 (170 mg).

ESI-MS m/z: 352.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound A25

Compound 25-2 (170 mg) was dissolved in methanol (4 mL), NaBH ₄ (60 mg) was added under ice bath, and after stirring at 0 °C for 1 hour, ice water was added, extracted with EA, the organic layer was washed with brine, and dried over Na ₂ SO ₄ , concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A25 (120 mg).

ESI-MS m/z: [M+H ⁺ -H ₂ O] ⁺ : 336.06.

Example 6 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) Synthesis of benzonitrile (Compound A26)

Step 1: Synthesis of Compound 26-1

Pd(dppf)Cl ₂ (110 mg), K ₂ CO ₃ (270 mg), 2-thiopheneboronic acid (200 mg) were added to compound 22-1 (410 mg) in dioxane (10 mL)/H ₂ O at room temperature (1 mL) of the mixed solution, replaced with nitrogen three times, and reacted at 90°C in a microwave for 3 hours. The reaction mixture was diluted with water, extracted with EA, dried over Na ₂ SO ₄ , and concentrated to obtain the target compound 26-1 (250 mg).

ESI-MS m/z: 375.0 [M+H ⁺ ] ⁺ .

Step 1: Synthesis of Compound A26

Referring to the preparation method of compound 1, compound 26-1 was reduced by NaBH ₄ to obtain the target compound A26.

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 359.02.

Example 7 2-Chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) Synthesis of benzonitrile (Compound A27)

Step 1: Synthesis of Compound 27-1

Under nitrogen protection, compound 22-1 (400 mg) was dissolved in a mixed solvent of dioxane (5 mL)/H ₂ O (5 mL), Pd(PPh ₃ ) ₄ (110 mg), K ₂ CO ₃ ( 400 mg) and vinylboronic acid pinacol ester (300 mg), reacted at 90 °C overnight, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to obtain the crude product, which was subjected to column chromatography (EA/PE =1:5) and purified to obtain the target compound 27-1 (200 mg).

ESI-MS m/z: 319.0 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 27-2

Compound 27-1 (200 mg) was dissolved in a mixed solvent of THF (5 mL) and H ₂ O (5 mL), NaIO ₄ (500 mg) and potassium osmate (20 mg) were added, the reaction was carried out at room temperature for 2 hours, extracted with EA, and the organic layer was Washed with brine, dried over Na ₂ SO ₄ , concentrated to give crude product, which was purified by Prep-TLC (EA/PE=1:4) to give target compound 27-2 (80 mg).

ESI-MS m/z: 321.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound 27-3

Under nitrogen protection, compound 27-2 (80 mg) was dissolved in DCM (4 mL), and DAST (98 mg) was added in an ice bath. After the dropwise addition, the mixture was returned to room temperature and stirred overnight. Quenched with saturated sodium bicarbonate, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to give crude product, which was purified by Prep-TLC (EA/PE=1:4) to give target compound 27 -3 (40 mg).

ESI-MS m/z: 343.0 [M+H ⁺ ] ⁺ .

Step 4: Synthesis of Compound A27

Compound 27-3 (40 mg) was dissolved in a mixed solvent of THF (5 mL) and H ₂ O (5 mL), NaBH ₄ (30 mg) was added under ice bath, the reaction was carried out at room temperature for half an hour, extracted with EA, and the organic layer was washed with brine , dried over Na ₂ SO ₄ , and concentrated to obtain the crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A27 (25 mg).

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 327.0.

Example 8 2-Chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) Synthesis of benzonitrile (Compound A28)

Step 1: Synthesis of Compound 28-1

Compound 22-1 (100 mg), dimethylphosphine oxide (30 mg), palladium acetate (10 mg), potassium phosphate (70 mg) and Xantphos (30 mg) were added to dioxane (5 mL), nitrogen was replaced three times, 100°C The reaction was carried out overnight, diluted with EA, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by Prep-TLC (DCM/MeOH=20:1) to obtain the target compound 28-1 (80 mg).

ESI-MS m/z: 369.0 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound A28

Referring to the preparation method of compound 1, compound 28-1 was reduced by NaBH ₄ to obtain the target compound A28.

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 353.0.

Example 9 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)benzyl Synthesis of Nitriles (Compound A45).

Step 1: Synthesis of Compound 45-1

Compound M2 (650mg), copper acetate (620mg) and 4A molecular sieves (700mg) were added to dichloromethane (7mL), then N,N-diisopropylethylamine (1.7mL) was added, stirred at room temperature for half an hour, oxygen Replace twice, stir overnight at room temperature, filter, spin dry the filtrate, column chromatography (PE/EA=5:1 to 1:1, eluent was added 10% DCM) to obtain compound 45-1 (900 mg).

ESI-MS m/z: 309.1 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 45-2

Compound 45-1 (200 mg) and Selectfluor (80 mg) were dissolved in methanol (10 mL), heated to 70 °C and stirred overnight, diluted with EA, washed with water, washed with saturated brine, dried and concentrated, and prepared by Prep-TLC to obtain compound 45-2 (100 mg).

ESI-MS m/z: 327.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound A45

Compound 45-2 (100 mg) was dissolved in methanol (3 mL) and THF (3 mL), cooled to 0 °C, sodium borohydride (30 mg) was added, stirred at room temperature for 1 hour, H ₂ O and EA were added, the layers were separated and saturated The organic phase was washed with brine, dried, and concentrated to obtain the crude product. The crude product was prepared by Prep-TLC to obtain the target compound A45.

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 311.1.

Example 10 5-(5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)-2- Synthesis of Fluorobenzonitrile (Compound A47)

Step 1: Synthesis of Compound 47-1

Compound 45-2 (310 mg) and NBS (340 mg) were dissolved in 1,2-dichloroethane (8 mL), AIBN (20 mg) was added, the temperature was raised to 80°C, stirred for 3 hours, and concentrated under reduced pressure to obtain a residue. The medium was diluted with water and EA, the liquid was separated, the organic phase was washed once with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE/EA=19:1 to 13:1) to obtain the target product 47- 1 (320 mg).

ESI-MS m/z: 405/407 [M+H ⁺ ] ⁺ .

Step 2: Synthesis of Compound 47-2

Compound 47-1 (320 mg) was dissolved in ethylene glycol dimethyl ether (4 mL) and water (0.8 mL), silver perchlorate (350 mg) was added, the temperature was raised to 50°C and stirred for 1 hour, diluted with EA, and saturated brine After washing, drying and concentration, the crude product was obtained. The crude product was prepared by Prep-TLC (PE/EA=2:1) to obtain the target product 47-2 (260 mg).

ESI-MS m/z: 343.0 [M+H ⁺ ] ⁺ .

Step 3: Synthesis of Compound 47-3

47-2 (260 mg) was dissolved in dichloromethane (4 mL), cooled to -78 °C, added DAST (0.2 mL), warmed to 0 °C, stirred for 1 hour, diluted with sodium bicarbonate aqueous solution and ethyl acetate, and separated. , the organic phase was washed with saturated brine, dried and concentrated to obtain the crude product, which was prepared by Prep-TLC (PE/EA=2:1) to obtain compound 47-3 (200 mg).

ESI-MS m/z: 345.0 [M+H ⁺ ] ⁺ .

Step 4: Synthesis of Compound A47

Compound 47-3 (130 mg) was dissolved in methanol (1 mL) and THF (1 mL), cooled to 0 °C, sodium borohydride (40 mg) was added, stirred at room temperature for 1 hour, diluted with EA and water, separated, and saturated brine The crude product was washed, dried and concentrated, and the crude product was prepared by Prep-TLC (2:1) to give compound A47 (70 mg).

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 329.

Example 11: (S)-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1 Synthesis of (4H)-yl)benzonitrile (Compound A11)

Compound 24-1 (50 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)] (12mg), stirred overnight at room temperature under nitrogen protection, concentrated, the crude product was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A11 (30mg, >98%ee) .

LC-MS: 344.92 [M ⁺ H ⁺ -H2O] ₊ .

Using substantially similar procedures to Examples 1-11, the examples in Table 1 below were prepared.

Table 1

The ¹ H NMR data of Examples 10, 16, 19, 55, 58 are shown below:

¹ H NMR (500MHz, DMSO) δ 8.30 (dd, J=5.4, 2.9Hz, 1H), 8.13 (s, 1H), 8.06 (ddd, J=9.0, 4.4, 3.0Hz, 1H), 7.80-7.71 (m, 1H), 6.37–6.19 (m, 2H), 5.42–5.21 (m, 1H), 4.96–4.82 (m, 1H). (Example 10)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.35-7.32 (m, 2H), 7.26-7.20 (m, 2H), 5.05 (dd, J=12.6, 4.0 Hz, 1H), 3.53-3.41 (m, 1H) ), 3.27 (td, J=16.0, 4.3 Hz, 1H), 2.36 (s, 1H). (Example 16)

¹ H NMR (500MHz, CDCl ₃ ) δ 7.69-7.64 (m, 1H), 7.62 (d, J=2.6Hz, 1H), 7.49 (dt, J=7.7, 3.9Hz, 1H), 7.25 (s, 1H), 5.10 (dt, J=25.7, 12.9 Hz, 1H), 3.60–3.42 (m, 1H), 3.35–3.25 (m, 1H), 2.47–2.42 (m, 1H). (Example 19)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53-7.46 (m, 2H), 7.28 (td, J=8.2, 1.0 Hz, 1H), 7.23 (dd, J=3.5, 1.2 Hz, 1H), 7.12 ( dd,J＝5.2,1.1Hz,1H),7.06(s,1H),6.98(dd,J＝5.1,3.5Hz,1H),5.10(dd,J＝13.0,6.0Hz,1H),3.47(td , J=15.4, 10.5Hz, 1H), 3.23 (td, J=16.2, 4.1Hz, 1H), 2.32 (dd, J=6.5, 2.2Hz, 1H). (Example 55)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61-7.49 (m, 1H), 7.43-7.35 (m, 1H), 7.26 (d, J=3.7 Hz, 1H), 7.22 (s, 1H), 5.12 ( dd, J＝12.6, 5.2Hz, 1H), 3.48 (td, J＝15.2, 10.5Hz, 1H), 3.27 (td, J＝16.0, 4.2Hz, 1H), 2.42 (dd, J＝5.7, 2.2Hz) , 1H). (Example 58)

Pharmacological experiments

Experimental Example 1 Detection of the compound of the present invention VEGFA ELISA (IC ₅₀ )

The 786-O cells grown in log phase were inoculated into 96-well plates, and the cell concentration was 65,000 cells per milliliter of culture medium, 180ul per well. The compound was diluted to the corresponding concentration, and 20ul of compound solutions of different concentrations were added to the corresponding cell wells, so that the final concentrations of the compounds were (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000, respectively. After culturing for 24 h, the cell culture supernatant was taken, and the VEGFA concentration was determined using an ELISA kit (purchased from _abcam ), and finally the reaction was terminated. At the same time, the cell viability was determined by CellTiter-Glo reagent.

The _IC50 data of the examples are provided in Table 2, wherein A means IC50≤0.5 μM; B means 0.5 μM nM< _IC50≤1.0 μM _; C means _IC50 >1.0 μM.

Table 2

Example number	IC50 (μM)
1	A
2	B
3	A
6	A
9	A
10	B
11	A
15	C
19	A

28	A
45	A
51	A
54	C
55	A
58	A
61	A
64	A

Luciferase assay

The luciferase LUC gene was stably transfected into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2α reporter cells (786-O-HIF2α-Luc cells). Experiments were performed when 786-O-HIF2α-Luc cells were in logarithmic growth phase, the 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 , Wash the cells with culture medium, 10% fetal bovine serum, 1% penicillin, and streptomycin to terminate the digestion. The cells were collected by centrifugation, rinsed twice with PBS, removed the phenol red in the medium, resuspended the cells to an appropriate concentration, detected the cell density and viability, and ensured that the cell viability was above 90% before being used in the experiment.

Use Echo550 (non-contact sonic pipetting system, purchased from Labcyte) to transfer gradient concentrations of compounds into 384 wells, 25nl/well; cells were seeded into 384-well plates, 4500 cells/well, 25μl medium, compound The final concentrations were 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5 nM, respectively. The cells were cultured at 37° C. in a 5% CO ₂ environment for 18-20 h; Steady-Glo ^™ luciferase assay system (purchased from Promega) was added to a 384-well plate, 25 μl/well; the luminescence value was detected by Envision. The % inhibition rate was calculated according to the RLU (Record Luminescence) signal value of each well, and then the IC ₅₀ of the corresponding compound was calculated by Graphpad 8.0 fitting. Exemplary compounds of the present invention have been found to have better _IC50s through experiments.

in vivo PK

Compounds were formulated with 5% DMSO, 5% Solutol and 90% NaCl. The animals were administered with SD rats and Balb/c mice. The intravenous dose was 1 mg/kg, and the orbital blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h; the oral dose was 5 mg. Orbital blood was collected at 15min, 30min, 1h, 2h, 4h, 7h, and 24h. After blood collection, centrifuge at 4000 rpm for 10 min, take the supernatant, add 200 μL of the internal standard solution to 30 μL of the supernatant for precipitation, vortex and shake at 12,000 rpm for 10 min, and take 100 μL of the supernatant solution and purified water to mix and inject at a ratio of 1:1. The concentration of compounds in plasma was detected by high performance liquid chromatography-mass spectrometry, and the concentration of compounds in plasma samples was quantitatively analyzed by internal standard quantification method. After the compound concentration was measured, the related pharmacokinetic parameters including CL, _Cmax , AUC were calculated by Winnonln software. Exemplary compounds of the present invention were found to have better in vivo PK properties through experiments.

Claims (32)

1. A compound represented by formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

   

   in,

   L is a bond, -O-, NH-, -CR _{d Re} -, -S-, -S(=O)-, -S(=O) ₂ -, -C=C- or -C≡C- ;

   X ₁ and X ₂ are each independently selected from C or N;

   X ₃ is CR ₈ or NR ₈ ;

   X ₄ is CR ₇ or NR ₇ ;

   and at least one of X ₁ , X ₂ and X ₄ is N;

   R ₁ is selected from C ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkenyl group, C ₂ -C ₁₀ alkynyl group, C ₁ -C ₁₀ alkoxy group, C ₆ -C ₁₀ aryl group, 5-18-membered hetero group Aryl, C ₃ -C ₁₀ cycloalkyl, 3-10-membered heterocyclic group; wherein, the 5-18-membered heteroaryl and 3-10-membered heterocyclic group optionally contain 1, 2 or 3 respectively independently Heteroatoms selected from N, O and S; the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkoxy, C ₆ - C ₁₀ aryl, 5-18 membered heteroaryl, C ₃ -C ₁₀ membered cycloalkyl and 3-10 membered heterocyclyl may be optionally replaced by one or more of H, halogen, hydroxy, cyano, oxo , amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₃ -C ₅ cycloalkyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ C ₆ haloalkoxy, -C ₁ -C ₆ alkylene-OR _c , -C ₁ -C ₆ alkylene-C=OR _c , -NO ₂ , -SR _c , -NR _a R _b , -C(=O)R _c , -C(=O)OR _c , -OC(=O)R _c , -C(=O)NR _a R _b , -NC(=O)R _c , -S(=O)R _c , -S(=O) ₂ R _c , -S(=O) ₂ NR _a R _b , -S(=O)(=NR _a )R _b , -P(=O ) R _a R _b and/or -P(=S) R _a R _b replaced;

   R ₂ is selected from H, -OH, amino, C ₁ -C ₁₀ alkoxy, -OC(=O)-C _1-3 alkyl-NR _a R _b , deuterium, halogen, -CN, =N-OH , C ₁ -C ₅ haloalkyl or -C(=O)-OC _1-3 alkyl;

   R ₃ is selected from H, -OH, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, -OC(=O)-C _1-3 alkyl, deuterium, halogen, -CN, =N-OH, -C(=O)-OC _1-3 alkyl, -OC(=O)-C _{1- 3} haloalkyl or -C(=O)-OC _1-3 haloalkyl, wherein the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ alkoxy, -OC(=O)-C _1-3 alkyl, -C(=O)-OC _1-3 alkyl, -C(=O)-OC _{1 -3} alkyl, -OC(=O)-C _1-3 haloalkyl and -C(=O)-OC _1-3 haloalkyl may be optionally replaced by one or more of H, halogen, -CN, -OH , amino, C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl;

   Or R ₂ and R ₃ together form an oxo group on the C atom to which it is attached;

   R ₄ and R ₅ are each independently selected from H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl; wherein, the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 independently selected from Heteroatoms of N, O and S; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkyne radicals, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl may be optionally replaced by one or more of H, halogen, -CN, -OH, oxo, amino, C ₁ -C ₅ alkyl , C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted; or R ₄ and R ₅ together with the C atom to which they are attached together form substituted or unsubstituted C ₃ -C ₄ cycloalkyl or C ₃ -C ₅ heterocyclyl;

   R ₆ is selected from H, -CN, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ - C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl, 3-6 membered heterocyclyl, -NO ₂ , -NH ₂ or oxo; wherein, the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₁₀ Alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₅ cycloalkyl and 3-6 membered heterocyclyl may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, oxo substituted with C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl; or both

   R ₆ together with the C atom to which it is attached forms a substituted or unsubstituted C ₃ -C ₅ cycloalkyl or 3-5 membered heterocyclyl;

   Or R ₆ and R ₅ together with the C atom to which they are attached together form a substituted or unsubstituted C ₃ -C ₄ cycloalkyl or 3-5 membered heterocyclic group;

   R _d and R _e are each independently selected from H, halogen, cyano, -NR _a R _b , C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl; or R _d and R _e are taken together at their attachment An oxo group is formed on the C atom of ;

   R ₇ is selected from H, -NO ₂ , -CN, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ - C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR _c , -SR _c , -NR _a R _b , -C(=O) R _c , -C(=O)OR _c , -OC(=O)R _c , -C(=O)NR _a R _b , -NC(=O) R _c , -S(=O) R _c , -S(=O) ₂ R _c , -S(=O) ₂ NR _a R _b , -S(=O)(=NR _a )R _b , -P(=O)R _a R _b , -P( =S) R _a R _b or -C ₁ -C ₆ alkylene-OR _c ; wherein, the 5-10-membered heteroaryl group and the 3-10-membered heterocyclic group optionally contain 1, 2 or 3 respectively Heteroatoms independently selected from N, O and S; the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl, C ₃ - _C10 cycloalkyl, 3-10 membered heterocyclyl, _C6 - _C10 membered heteroaryl, and 5-10 membered heteroaryl may be optionally replaced by one or more of H, halogen, hydroxy, cyano, oxo , amino, C ₁ -C ₆ alkyl, C _1-6 alkoxy, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₅ cycloalkane base, 3-6 membered heterocyclic group, P(=O)Me ₂ , P(=S)Me ₂ , -S(=O) ₂ -C ₁₃ alkyl, -S(=O) ₂ -C _{3- 5} -cycloalkyl, -S(=O)-C _1-3 alkyl, -S(=O)-C _3-5 cycloalkyl, -S(=O)-C _1-3 haloalkyl or -S (=O) ₂ -C _1-3 haloalkyl substituted;

   R ₈ is selected from absent, H, -CN, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, oxo and -NR _a R _b ; The C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl and C ₃ -C ₁₀ cycloalkyl groups may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted;

   R _a , R _b and R _c are each independently selected from H, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ haloalkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ - C ₁₀ -membered cycloalkyl, 3-10-membered heterocyclic group, C ₆ -C ₁₀ -membered aryl group or 5-10-membered heteroaryl group; wherein, the 3-10-membered heterocyclic group and 5-10-membered heteroaryl group are any contains 1, 2 or 3 heteroatoms independently selected from N, O and S;

   m is 0, 1 or 2.
2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein: The L is a bond, -CH ₂ -, -S(=O) ₂ -, -C=C-, -C=O-, -C≡C- or C ₃ -C ₅ cycloalkyl.
3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that In that, the L is a bond or -CR _{d Re} -.
4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, said R ₄ and R ₅ are independently H, halogen or C ₁ -C ₆ alkyl, wherein, said C ₁ -C ₆ alkyl can be optionally replaced by one or more H, halogen , -CN, -OH, amino or oxo substituted.
5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that said R ₄ and R ₅ are each independently H or halogen.
6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, the R ₂ is halogen, -CN or -OH.
7. The compound of any one of claims 1-6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, the R ₂ is -OH.
8. The compound of any one of claims 1-7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that R ₃ is H, deuterium, C ₁ -C ₃ alkyl group or C ₂ -C ₅ alkenyl group, wherein, the C ₁ -C ₃ alkyl group and C ₂ -C ₅ alkenyl group can be optionally Substituted with one or more H, halogen, -CN, -OH, amino, _C1 - _C5 haloalkyl.
9. The compound of any one of claims 1-8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that R ₃ is H, deuterium or C ₁ -C ₃ alkyl, or said R ₂ and R ₃ together form an oxo group on the C atom to which it is attached.
10. The compound of any one of claims 1-9, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, R ₁ is a C ₆ -C ₈ aryl group or a 5-8-membered heteroaryl group, and the 5-8-membered heteroaryl group optionally contains 1, 2 or 3 independently selected from N, O and A heteroatom of S, wherein the C ₆ -C ₈ aryl and 5-8 membered heteroaryl may be optionally replaced by one or more halogen, -OH, -CN, oxo, amino, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene-OR _c , -C ₀ -C ₆ alkylene-C=OR _c , _-NO2 , -C(=O) _ORc or -S(=O _{) 2Rc} .
11. The compound of any one of claims 1-10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, said R ₁ is phenyl or 5-6-membered heteroaryl; wherein, said 5-6-membered heteroaryl optionally contains a heteroatom selected from N, O and S, and said phenyl and 5-6 membered heteroaryl can be optionally replaced by one or more halogen, -OH, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene-OR _c or -CN substituted.
12. The compound of any one of claims 1-11, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, said R ₁ is phenyl or 5-6-membered heteroaryl, wherein, said 5-6-membered heteroaryl optionally contains 1, 2 or 3 independently selected from N, O and S. The heteroatoms of the phenyl and 5-6 membered heteroaryl groups may be optionally substituted with one or more halogen, cyano or C ₁ -C ₆ haloalkyl groups.
13. The compound of any one of claims 1-12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, the R ₁ is phenyl or pyridyl, and the phenyl and pyridyl can be optionally replaced by one or more halogens, -OH, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene -OR _c or -CN substituted.
14. The compound of any one of claims 1-13, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterised in that the R ₆ is H, -CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl, wherein the C ₁ -C ₆ Alkyl, _{C1 - C6alkoxy} or _C1 -C6haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo or amino.
15. The compound of any one of claims 1-14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that said R ₆ is H, halogen or C ₁ -C ₆ alkyl.
16. The compound of any one of claims 1-15, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, the R ₈ is H, -CN, -NH ₂ , halogen, C ₁ -C ₃ alkyl or cyclopropyl.
17. The compound of any one of claims 1-16, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, said R ₈ is H or halogen.
18. A compound according to any one of claims 1-17, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, the R ₇ is selected from H, -CN, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -S(=O)R _c , -C ₁ -C ₆ alkylene-OR _c , -S(=O) ₂ R _c and P( =O) R _a R _b ; wherein, the 5-10-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C ₁ -C ₁₀ alkane radicals, C ₂ -C ₁₀ alkenyl, C ₁ -C ₁₀ haloalkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl may be optionally replaced by one or more halogen, hydroxyl, P(=O)Me ₂ , P(=S)Me ₂ , -S(=O) ₂ -C _1-3 alkyl, -S(=O) ₂ -C _3-5 cycloalkane base, -S(=O)-C _1-3 alkyl, -S(=O)-C _1-3 haloalkyl, -S(=O)-C _3-5 cycloalkyl, cyano, C ₁ -C ₆ alkyl and/or C ₁ -C ₆ haloalkyl.
19. The compound of any one of claims 1-18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, It is characterized in that, said R ₇ is selected from C ₁ -C ₆ haloalkyl, cyano, -S(=O) ₂ R _c , -P(=O)Me ₂ or 5-membered heteroaryl, wherein said 5-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S _; -C ₃ alkyl or C ₁ -C ₃ haloalkyl substituted.
20. The compound according to claims 1-19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that In that, the R ₇ is selected from C ₁ -C ₆ haloalkyl, -S(=O) ₂ R _c or 5-membered heteroaryl, wherein the 5-membered heteroaryl optionally contains 1, 2 or 3 Heteroatoms independently selected from N, O, and S; the 5-membered heteroaryl may be optionally substituted by one or more H, halogen, _{C1 -} C3 alkyl or _{C1 -} C3 haloalkyl replace.
21. The compound of claims 1-20, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that In that, the R _a and R _b are each independently H or C ₁ -C ₆ alkyl.
22. The compound of claims 1-21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein In that, the R _c is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.
23. The compound according to claims 1-22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, characterized in that In that, the compound is represented by formula (II-1), formula (II-2) or formula (II-3),

    
24. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein: The compound is selected from:

    1) 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1-yl]-2-fluorobenzonitrile;

    2) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopento[b]pyrrole-3-carbonitrile;

    3) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    4) 2-Chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)- base) benzonitrile;

    5) 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    6) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) benzonitrile;

    7) 2-Chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    8) 2-Chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl ) benzonitrile;

    9) 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile ;

    10) 5-(5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro benzonitrile;

    11) (S)-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H) )-yl)benzonitrile;

    12) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)phthalate Nitrile;

    13) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro benzonitrile;

    14) 2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    15) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-4(1H) -ketone;

    16) 3-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    17) 3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluoro benzonitrile

    18) 5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalic acid Nitrile;

    19) 2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    20) 2-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluoro benzonitrile

    21) 5-Chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    22) 1-(4-Chloro-2-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

    23) 1-(4-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

    24) 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

    25) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)benzonitrile;

    26) 5-(5,5-Difluoro-4-hydroxy-3-(thiazol-4-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalene formonitrile;

    27) 3-(5,5-Difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5- Fluorobenzonitrile;

    28) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

    29) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[b]pyrrol-1(4H)-yl)benzonitrile;

    30) 1-(3-Chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[ b] pyrrol-4-ol;

    31) 5-(5,5-Difluoro-4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl) isophthalonitrile;

    32) 2-Chloro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile ;

    33) 2-Chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    34) 2-Chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)- base) benzonitrile;

    35) 5-(3-Chloro-5-fluorophenyl)-2,2-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

    36) 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    37) 1-(6-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    38) 1-(5-chloropyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    39) 1-(5-Aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    40) 5,5-Difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-4 -alcohol;

    41) 5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro - Cyanopyridine;

    42) 1-(5-Chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

    43) 1-(3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)- 5-Fluorophenyl)ethyl-1-one;

    44) 4-(5,5-Difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl )-2-hydroxybenzonitrile;

    45) 2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl- 4-deuterium) benzonitrile;

    46) 3-5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorocyanide benzene;

    47) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole -4-ol;

    48) 5-(3-Chloro-5-fluorophenyl)-2,3-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

    49) 3-(3-Chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-pyrrole[1,2-c]imidazole -7-ol;

    50) 5-(3-chloro-5-fluorophenyl)-2-fluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolizin-1-ol;

    51) (S)-2-Fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentoyl[b]pyrrole-1( 4H)-yl)benzonitrile;

    52) 5,5-Difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b ] pyrrol-4-ol;

    53) 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

    54) 5-(5,5-Difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl)-2 - Fluorobenzonitrile;

    55) 5-(5,5-Difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl)-2 - Fluorobenzonitrile;

    56) 4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-methyl oxybenzonitrile;

    57) 5,5-Difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole -4-ol;

    58) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[b]pyrrol-1(4H)-yl )-2-fluorobenzonitrile;

    59) (S)-5,5-difluoro-1-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro Cyclopenta[b]pyrrol-4-ol;

    60) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -3-(difluoromethyl)-2-fluorobenzonitrile;

    61) (S)-4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -2-(difluoromethyl)benzonitrile;

    62) (S)-1-(3-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole- 4-alcohol;

    63) (S)-3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) benzonitrile;

    64) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetra Hydrocyclopenta[b]pyrrol-4-ol;

    65) (S)-5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro Cyclopenta[b]pyrrol-4-ol; or

    66) (S)-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl) -2,3-Difluorobenzonitrile;

    67) 5-((4S,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

    68) 5-((4S,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile

    69) 5-((4S,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

    70) 5-((4S,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

    71) 5-((4R,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

    72) 5-((4R,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile;

    73) 5-((4R,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile; or

    74) 5-((4R,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrole-1( 4H)-yl)-2-fluorobenzonitrile.
25. A pharmaceutical composition, characterized in that it comprises at least one therapeutically effective amount of the compound described in any one of claims 1-24 or its stereoisomer, tautomer, pharmaceutically acceptable salt, pro- drug, chelate, non-covalent complex or solvate and at least one pharmaceutically acceptable excipient.
26. A compound according to any one of claims 1-24 or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof Or the use of the pharmaceutical composition of claim 25 in the preparation of a medicament for treating, delaying or preventing a disease mediated by HIF-2α.
27. The use according to claim 26, wherein the disease mediated by HIF-2α is VHL syndrome, autoimmune disease, metabolic disease, inflammatory disease and/or cancer.
28. The use according to claim 27, wherein the cancer is selected from hematological cancers and solid tumors.
29. The use according to claim 28, wherein the cancer is selected from the group consisting of glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningeal cancer, neurocytoma, glioblastoma, meningioma and medulloblastoma.
30. A method for treating and/or preventing a disease mediated by HIF-2α, characterized in that a therapeutically effective amount of the compound according to any one of claims 1-24 or a stereoisomer, a mutual Variant, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate or the pharmaceutical composition of claim 25.
31. The method of claim 30, wherein the HIF-2α mediated disease VHL syndrome, autoimmune disease, metabolic disease, inflammatory disease or cancer.
32. The method of claim 31, wherein the cancer is selected from the group consisting of glioma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, Kidney cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningeal cancer, neurocytoma, glioblastoma, meningioma and medulloblastoma.