Bicyclic compounds and their applications

Abstract

The present invention relates to compounds represented by formula (I), and also provides compositions and preparations containing such compounds, and methods for using and preparing such compounds.

Description

Technical Field

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

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

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

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

[0005] The activation of HIF-2α and the formation of heterodimers with HIF-1β are the key factors leading to downstream activation, and the PAS binding domains of the two are the binding sites for the formation of heterodimers. Based on this, Peloton's R&D team developed two small molecule HIF-2α inhibitors, the first-generation PT2385 and the second-generation PT2977, which exert anti-tumor effects by inhibiting the binding of HIF-2α and HIF-1β.

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

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

[0008]

[0009] in,

[0010] L is a bond, -O-, NH-, -CR d R e -, -S-, -S(=O)-, -S(=O)2-, -C=C- or -C≡C-;

[0011] X1 and X2 are independently selected from C or N;

[0012] X3 is CR8 or NR8;

[0013] X4 is CR7 or NR7;

[0014] And at least one of X1, X2 and X4 is N;

[0015] R1 is selected from C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 wherein the 5-18-membered heteroaryl and the 3-10-membered heterocyclic group arbitrarily contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 5-18 membered heteroaryl, C3-C 10 The cycloalkyl and 3-10 membered heterocyclyl groups may be optionally substituted with one or more H, halogen, hydroxy, cyano, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C1-C6 alkylene-OR c 、-C1-C6 alkylene-C=OR c 、-NO2、-SR c 、-NR a R b 、-C(=O)R c 、-OC(=O)R c 、-C(=O)OR c 、-C(=O)NR a R b 、-NC(=O)R c 、-S(=O)R c 、-S(=O)2R c 、-S(=O)2NR a R b 、-S(=O)(=NR a )R b 、-P(=O)R a R b or -P(=S)R a R b replaced by;

[0016] R2 is selected from H, -OH, amino, C1-C 10 Alkoxy, -OC(=O)-C 1-3Alkyl, -NR a R b , deuterium, halogen, -CN, =N-OH, C1-C5 haloalkyl or -C(=O)-OC 1-3 alkyl;

[0017] R3 is selected from H, -OH, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, -OC(=O)-C 1-3 Alkyl, deuterium, halogen, -CN, =N-OH, -C(=O)-OC 1-3 Alkyl, -OC(=O)-C 1-3 Haloalkyl or -C(=O)-OC 1-3 Haloalkyl, wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-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 The haloalkyl group may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl, or C1-C5 haloalkyl;

[0018] or R2 and R3 together form an oxo group on the C atom to which they are attached;

[0019] R4 and R5 are independently selected from H, halogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclic group; wherein the 3-6 membered heterocyclic group arbitrarily 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, C2-C 10Alkynyl, C3-C5 cycloalkyl and 3-6 membered heterocyclyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, amino, C1-C5 alkyl, C2-C6 alkenyl or C1-C5 haloalkyl; or R4 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl or C3-C5 heterocyclyl;

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

[0021] or R6 and R5 together with the C atom to which they are attached form a substituted or unsubstituted C3-C4 cycloalkyl or 3-5 membered heterocyclic group;

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

[0023] R7 is selected from H, -NO2, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR c 、-SR c 、-NR a R b、-C(=O)R c 、-C(=O)OR c 、-C(=O)NR a R b 、-NC(=O)R c 、-S(=O)R c 、-S(=O)2R c 、-S(=O)2NR a 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 -C1-C6 alkylene-OR c wherein the 5-10 membered heteroaryl and the 3-10 membered heterocyclic group optionally contain 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 The aryl and 5-10 membered heteroaryl groups may be optionally substituted with one or more H, halogen, hydroxy, cyano, oxo, amino, C1-C6 alkyl, C 1-6 Alkoxy, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 cycloalkyl, 3-6 membered heterocyclic group, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-C 3-5 Cycloalkyl, -S(=O)-C 1-3 Alkyl, -S(=O)-C 3-5 Cycloalkyl, -S(=O)2-C 1-3 Haloalkyl or -S(=O)-C 1-3 substituted with haloalkyl;

[0024] R8 is selected from the group consisting of absent, H, -CN, halogen, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, oxo and -NR a R b ; said C1-C 10 Alkyl, C1-C 10 Haloalkyl and C3-C10 Cycloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 alkyl, C2-C6 alkenyl, or C1-C5 haloalkyl;

[0025] R a , R b and R c are independently selected from H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the 3-10 membered heterocyclic group or 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0026] m is 0, 1 or 2.

[0027] In some embodiments, X1 is N.

[0028] In some embodiments, X2 is N.

[0029] In some embodiments, X3 is CR8.

[0030] In some embodiments, X4 is CR7.

[0031] In some embodiments, the X4 is NR7.

[0032] In some embodiments, L is a bond, -CH2-, -S(=O)2-, -C=C-, -C=O-, -C≡C-, or C3-C5 cycloalkyl.

[0033] In some embodiments, L is a bond or -CR d R e -.

[0034] In some embodiments, L is a bond.

[0035] In some embodiments, the R4 and R5 are independently selected from H, halogen and C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino or oxo.

[0036] In some embodiments, R4 and R5 are each independently selected from H, halogen, and C1-C6 alkyl.

[0037] In some embodiments, R4 and R5 are each independently H or halogen.

[0038] In some embodiments, R4 and R5 are each independently H or F.

[0039] In some embodiments, R4 is F.

[0040] In some embodiments, R5 is F.

[0041] In some embodiments, R2 is halogen, -CN, -OH, or =N-OH.

[0042] In some embodiments, R2 is halogen, -CN or -OH.

[0043] In some embodiments, R2 is F, -CN or -OH.

[0044] In some embodiments, R2 is halogen.

[0045] In some embodiments, R2 is hydroxy.

[0046] In some embodiments, R2 and R3 together form an oxo group.

[0047] In some embodiments, R3 is H, deuterium, C1-C 10 Alkyl or C2-C 10 alkenyl; wherein the C1-C 10 Alkyl and C2-C 10 The alkenyl group may be optionally substituted with one or more H, halogen, -CN, -OH, amino or C1-C5 haloalkyl.

[0048] In some embodiments, R3 is H, deuterium or C1-C3 alkyl, C2-C5 alkenyl, wherein the C1-C3 alkyl and C2-C5 alkenyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 haloalkyl.

[0049] In some embodiments, R3 is H, deuterium or C1-C3 alkyl, which may be optionally substituted with one or more H, halogen, -CN, -OH, amino or C1-C5 haloalkyl.

[0050] In some embodiments, R3 is selected from H, deuterium, or C1-C3 alkyl.

[0051] Preferably, in some embodiments, R3 is H or deuterium.

[0052] Preferably, in some embodiments, R3 is H.

[0053] In some embodiments, R2 is -OH, -CN or halogen, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0054] In some embodiments, R2 is -OH, -CN or -F, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0055] In some embodiments, R2 is -OH, and R3 is H or deuterium; or R2 and R3 together form an oxo group.

[0056] In some embodiments, R1 is C6-C 10 Aryl, 5-18 membered heteroaryl or C3-C 10 The 5- to 18-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0057] In some embodiments, the R1 is C6-C 10 The 5- to 18-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S.

[0058] In some embodiments, R1 is phenyl or a 5-6 membered heteroaryl; the 5-6 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.

[0059] In some embodiments, R1 is phenyl or a 6-membered heteroaryl; the 6-membered heteroaryl optionally contains 1, 2 or 3 N heteroatoms.

[0060] In some embodiments, R1 is C6-C8 aryl or 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the C6-C8 aryl and 5-8 membered heteroaryl may be optionally substituted by one or more H, halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c 、-C0-C6 alkylene-C=OR c 、-NO2、-C(=O)OR c or -S(=O)2R c replaced.

[0061] In some embodiments, R1 is phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the phenyl and 5-6 membered heteroaryl may be optionally substituted by one or more H, halogen, -OH, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c or -CN.

[0062] In some embodiments, R1 is phenyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the phenyl or 5-6 membered heteroaryl may be optionally substituted with one or more halogen, cyano and / or C1-C6 haloalkyl.

[0063] In some embodiments, R1 is phenyl or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the phenyl or 5-6 membered heteroaryl may be optionally substituted with one or more halogen, cyano and / or trifluoromethyl.

[0064] In some embodiments, the R1 may be optionally substituted by one or more halogen and / or cyano groups.

[0065] In some embodiments, the R1 is phenyl.

[0066] In some embodiments, the R1 is pyridyl.

[0067] In some embodiments, the R1 is pyrimidinyl, pyrazinyl or pyridazinyl.

[0068] In some embodiments, R1 is phenyl or pyridyl, which may be optionally substituted with one or more halogen, -OH, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c or -CN.

[0069] In some embodiments, the R1 is phenyl or pyridyl, and the phenyl or pyridyl may be optionally substituted with one or more halogen, -CN or C1-C6 haloalkyl.

[0070] In some embodiments, R1 is phenyl or pyridyl, which may be optionally substituted with one or more halogen, -CN, -CHF2, -CF3, -CH2CHF2 and / or -CH2CF3.

[0071] In some embodiments, R6 is H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, amino.

[0072] In some embodiments, R6 is H, halogen or C1-C6 alkyl, and the C1-C6 alkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, amino.

[0073] In some embodiments, R6 is H, halogen, or C1-C6 alkyl.

[0074] In some embodiments, R6 is H and / or halogen.

[0075] In some embodiments, R6 is H, F, Cl or Br.

[0076] In some embodiments, R6 is H or F.

[0077] In some embodiments, R6 is H.

[0078] In some embodiments, two R6 together with the C atom to which they are attached form a cyclopropyl group.

[0079] In some embodiments, R8 is H, -CN, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0080] In some embodiments, R8 is H, -CN or halogen.

[0081] In some embodiments, R8 is selected from H, -CN, -NH2, halogen, C1-C3 alkyl and cyclopropyl.

[0082] In some embodiments, R8 is H or halogen.

[0083] In some embodiments, R8 is H, -CN, -F, -Cl, -Br or -CF3.

[0084] In some embodiments, R8 is H.

[0085] In some embodiments, R7 is selected from H, -CN, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -S(=O)R c 、-C1-C6 alkylene-OR c 、-S(=O)2R c or P(=O)R a R b The 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Halogenated alkyl, C3-C 10 Cycloalkyl, C6-C 10The aryl group and the 5-10 membered heteroaryl group may be optionally substituted with one or more halogen, hydroxyl, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-C 3-5 Cycloalkyl, -S(=O)-C 1-3 Alkyl, -S(=O)-C 1-3 Haloalkyl, -S(=O)-C 3-5 is substituted by cycloalkyl, cyano, C1-C6 alkyl or C1-C6 haloalkyl;

[0086] The R a and R b Each independently selected from H, C1-C6 alkyl;

[0087] The R c Selected from H, C1-C6 alkyl or C1-C6 haloalkyl.

[0088] In some embodiments, R7 is selected from halogen, cyano, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered heteroaryl, S(=O)R c 、-S(=O)2R c 、-S(=O)(=NR a )R b Or P(=O)Me2; wherein the 5-membered heteroaryl group arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C3-C6 cycloalkyl group and the 5-membered heteroaryl group may be optionally substituted by H, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.

[0089] In some embodiments, R7 is selected from halogen, cyano, C1-C4 haloalkyl, C3-C5 cycloalkyl, 5-membered heteroaryl, S(=O)R c 、-S(=O)2R c 、-S(=O)(=NR a )R b Or -P(=O)Me2; wherein the 5-membered heteroaryl group arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C3-C5 cycloalkyl and 5-membered heteroaryl groups may be optionally substituted by H, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.

[0090] In some embodiments, the R7 is selected from C1-C6 haloalkyl, cyano, -S(=O)2R c, -P(=O)Me2 or a 5-membered heteroaryl, wherein the 5-membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl may be optionally substituted by one or more H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0091] In some embodiments, the R7 is selected from C1-C6 haloalkyl, -S(=O)2R c or a 5-membered heteroaryl, wherein the 5-membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl may be optionally substituted by one or more H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0092] In some embodiments, the R7 is selected from trifluoromethyl, difluoromethyl, cyano, -S(=O)2-R c or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein R c Selected from C1-C6 alkyl or C1-C6 haloalkyl.

[0093] In some embodiments, the R7 is a C1-C4 haloalkyl group.

[0094] In some embodiments, the R7 is -S(=O)2-R c , the R c Selected from C1-C6 alkyl or C1-C6 haloalkyl.

[0095] In some embodiments, the R a and R b Each is independently selected from H, C1-C4 alkyl.

[0096] In some embodiments, the R c Selected from H, C1-C3 alkyl or C1-C3 haloalkyl.

[0097] In some embodiments, the R7 is selected from

[0098] In some embodiments, the R7 is selected from

[0099] In some embodiments, the compound is as shown in formula (II-1), formula (II-2) or formula (II-3),

[0100]

[0101] The R1, R2, R3, R4, R5, R6, R7, R8, L and m are as described in the above embodiment.

[0102] In some embodiments, the compound is as shown in formula (III-1), formula (III-2) or formula (III-3),

[0103]

[0104] The R1, R6, R7, R8 and m are as described in the above embodiment.

[0105] The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0106] 1) 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1-yl]-2-fluorobenzonitrile;

[0107] 2) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonitrile;

[0108] 3) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0109] 4) 2-chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0110] 5) 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0111] 6) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0112] 7) 2-chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0113] 8) 2-chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0114] 9) 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0115] 10) 5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0116] 11) (S)-2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0117] 12) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)phthalonitrile;

[0118] 13) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0119] 14) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0120] 15) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one;

[0121] 16) 3-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0122] 17) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile

[0123] 18) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalonitrile;

[0124] 19) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0125] 20) 2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile

[0126] 21) 5-chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0127] 22) 1-(4-chloro-2-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0128] 23) 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0129] 24) 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0130] 25) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0131] 26) 5-(5,5-difluoro-4-hydroxy-3-(thiazol-4-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalonitrile;

[0132] 27) 3-(5,5-difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile;

[0133] 28) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0134] 29) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0135] 30) 1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0136] 31) 5-(5,5-difluoro-4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydrocyclopenta[b]pyrrole-1(4H)-yl)isophthalonitrile;

[0137] 32) 2-chloro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0138] 33) 2-chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0139] 34) 2-chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0140] 35) 5-(3-chloro-5-fluorophenyl)-2,2-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

[0141] 36) 1-(2-chloropyridin-4-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0142] 37) 1-(6-chloropyridin-3-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0143] 38) 1-(5-chloropyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0144] 39) 1-(5-aminopyridin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0145] 40) 5,5-difluoro-1-(6-fluoropyridin-3-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0146] 41) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro-cyanopyridine;

[0147] 42) 1-(5-chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0148] 43) 1-(3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorophenyl)ethyl-1-one;

[0149] 44) 4-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-hydroxybenzonitrile;

[0150] 45) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl-4-deutero)benzonitrile;

[0151] 46) 3-5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorocyanobenzene;

[0152] 47) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-ol;

[0153] 48) 5-(3-chloro-5-fluorophenyl)-2,3-difluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolidin-1-ol;

[0154] 49) 3-(3-chloro-5-fluorophenyl)-6,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;

[0155] 50) 5-(3-chloro-5-fluorophenyl)-2-fluoro-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolizin-1-ol;

[0156] 51)(S)-2-Fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0157] 52) 5,5-difluoro-1-(1-methyl-1H-pyrrol-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0158] 53) 5,5-difluoro-1-(furan-2-yl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0159] 54) 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0160] 55) 5-(5,5-difluoro-4-hydroxy-3-(thien-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0161] 56) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-methoxybenzonitrile;

[0162] 57) 5,5-difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0163] 58) (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0164] 59) (S)-5,5-difluoro-1-(3-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0165] 60)(S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-3-(difluoromethyl)-2-fluorobenzonitrile;

[0166] 61)(S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-(difluoromethyl)benzonitrile;

[0167] 62) (S)-1-(3-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0168] 63) (S)-3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;

[0169] 64) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0170] 65) (S)-5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol;

[0171] 66) (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2,3-difluorobenzonitrile;

[0172] 67) 5-((4S,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0173] 68) 5-((4S,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile

[0174] 69) 5-((4S,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0175] 70) 5-((4S,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0176] 71) 5-((4R,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0177] 72) 5-((4R,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile;

[0178] 73) 5-((4R,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; or

[0179] 74) 5-((4R,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile.

[0180] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates and a pharmaceutically acceptable excipient, such as hydroxypropyl methylcellulose. In some compositions, the weight ratio of the compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates to the excipients is about 0.001 to 10.

[0181] In addition, the present invention also provides a method for treating a subject suffering from a HIF-2α-mediated disease or condition, comprising administering a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates.

[0182] In some aspects, the disease or illness are selected from VHL syndrome, autoimmune diseases, inflammatory diseases, metabolic diseases, neurodegenerative diseases, cardiovascular disorders, kidney disease, viral infection and obesity. In some aspects, the disease or illness are selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airway disease, pneumonia, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), the acute rejection of transplanted organs. In some aspects, the disease or illness are cancer, including hematological cancer, lymphoma, multiple myeloma, digestive system tumor, reproductive system tumor, brain tumor, nervous system tumor neoplasm.

[0183] In certain aspects, the disease or disorder is a tumor or cancer of the glioma, pheochromocytoma, paraganglioma, colon, rectum, prostate (e.g., castrate resistant prostate cancer), lung (e.g., non-small cell lung cancer and / or small cell lung cancer), pancreas, liver, kidney, cervix, uterus, stomach, ovary, breast (e.g., basal or basal-like breast cancer and / or triple negative breast cancer), skin (e.g., melanoma), nervous system (including brain, meninges, and central nervous system, including neuroblastoma, glioblastoma, meningioma, and medulloblastoma).

[0184] In some aspects, the disease or condition is VHL syndrome. In some aspects, the disease or condition is renal cancer. In some aspects, the subject is a human.

[0185] In certain aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally or orally. In one aspect, the compound is administered orally.

[0186] The present invention also provides the use of the compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates in the preparation of drugs for treating diseases or disorders mediated by HIF-2α.

[0187] The present invention also provides a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof for treatment. Further provided is a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof for treating a subject suffering from a disease or condition mediated by HIF-2α. 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.

[0188] 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 The "C" in the alkyl 1-6 ” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched form.

[0189] The term "alkoxy" refers to an oxygen ether formed from the above-mentioned straight chain, branched chain or cyclic alkyl groups.

[0190] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two CH bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C 1-4 The "C" in the alkylene 1-4 ” refers to an alkylene group containing 1, 2, 3 or 4 carbon atoms.

[0191] The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced by a halogen atom. The term "haloalkoxy" refers to the group -O-haloalkyl.

[0192] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a dimethyl substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom.

[0193] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0194] The term "aryl" refers to a substituted or unsubstituted stable aromatic hydrocarbon group of 6 to 10 ring carbon atoms, which may contain one aromatic ring or multiple aromatic rings (e.g., fused and bicyclic). The aromatic ring does not contain heteroatoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, indenyl, etc.

[0195] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocyclic ring having at least one heteroatom ring member, wherein the heteroatom is selected from N, O and / or S. The "3-10 members" in the 3-10 membered heteroaryl refers to a heteroaryl group consisting of 3-10 carbon atoms or ring atoms of N, O or S. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl, and the like.

[0196] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-10 The "C" in cycloalkyl 3-10 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The cycloalkyl group may include a monocyclic ring and a polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, and cyclocyclic rings). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; in some embodiments, the cycloalkyl group also includes a portion having one or more aromatic rings fused to the cyclized alkyl ring, such as benzo or thienyl derivatives of cyclohexane, etc.

[0197] The term "cycloalkenyl" refers to a ring system having at least one cyclized alkenyl group having one or more carbon-carbon double bonds. 3-10 The "C" in cycloalkenyl 3-10 " means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The cycloalkenyl group may include a single ring and a multiple ring (e.g., having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkenyl group includes but is not limited to cyclohexenyl, cyclohexadiene, cycloheptatrienyl, etc.; in some embodiments, the cycloalkenyl group also includes a portion having one or more aromatic rings fused to the cyclized alkenyl ring, such as a benzo or thienyl derivative of a cyclohexene ring, etc.

[0198] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl containing a heterocyclic ring, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. The "5-18 yuan" in a 5-18 membered heterocyclyl refers to a heterocyclyl consisting of 5-18 carbon atoms or N, O or S ring-forming atoms. The definition of the heterocyclyl also includes a portion having one or more aromatic rings fused to a cyclized alkyl or cyclized alkenyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, etc. In some embodiments, heterocyclyl includes but is not limited to pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepane, dihydrobenzofuranyl, etc.

[0199] The term "composition" in the present invention is intended to include products containing a specific number of specific components, and also includes any product obtained directly or indirectly from a specific number of specific components. Therefore, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods for preparing the compounds are also contents of the present invention. Moreover, the crystal forms of some compounds can exist in polymorphic forms, which are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and these solvates are also included in the present invention.

[0200] Prodrugs (prodrugs) of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the treatment methods provided by the present invention includes the administration of the compounds disclosed in the present invention, or although not explicitly disclosed, it can be converted into the prodrug compound disclosed in the present invention in vivo after administration to the subject. Conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs" (ed. H. Bundgaard, Elsevier, 1985).

[0201] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select substituents or substitution patterns of the compounds of the present invention by means of prior art means and the methods described in the present invention to provide chemically stable and easily synthesized compounds.

[0202] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0203] The above formula (I) does not precisely define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. In the synthetic process for preparing such compounds, or in the process using racemization or epimerization methods known to those of ordinary skill in the art, the obtained product may be a mixture of stereoisomers.

[0204] When the compound represented by formula (I) exists in tautomerism, unless otherwise stated, the present invention includes any possible tautomerism and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0205] When compound shown in formula (I) and pharmaceutically acceptable salt thereof are in the form of solvate or polymorph, the present invention includes any possible solvate and polymorph. The solvent type forming solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, similar solvents such as water, ethanol, propanol, acetone can be adopted.

[0206] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Non-toxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N′, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0207] When compound provided by the invention is alkali, can be from pharmaceutically acceptable nontoxic acid, including inorganic acid and organic acid, conveniently make its corresponding salt.Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, embroic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc.Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.More preferably, formic acid and hydrochloric acid. Since the compound of formula (I) is to be used as a pharmaceutical, it is preferably used in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight).

[0208] The pharmaceutical composition provided by the present invention includes a compound shown in formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable mode of administration of the active ingredient depends on the specific subject, subject property and severity of the disease to be administered, the pharmaceutical composition of the present invention includes a pharmaceutical composition suitable for oral, rectal, local and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration. The pharmaceutical composition of the present invention can be conveniently prepared in unit dosage forms known in the art and any preparation method known in the pharmaceutical field.

[0209] In fact, according to conventional drug mixing technology, the compound shown in formula (I) of the present invention, or a drug precursor, or a metabolite, or a pharmaceutically acceptable salt, can be used as an active ingredient and mixed with a drug carrier to form a pharmaceutical composition. The drug carrier can take a variety of forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention can be in the form of an independent unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of a powder, granule, solution, aqueous suspension, non-aqueous liquid, water-in-oil emulsion, or oil-in-water emulsion. In addition, in addition to the common dosage forms mentioned above, the compound shown in formula (I) or its pharmaceutically acceptable salt can also be administered by controlled release and / or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier constituting one or more essential components. Generally, the pharmaceutical composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. The product can then be conveniently prepared into the desired presentation.

[0210] Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and one or more other therapeutically active compounds are also included in the pharmaceutical composition of the present invention.

[0211] The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. Gas carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. can be used for oral solid preparations such as powders, capsules and tablets. Considering the ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Optionally, tablet coating can use standard aqueous preparation or non-aqueous preparation technology.

[0212] Tablets containing the compounds or pharmaceutical compositions of the present invention may be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules, mixed with a binder, lubricant, inert diluent, surfactant or dispersant, in a suitable machine. Molded tablets may be prepared by wetting the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of the active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of the active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of the active ingredient, compounded with an appropriate and conveniently metered auxiliary material, which auxiliary material accounts for about 5% to 95% of the total pharmaceutical composition. Dosage unit forms generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0213] The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared into an aqueous solution or suspension by adding the active ingredient into water. Suitable surfactants such as hydroxypropylcellulose can be included. In glycerol, liquid polyethylene glycol, and mixtures thereof in oil, dispersions can also be prepared. Further, preservatives can also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

[0214] The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above-mentioned pharmaceutical compositions can be prepared into the form of sterile powders that can be used for instant preparation of sterile injections or dispersions. In any case, the final injection form must be sterile, and in order to be easy to inject, must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferred to preserve against microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils and suitable mixtures thereof.

[0215] The pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, an aerosol, emulsion, ointment, lotion, dusting powder or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use with a transdermal drug delivery device. These preparations can be prepared using the compound shown in formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. As an example, the preparation of an emulsion or ointment is by adding a hydrophilic material and water to about 5wt% to 10wt% of the above-mentioned compound to obtain an emulsion or ointment with the desired consistency.

[0216] The pharmaceutical composition provided by the present invention can be prepared in a form suitable for rectal administration with a solid as a carrier. The preferred dosage form is a suppository in which the mixture forms a unit dose. Suitable adjuvants include cocoa butter and other materials commonly used in the art. Suppositories can be easily prepared by first mixing the pharmaceutical composition with a softened or melted adjuvant, and then cooling and molding the mixture into a mold.

[0217] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, where appropriate, one or more additional auxiliary components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants and preservatives (including antioxidants), etc. In addition, other adjuvants may also include osmotic agents that regulate the osmotic pressure of the drug and blood. The pharmaceutical composition comprising the compound shown in formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or a concentrated solution.

[0218] Generally, the dosage level of the drug for treating the above-mentioned conditions or discomforts is about 0.01 mg / kg body weight to 150 mg / kg body weight per day, or 0.5 mg to 7 g per patient per day. However, it is understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health status, sex, diet, administration time, administration route, excretion rate, drug combination and the severity of the specific disease being treated. DETAILED DESCRIPTION

[0219] In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with examples. These examples are only for illustrative purposes and are not limited to the scope of application of the present invention. Specific experimental methods not mentioned in the following examples are usually carried out according to conventional experimental methods.

[0220] Unless otherwise indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius.

[0221] The following abbreviations are used in the examples:

[0222] ACN: acetonitrile;

[0223] AcOH: acetic acid;

[0224] AIBN: azobisisobutyronitrile;

[0225] Cul: cuprous iodide;

[0226] DAST: diethylaminosulfur trifluoride;

[0227] DCM: dichloromethane;

[0228] DMSO: dimethyl sulfoxide;

[0229] DMF: N,N-dimethylformamide;

[0230] EA: ethyl acetate;

[0231] ESI-MS: electrospray ionization mass spectrometry;

[0232] m-CPBA: meta-chloroperbenzoic acid;

[0233] NaH: sodium hydride;

[0234] LiHMDS: lithium bis(trimethylsilyl)amide;

[0235] PE: petroleum ether;

[0236] PBS: phosphate buffered saline;

[0237] Na2SO4: sodium sulfate;

[0238] NaBH4: sodium borohydride;

[0239] NBS: N-bromosuccinimide;

[0240] NFSI: N-fluorobis(benzenesulfonamide);

[0241] NIS: N-iodosuccinimide;

[0242] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0243] Pd(PPh3)4: tetrakis(triphenylphosphine)palladium;

[0244] Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;

[0245] Prep-TLC: Preparative thin layer chromatography;

[0246] Selectfluor: 1-chloromethyl-4-fluoro-1,4-azoniabicyclo[22.2]octanebis(tetrafluoroborate);

[0247] TEA: triethylamine;

[0248] THF: tetrahydrofuran;

[0249] TFA: trifluoroacetic acid;

[0250] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0251] 1 H NMR: nuclear magnetic resonance

[0252] [(R,R)-Ts-DPEN]RuCl(p-cymene)]: {[(1R,2R)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-cymene)ruthenium(II) chloride.

[0253] Synthesis of Intermediate M1 (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one)

[0254]

[0255] Step 1: Synthesis of compound M1-1

[0256] Under nitrogen protection, 2-pyrrolecarboxaldehyde (30 g) was dissolved in THF (300 mL), 60% NaH (19 g) was slowly added under ice bath, and after stirring for 1 hour, benzenesulfonyl chloride (66 g) was added. The reaction solution was stirred at 0°C for 3 hours, and the reaction solution was poured into a mixture of ice water (1000 mL), extracted with EA (500 mL*3), washed with saturated brine (500 mL*2), dried with Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1-1 (68 g).

[0257] ESI-MS m / z: 236.06 [M+H + ] + .

[0258] Step 2: Synthesis of Compound M1-2

[0259] 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 M1-1 (68 g) was added in batches after stirring at room temperature for 1 hour. The reaction solution was 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 with Na2SO4, and concentrated to obtain a crude product M1-2 (95 g). The crude product was used directly in the next step.

[0260] ESI-MS m / z:276.05[Mt-Bu + ] - .

[0261] Step 3: Synthesis of Compound M1-3

[0262] At room temperature, M1-2 (95 g) was dissolved in MeOH (1000 mL), Pd / C (10%, 10 g) was added to the reaction system, and stirred overnight under H2 atmosphere. The reaction solution was filtered and concentrated to obtain the target compound M1-3 (95 g), which was directly used in the next step.

[0263] ESI-MS m / z:278.06[Mt-Bu + ] - .

[0264] Step 4: Synthesis of Compound M1-4

[0265] 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 (80 g), which was directly used in the next step.

[0266] Step 5: Synthesis of Compound M1-5

[0267] Under ice bath, oxalyl chloride (48 mL) was added dropwise to a solution of M1-4 (80 g) and DMF (1 mL) in DCM (800 mL), then stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness. The residue was dissolved in DCM (800 mL), cooled to 0°C, AlCl3 (95 g) was added in batches, and stirring was continued at room temperature for 2 hours. The reaction solution was poured into an ice-water mixture to quench, extracted with EA, dried with Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1-5 (33 g).

[0268] ESI-MS m / z: 262.05 [M+H + ] + .

[0269] Step 6: Synthesis of Compound M1-6

[0270] Under ice bath, add NaOH (92 g) to MeOH (300 mL) of M1-5 (33 g), stir at room temperature for 15 minutes, remove most of the solvent under reduced pressure, dilute with water, extract with EA, dry with Na2SO4, filter, concentrate, and purify the crude product by column chromatography (EA / PE=1:5) to obtain the target compound M1-6 (15 g).

[0271] ESI-MS m / z: 122.09 [M+H + ] + .

[0272] Step 7: Synthesis of Compound M1-7

[0273] Under nitrogen protection, M1-6 (15 g) was dissolved in THF (150 mL), 60% NaH (7.4 g) was slowly added under ice bath, and after stirring for half an hour, triisopropylsilyl chloride (28.5 g) was added, and the reaction mixture was stirred at 0°C for 3 hours. The reaction solution was poured into a mixture of ice water (500 mL), extracted with ethyl acetate (500 mL*2), washed with saturated brine (500 mL*2), dried with Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1-7 (28 g).

[0274] ESI-MS m / z: 278.23 [M+H + ] + .

[0275] Step 8: Synthesis of Compound M1-8

[0276] Under nitrogen protection, compound M1-7 (28 g) was dissolved in ACN (100 mL), NIS (27 g) was added in batches, and the temperature was raised to 60°C and stirred for 5 hours. The reaction solution was then poured into a mixture of ice water (500 mL), extracted with EA (500 mL*2), washed with saturated brine (500 mL*2), dried with Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1-8 (18 g).

[0277] Step 9: Synthesis of Compound M1

[0278] Compound M1-8 (2.5 g) was dissolved in THF (30 mL), cooled to -78°C, and a solution of LiHMDS in tetrahydrofuran (1.0 M, 17.5 mL) was slowly added dropwise. After stirring for half an hour, a solution of NFSI (4.1 g) in tetrahydrofuran (10 mL) was added dropwise, and stirring was continued at -78°C for two hours. After the reaction was quenched with a saturated aqueous solution of ammonium chloride, it was extracted twice with ethyl acetate, washed twice with saturated brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:10) to obtain the target compound M1 (700 mg).

[0279] ESI-MS m / z: 283.97 [M+H + ] + .

[0280] Synthesis of Intermediate M2 (5,5-difluoro-3-iodo-1,5,6,7-tetrahydro-4H-indol-4-one)

[0281]

[0282] Step 1: Synthesis of compound M2-1

[0283] Dissolve ethyl 4,4,4-trifluoro-3-oxobutanoate (50 g) in AcOH (80 mL), cool in an ice-water bath, add dropwise a solution of sodium nitrite (19 g) in water (50 mL) below 10°C, warm to room temperature after the addition, concentrate after 2 hours, dilute with EA, wash with water, combine the organic phases, dry and concentrate the target compound M2-1 (59 g).

[0284] Step 2: Synthesis of Compound M2

[0285] Dissolve cyclopentanedione (21 g) in acetic acid (125 mL), heat to 60°C, then add a solution of M2-1 in water (65 mL), stir at 60°C for 10 minutes, then add zinc powder (28 g) in batches, stir at 60°C for 0.5 hours, then heat to 90°C to react overnight, concentrate, dilute with EA, adjust the pH to about 8 with saturated sodium bicarbonate, filter, separate the liquids, extract the aqueous phase twice with EA, combine the organic phases, dry, concentrate, and purify by column chromatography to obtain the target compound M2 (12 g).

[0286] Example 1 Synthesis of 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-2-hydrocyclopenta[b]pyrrol-1-yl]-2-fluorobenzonitrile (Compound A1)

[0287]

[0288] Step 1: Synthesis of compound 1-1

[0289] Compound M1 (200 mg) was dissolved in DCM (20 mL), and copper acetate (60 mg), 3-cyano-4-fluorophenylboronic acid (300 mg) and TEA (300 mg) were added, and stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed twice with saturated brine, dried, and concentrated to obtain a crude product, which was purified by column chromatography (EA / PE=1:5) to obtain the target compound 1-1 (110 mg).

[0290] ESI-MS m / z:403[M+H + ] + .

[0291] Step 2: Synthesis of compound 1-2

[0292] Under nitrogen protection, compound 1-1 (50 mg) was dissolved in DMF (5 mL), and Pd2(dba)3 (23 mg), CuI (28 mg) and methyl fluorosulfonyldifluoroacetate (71 mg) were added, stirred at 100°C overnight, extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:5) to obtain the target compound 1-2 (30 mg).

[0293] ESI-MS m / z: 345 [M+H + ] + .

[0294] Step 3: Synthesis of Compound A1

[0295] Compound 1-2 (30 mg) was dissolved in THF (4 mL), and NaBH4 (10 mg) was added. After stirring at room temperature for 3 hours, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A1 (10 mg).

[0296] ESI-MS m / z: 328.95 [M+H + -H2O] + .

[0297] Example 21-(3-Chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonitrile (Compound A2)

[0298]

[0299] Step 1: Synthesis of compound 2-1

[0300] Replace boric acid with 3-chloro-5-fluorophenylboronic acid and refer to the preparation method of compound 1-1 to obtain compound 2-1.

[0301] ESI-MS m / z:411.9[M+H + ] + .

[0302] Step 2: Synthesis of compound 2-2

[0303] Under nitrogen protection, compound 2-1 (212 mg) was dissolved in DMF (5 mL), and Zn(CN)2 (150 mg) and Pd(PPh3)4 (80 mg) were added. The mixture was stirred at 120°C overnight and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:3) to obtain the target compound 2-2 (120 mg).

[0304] ESI-MS m / z: 311.0 [M+H + ] + .

[0305] Step 3: Synthesis of Compound A2

[0306] Referring to the preparation method of compound 1, compound 2-2 was reduced with NaBH4 to obtain the target compound A2.

[0307] Example 3 Synthesis of 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-2-hydrocyclopentyl[b]pyrrol-1(4H)-yl)benzonitrile (Compound A22)

[0308]

[0309] Step 1: Synthesis of compound 22-1

[0310] Replace boric acid with 4-chloro-3-cyanophenylboronic acid and refer to the preparation method of compound 1-1 to obtain compound 22-1.

[0311] ESI-MS m / z: 418.9 [M+H + ] + .

[0312] Step 2: Synthesis of compound 22-2

[0313] Compound 22-1 (380 mg), methyl 3-sulfanylpropionate (300 mg), Xantphos (116 mg) and Pd2(dba)3 (89 mg) were added to toluene (10 mL), stirred at 70°C overnight, concentrated to obtain a residue, and the residue was purified by column chromatography to obtain the target compound 22-2 (200 mg).

[0314] ESI-MS m / z:411.0[M+H + ] + .

[0315] Step 3: Synthesis of compound 22-3

[0316] At -78°C, potassium tert-butoxide (50 mg) was added to a solution of compound 22-2 (120 mg) in THF (10 mL), and the mixture was stirred at room temperature until the starting material disappeared. Iodomethane (100 mg) was added and stirred at room temperature for 5 hours. The mixture was quenched with saturated ammonium chloride, extracted with EA, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound 22-3 (70 mg).

[0317] ESI-MS m / z: 339.0 [M+H + ] + .

[0318] Step 4: Synthesis of compound 22-4

[0319] At room temperature, m-CPBA (300 mg) was added to a solution of compound 22-3 (130 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 10 hours. The reaction mixture was extracted with aqueous sodium thiosulfate solution, diluted with DCM, washed with aqueous NaHCO3 solution, washed with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound 22-4 (60 mg).

[0320] ESI-MS m / z: 371.0 [M+H + ] + .

[0321] Step 5: Synthesis of Compound A22

[0322] Referring to the preparation method of compound 1, compound 22-4 was reduced with NaBH4 to obtain the target compound A22.

[0323] LCMS: 355.01 [M+H + -H2O] + .

[0324] Example 4 Synthesis of 2-chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A24)

[0325]

[0326] Step 1: Synthesis of compound 24-1

[0327] Compound 24-1 was prepared by replacing 3-cyano-4-fluorophenylboronic acid with 3-cyano-4-chlorophenylboronic acid and referring to the method of step 1 and step 2 of Example 1.

[0328] ESI-MS m / z: 361.0 [M+H + ] + .

[0329] Step 2: Synthesis of compound 24-2

[0330] Under nitrogen protection, compound 24-1 (100 mg) was dissolved in acetonitrile (5 mL), Selectfluor (150 mg) was added, and the mixture was stirred at 80°C overnight. The mixture was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound 24-2 (20 mg).

[0331] ESI-MS m / z: 379.0 [M+H + ] + .

[0332] Step 3: Synthesis of Compound A24

[0333] Compound 24-2 (20 mg) was dissolved in a mixed solvent of THF (2 mL) and H2O (1 mL), and NaBH4 (20 mg) was added under ice bath, and stirred at 0°C for 1 hour. Ice water was added to the reaction solution, and EA was extracted. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product, which was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound A24 (15 mg).

[0334] ESI-MS m / z: 363.01 [M+H + -H2O] + .

[0335] Example 5 Synthesis of 1-(3,5-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol (Compound A25)

[0336]

[0337] Step 1: Synthesis of compound 25-1

[0338] The intermediate M1 (300 mg) was dissolved in DMF (10 mL), K2CO3 (300 mg) and 3,5-difluorobenzyl bromide (300 mg) were added, and 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).

[0339] ESI-MS m / z:410.0[M+H + ] + .

[0340] Step 2: Synthesis of compound 25-2

[0341] Under nitrogen protection, compound 25-1 (320 mg) was dissolved in DMF (5 mL), and Pd2(dba)3 (192 mg), CuI (133 mg) and methyl fluorosulfonyl difluoroacetate (300 mg) were added. The mixture was stirred at 100°C for three hours. The reaction solution was extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:10) to obtain the target compound 25-2 (170 mg).

[0342] ESI-MS m / z: 352.0 [M+H + ]+ .

[0343] Step 3: Synthesis of Compound A25

[0344] Compound 25-2 (170 mg) was dissolved in methanol (4 mL), and NaBH4 (60 mg) was added under ice bath. After stirring at 0°C for 1 hour, ice water was added and extracted with EA. The organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The target compound A25 (120 mg) was purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A25 (120 mg).

[0345] ESI-MS m / z: [M+H + -H2O] + :336.06.

[0346] Example 6 Synthesis of 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A26)

[0347]

[0348] Step 1: Synthesis of compound 26-1

[0349] At room temperature, Pd(dppf)Cl2 (110 mg), K2CO3 (270 mg), and 2-thiopheneboronic acid (200 mg) were added to a mixed solution of compound 22-1 (410 mg) in dioxane (10 mL) / H2O (1 mL), and the mixture was replaced with nitrogen three times. The mixture was reacted at 90°C in a microwave for 3 hours. The reaction mixture was diluted with water, extracted with EA, dried over Na2SO4, and concentrated to obtain the target compound 26-1 (250 mg).

[0350] ESI-MS m / z: 375.0 [M+H + ] + .

[0351] Step 1: Synthesis of Compound A26

[0352] Referring to the preparation method of compound 1, compound 26-1 was reduced with NaBH4 to obtain the target compound A26.

[0353] LCMS: [M+H + -H2O] + :359.02.

[0354] Example 7 Synthesis of 2-chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A27)

[0355]

[0356] Step 1: Synthesis of compound 27-1

[0357] Under nitrogen protection, compound 22-1 (400 mg) was dissolved in a mixed solvent of dioxane (5 mL) / H2O (5 mL), and Pd(PPh3)4 (110 mg), K2CO3 (400 mg) and vinylboronic acid pinacol ester (300 mg) were added. The reaction was allowed to proceed overnight at 90°C, and the mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE=1:5) to obtain the target compound 27-1 (200 mg).

[0358] ESI-MS m / z: 319.0 [M+H + ] + .

[0359] Step 2: Synthesis of compound 27-2

[0360] Compound 27-1 (200 mg) was dissolved in a mixed solvent of THF (5 mL) and H2O (5 mL), and NaIO4 (500 mg) and potassium osmate (20 mg) were added. The mixture was reacted at room temperature for 2 hours, extracted with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:4) to obtain the target compound 27-2 (80 mg).

[0361] ESI-MS m / z: 321.0 [M+H + ] + .

[0362] Step 3: Synthesis of compound 27-3

[0363] Under nitrogen protection, compound 27-2 (80 mg) was dissolved in DCM (4 mL), and DAST (98 mg) was added under ice bath. After the addition was complete, the mixture was returned to room temperature and stirred overnight. The mixture was quenched with saturated sodium bicarbonate and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:4) to obtain the target compound 27-3 (40 mg).

[0364] ESI-MS m / z: 343.0 [M+H + ] + .

[0365] Step 4: Synthesis of Compound A27

[0366] Compound 27-3 (40 mg) was dissolved in a mixed solvent of THF (5 mL) and H2O (5 mL), NaBH4 (30 mg) was added under ice bath, reacted at room temperature for half an hour, extracted with EA, the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (EA / PE=1:3) to obtain the target compound A27 (25 mg).

[0367] LCMS: [M+H + -H2O] + :327.0.

[0368] Example 8 Synthesis of 2-chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A28)

[0369]

[0370] Step 1: Synthesis of compound 28-1

[0371] 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), replaced with nitrogen three times, reacted at 100°C overnight, diluted with EA, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by Prep-TLC (DCM / MeOH=20:1) to obtain the target compound 28-1 (80 mg).

[0372] ESI-MS m / z: 369.0 [M+H + ] + .

[0373] Step 2: Synthesis of Compound A28

[0374] Referring to the preparation method of compound 1, compound 28-1 was reduced with NaBH4 to obtain the target compound A28.

[0375] LCMS: [M+H + -H2O] + :353.0.

[0376] Example 9 Synthesis of 2-fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A45).

[0377]

[0378] Step 1: Synthesis of compound 45-1

[0379] Compound M2 (650 mg), copper acetate (620 mg) and 4A molecular sieves (700 mg) were added to dichloromethane (7 mL), and then N, N-diisopropylethylamine (1.7 mL) was added, stirred at room temperature for half an hour, oxygen was replaced twice, stirred at room temperature overnight, filtered, the filtrate was spin-dried, and column chromatography (PE / EA=5:1 to 1:1, 10% DCM was added as eluent) to obtain compound 45-1 (900 mg).

[0380] ESI-MS m / z: 309.1 [M+H + ] + .

[0381] Step 2: Synthesis of compound 45-2

[0382] 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 Prep-TLC prepared compound 45-2 (100 mg).

[0383] ESI-MS m / z: 327.0 [M+H + ] + .

[0384] Step 3: Synthesis of Compound A45

[0385] 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, and stirred at room temperature for 1 hour. H2O and EA were added, the layers were separated, the organic phase was washed with saturated brine, dried, and concentrated to obtain a crude product. The crude product was subjected to Prep-TLC to obtain the target compound A45.

[0386] LCMS: [M+H + -H2O] + :311.1.

[0387] Example 10 Synthesis of 5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile (Compound A47)

[0388]

[0389] Step 1: Synthesis of compound 47-1

[0390] 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 and stirred for 3 hours, and the residue was concentrated under reduced pressure. Water and EA were added to the residue for dilution, the liquids were separated, the organic phase was washed once with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA=19:1 to 13:1) to obtain the target product 47-1 (320 mg).

[0391] ESI-MS m / z:405 / 407[M+H + ] + .

[0392] Step 2: Synthesis of compound 47-2

[0393] Compound 47-1 (320 mg) was dissolved in ethylene glycol dimethyl ether (4 mL) and water (0.8 mL), and silver perchlorate (350 mg) was added. The temperature was raised to 50°C and stirred for 1 hour. The mixture was diluted with EA, washed with saturated brine, dried and concentrated to obtain a crude product. The crude product was prepared by Prep-TLC (PE / EA=2:1) ​​to obtain the target product 47-2 (260 mg).

[0394] ESI-MS m / z: 343.0 [M+H + ] + .

[0395] Step 3: Synthesis of compound 47-3

[0396] 47-2 (260 mg) was dissolved in dichloromethane (4 mL), cooled to -78 °C, DAST (0.2 mL) was added, the temperature was raised to 0 °C and stirred for 1 hour, aqueous sodium bicarbonate solution and ethyl acetate were added to dilute, the layers were separated, the organic phase was washed with saturated brine, dried and concentrated to obtain a crude product, and the crude product was prepared by Prep-TLC (PE / EA=2:1) ​​to obtain compound 47-3 (200 mg).

[0397] ESI-MS m / z: 345.0 [M+H + ] + .

[0398] Step 4: Synthesis of Compound A47

[0399] Compound 47-3 (130 mg) was dissolved in methanol (1 mL) and THF (1 mL), cooled to 0°C, sodium borohydride (40 mg) was added, stirred at room temperature for 1 hour, diluted with EA and water, separated, washed with saturated brine, dried and concentrated, and the crude product was prepared by Prep-TLC (2:1) to obtain compound A47 (70 mg).

[0400] LCMS: [M+H + -H2O] + :329.

[0401] Example 11: Synthesis of (S)-2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile (Compound A11)

[0402]

[0403] Compound 24-1 (50 mg) was dissolved in dichloromethane (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, and the reaction mixture was bubbled with nitrogen. [(R,R)-Ts-DPEN]RuCl(p-cymene)] (12 mg) was added and stirred at room temperature overnight under nitrogen protection. The crude product was concentrated and purified by Prep-TLC (EA / PE=1:5) to obtain the target compound A11 (30 mg, >98% ee).

[0404] LC-MS: 344.92 [M+H + -H2O] + .

[0405] The examples in Table 1 below were prepared using substantially similar procedures as Examples 1-11.

[0406] Table 1

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] Embodiments 10, 16, 19, 55, 58 1 The H NMR data are shown below:

[0418] 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)

[0419] 1 H NMR (500 MHz, CDCl3) 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)

[0420] 1 H NMR (500 MHz, CDCl3) 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)

[0421] 1 H NMR (500 MHz, CDCl3) 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)

[0422] 1H NMR (500 MHz, CDCl3) 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)

[0423] Pharmacological experiments

[0424] Experimental Example 1 Detection of VEGFA ELISA of the compounds of the present invention (IC 50 )

[0425] 786-O cells in logarithmic phase were inoculated in 96-well plates, with a cell concentration of 65,000 cells per ml of culture medium, 180ul per well. The compound was diluted to the corresponding concentration, and 20ul of compound solution of different concentrations was added to the corresponding cell wells, so that the final concentrations of the compound were (nM): 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. After 24h of culture, the cell culture supernatant was taken, and the VEGFA concentration was determined using an ELISA kit (purchased from abcam). Finally, the reaction was terminated, and the light absorbance of each well was measured at a wavelength of 450nm using an ELISA reader, and the IC was calculated using GraphPadPrism. 50 Meanwhile, CellTiter-Glo reagent was used to determine cell viability.

[0426] Example IC 50 The data are provided in Table 2, where A represents IC 50 ≤0.5μM; B means 0.5μM nM<IC 50 ≤1.0μM; C represents IC 50 >1.0μM.

[0427] Table 2

[0428]

[0429]

[0430] Luciferase assay

[0431] The luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF2α reporter gene cells (786-O-HIF2α-Luc cells). The experiment was carried out when the 786-O-HIF2α-Luc cells were in the logarithmic growth phase, the culture medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, and PBS was rinsed three times; trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells, and the cells were washed with culture medium, 10% fetal bovine serum, 1% penicillin, and streptomycin to terminate the digestion. The cells were collected by centrifugation, washed twice with PBS to remove the phenol red in the culture medium, and the cells were resuspended to an appropriate concentration. The cell density and viability were detected to ensure that the cell viability was above 90% before it could be used for the experiment.

[0432] Use Echo550 (non-contact sonic liquid transfer system, purchased from Labcyte) to transfer the gradient concentration compound to 384 wells, 25nl / well; plant cells in 384-well plates, 4500 cells / well, 25μl culture medium, so that the final concentration of the compound is 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM. Incubate the cells at 37℃, 5% CO2 for 18-20h; add Steady-Glo TM Luciferase assay system (purchased from Promega) was added to a 384-well plate, 25 μl / well; Envision was used to detect the luminescence value. The inhibition rate was calculated based on the RLU (Record Luminescence) signal value of each well, and then the IC of the corresponding compound was calculated by fitting using Graphpad 8.0. 50 The experimental results show that the exemplary compounds of the present invention have good IC 50 .

[0433] In vivo PK

[0434] The compound was prepared with 5% DMSO, 5% Solutol and 90% NaCl. SD rats and Balb / c mice were used for drug administration. The intravenous dose was 1 mg / kg, and blood was collected from the eye sockets at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. The oral dose was 5 mg / kg, and blood was collected from the eye sockets at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. After blood collection, centrifuge at 4000 rpm for 10 min, take the supernatant, add 200 μL of internal standard solution to 30 μL supernatant for precipitation, vortex and centrifuge at 12000 rpm for 10 min, take 100 μL of supernatant solution and mix with pure water in a 1:1 ratio for injection. The concentration of compounds in plasma was detected by HPLC-MS, and the concentration of compounds in plasma samples was quantitatively analyzed by internal standard quantification method. After the compound concentration was measured, Winnonln software was used to calculate CL, C max , AUC and other related pharmacokinetic parameters. The experiments show that the exemplary compounds of the present invention have good in vivo PK properties.

Claims

1. A compound represented by formula (II-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in, L is a key; R1 is a C6-C8 aryl group or a 5-8 membered heteroaryl group, wherein the 5-8 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the C6-C8 aryl group and the 5-8 membered heteroaryl group may be optionally substituted by one or more halogen, -OH, -CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c 、-C0-C6 alkylene-C=OR c 、-NO2、-C(=O)OR c or -S(=O)2R c replaced by; R2 is halogen, -CN or -OH; R3 is H, deuterium, C1-C3 alkyl or C2-C5 alkenyl, wherein the C1-C3 alkyl and C2-C5 alkenyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino, C1-C5 haloalkyl; or R2 and R3 together form an oxo group on the C atom to which they are attached; R4 is halogen; R5 is H, halogen or C1-C6 alkyl, wherein the C1-C6 alkyl may be optionally substituted with one or more H, halogen, -CN, -OH, amino or oxo; R6 is H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo or amino; R7 is selected from -CN, halogen, C1-C 10 Halogenated alkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, -S(=O)R c 、-C1-C6 alkylene-OR c 、-S(=O)2R c and P(=O)R a R b wherein the 5-10 membered heteroaryl group optionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the C1-C 10 Halogenated alkyl, C6-C 10 The aryl group and the 5-10 membered heteroaryl group may be optionally substituted with one or more halogen, hydroxyl, P(=O)Me2, P(=S)Me2, -S(=O)2-C 1-3 Alkyl, -S(=O)2-C 3-5 Cycloalkyl, -S(=O)-C 1-3 Alkyl, -S(=O)-C 1-3 Haloalkyl, -S(=O)-C 3-5 Substituted by cycloalkyl, cyano, C1-C6 alkyl and / or C1-C6 haloalkyl; R8 is H, -CN, -NH2, halogen, C1-C3 alkyl or cyclopropyl; R a and R b Each independently represents H or C1-C6 alkyl; R c is H, C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1 or 2.

2. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R5 is H or halogen.

3. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R2 is -OH.

4. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: R3 is H, deuterium or C1-C3 alkyl, or said R2 and R3 together form an oxo group on the C atom to which they are attached.

5. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R1 is a phenyl group or a 5-6 membered heteroaryl group; wherein the 5-6 membered heteroaryl group optionally contains a heteroatom selected from N, O and S, and the phenyl group and the 5-6 membered heteroaryl group may be optionally substituted by one or more halogen, -OH, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-OR c or -CN.

6. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R1 is a phenyl group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S, and the phenyl group and the 5-6 membered heteroaryl group may be optionally substituted by one or more halogens, cyano groups or C1-C6 haloalkyl groups.

7. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R1 is phenyl or pyridyl, and the phenyl and pyridyl groups may be optionally substituted with one or more halogen, -OH, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene, -OR c or -CN.

8. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R6 is H, halogen or C1-C6 alkyl.

9. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R8 is H or halogen.

10. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt, characterized in that: The R7 is selected from C1-C6 haloalkyl, cyano, -S(=O)2R c , -P(=O)Me2 or a 5-membered heteroaryl, wherein the 5-membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl may be optionally substituted by one or more H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

11. The compound according to claim 1, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, characterized in that R7 is selected from C1-C6 haloalkyl, -S(=O)2R c or a 5-membered heteroaryl, wherein the 5-membered heteroaryl arbitrarily contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the 5-membered heteroaryl may be optionally substituted by one or more H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

12. The compound according to claim 1, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from: 1) 5-[5,5-difluoro-4-hydroxy-3(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1-yl]-2-fluorobenzonitrile; 2) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-4-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonitrile; 3) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 4) 2-chloro-5-(2,5,5-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 6) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 7) 2-chloro-5-(3-(difluoromethyl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 8) 2-chloro-5-(3-(dimethylphosphoryl)-5,5-difluoro-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 9) 2-Fluoro-5-(5-fluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 10) 5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 11) (S)-2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 12) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)phthalonitrile; 13) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 14) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 15) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-4(1H)-one; 16) 3-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 17) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile 18) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalonitrile; 19) 2-chloro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 20) 2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile 21) 5-chloro-2-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 22) 1-(4-chloro-2-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 23) 1-(4-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 24) 5,5-difluoro-1-(4-fluorophenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 25) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 26) 5-(5,5-difluoro-4-hydroxy-3-(thiazol-4-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)isophthalonitrile; 27) 3-(5,5-difluoro-3-(furan-3-yl)-4-hydroxy-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzonitrile; 28) 1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 29) 3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[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-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 33) 2-chloro-5-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 34) 2-chloro-5-(5,5,6-trifluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 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-chloropyridin-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-tetrahydrocyclopenta[b]pyrrol-4-ol; 41) 5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluoro-cyanopyridine; 42) 1-(5-chloropyrazin-2-yl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 43) 1-(3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorophenyl)ethyl-1-one; 44) 4-(5,5-difluoro-4-hydroxy-4-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-hydroxybenzonitrile; 45) 2-chloro-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl-4-deutero)benzonitrile; 46) 3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-5-fluorobenzenecyanate; 51)(S)-2-Fluoro-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[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-tetrahydrocyclopenta[b]pyrrol-4-ol; 54) 5-(5,5-difluoro-4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 55) 5-(5,5-difluoro-4-hydroxy-3-(thiophen-2-yl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 56) 4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-methoxybenzonitrile; 57) 5,5-difluoro-1-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 58) (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[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-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-3-(difluoromethyl)-2-fluorobenzonitrile; 61)(S)-4-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-(difluoromethyl)benzonitrile; 62)(S)-1-(3-chlorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol; 63) (S)-3-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile; 64)(S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[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; or 66) (S)-5-(5,5-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2,3-difluorobenzonitrile; 67) 5-((4S,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]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,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 70) 5-((4S,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 71) 5-((4R,5R,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 72) 5-((4R,5S,6S)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; 73) 5-((4R,5R,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile; or 74) 5-((4R,5S,6R)-(5,6-difluoro-4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)-2-fluorobenzonitrile.

13. A pharmaceutical composition, characterized in that The method comprises at least one therapeutically effective amount of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

14. Use of a compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 13, in the preparation of a medicament for treating, delaying or preventing a disease mediated by HIF-2α; the disease mediated by HIF-2α is VHL syndrome, autoimmune disease, metabolic disease and / or inflammatory disease.

15. Use of the compound according to any one of claims 1 to 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating, delaying or preventing a disease mediated by HIF-2α; the disease mediated by HIF-2α is cancer.

16. The use according to claim 15, characterized in that The cancer is selected from the group consisting of hematological cancers and solid tumors.

17. The use according to claim 15, characterized in that: The cancer is selected from the group consisting of pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, meningeal cancer, neuroblastoma, glioblastoma, meningioma and medulloblastoma.

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