TW202220955A - 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, pharmaceutical compositions containing the same and uses thereof

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

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, of 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, It then activates the hypoxia response element (HRE), regulates the up-regulation of downstream cancer-related genes such as VEGFA, CXCR4, Cyclin D1, etc., and promotes tumor angiogenesis; 2. HIF-2α also participates in the transmission 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 initiation 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), 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 enables the continuous activation of HIF-2α.

The activation of HIF-2α and the formation of heterodimers of HIF-1β are the key factors leading to downstream initiation, 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.

式 （I） 其中， L為鍵、-O-、NH-、-CR _dR _e-、-S-、-S(=O)-、-S(=O) ₂-、-C=C-或-C≡C-； X ₁和X ₂分別獨立地選自C或N； X ₃為CR ₈或NR ₈； X ₄為CR ₇或NR ₇； 且X ₁、X ₂和X ₄至少有一個為N； R ₁選自C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀烷氧基、C ₆-C ₁₀芳基、5-18員雜芳基、C ₃-C ₁₀環烷基、3-10員雜環基；其中，所述5-18員雜芳基和3-10員雜環基任意地含有1、2或3個分別獨立地選自N、O和S的雜原子；所述C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀烷氧基、C ₆-C ₁₀芳基、5-18員雜芳基、C ₃-C ₁₀環烷基和3-10員雜環基可任選地被一個或多個H、鹵素、羥基、氰基、氧代基、氨基、C ₁-C ₆烷基、C ₁-C ₆烷氧基、C ₂-C ₆烯基、C ₃-C ₅環烷基、C ₂-C ₆炔基、C ₁-C ₆鹵代烷基、C ₁-C ₆鹵代烷氧基、-C ₁-C ₆亞烷基-OR _c、-C ₁-C ₆亞烷基-C=O-R _c、-NO ₂、-SR _c、-NR _aR _b、-C(=O)R _c、-OC(=O)R _c、-C(=O)OR _c、-C(=O)NR _aR _b、-NC(=O)R _c、-S(=O)R _c、-S(=O) ₂R _c、-S(=O) ₂NR _aR _b、-S(=O)(=NR _a)R _b、-P(=O)R _aR _b或-P(=S)R _aR _b所取代； R ₂選自H、-OH、氨基、C ₁-C ₁₀烷氧基、-O-C(=O)-C _1-3烷基、-NR _aR _b、氘、鹵素、-CN、=N-OH、C ₁-C ₅鹵代烷基或-C(=O)-O-C _1-3烷基； R ₃選自H、-OH、C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀烷氧基、C ₁-C ₁₀鹵代烷基、-O-C(=O)-C _1-3烷基、氘、鹵素、-CN、=N-OH、-C(=O)-O-C _1-3烷基、-O-C(=O)-C _1-3鹵代烷基或-C(=O)-O-C _1-3鹵代烷基，其中，所述C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀鹵代烷基、C ₁-C ₁₀烷氧基、-C(=O)-O-C _1-3烷基、-C(=O)-O-C _1-3烷基、-O-C(=O)-C _1-3鹵代烷基和-C(=O)-O-C _1-3鹵代烷基可任選地被一個或多個H、鹵素、-CN、-OH、氨基、C ₁-C ₅烷基、C ₂-C ₆烯基或C ₁-C ₅鹵代烷基所取代；或 R ₂和R ₃一起在其連接的C原子上形成氧代基； R ₄和R ₅分別獨立地選自H、鹵素、-OH、C ₁-C ₆烷基、C ₁-C ₆烷氧基、C ₁-C ₆鹵代烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₃-C ₅環烷基和3-6員雜環基；其中，所述3-6員雜環基任意地含有1、2或3個分別獨立地選自N、O和S的雜原子；所述C ₁-C ₆烷基、C ₁-C ₆烷氧基、C ₁-C ₆鹵代烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₃-C ₅環烷基和3-6員雜環基可任選地被一個或多個H、鹵素、-CN、-OH、氧代基、氨基、C ₁-C ₅烷基、C ₂-C ₆烯基或C ₁-C ₅鹵代烷基所取代；或R ₄和R ₅與連同其所連接的C原子共同形取代或未被取代的C ₃-C ₄環烷基或C ₃-C ₅雜環基； R ₆選自H、-CN、鹵素、-OH、C ₁-C ₆烷基、C ₁-C ₆烷氧基、C ₁-C ₆鹵代烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₃-C ₅環烷基、3-6員雜環基、-NO ₂、-NH ₂或氧代基；其中，所述3-6員雜環基任意地含有1、2或3個分別獨立地選自N、O和S的雜原子；所述C ₁-C ₆烷基、C ₁-C ₆烷氧基、C ₁-C ₆鹵代烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₃-C ₅環烷基和3-6員雜環基可任選地被一個或多個H、鹵素、-CN、-OH、氨基、氧代基、C ₁-C ₅烷基、C ₂-C ₆烯基或C ₁-C ₅鹵代烷基所取代；或兩個R ₆連同其所連接的C原子共同形成取代或未取代的C ₃-C ₅環烷基或3-5員雜環基；或 R ₆與R ₅連同其所連接的C原子共同形成取代或未取代的C ₃-C ₄環烷基或3-5員雜環基； R _d和R _e分別獨立地選自H、鹵素、氰基、-NR _aR _b、C ₁-C ₁₀烷基或C ₃-C ₁₀環烷基；或R _d和R _e一起在其連接的C原子上形成氧代基； R ₇選自H、-NO ₂、-CN、鹵素、C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀鹵代烷基、C ₃-C ₁₀環烷基、3-10員雜環基、C ₆-C ₁₀芳基、5-10員雜芳基、-OR _c、-SR _c、-NR _aR _b、-C(=O)R _c、-C(=O)OR _c、-C(=O)NR _aR _b、-NC(=O)R _c、-S(=O)R _c、-S(=O) ₂R _c、-S(=O) ₂NR _aR _b、-S(=O)(=NR _a)R _b、-P(=O)R _aR _b、-P(=S)R _aR _b、-OC(=O)R _c或-C ₁-C ₆亞烷基-OR _c；其中，所述5-10員雜芳基和3-10員雜環基任意地含有1、2或3個分別獨立地選自N、O和S的雜原子；所述C ₁-C ₁₀烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₁-C ₁₀鹵代烷基、C ₃-C ₁₀環烷基、3-10員雜環基、C ₆-C ₁₀芳基和5-10員雜芳基可任選地被一個或多個H、鹵素、羥基、氰基、氧代基、氨基、C ₁-C ₆烷基、C _1-6烷氧基、C ₁-C ₆鹵代烷基、C ₂-C ₆烯基、C ₂-C ₆炔基、C ₃-C ₅環烷基、3-6員雜環基、P(=O)Me ₂、P(=S)Me ₂、-S(=O) ₂-C _1-3烷基、-S(=O) ₂-C _3-5環烷基、-S(=O)-C _1-3烷基、-S(=O)-C _3-5環烷基、-S(=O) ₂-C _1-3鹵代烷基或-S(=O)-C _1-3鹵代烷基所取代； R ₈選自不存在、H、-CN、鹵素、C ₁-C ₁₀烷基、C ₁-C ₁₀鹵代烷基、C ₃-C ₁₀環烷基、氧代基和-NR _aR _b；所述C ₁-C ₁₀烷基、C ₁-C ₁₀鹵代烷基和C ₃-C ₁₀環烷基可任選地被一個或多個H、鹵素、-CN、-OH、氨基、C ₁-C ₅烷基、C ₂-C ₆烯基或C ₁-C ₅鹵代烷基所取代； R _a、R _b和R _c分別獨立地選自H、C ₁-C ₁₀烷基、C ₁-C ₁₀鹵代烷基、C ₂-C ₁₀烯基、C ₂-C ₁₀炔基、C ₃-C ₁₀環烷基、3-10員雜環基、C ₆-C ₁₀芳基或5-10員雜芳基；其中，所述3-10員雜環基、5-10員雜芳基任意地含有1、2或3個分別獨立地選自N、O和S的雜原子； m為0、1或2。 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,

Formula (I) wherein, L is a bond, -O-, NH-, -CR _d R _e -, -S-, -S(=O)-, -S(=O) ₂ -, -C=C- or -C≡C-; X ₁ and X ₂ are independently selected from C or N; X ₃ is CR ₈ or NR ₈ ; X ₄ is CR ₇ or NR ₇ ; and X ₁ , X ₂ and X ₄ at least have One is N; R ₁ is selected from 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, 3-10-membered heterocyclyl; wherein, the 5-18-membered heteroaryl and 3-10-membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkenyl group, C ₂ -C ₁₀ alkynyl group, C ₁ -C ₁₀ alkoxy group , C ₆ -C ₁₀ aryl, 5-18 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl and 3-10 membered heterocyclyl may be optionally replaced by one or more H, halogen, hydroxyl, 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 , _-NRaRb ,-C(=O) _Rc ,-OC(=O) _Rc ,-C(=O) _ORc ,-C( ₌ O _{) NRaRb} ,-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 substituted; 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 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 haloalkane group or -C(=O)-OC _1-3 haloalkyl, wherein the C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkene base, 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, 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 N, Heteroatoms of 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, 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 group; wherein, the 3-6 membered heterocyclic group The cyclic group 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 haloalkanes group, 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, 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 form a substitution 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 heterocyclyl; 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 _Re together form an oxo group on the C atom to which it is attached; 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 membered aryl, 5-10 membered heterocyclic Aryl, _-ORc , _-SRc , _-NRaRb ,-C(=O) _Rc ,-C(=O) _ORc ,-C( ₌ O _{) NRaRb} ,-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 and 3-10-membered heterocyclyl optionally contain 1, 2 or 3 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 -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ membered aryl and 5-10 membered heterocyclyl Aryl can be optionally replaced by one or more of H, halogen, hydroxy, cyano, oxo, amino, _C1 - _C6 alkyl, _C1-6 alkoxy, _C1 - _C6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₅ cycloalkyl, 3-6 membered heterocyclyl, 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 absence, 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 can be optionally replaced by one or more of H, halogen, -CN, -OH, amino, C ₁ -C ₅ alkyl, C ₂ -C ₆ alkene R _a , R _b and R _c are 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 cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10-membered heteroaryl; wherein, the 3-10-membered heterocyclic group and 5-10-membered heteroaryl optionally contain 1, 2 or 3 independently selected from N, O and S. Heteroatom; 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 _{- C5} cycloalkyl.

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, R ₃ 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 atoms independently selected from N , O and S heteroatoms.

In some embodiments, the R ₁ is phenyl or 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 members independently selected from N, O and S heteroatoms; 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 Replaced by =OR _c , -NO ₂ , -C(=O)OR _c or -S(=O) ₂ R _c .

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 may 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 C ₃ -C ₆ cycloalkyl, 5-membered heteroaryl may be optionally replaced by H, halogen, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ 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 independent 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; the ₅ -membered heteroaryl group may be optionally 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 a 5-membered heteroaryl, the 5-membered heteroaryl 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.

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 In some embodiments, the R ₇ is selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

、

、

、

、、

、

、

、

、

或

。 In some embodiments, the R ₇ is selected from

,

,

,

,,

,

,

,

,

or

.

式（II-1）                式（II-2）                    式（II-3）  ； 所述R ₁，R ₂，R ₃，R ₄，R ₅，R ₆，R ₇，R ₈，L和m如前述實施方式所述。 In some embodiments, the compound is represented by formula (II-1), formula (II-2) or formula (II-3),

Formula (II-1) Formula (II-2) 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 above described in the embodiment.

式（III-1）                   式（III-2）              式（III-3）； 所述R ₁，R ₆，R ₇，R ₈和m如前述實施方式所述。 In some embodiments, the compound is represented by formula (III-1), formula (III-2) or formula (III-3),

Formula (III-1) Formula (III-2) 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-Dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 4) 2-chloro-5-(2,5,5-trifluoro-4-hydroxy-3 -(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 5) 1-(3,5-difluorobenzyl)-5 ,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 6) 2-chloro-5-(5,5- Difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 7) 2-chloro-5 -(3-(Difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 8) 2-Chloro-5-(3-(dimethylphosphoronyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl ) benzonitrile; 9) 2-fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H ) -yl)benzonitrile; 10) 5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1( 4H) )-yl)-2-fluorobenzonitrile; 11) ( S )-2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-difluoromethyl) Hydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 12) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6- Dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)phthalonitrile; 13) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5 ,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 14) 2-chloro-4-(5,5-difluoro-4-hydroxy-3 -(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 15) 1-(3-chloro-5-fluorophenyl)- 5,5-Difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-4( 1H )-one; 16) 3-chloro-5-(5,5 -Difluoro-4-hydroxy-3-(trifluoromethyl) yl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 17) 3-(5,5-difluoro-4-hydroxy-3-(trifluoro) Methyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzonitrile 18)5-(5,5-difluoro-4-hydroxy-3 -(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)isophthalonitrile; 19) 2-chloro-5-(5,5-dicarbonitrile) Fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 20) 2-(5,5- Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzonitrile 21)5-chloro -2-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ 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-ol; 23) 1-(4-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrole- 4-ol; 24) 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrole- 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-dihydrocyclopento[ b ]pyrrole-1( 4H ) -yl)isophthalonitrile; 27) 3-(5,5-difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-5-fluorobenzonitrile; 28) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4 ,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 29) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydro Cyclopenta[ 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-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)isophthalonitrile; 32) 2-chloro-5-( 5-Fluoro-4-hydroxy-3-(trifluoromethyl)-5,6 -dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 33) 2-chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl) )-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 34) 2-chloro-5-(5,5,6-trifluoro-4-hydroxy- 3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)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 ]pyrrol-4-ol; 37) 1-(6-chloropyridin-3-yl )-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 38) 1-(5-chloropyridine- 2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 39) 1-(5- Aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 40) 5, 5-Difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 41 ) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluoro -cyanopyridine; 42) 1-(5-Chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 43) 1-(3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole- 1( 4H )-yl)-5-fluorophenyl)ethyl-1-one; 44) 4-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl) )-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-hydroxybenzonitrile; 45) 2-chloro-4-(5,5-difluoro-4- Hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H )-yl-4-deutero)benzonitrile; 46) 3-5,6-di Fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluorocyanobenzene; 47) 1-(3 -Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ c ]pyrazol-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 ]imidazol-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-hydroxyl) -3-(trifluoromethyl)-5,6-dihydrocyclopentanoyl[ b ]pyrrol-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-tetrahydrocyclopento[ b ]pyrrol-4-ol; 54) 5-(5 ,5-Difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopentanoyl[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile 55) 5-(5,5-Difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopentanoyl[ b ]pyrrol-1( 4H )-yl) -2-Fluorobenzonitrile; 56) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1(4 H )-yl)-2-methoxybenzonitrile; 57) 5,5-difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1 ,4,5,6-tetrahydrocyclopento[ b ]pyrrol-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-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 60)( S )-5 -(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-3-(difluoro Methyl)-2-fluorobenzonitrile; 61) ( S )-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-(difluoromethyl)benzonitrile; 62)( S )-1-(3-chlorophenyl)-5,5-difluoro-3- (Trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 63)( S )-3-(5,5-difluoro-4-hydroxy-3 -(Trifluoromethyl)-5,6-dihydrocyclopentane [ b ]pyrrol-1( 4H )-yl)benzonitrile; 64)( S )-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro- 3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 65)( S )-5,5-difluoro-1-(4-fluoro -3-(Fluoromethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 66)( S )-5 -(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2,3-di Fluorobenzonitrile; 67) 5-((4 S ,5 S ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentane [ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 68)5-(( 4S , 5S , 6S )-(5,6-difluoro-4-hydroxy- 3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile 69)5-(( 4S , 5R , 6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2- Fluorobenzonitrile; 70) 5-((4 S ,5 R ,6 S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentane [ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 71) 5-(( 4R , 5R , 6S )-(5,6-difluoro-4-hydroxy- 3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 72)5-(( 4R , 5S , 6S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2 -Fluorobenzonitrile; 73) 5-((4 R ,5 R ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocycle Pento [ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; or 74)5-(( 4R ,5S, 6R )-(5,6-difluoro-4- Hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-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-covalent complex thereof Or solvates and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose. In some compositions, the weight of the compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate with the excipient The ratio is about 0.001 to 10.

In addition, the present invention also provides a method of treating a subject suffering from a disease or disorder mediated by HIF-2α, comprising administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer thereof body, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate.

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), transplantation Acute rejection of 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 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), nerve Tumors or cancers of the 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 manufacture of a therapeutic Use in the medicament of a disease or disorder mediated by HIF-2α.

The present invention also provides the compound represented by formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate for use in therapy . Further provided are compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or stereoisomers, tautomers, pharmaceutically acceptable salts, Chelates, non-covalent complexes or solvates. In the present invention, unless otherwise specified, 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 terylene or terpenyl or N-oxide group group.

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

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. The "3-10-membered" in the 3-10-membered heteroaryl group refers to a heteroaryl group containing 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 consisting of 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 pyridine, morpholine, etc. . In some embodiments, heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, pyridinyl, morpholinyl, azepan, 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 procedures 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 a person 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 compound 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) has tautomers, unless otherwise stated, the present invention includes any possible tautomers 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-Ethylpyridine, Reduced Glucosamine, Glucosamine, Histidine, Haramine, Isopropylamine, Lysine, methylglucamine, morpholine, oxazine, quagidine, 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, for example, at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight Compare).

The pharmaceutical composition provided by the present invention includes the 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 excipients . 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 the conventional drug mixing technology, the compound represented by formula (I) of the present invention, or the prodrug, or the metabolite, or the pharmaceutically acceptable salt, can be used as the active component, mixed with a drug carrier to form a drug 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 represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by means of controlled release and/or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of 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, coloring agents, etc. can be used in oral liquid preparations such as suspensions, elixirs and solutions; Crystalline 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 the active ingredient in a free-flowing form such as powder or granules with a binder, lubricant, inert diluent, surface active or dispersing agent, by compression in a suitable machine. 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 about 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 microbial contamination such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyvalent alcohol (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 preparations 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 wt % to 10 wt % 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 forms are admixtures 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, 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, for the treatment of the conditions or disorders indicated above, the dosage level of the drug is about 0.01 mg/kg to 150 mg/kg of body weight per day, or 0.5 mg to 7 g per patient per day. 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 drug use, and treatment received. the severity of the particular disease.

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 : dimethylsulfoxide; 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-bromobutane Diimide; NFSI: N-fluorobisbenzenesulfonamide; NIS: N-iodobutanediimide; Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium; Pd(PPh ₃ ) ₄ : Tetrakis(triphenylphosphine)palladium; Pd(dppf)Cl2: [1,1' _- bis(diphenylphosphino)ferrocene]dichloropalladium(II); Prep-TLC: Preparation 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: 1H NMR [(R,R)-Ts-DPEN]RuCl(p- cymene)] : Chlorine {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amine}(P-isopropyltoluene)ruthenium(II ).

Synthesis of Intermediate M 1 (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 an 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 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 ice bath, and after stirring at room temperature for 1 hour, added in batches M1-1 (68 g). The reaction solution was further stirred for 3 hours, poured into a mixture of ice water (1000 mL), extracted with EA (1000 mL*3), washed with saturated brine (1000 mL*2), dried over Na ₂ SO ₄ and concentrated to obtain crude Product M1-2 (95 g). The crude product was used directly in the next step.

ESI-MS m/z: 276.05[M- t -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 ₂ atmosphere, the reaction solution was filtered and concentrated to obtain The target compound M1-3 (95 g) was used directly in the next step.

ESI-MS m/z: 278.06[M- t -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 ice bath, and stirred for 2 hours. The reaction solution was concentrated to dryness to obtain the target compound M1-4 (80g), used directly in the next step.

Step 5: Synthesis of Compounds M1-5

Under ice bath, oxalic 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, AlCl ₃ (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 Dry over _SO4 , filter, concentrate, and the crude product was purified by column chromatography (EA/PE=1:5) to give 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, triisopropylchlorosilane (28.5 g) was added , the reaction mixture was stirred at 0 °C for 3 hours. The reaction solution was poured into ice-water (500 mL) mixture, 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. Column chromatography (EA/PE=1:10) was purified 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 a mixture of ice and water (500 mL), extracted with EA (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 filtered through a 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 LiHMDS tetrahydrofuran solution (1.0 M, 17.5 mL) was slowly added dropwise. 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 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 the 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

Dissolve ethyl 4,4,4-trifluoro-3-oxobutyrate (50 g) in AcOH (80 mL), cool in an ice-water bath, and add dropwise sodium nitrite (19 g) in water below 10 °C (50 mL) solution was added and warmed to room temperature. 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

Dissolve cyclopentanedione (21 g) in acetic acid (125 mL), heat it to 60 °C, then add a solution of M2-1 in water (65 mL), stir at 60 °C for 10 minutes after the addition, and then add zinc powder in batches (28 g), stirred at 60 °C for 0.5 hours after adding, then heated to 90 °C and reacted overnight, concentrated, diluted with EA, adjusted to pH 8 with saturated sodium bicarbonate, filtered, separated, the aqueous phase was extracted twice with EA, and combined The organic phase was dried, concentrated, and purified by column chromatography to obtain the target compound M2 (12 g).

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 fluorosulfonyl difluoroacetate were added (71 mg), stirred at 100 °C overnight, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to obtain crude product, which was 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, stirred at room temperature for 3 hours, quenched by adding saturated ammonium chloride solution, 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=1:5) 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, and the mixture was stirred at 120 °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. The crude product 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 ]pyrrole-1( 4H )- base) 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), 70°C It was stirred overnight and concentrated to obtain a residue, which 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 starting material disappeared, and methyl iodide (100 mg) was added, and the It was stirred at a temperature for 5 hours, quenched with saturated ammonium chloride, extracted with EA, and concentrated to obtain the crude product. The crude product 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 hours, the reaction mixture was extracted with aqueous sodium thiosulfate solution, and DCM Diluted, washed with NaHCO ₃ aqueous solution, washed with saturated brine, dried and concentrated to obtain crude product, which was purified by column chromatography to obtain 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 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 Na2SO4} , The crude product was concentrated to obtain the crude product, which 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 an 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 a crude product, which was purified by Prep-TLC (EA/PE=1:3) to obtain the target compound A24 ( 15 mg).

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 fluorosulfonyl difluoroacetate were added (300 mg), stirred at 100 °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 the crude product, which was purified by column chromatography (EA/PE=1:10). , the target compound 25-2 (170 mg) was obtained.

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 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 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 ]pyrrole-1( 4H )- base) 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 mg) at room temperature mL)/H ₂ O (1 mL) mixed solution, replaced with nitrogen for 3 times, 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), added with Pd (PPh ₃ ) ₄ (110 mg), K ₂ CO ₃ (400 mg) and vinylboronic acid pinacol ester (300 mg) were reacted at 90 °C overnight, extracted with EA, the organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to obtain crude product, which was passed through column Purified by chromatography (EA/PE=1:5) 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, and the reaction was carried out at room temperature for 2 hours , 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=1:4) to obtain the 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, and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ , and concentrated to give the crude product, which was purified by Prep-TLC (EA/PE=1:3) to give the target compound A27 (25 mg).

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 327.0.

Example 8 2-Chloro-5-(3-(dimethylphosphoronyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[ b ]pyrrole-1( 4H ) -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 replaced three times, reacted at 100 °C overnight, diluted with EA, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain crude product, which 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)benzene Synthesis of carbonitrile (compound A45).

Step 1: Synthesis of Compound 45-1

Compound M2 (650 mg), copper acetate (620 mg) and 4A molecular sieves (700 mg) were added to dichloromethane (7 mL), followed by N,N-diisopropylethylamine (1.7 mL), room temperature Stir for half an hour, replace with oxygen twice, stir at room temperature overnight, filter, spin dry the filtrate, column chromatography (PE/EA=5:1 to 1:1, add 10% DCM as eluent) 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 the compound was prepared by Prep-TLC. 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 liquids were separated, the organic phase was washed with saturated 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 residue was diluted with water and EA, the layers were separated, the organic phase was washed once with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE/EA=19:1 to 13:1), The target product 47-1 (320 mg) was obtained.

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, Washed with saturated brine, dried and concentrated to obtain the crude product, which 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, The layers were separated, the organic phase was washed with saturated brine, dried and concentrated to obtain the crude product. The crude product 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, and separated. The solution was washed with saturated brine, and the crude product was dried and concentrated. The crude product was prepared by Prep-TLC (2:1) to obtain compound A47 (70 mg).

LCMS: [M ⁺ H ⁺ -H2O] ₊ : 329.

Example 11: ( S )-2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ 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)] (12 mg), stirred overnight at room temperature under nitrogen protection, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1:5) to obtain the target compound A11 (30 mg, >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.

4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)鄰苯二甲腈 [M+H ⁺-H ₂O] ⁺：336.10 13

4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺：328.95 14

2-氯-4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：344.90 15

1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-4(1 H)-酮 [M+H ⁺+H ₂O] ⁺：372.05 16

3-氯-5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：344.90 17

3-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)-5-氟苯甲腈 [M+H ⁺-H ₂O] ⁺：328.95 18

5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)間苯二甲腈 [M+H ⁺-H ₂O] ⁺：336.10 19

2-氯-5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：344.90 20

2-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)-5-氟苯甲腈 [M+H ⁺-H ₂O] ⁺：328.95 21

5-氯-2-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：344.90 22

1-(4-氯-2-氟苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：338.42 23

1-(4-氯苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：320.03 24

5,5-二氟-1-(4-氟苯基)-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：304.06 25

4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：311.06 26

5-(5,5-二氟-4-羥基-3-(噻唑-4-基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)間苯二甲腈 [M+H ⁺-H ₂O] ⁺：351.02 27

3-(5,5-二氟-3-(呋喃-3-基)-4-羥基-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-5-氟苯甲腈 [M+H ⁺-H ₂O] ⁺：327.08 28

1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：338.42 29

3-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：311.06 30

1-(3-氯-5-氟苯基)-3-((二氟甲基)磺醯基)-5,5-二氟-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：383.9 31

5-(5,5-二氟-4-羥基-3-(1-甲基-1 H-吡唑-5-基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)間苯二甲腈 [M+H ⁺-H ₂O] ⁺：348.1 32

2-氯-5-(5-氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺：327.03 33

2-氯-5-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺： 344.90 34

2-氯-5-(5,5,6-三氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺： 363.01 35

5-(3-氯-5-氟苯基)-2,2-二氟-7-(三氟甲基)-2,3-二氫-1 H-吡咯烷-1-醇 [M+H ⁺-H ₂O] ⁺： 338.42 36

1-(2-氯吡啶-4-基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 321.02 37

1-(6-氯吡啶-3-基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 321.02 38

1-(5-氯吡啶-2-基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 321.02 39

1-(5-氨基吡啶-2-基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 302.03 40

5,5-二氟-1-(6-氟吡啶-3-基)-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 305.05 41

5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)-2-氟-氰吡啶 [M+H ⁺-H ₂O] ⁺： 330.05 42

1-(5-氯吡嗪-2-基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺：322.02 43

1-(3-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-5-氟苯基)乙基-1-酮 [M+H ⁺-H ₂O] ⁺： 346.05 44

4-(5,5-二氟-4-羥基-4-甲基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-羥基苯甲腈 [M+H ⁺-H ₂O] ⁺： 341.05 45

2-氯-4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基-4-氘)苯甲腈 [M+HCOOH-H] ^-： 408.03 46

3-5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊[ b]吡咯-1(4 H)-基)-5-氟氰苯 [M+H ⁺-H ₂O] ⁺: 329.05 47

1-(3-氯-5-氟苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊[ c]吡唑-4-醇 [M+H ⁺] ⁺： 357.10 48

5-(3-氯-5-氟苯基)-2,3-二氟-7-(三氟甲基)-2,3-二氫-1 H-吡咯烷-1-醇 [M+H ⁺-H ₂O] ⁺： 338.02 49

3-(3-氯-5-氟苯基)-6,6-二氟-1-(三氟甲基)-6,7-二氫-5 H-吡咯[1,2- c]咪唑-7-醇 [M+H ⁺] ⁺： 357.10 50

5-(3-氯-5-氟苯基)-2-氟-7-(三氟甲基)-2,3-二氫-1 H-吡咯裡嗪-1-醇 [M+H ⁺-H ₂O] ⁺： 320.10 51

( S) -2-氟-5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊基[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺： 330.05 52

5,5-二氟-1-(1-甲基-1 H-吡咯-2-基)-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 289.07 53   

5,5-二氟-1-(呋喃-2-基)-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 276.03 54   

5-(5,5-二氟-4-氧代-3-(三氟甲基)-5,6-二氫環戊基[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 345.25 55

5-(5,5-二氟-4-羥基-3-(噻吩-2-基)-5,6-二氫環戊基[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 343.12 56

4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-甲氧基苯甲腈 [M+H ⁺-H ₂O] ⁺： 341.05 57   

5,5-二氟-1-(3-(甲基磺醯基)苯基)-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 364.05 58

( S) -5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊基[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.06    59

( S)-5,5-二氟-1-(3-氟-5-(羥甲基)苯基)-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 334.05 60

( S)-5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-3-(二氟甲基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 379.05 61

( S)-4-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-(二氟甲基)苯甲腈 [M+H ⁺-H ₂O] ⁺： 361.05 62

( S)-1-(3-氯苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 320.02 63

( S)-3-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)苯甲腈 [M+H ⁺-H ₂O] ⁺： 311.07 64

( S)-1-(3-(二氟甲基)-4-氟苯基)-5,5-二氟-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 354.04 65

( S)-5,5-二氟-1-(4-氟-3-(氟甲基)苯基)-3-(三氟甲基)-1,4,5,6-四氫環戊并[ b]吡咯-4-醇 [M+H ⁺-H ₂O] ⁺： 336.06 66

( S)-5-(5,5-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2,3-二氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 347.05 67

5-((4 S,5 S,6 R)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 68

5-((4 S,5 S,6 S)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 69

5-((4 S,5 R,6 R)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 70

5-((4 S,5 R,6 S)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 71

5-((4 R,5 R,6 S)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 72

5-((4 R,5 S,6 S)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 73

5-((4 R,5 R,6 R)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 74

5-((4 R,5 S,6 R)-(5,6-二氟-4-羥基-3-(三氟甲基)-5,6-二氫環戊并[ b]吡咯-1(4 H)-基)-2-氟苯甲腈 [M+H ⁺-H ₂O] ⁺： 329.05 Table 1 Example Structural formula name LC-MS 12

4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)phthalonitrile [M+H ⁺ -H ₂ O] ⁺ : 336.10 13

4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 328.95 14

2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 344.90 15

1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-4( 1H )-one [M+H ⁺ +H ₂ O] ⁺ : 372.05 16

3-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 344.90 17

3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 328.95 18

5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)isophthalonitrile [M+H ⁺ -H ₂ O] ⁺ : 336.10 19

2-Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 344.90 20

2-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 328.95 twenty one

5-Chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 344.90 twenty two

1-(4-Chloro-2-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 338.42 twenty three

1-(4-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 320.03 twenty four

5,5-Difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 304.06 25

4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 311.06 26

5-(5,5-Difluoro-4-hydroxy-3-(thiazol-4-yl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)isoxylylene Nitrile [M+H ⁺ -H ₂ O] ⁺ : 351.02 27

3-(5,5-Difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluoro benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 327.08 28

1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 338.42 29

3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 311.06 30

1-(3-Chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 383.9 31

5-(5,5-Difluoro-4-hydroxy-3-(1-methyl- 1H -pyrazol-5-yl)-5,6-dihydrocyclopento[ b ]pyrrole-1(4 H )-yl)isophthalonitrile [M+H ⁺ -H ₂ O] ⁺ : 348.1 32

2-Chloro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 327.03 33

2-Chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)benzyl Nitrile [M+H ⁺ -H ₂ O] ⁺ : 344.90 34

2-Chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl) benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 363.01 35

5-(3-Chloro-5-fluorophenyl)-2,2-difluoro-7-(trifluoromethyl)-2,3-dihydro- 1H -pyrrolidin-1-ol [M+H ⁺ -H ₂ O] ⁺ : 338.42 36

1-(2-Chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 321.02 37

1-(6-Chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 321.02 38

1-(5-Chloropyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 321.02 39

1-(5-Aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 302.03 40

5,5-Difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 305.05 41

5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-2-fluoro-cyano Pyridine [M+H ⁺ -H ₂ O] ⁺ : 330.05 42

1-(5-Chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 322.02 43

1-(3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5 -Fluorophenyl)ethyl-1-one [M+H ⁺ -H ₂ O] ⁺ : 346.05 44

4-(5,5-Difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl) -2-Hydroxybenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 341.05 45

2-Chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl-4 -deuterium)benzonitrile [M+HCOOH-H] ^- : 408.03 46

3-5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrol-1( 4H )-yl)-5-fluorocyanobenzene [M+H ⁺ -H ₂ O] ⁺ : 329.05 47

1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ c ]pyrazole-4- alcohol [M+H ⁺ ] ⁺ : 357.10 48

5-(3-Chloro-5-fluorophenyl)-2,3-difluoro-7-(trifluoromethyl)-2,3-dihydro- 1H -pyrrolidin-1-ol [M+H ⁺ -H ₂ O] ⁺ : 338.02 49

3-(3-Chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-6,7-dihydro- 5H -pyrro[1,2- c ]imidazole- 7-ol [M+H ⁺ ] ⁺ : 357.10 50

5-(3-Chloro-5-fluorophenyl)-2-fluoro-7-(trifluoromethyl)-2,3-dihydro- 1H -pyrrolizin-1-ol [M+H ⁺ -H ₂ O] ⁺ : 320.10 51

( S )-2-Fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[ b ]pyrrole-1( 4H ) - base) benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 330.05 52

5,5-Difluoro-1-(1-methyl- 1H -pyrrol-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ] Pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 289.07 53

5,5-Difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 276.03 54

5-(5,5-Difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[ b ]pyrrol-1( 4H )-yl)-2-fluoro benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 345.25 55

5-(5,5-Difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopentyl[ b ]pyrrol-1( 4H )-yl)-2-fluoro benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 343.12 56

4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-methoxy benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 341.05 57

5,5-Difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrole- 4-ol [M+H ⁺ -H ₂ O] ⁺ : 364.05 58

( S )-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[ b ]pyrrol-1( 4H )-yl)- 2-Fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.06 59

( S )-5,5-difluoro-1-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopentane [ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 334.05 60

( S )-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)- 3-(Difluoromethyl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 379.05 61

( S )-4-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)- 2-(Difluoromethyl)benzonitrile [M+H ⁺ -H ₂ O] ⁺ : 361.05 62

( S )-1-(3-Chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrole-4- alcohol [M+H ⁺ -H ₂ O] ⁺ : 320.02 63

( S )-3-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzene Formonitrile [M+H ⁺ -H ₂ O] ⁺ : 311.07 64

( S )-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocycle Pento[ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 354.04 65

( S )-5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopentane [ b ]pyrrol-4-ol [M+H ⁺ -H ₂ O] ⁺ : 336.06 66

( S )-5-(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)- 2,3-Difluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 347.05 67

5-(( 4S , 5S , 6R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 68

5-((4 S ,5 S ,6 S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 69

5-((4 S ,5 R ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 70

5-((4 S ,5 R ,6 S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 71

5-((4 R ,5 R ,6 S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 72

5-((4 R ,5 S ,6 S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 73

5-((4 R ,5 R ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05 74

5-((4 R ,5 S ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1 ( 4H )-yl)-2-fluorobenzonitrile [M+H ⁺ -H ₂ O] ⁺ : 329.05

The ¹ H NMR data for Examples 10, 16, 19, 55, 58 are shown below: ¹ H NMR (500 MHz, DMSO) δ 8.30 (dd, J = 5.4, 2.9 Hz, 1H), 8.13 (s, 1H) , 8.06 (ddd, J = 9.0, 4.4, 3.0 Hz, 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 (500 MHz, CDCl ₃ ) δ 7.69 - 7.64 (m, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.49 (dt, J = 7.7, 3.9 Hz, 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, 1.1 Hz, 1H), 7.06 (s, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 5.10 (dd, J = 13.0, 6.0 Hz, 1H) ), 3.47 (td, J = 15.4, 10.5 Hz, 1H), 3.23 (td, J = 16.2, 4.1 Hz, 1H), 2.32 (dd, J = 6.5, 2.2 Hz, 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, 5.2 Hz, 1H), 3.48 (td, J = 15.2, 10.5 Hz, 1H), 3.27 (td, J = 16.0, 4.2 Hz, 1H), 2.42 (dd, J = 5.7, 2.2 Hz, 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 gene 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, and the The cells were washed with 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 concentration compounds into 384 wells, 25nl/well; cells are seeded into 384 well plates, 4500 cells/well, 25μl medium, make compound final. The concentrations were 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5 nM, respectively. The cells were incubated 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 with Envision. According to the RLU (Record Luminescence) signal value of each well, the % inhibition rate was calculated, 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 in 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 5min, 15min, 30min, 1h, 2h, 4h, 7h, and 24h; the oral dose was 5 mg/kg, the 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.

none.

none.

none.

Claims (29)

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

Formula (I) wherein, L is a bond, -O-, NH-, -CR _d R _e -, -S-, -S(=O)-, -S(=O) ₂ -, -C=C- or -C≡C-; X ₁ and X ₂ are independently selected from C or N; X ₃ is CR ₈ or NR ₈ ; X ₄ is CR ₇ or NR ₇ ; and X ₁ , X ₂ and X ₄ at least have One is N; R ₁ is selected from 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, 3-10-membered heterocyclyl; wherein, the 5-18-membered heteroaryl and 3-10-membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C ₁ -C ₁₀ alkyl group, C ₂ -C ₁₀ alkenyl group, C ₂ -C ₁₀ alkynyl group, C ₁ -C ₁₀ alkoxy group , C ₆ -C ₁₀ aryl, 5-18 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl and 3-10 membered heterocyclyl may be optionally replaced by one or more H, halogen, hydroxyl, 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 , _-NRaRb ,-C(=O) _Rc ,-C(=O) _ORc ,-OC(=O) _Rc ,-C( ₌ O _{) NRaRb} ,-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 , - Replaced by P(=O)R _a R _b and/or -P(=S)R _a R _b ; 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 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 haloalkane group 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 can be optionally One or more H, halogen, -CN, -OH, amino, C ₁ -C ₅ alkyl, C ₂ -C ₆ alkenyl or C ₁ -C ₅ haloalkyl substituted; or R ₂ and R ₃ together An oxo group is formed on the C atom to which it is attached; R ₄ and R ₅ are 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 is optionally Contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C2 -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, oxygen substituted with substituted group, amino group, C ₁ -C ₅ alkyl group, C ₂ -C ₆ alkenyl group or C ₁ -C ₅ haloalkyl group; or R ₄ and R ₅ are substituted or unsubstituted together with the C atom to which they are attached. Substituted 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 base, 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 group; wherein, the 3-6 membered heterocyclic group 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 can be any optionally substituted with one or more of H, halogen, -CN, -OH, amino, oxo, _C1 - _C5 alkyl, C2 _{- C6} alkenyl, or _C1 - _C5 haloalkyl; or Two R ₆ together with the C atom to which it is attached together form a substituted or unsubstituted C ₃ -C ₅ cycloalkyl or 3-5 membered heterocyclic group; or R ₆ and R ₅ together with the C atom to which it is attached together form Substituted or unsubstituted C ₃ -C ₄ cycloalkyl or 3-5 membered heterocyclyl; R _d and R _e are 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 together form an oxo group on the C atom to which it is attached; 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 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 -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ - C ₁₀ aryl and 5-10 membered heteroaryl can be optionally replaced by one or more of H, halogen, hydroxy, cyano, oxo, amino, C ₁ -C ₆ alkyl, C _1-6 alkoxy base, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₅ cycloalkyl, 3-6 membered heterocyclyl, 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 alkane _{R 8 _ _ _} 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 - _C10 alkyl, _C1 - _C10 haloalkyl and C3 _{- C10} cycloalkyl may be optionally replaced by one or more of H, halogen, -CN, -OH, amino, _C1 - _C5 alkane R _a , R _b and R _c are 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 cycloalkyl, 3-1 0-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 optionally contain 1, 2 or 3 heteroatoms independently selected from N, O, and S; m is 0, 1, or 2. The compound according to 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. The compound according to claim 1 or 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the Said L is a bond or -CR _d R _e -. The compound of any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₄ and R ₅ are independently H, halogen or C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl can be optionally replaced by one or more H, halogen, -CN, -OH, amino or oxo substituted. The compound of any one of claims 1 to 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₄ and R ₅ are each independently H or halogen. The compound of any one of claims 1 to 5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, the R ₂ is halogen, -CN or -OH. The compound of any one of claims 1 to 6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₂ is -OH. The compound of any one of claims 1 to 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₃ is H, deuterium, C ₁ -C ₃ alkyl or C ₂ -C ₅ alkenyl, wherein the C ₁ -C ₃ alkyl and C ₂ -C ₅ alkenyl can be optional is substituted with one or more of H, halogen, -CN, -OH, amino, _C1 - _C5 haloalkyl. The compound of any one of claims 1 to 8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₃ is H, deuterium or a C ₁ -C ₃ alkyl group, or the R ₂ and R ₃ together form an oxo group on the C atom to which it is attached. The compound of any one of claims 1 to 9, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, the 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 the heteroatom of S, wherein the _C6 -C8 aryl and _5-8 membered heteroaryl may be optionally replaced by one or more halogen, -OH, -CN, oxo, amino, _C1 -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 , -NO ₂ , -C(=O)OR _c or -S(=O) ₂ R _c . The compound of any one of claims 1 to 10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, the R ₁ is phenyl or 5-6 membered heteroaryl; wherein, the 5-6 membered heteroaryl optionally contains a heteroatom selected from N, O and S, the phenyl and 5 -6-membered heteroaryl can be optionally replaced by one or more halogen, -OH, amino, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _-C1 -C ₆ alkylene -OR _c or -CN substituted. The compound of any one of claims 1 to 11, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₁ is phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl optionally contains 1, 2 or 3 independently selected from N, O and S. Heteroatoms, the phenyl and 5-6 membered heteroaryl groups may be optionally substituted with one or more halogen, cyano, or _C1 - _C6 haloalkyl. The compound of any one of claims 1 to 12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, 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 substituted by alkoxy, C ₁ -C ₆ haloalkyl, -C ₁ -C ₆ alkylene-OR _c or -CN. The compound of any one of claims 1 to 13, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein 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 alkane _{C1 - C6alkoxy} or _C1 -C6haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, or amino. The compound of any one of claims 1 to 14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein the R ₆ is H, halogen or C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 15, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, the R ₈ is H, -CN, -NH ₂ , halogen, C ₁ -C ₃ alkyl or cyclopropyl. The compound of any one of claims 1 to 16, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, the R ₈ is H or halogen. The compound of any one of claims 1 to 17, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, 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 alkyl group , 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 cycloalkyl , -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. The compound of any one of claims 1 to 18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof , wherein, 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, wherein the 5 A membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the ₅ -membered heteroaryl group may be optionally C ₃ alkyl or C ₁ -C ₃ haloalkyl substituted. The compound of claims 1 to 19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the 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 independently A heteroatom selected from N, O, and S; the 5-membered heteroaryl group may be optionally substituted with one or more H, halogen, _{C1 -} C3 alkyl or _{C1 -} C3 haloalkyl. The compound of claims 1 to 20, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the Said R _a and R _b are each independently H or C ₁ -C ₆ alkyl. The compound of claims 1 to 21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the Said R _c is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claims 1 to 22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the The compound is represented by formula (II-1), formula (II-2) or formula (II-3),

Formula (II-1) Formula (II-2) Formula (II-3). The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound Selected from: 1) 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1-yl]-2-fluorobenzene nitrile; 2) 1-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopento[ b ]pyrrole-3-carbon nitrile; 3) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[ b ]pyrrole-1( 4H) )-yl)benzonitrile; 4) 2-chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 5) 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4, 5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 6) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5, 6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 7) 2-chloro-5-(3-(difluoromethyl)-5,5-difluoro-4 -Hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 8) 2-chloro-5-(3-(dimethylphosphoronyl)-5 ,5-difluoro-4-hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 9) 2-fluoro-5-(5-fluoro-4 -Hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 10) 5-(5,6-difluoro- 4-Hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 11)( S )-2 -Chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzyl nitrile; 12) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)o- phthalonitrile; 13) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H )- yl)-2-fluorobenzonitrile; 14) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 15) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6 -Dihydrocyclopento[ b ]pyrrole-4( 1H )- ketone; 16) 3-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H ) -yl)benzonitrile; 17) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H) )-yl)-5-fluorobenzonitrile 18) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole- 1( 4H )-yl)isophthalonitrile; 19) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocycle pentano[ b ]pyrrol-1( 4H )-yl)benzonitrile; 20) 2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydro Cyclopenta[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzonitrile 21)5-chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl) )-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 22) 1-(4-chloro-2-fluorophenyl)-5,5-difluoro -3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 23) 1-(4-chlorophenyl)-5,5-difluoro -3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 24) 5,5-difluoro-1-(4-fluorophenyl) -3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ 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-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)isophthalonitrile; 27) 3-(5,5-difluoro-3 -(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluorobenzonitrile; 28)1-(3- chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 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 ]pyrrol-1( 4H )-yl)isophthalonitrile; 32) 2-Chloro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzyl nitrile; 33) 2-chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H ) -yl)benzonitrile; 34) 2-chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[ b ] Pyrrol-1( 4H )-yl)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-Tetrahydrocyclopento[ b ]pyrrol-4-ol; 37) 1-(6-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4 ,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 38) 1-(5-chloropyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)- 1,4,5,6-Tetrahydrocyclopento[ b ]pyrrol-4-ol; 39) 1-(5-aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl) yl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 40) 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-( Trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; 41)5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl) yl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H )-yl)-2-fluoro-cyanopyridine; 42) 1-(5-chloropyrazin-2-yl)-5 ,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 43) 1-(3-(5,5-diol) Fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-5-fluorophenyl)ethyl-1-one ; 44) 4-(5,5-Difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H ) -yl)-2-hydroxybenzonitrile; 45) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H )-yl-4-deutero)benzonitrile; 46) 3-5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydro Cyclopenta[ b ]pyrrol-1( 4H )-yl)-5-fluorocyanobenzene; 47) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluorophenyl) Fluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ c ]pyrazole-4 - alcohol; 48) 5-(3-chloro-5-fluorophenyl)-2,3-difluoro-7-(trifluoromethyl)-2,3-dihydro- 1H -pyrrolidine-1- alcohol; 49) 3-(3-Chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-6,7-dihydro- 5H -pyrrole[1,2- c ] Imidazol-7-ol; 50) 5-(3-Chloro-5-fluorophenyl)-2-fluoro-7-(trifluoromethyl)-2,3-dihydro- 1H -pyrrolizine -1-ol; 51) ( S )-2-fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentyl[ b ]pyrrol-1( 4H )-yl)benzonitrile; 52) 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)- 1,4,5,6-Tetrahydrocyclopento[ 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-(thiophene- 2-yl)-5,6-dihydrocyclopentyl[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 56) 4-(5,5-difluoro-4- Hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-methoxybenzonitrile; 57) 5,5-di Fluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-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-tetrahydrocyclopento[ b ]pyrrol-4-ol; 60)( S )-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)- 5,6-Dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-3-(difluoromethyl)-2-fluorobenzonitrile; 61)( S )-4-(5, 5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-(difluoromethyl)benzene carbonitrile; 62) ( S )-1-(3-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[ b ]pyrrol-4-ol; 63)( S )-3 -(5,5-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)benzonitrile; 64) ( S )-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocycle Pento[ b ]pyrrol-4-ol; 65) ( S )-5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl) -1,4,5,6-tetrahydrocyclopento[ b ]pyrrol-4-ol; or 66)( S )-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl) yl)-5,6-dihydrocyclopento[ b ]pyrrole-1( 4H )-yl)-2,3-difluorobenzonitrile; 67)5-(( 4S , 5S , 6R )-(5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzene carbonitrile; 68) 5-(( 4S , 5S , 6S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile69)5-(( 4S , 5R , 6R )-(5,6-difluoro-4-hydroxy-3-( Trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 70)5-(( 4S , 5R , 6S )-(5,6-Difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzene carbonitrile; 71) 5-(( 4R , 5R , 6S )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 72)5-(( 4R , 5S , 6S )-(5,6-difluoro-4-hydroxy-3- (Trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile; 73)5-(( 4R , 5R ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopento[ b ]pyrrol-1( 4H )-yl)-2-fluoro benzonitrile; or 74) 5-((4 R ,5 S ,6 R )-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopentane) [ b ]pyrrol-1( 4H )-yl)-2-fluorobenzonitrile. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound as described in any one of claims 1 to 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate thereof compound, non-covalent complex or solvate; and at least one pharmaceutically acceptable excipient. A compound as described in any one of claims 1 to 24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof Use of the substance or the pharmaceutical composition as claimed in claim 25 in the manufacture of a medicament for treating, delaying or preventing a disease mediated by HIF-2α. 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. The use of claim 27, wherein the cancer is selected from hematological cancers and solid tumors. 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, Cervical, uterine, gastric, ovarian, breast, skin, brain, meningeal, neurocytoma, glioblastoma, meningioma, and medulloblastoma.