CN116134017A - Bicyclic compounds and uses thereof - Google Patents

Bicyclic compounds and uses thereof Download PDF

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CN116134017A
CN116134017A CN202180047707.6A CN202180047707A CN116134017A CN 116134017 A CN116134017 A CN 116134017A CN 202180047707 A CN202180047707 A CN 202180047707A CN 116134017 A CN116134017 A CN 116134017A
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difluoro
pyrrol
trifluoromethyl
hydroxy
alkyl
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杨荣文
孙云
张健
刘向凯
王萍萍
马腾
伊学刚
张贇
兰宏
丁列明
王家炳
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Abstract

The invention relates to compounds of formula (I), compositions and formulations comprising such compounds, and methods of using and preparing such compounds.

Description

Bicyclic compounds and uses thereof Technical Field
The present invention relates to bicyclic compounds, compositions and formulations comprising such compounds, and methods of using and making such compounds.
Background
HIFs (Hypoxia inducible factors), a member of the transcription factor family, is a pathway for the organism to sense oxygen changes, also known as hypoxia inducible factor, and mediates cellular hypoxia response by controlling more than 40 hypoxia adaptive genes downstream. It is mainly composed of two parts of HIFα (HIF-1α, HIF-2α, HIF-3α) and HIF-1β, wherein HIF-1β is always in the nucleus and HIFα is in the cytoplasm. Under the condition of sufficient oxygen, HIFα can undergo the processes of PHD prolyl hydroxylase hydroxylation, VHL (Von Hippel-Lindau Syndrome) ubiquitin enzyme ubiquitination marking and the like, and finally is degraded by a proteasome, and the biological effect is not exerted in the process. However, when the metabolic pathway is abnormal, HIFα cannot be degraded, and thus accumulates in the nucleus, and combines with HIF-1. Beta. To form heterodimers, which activate hypoxia response elements (Hypoxia response element, HRE) in downstream gene promoters, thereby regulating transcription of the relevant genes, and allowing cells to survive under hypoxia conditions. These genes are involved in tumor angiogenesis, cell proliferation, survival, metabolism, invasion and metastasis, drug resistance, inflammation, immunity, and the like. Wherein HIF-2 alpha mediates chronic hypoxia, can be continuously activated under the condition of physiological hypoxia, and has more key effects on the occurrence and development of tumors.
Current studies indicate that HIF-2 a mediated mechanisms for the development of tumorigenesis mainly include: 1. under the conditions of hypoxia or VHL mutation and the like, the HIF-2 alpha metabolic pathway is blocked and accumulated into the cell nucleus to form heterodimers with HIF-1 beta, so as to activate Hypoxia Response Elements (HRE), regulate and control the up-regulation of cancer related genes such as downstream VEGFA, CXCR4, cyclin D1 and the like and promote tumor angiogenesis; 2. HIF-2 a is also involved in immunosuppressive signaling by upregulating CD73 expression, and thus targeting HIF-2 a restores or enhances antitumor immune function in mature DC cells, activated B cells, and NK cells.
Activation of the HIF-2 a pathway is closely related to the development of renal cell carcinoma, glioma, neuroblastoma, pheochromocytoma, and the like. VHL proteins are an important component of the E3 ubiquitin ligase, mediating proteasome degradation of proteins. The VHL gene has a high mutation rate of 57% or a heterozygous deletion of 98% in kidney cancer cells (renal cell carcinoma; RCC), resulting in pseudohypoxia and induction of HIF-2. Alpha. Activation into the nucleus. Wherein clear cell renal cell carcinoma (Clear cell renal cell carcinoma; ccRCC) accounts for 70% -75% of primary renal cell carcinoma, while more than 90% of ccRCC patients have VHL protein deficiency. Under the condition of no vascularization, the glioma has unstable blood supply to lead to a hypoxia microenvironment, thereby inducing the local high expression of HIF-2 alpha and promoting the growth of tumors. In pheochromocytoma and paraganglioma, the mutation rate of AA at 529-532 position of HIF-2 alpha is up to 81%, and the hydroxylation degradation of HIF-2 alpha is directly affected, so that HIF-2 alpha is continuously activated.
HIF-2α activation and heterodimer formation by HIF-1β are key factors for downstream activation, and the PAS binding domain of both are binding sites for heterodimer formation, on which two small molecule HIF-2α inhibitors, one generation PT2385 and two generation PT2977, were developed by the development team of Peloton corporation, and anti-tumor effects were exerted by inhibiting HIF-2α binding to HIF-1β.
Based on the very important close relationship between HIF-2 a pathway and tumorigenesis and migration, it is highly necessary to develop more efficient new molecular entities.
Disclosure of Invention
The invention firstly provides a compound shown in a formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a chelate, a non-covalent complex or a solvate thereof,
Figure PCTCN2021119569-APPB-000001
wherein,
l is a bond, -O-, NH-, -CR d R e -、-S-、-S(＝O)-、-S(＝O) 2 -, -c=c-, or-c≡c-;
X 1 and X 2 Each independently selected from C or N;
X 3 is CR (CR) 8 Or NR (NR) 8 ；
X 4 Is CR (CR) 7 Or NR (NR) 7 ；
And X is 1 、X 2 And X 4 At least one of which is N;
R 1 selected from C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 6 -C 10 Aryl, 5-18 membered heteroaryl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl; wherein the 5-18 membered heteroaryl and 3-10 membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 6 -C 10 Aryl, 5-18 membered heteroaryl, C 3 -C 10 Cycloalkyl and 3-10 membered heterocyclyl may optionally be substituted with oneOne or more H, halogen, hydroxy, cyano, oxo, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy, -C 1 -C 6 alkylene-OR c 、-C 1 -C 6 alkylene-c=o-R c 、-NO 2 、-SR c 、-NR a R b 、-C(＝O)R c 、-OC(＝O)R c 、-C(＝O)OR c 、-C(＝O)NR a R b 、-NC(＝O)R c 、-S(＝O)R c 、-S(＝O) 2 R c 、-S(＝O) 2 NR a R b 、-S(＝O)(＝NR a )R b 、-P(＝O)R a R b or-P (=s) R a R b Substituted;
R 2 selected from H, -OH, amino, C 1 -C 10 Alkoxy, -O-C (=o) -C 1-3 Alkyl, -NR a R b Deuterium, halogen, -CN, =n-OH, C 1 -C 5 Haloalkyl or-C (=o) -O-C 1-3 An alkyl group;
R 3 selected from H, -OH, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 1 -C 10 Haloalkyl, -O-C (=o) -C 1-3 Alkyl, deuterium, halogen, -CN, =n-OH, -C (=o) -O-C 1-3 Alkyl, -O-C (=o) -C 1-3 Haloalkyl or-C (=o) -O-C 1-3 Haloalkyl, wherein the C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 1 -C 10 Alkoxy, -C (=o) -O-C 1-3 Alkyl, -C (=o) -O-C 1-3 Alkyl, -O-C (=o) -C 1-3 Haloalkyl and-C (=o) -O-C 1-3 Haloalkyl can optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl;
or R is 2 And R is 3 Together form an oxo group on the C atom to which it is attached;
R 4 And R is 5 Are each independently selected from H, halogen, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl; wherein the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl may optionally be substituted with one or more H, halogen, -CN, -OH, oxo, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl; or R is 4 And R is 5 C being isomorphously substituted or unsubstituted with the C atom to which it is attached 3 -C 4 Cycloalkyl or C 3 -C 5 A heterocyclic group;
R 6 selected from H, -CN, halogen, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl, 3-6 membered heterocyclyl, -NO 2 、-NH 2 Or oxo; wherein the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl may optionally be substituted with one or more H, halogen, -CN, -OH, amino, oxo, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl; or two R 6 Together with the C atom to which they are attached form a substituted or unsubstituted C 3 -C 5 Cycloalkyl or 3-5 membered heterocyclyl;
or R is 6 And R is R 5 Together with the C atom to which they are attached form a substituted or unsubstituted C 3 -C 4 Cycloalkyl or 3-5 membered heterocyclyl;
R d and R is e Are each independently selected from H, halogen, cyano, -NR a R b 、C 1 -C 10 Alkyl or C 3 -C 10 Cycloalkyl; or R is d And R is e Together form an oxo group on the C atom to which it is attached;
R 7 selected from H, -NO 2 -CN, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR c 、-SR c 、-NR a R b 、-C(＝O)R c 、-C(＝O)OR c 、-C(＝O)NR a R b 、-NC(＝O)R c 、-S(＝O)R c 、-S(＝O) 2 R c 、-S(＝O) 2 NR a R b 、-S(＝O)(＝NR a )R b 、-P(＝O)R a R b 、-P(＝S)R a R b 、-OC(＝O)R c or-C 1 -C 6 alkylene-OR c The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl and 5-10 membered heteroaryl groups can optionally be substituted with one or more H, halogen, hydroxy, cyano, oxo, amino, C 1 -C 6 Alkyl, C 1-6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 5 Cycloalkyl, 3-6 membered heterocyclyl, P (=o) Me 2 、P(＝S)Me 2 、-S(＝O) 2 -C 1-3 Alkyl, -S (=o) 2 -C 3-5 Cycloalkyl, -S (=o) -C 1-3 Alkyl, -S (=o) -C 3-5 Cycloalkyl group,-S(＝O) 2 -C 1-3 Haloalkyl or-S (=o) -C 1-3 Haloalkyl;
R 8 selected from the group consisting of absent, H, -CN, halogen, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, oxo and-NR a R b The method comprises the steps of carrying out a first treatment on the surface of the The C is 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl and C 3 -C 10 Cycloalkyl groups may optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl;
R a 、R b and R is c Are respectively and independently selected from H, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl; wherein the 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S;
m is 0, 1 or 2.
In some embodiments, the X 1 Is N.
In some embodiments, the X 2 Is N.
In some embodiments, the X 3 Is CR (CR) 8 。
In some embodiments, the X 4 Is CR (CR) 7 。
In some embodiments, the X 4 Is NR (NR) 7 。
In some embodiments of the present invention,l is a bond, -CH 2 -、-S(＝O) 2 -, -C=C-, -C=O-, -C≡C-, or C 3 -C 5 Cycloalkyl groups.
In some embodiments, L is a bond or-CR d R e -。
In some embodiments, L is a bond.
In some embodiments, the R 4 And R is 5 Each independently optionally selected from H, halogen and C 1 -C 6 Alkyl, said C 1 -C 6 The alkyl group may be optionally substituted with one or more H, halogen, -CN, -OH, amino or oxo groups.
In some embodiments, R 4 And R is 5 Each independently optionally selected from H, halogen and C 1 -C 6 An alkyl group.
In some embodiments, R 4 And R is 5 Each independently is H or halogen.
In some embodiments, R 4 And R is 5 Each independently is H or F.
In some embodiments, R 4 F.
In some embodiments, R 5 F.
In some embodiments, R 2 Halogen, -CN, -OH or = N-OH.
In some embodiments, R 2 Halogen, -CN or-OH.
In some embodiments, R 2 F, -CN or-OH.
In some embodiments, R 2 Is halogen.
In some embodiments, R 2 Is hydroxyl.
In some embodiments, R 2 And R is R 3 Together forming an oxo group.
In some embodiments, R 3 Is H, deuterium, C 1 -C 10 Alkyl or C 2 -C 10 Alkenyl groups; wherein the C 1 -C 10 Alkyl and C 2 -C 10 Alkenyl groups may optionally be substituted with one or more H, halogen, -CN, -OH, amino or C 1 -C 5 Haloalkyl.
In some embodiments, R 3 Is H, deuterium or C 1 -C 3 Alkyl, C 2 -C 5 Alkenyl group, wherein the C 1 -C 3 Alkyl and C 2 -C 5 Alkenyl groups may optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Haloalkyl.
In some embodiments, R 3 Is H, deuterium or C 1 -C 3 Alkyl, said C 1 -C 3 Alkyl groups optionally being substituted by one or more H, halogen, -CN, -OH, amino or C 1 -C 5 Haloalkyl.
In some embodiments, R 3 Selected from H, deuterium or C 1 -C 3 An alkyl group.
Preferably, in some embodiments, R 3 Is H or deuterium.
Preferably, in some embodiments, R 3 H.
In some embodiments, R 2 is-OH, -CN or halogen, and R 3 Is H or deuterium; or R is 2 And R is R 3 Together forming an oxo group.
In some embodiments, R 2 is-OH, -CN or-F, and R 3 Is H or deuterium; or R is 2 And R is R 3 Together forming an oxo group.
In some embodiments, R 2 is-OH and R 3 Is H or deuterium; or R is 2 And R is R 3 Together forming an oxo group.
In some embodiments, R 1 Is C 6 -C 10 Aryl, 5-18 membered heteroaryl or C 3 -C 10 Cycloalkyl, said 5-18 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S.
In some embodiments, the R 1 Is C 6 -C 10 Aryl or 5-18 membered heteroaryl, said 5-18 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S.
In some embodiments, the R 1 Is phenyl or 5-6 membered heteroaryl; the 5-6 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms selected from N, O and S.
In some embodiments, the R 1 Is phenyl or 6 membered heteroaryl; the 6 membered heteroaryl optionally contains 1, 2 or 3N heteroatoms.
In some embodiments, R 1 Is C 6 -C 8 Aryl or 5-8 membered heteroaryl, said 5-8 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; wherein the C 6 -C 8 Aryl and 5-8 membered heteroaryl groups can optionally be substituted with one or more H, halogen, -OH, -CN, oxo, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c 、-C 0 -C 6 alkylene-c=o-R c 、-NO 2 、-C(＝O)OR c or-S (=o) 2 R c Substituted.
In some embodiments, R 1 Is phenyl or a 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said phenyl and 5-6 membered heteroaryl optionally being substituted with one or more H, halogen, -OH, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c or-CN.
In some embodiments, R 1 Is phenyl or a 5-6 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said phenyl or 5-6 membered heteroaryl optionally being substituted with one or more halogen, cyano and/or C 1 -C 6 Haloalkyl.
In some embodiments, R 1 Is phenyl or a 5-6 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms independently selected from N, O and S, respectively, said phenyl or 5-6 membered heteroaryl optionally being substituted with one or more halogen, cyano and/or trifluoromethyl groups.
In some embodiments, the R 1 Optionally substituted with one or more halogens and/or cyano groups.
In some embodiments, the R 1 Is phenyl.
In some embodiments, the R 1 Is a pyridyl group.
In some embodiments, the R 1 Is pyrimidinyl, pyrazinyl or pyridazinyl.
In some embodiments, the R 1 Is phenyl or pyridinyl, which may optionally be substituted with one or more halogen, -OH, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c or-CN.
In some embodiments, the R 1 Is phenyl or pyridinyl, which may optionally be substituted with one or more halogen, -CN or C 1 -C 6 Taken from haloalkylAnd (3) replacing.
In some embodiments, the R 1 Is phenyl or pyridinyl, which may optionally be substituted with one or more halogens, -CN, -CHF 2 、-CF 3 、-CH 2 CHF 2 and/or-CH 2 CF 3 Substituted.
In some embodiments, the R 6 Is H, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkyl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, amino.
In some embodiments, R 6 Is H, halogen or C 1 -C 6 Alkyl, said C 1 -C 6 The alkyl group may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, amino.
In some embodiments, R 6 Is H, halogen or C 1 -C 6 An alkyl group.
In some embodiments, R 6 Is H and/or halogen.
In some embodiments, R 6 H, F, cl or Br.
In some embodiments, R 6 H or F.
In some embodiments, R 6 H.
In some embodiments, two R 6 Together with the C atom to which it is attached form a cyclopropyl group.
In some embodiments, R 8 Is H, -CN, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments, R 8 Is H, -CN or halogen.
In some embodiments, R 8 Selected from H, -CN, -NH 2 Halogen, C 1 -C 3 Alkyl and cyclopropyl.
In some embodiments, R 8 Is H or halogen.
In some embodiments, R 8 Is H, -CN, -F, -Cl, -Br or-CF 3 。
In some embodiments, R 8 H.
In some embodiments, the R 7 Selected from H, -CN, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, -S (=o) R, a 5-10 membered heteroaryl c 、-C 1 -C 6 alkylene-OR c 、-S(＝O) 2 R c Or P (=O) R a R b The method comprises the steps of carrying out a first treatment on the surface of the The 5-10 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; wherein the C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl may optionally be substituted with one or more halogen, hydroxy, P (=o) Me 2 、P(＝S)Me 2 、-S(＝O) 2 -C 1-3 Alkyl, -S (=o) 2 -C 3-5 Cycloalkyl, -S (=o) -C 1-3 Alkyl, -S (=o) -C 1-3 Haloalkyl, -S (=o) -C 3-5 Cycloalkyl, cyano, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl;
the R is a And R is b Are respectively and independently selected from H, C 1 -C 6 An alkyl group;
the R is c Selected from H, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments, R 7 Selected from halogen, cyano, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, 5 membered heteroaryl, S (=o) R c 、-S(＝O) 2 R c 、-S(＝O)(＝NR a )R b Or P (=O) Me 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 3 -C 6 Cycloalkyl, 5 membered heteroaryl groups optionally being substituted by H, halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 3 Haloalkyl.
In some embodiments, the R 7 Selected from halogen, cyano, C 1 -C 4 Haloalkyl, C 3 -C 5 Cycloalkyl, 5 membered heteroaryl, S (=o) R c 、-S(＝O) 2 R c 、-S(＝O)(＝NR a )R b or-P (=O) Me 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 3 -C 5 Cycloalkyl and 5 membered heteroaryl groups can optionally be substituted with H, halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 3 Haloalkyl.
In some embodiments, the R 7 Selected from C 1 -C 6 Haloalkyl, cyano, -S (=o) 2 R c 、-P(＝O)Me 2 Or a 5-membered heteroaryl, optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; the 5 membered heteroaryl may optionally be substituted with one or more H, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Haloalkyl.
In some embodiments, the R 7 Selected from C 1 -C 6 Haloalkyl, -S (=o) 2 R c Or a 5-membered heteroaryl, optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; the 5 membered heteroaryl may optionally be substituted with one or more H, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Haloalkyl.
In some embodiments, the R 7 Selected from trifluoromethyl, difluoromethyl, cyano, -S (=o) 2 -R c Or a 5-membered heteroaryl, optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; the R is c Selected from C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments, the R 7 Is C 1 -C 4 A haloalkyl group.
In some embodiments, the R 7 is-S (=O) 2 -R c The R is c Selected from C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments, the R a And R is b Are respectively and independently selected from H, C 1 -C 4 An alkyl group.
In some embodiments, the R c Selected from H, C 1 -C 3 Alkyl or C 1 -C 3 A haloalkyl group.
In some embodiments, the R 7 Selected from the group consisting of
Figure PCTCN2021119569-APPB-000002
Figure PCTCN2021119569-APPB-000003
In some embodiments, the R 7 Selected from the group consisting of
Figure PCTCN2021119569-APPB-000004
Figure PCTCN2021119569-APPB-000005
In some embodiments, the compound is represented by formula (II-1), formula (II-2) or formula (II-3),
Figure PCTCN2021119569-APPB-000006
the R is 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 ，R 7 ，R 8 L and m are as described in the previous embodiments.
In some embodiments, the compound is represented by formula (III-1), formula (III-2) or formula (III-3),
Figure PCTCN2021119569-APPB-000007
the R is 1 ，R 6 ，R 7 ，R 8 And m is as described in the previous embodiments.
The invention further provides a compound or a pharmaceutically acceptable salt thereof, which is:
1) 5- [5, 5-difluoro-4-hydroxy-3 (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
4) 2-chloro-5- (2, 5-trifluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
5) 1- (3, 5-difluorobenzyl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
6) 2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (thiophen-2-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
7) 2-chloro-5- (3- (difluoromethyl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
8) 2-chloro-5- (3- (dimethylphosphoryl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
9) 2-fluoro-5- (5-fluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
10 5- (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
11 (S) -2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
12 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) phthalonitrile;
13 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
14 2-chloro-4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
15 1- (3-chloro-5-fluorophenyl) -5, 5-difluoro-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-4 (1H) -one;
16 3-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
17 3- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorobenzonitrile
18 5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
19 2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
20 2- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorobenzonitrile
21 5-chloro-2- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
26 5- (5, 5-difluoro-4-hydroxy-3- (thiazol-4-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
27 3- (5, 5-difluoro-3- (furan-3-yl) -4-hydroxy-5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
30 1- (3-chloro-5-fluorophenyl) -3- ((difluoromethyl) sulfonyl) -5, 5-difluoro-1, 4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
31 5- (5, 5-difluoro-4-hydroxy-3- (1-methyl-1H-pyrazol-5-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
32 2-chloro-5- (5-fluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
33 2-chloro-5- (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
34 2-chloro-5- (5, 6-trifluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
35 5- (3-chloro-5-fluorophenyl) -2, 2-difluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolidin-1-ol;
36 1- (2-chloropyridin-4-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
37 1- (6-chloropyridin-3-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
38 1- (5-chloropyridin-2-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
39 1- (5-aminopyridin-2-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
40 5, 5-difluoro-1- (6-fluoropyridin-3-yl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
41 5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -5-fluorophenyl) ethyl-1-one;
44 4- (5, 5-difluoro-4-hydroxy-4-methyl-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-hydroxybenzonitrile;
45 2-chloro-4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl-4-deuterium) benzonitrile;
46 3-5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorocyanophene;
47 1- (3-chloro-5-fluorophenyl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-4-ol;
48 5- (3-chloro-5-fluorophenyl) -2, 3-difluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolidin-1-ol;
49 3- (3-chloro-5-fluorophenyl) -6, 6-difluoro-1- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-7-ol;
50 5- (3-chloro-5-fluorophenyl) -2-fluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolizin-1-ol;
51 (S) -2-fluoro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
55 5- (5, 5-difluoro-4-hydroxy-3- (thiophen-2-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
56 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydropyrrolo [ 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-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -3- (difluoromethyl) -2-fluorobenzonitrile;
61 (S) -4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ 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-dihydropyrrolo [ 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;
66 (S) -5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -2, 3-difluorobenzonitrile;
67 5- ((4S, 5S, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
68 5- ((4S, 5S, 6S) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile
69 5- ((4S, 5R, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
70 5- ((4S, 5R, 6S) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
71 5- ((4 r,5r,6 s) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
72 5- ((4 r,5s,6 s) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
73 5- ((4 r,5r,6 r) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile; or (b)
74 5- ((4R, 5S, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile).
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates thereof, and pharmaceutically acceptable excipients, such as hydroxypropyl methylcellulose. In some compositions, the weight ratio of the compound or stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof to the adjuvant is about 0.001 to 10.
In addition, the invention provides a method of treating a subject having a HIF-2α -mediated disease or condition, comprising administering a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof.
In certain aspects, the disease or disorder is selected from the group consisting of VHL syndrome, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, cardiovascular disorder, renal disorder, viral infection, and obesity. In certain aspects, the disease or disorder is selected from rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, asthma, chronic obstructive airways disease, pneumonia, dermatitis, hair loss, nephritis, vasculitis, atherosclerosis, alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), acute rejection of transplanted organs. In certain aspects, the disease or disorder is cancer, including hematological cancer, lymphoma, multiple myeloma, digestive system tumor, reproductive system tumor, brain tumor, nervous system tumor neoplasm.
In certain aspects, the disease or disorder is a permatism, pheochromocytoma, paraganglioma, colon, rectum, prostate (e.g., castration resistant (castrate resistant) prostate cancer), lung cancer (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), neoplasms or cancers of the nervous system (including brain, meninges, and central nervous system, including neuroblastomas, glioblastomas, meningiomas, and medulloblastomas).
In certain aspects, the disease or disorder is VHL syndrome. In certain aspects, the disease or disorder is renal cancer. In certain aspects, the subject is a human.
In certain aspects, the compound is administered intravenously, intramuscularly, parenterally, nasally, or orally. In one aspect, the compound is administered orally.
The invention also provides the use of a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, in the manufacture of a medicament for treating a disease or disorder mediated by HIF-2α.
The invention also provides a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof for use in therapy. Further provided are compounds of formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates thereof, for use in treating a subject having a disease or condition mediated by HIF-2 a. In the present invention, the term "halogen" (halogen) means fluorine, chlorine, bromine or iodine unless otherwise specified. Preferred halogen groups are fluorine, chlorine and bromine.
In the present invention, the term "alkyl" includes, unless otherwise indicated, straight, branched or cyclic saturated monovalent hydrocarbon radicals. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C 1-6 "C" in alkyl 1-6 "refers to a group containing 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain.
The term "alkoxy" refers to an oxyether formed from a straight, branched or cyclic alkyl group as described above.
The term "alkylene" refers to a divalent alkyl linking group. Alkylene refers formally to an alkane in which two C-H bonds are replaced with points of attachment of the alkylene group to the rest of the compound. Similarly, C 1-4 "C" in alkylene 1-4 "refers to an alkylene group containing 1, 2, 3 or 4 carbon atoms.
The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced with a halogen atom. The term "haloalkoxy" refers to a group of an-O-haloalkyl group.
The term "oxo" or "oxo" refers to an oxygen atom in the form of a dimethyl substituent that forms a carbonyl group when attached to C and a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom.
In the present invention, unless otherwise indicated, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" is a carbocyclic or heterocyclic ring of polyunsaturated rings having aromatic character (having (4n+2) delocalized pi electrons, where n is an integer).
The term "aryl" substituted or unsubstituted stable aromatic hydrocarbon groups of 6 to 10 ring carbon atoms, which may contain 1 aromatic ring or multiple aromatic rings (e.g., fused bicyclic rings). The aromatic ring does not contain heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and the like.
The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member selected from N, O and/or S. "3-to 10-membered" in a 3-to 10-membered heteroaryl refers to a heteroaryl group consisting of 3-to 10-carbon atoms or N, O or S ring-forming atoms. Examples of such heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, benzimidazole, benzothienyl, benzofuranyl, and the like.
The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Term C 3-10 "C" in cycloalkyl 3-10 "means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring members. Cycloalkyl groups may be includedIncluding monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings, spiro, fused rings, etc.). Some embodiments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; in some embodiments cycloalkyl also includes moieties having one or more aromatic rings fused to a cyclized alkyl ring, such as benzo or thienyl derivatives of cyclohexane, and the like.
The term "cycloalkenyl" refers to a ring system having at least one cycloalkenyl group with one or more carbon-carbon double bonds therein. Term C 3-10 "C" in cycloalkenyl 3-10 "means that the cycloalkenyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 ring members. Cycloalkenyl groups can include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). Some embodiments include, but are not limited to, cyclohexenyl, cyclohexadiene, cycloheptatrienyl, and the like; in some embodiments cycloalkenyl further includes moieties having one or more aromatic rings fused to the cycloalkenyl ring, such as benzo or thienyl derivatives of cyclohexene ring, and the like.
The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom selected from N, O and/or S. The heterocyclyl may include single or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group may be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. "5-18 membered" in a 5-18 membered heterocyclic group means a heterocyclic group consisting of 5-18 carbon atoms or N, O or S ring-forming atoms. Also included in the definition of heterocyclyl are benzo or thienyl derivatives having one or more aromatic rings fused to a cyclized alkyl or cyclized alkenyl ring, such as piperidine, morpholine and the like. In some embodiments, heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, morpholinyl, azepane, dihydrobenzofuranyl, and the like.
The term "composition" as used herein is intended to include products comprising the specified amounts of the specified components as well as any product that results, directly or indirectly, from the specified amounts of the specified components. Accordingly, pharmaceutical compositions comprising the compounds of the present invention as active ingredients and methods of preparing the compounds are also within the scope of the present invention. Furthermore, the crystalline forms of some of the compounds may exist as polymorphs, which are also included in the present invention. In addition, some compounds form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also encompassed within the present invention.
Prodrugs (prodrugs) of the compounds of the present invention are included within the scope of the present invention. Typically, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. Thus, the term "administering" in the methods of treatment provided herein includes administration of a compound disclosed herein, or a prodrug compound that is capable of being converted in vivo to a compound disclosed herein after administration to a subject, although not explicitly disclosed. Conventional methods for the selection and preparation of suitable prodrug derivatives have been described in, for example, the book "prodrug design" (Design of Prodrugs, ed.H.Bundgaard, elsevier, 1985).
Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of the other positions in the molecule. It will be readily appreciated that one of ordinary skill in the art can select substituents or substituted forms of the compounds of the invention by prior art means and methods described herein to provide compounds that are chemically stable and readily synthesized.
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, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The above formula (I) does not define exactly the steric structure of a certain position of the compound. The invention includes all stereoisomers of the compounds of formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the invention. During the synthesis of preparing such compounds, or using racemization or epimerization methods well known to those of ordinary skill in the art, the resulting product may be a mixture of stereoisomers.
When a tautomer of the compound of formula (I) exists, the present invention includes any of the possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise indicated.
When the compounds of formula (I) and pharmaceutically acceptable salts thereof are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like may be used.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided herein are acids, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (both higher and lower), ferric, ferrous, lithium, magnesium, manganese (both higher and lower), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases capable of derivatizing into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituent-containing amines, such as naturally occurring and synthetic substituent-containing amines. Other pharmaceutically acceptable non-toxic organic bases capable of salt formation include ion exchange resins as well as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, halamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compounds provided by the present invention are bases, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharin acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like. 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 compounds of formula (I) will be used as pharmaceuticals, it is preferred to use substantially pure forms, for example at least 60% pure, more suitably at least 75% pure, in particular at least 98% pure (% by weight).
The pharmaceutical composition provided by the invention comprises a compound (or pharmaceutically acceptable salt thereof) shown in a formula (I) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular subject, nature of the subject and severity of the condition being administered, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently presented in unit dosage form well known in the art and prepared by any of the methods of manufacture well known in the pharmaceutical arts.
In fact, the compounds of formula (I) of the present invention, or prodrugs, or metabolites, or pharmaceutically acceptable salts thereof, may be admixed with pharmaceutical carriers as active ingredients to pharmaceutical compositions according to conventional pharmaceutical compounding techniques. The pharmaceutical carrier may take a variety of forms depending on the mode of administration desired to be employed, for example, orally or by injection (including intravenous injection). Thus, the pharmaceutical compositions of the present invention may take the form of individual units suitable for oral administration, such as capsules, cachets or tablets containing the predetermined dose of the active ingredient. Further, the pharmaceutical compositions of the present invention may take the form of powders, granules, solutions, aqueous suspensions, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition, in addition to the usual dosage forms mentioned above, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered by means of controlled release and/or delivery means. The pharmaceutical compositions of the present invention may be prepared by any pharmaceutical method. Typically, such methods include the step of associating the active ingredient with a carrier that constitutes one or more of the necessary ingredients. Typically, the pharmaceutical compositions are prepared by intimate mixing of the active ingredient with a liquid carrier or finely divided solid carrier or a mixture of both. The product can then be conveniently prepared to the desired appearance.
Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) or pharmaceutically acceptable salts thereof, and one or more other therapeutically active compounds are also included in the pharmaceutical compositions of the present invention.
The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Solid carriers including lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers include syrup, peanut oil, olive oil, and water. And a gas carrier including carbon dioxide and nitrogen. Any convenient pharmaceutically acceptable medium may be used in the preparation of the pharmaceutical oral formulation. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used in liquid preparations for oral administration such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used in the oral solid preparations such as powders, capsules and tablets. In view of ease of administration, oral formulations are preferably tablets and capsules, where solid pharmaceutical carriers are employed. Alternatively, tablet coatings may use standard aqueous or non-aqueous formulation techniques.
Tablets containing a compound or pharmaceutical composition of the invention may be prepared by compression or molding, optionally together with one or more accessory ingredients or adjuvants. The active ingredient is in free-flowing form, such as a powder or granules, admixed with binders, lubricants, inert diluents, surfactants or dispersants and compressed tablets may be prepared by compression in a suitable machine. Molded tablets may be made by impregnating the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine. Preferably, each tablet contains about 0.05mg to 5g of active ingredient and each cachet or capsule contains about 0.05mg to 5g of active ingredient. For example, dosage forms intended for oral administration to humans comprise from about 0.5mg to about 5g of the active ingredient in combination with suitable and conveniently metered auxiliary materials, which auxiliary materials constitute from about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains from about 1mg to about 2g of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
The pharmaceutical compositions provided herein suitable for parenteral administration may be prepared as aqueous solutions or suspensions of the active ingredient in water. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical compositions of the present invention to prevent the growth of detrimental microorganisms.
The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions. Further, the above pharmaceutical composition may be prepared in the form of a sterile powder which can be used to prepare sterile injectable solutions or dispersions on-the-fly. In any event, the final injection form must be sterile and must be readily flowable for ease of injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Thus, preservation against microbial, such as bacterial and fungal contamination is preferred. The carrier may 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.
The pharmaceutical compositions provided herein may be in a form suitable for topical administration, for example, as an aerosol, emulsion, ointment, lotion, dusting powder, or other similar dosage form. Further, the pharmaceutical compositions provided herein may take a form suitable for use with transdermal drug delivery devices. These formulations can be prepared by conventional processing methods using the compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof. As an example, a cream or ointment may be prepared by adding hydrophilic materials and water to about 5wt% to about 10wt% of the above-mentioned compounds to produce a cream or ointment having the desired consistency.
The pharmaceutical composition provided by the invention can be prepared into a form which takes a solid as a carrier and is suitable for rectal administration. The preferred dosage form is a mixture forming a unit dose suppository. Suitable adjuvants include cocoa butter and other materials commonly used in the art. Suppositories may be conveniently prepared by first mixing the pharmaceutical composition with the softened or melted excipients and then cooling and molding the mixture.
In addition to the carrier components mentioned above, the above pharmaceutical formulations may include, as appropriate, one or more additional auxiliary components such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants and preservatives (including antioxidants) and the like. In addition, other adjuvants may include permeation enhancers that regulate the isotonic pressure of the drug and blood. Pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or concentrate.
Typically, the dosage level of the drug is about 0.01mg/kg body weight to 150mg/kg body weight per day, or 0.5mg to 7g per patient per day, for the treatment of the conditions or discomfort indicated above. However, it will be appreciated that the specific dosage level for any particular patient will depend on a variety of factors including the age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Detailed Description
In order that the invention may be more readily understood, the invention will be described in more detail with reference to the following examples, which are intended to be illustrative only and are not intended to limit the scope of the invention, and the specific experimental methods not mentioned in the following examples are generally carried out in accordance with conventional experimental methods.
All parts and percentages are by weight and all temperatures are in degrees celsius unless otherwise indicated.
The following abbreviations are used in the examples:
ACN: acetonitrile;
AcOH: acetic acid;
AIBN: azobisisobutyronitrile;
CuI: cuprous iodide;
DAST: diethylaminosulfur trifluoride;
DCM: dichloromethane;
DMSO: dimethyl sulfoxide;
DMF: n, N-dimethylformamide;
EA: ethyl acetate;
ESI-MS: electrospray ionization mass spectrometry;
m-CPBA: m-chloroperoxybenzoic acid;
NaH: sodium hydride;
LiHMDS: lithium bis (trimethylsilyl) amide;
PE: petroleum ether;
PBS: phosphate buffered saline;
Na 2 SO 4 : sodium sulfate;
NaBH 4 : sodium borohydride;
NBS: n-bromosuccinimide;
NFSI: n-fluoro bis-benzenesulfonamide;
NIS: n-iodosuccinimide;
Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium;
Pd(PPh 3 ) 4 : tetrakis (triphenylphosphine) palladium;
Pd(dppf)Cl 2 : [1,1' -bis (diphenylphosphine) ferrocene ]Palladium (II) dichloride;
Prep-TLC: preparing thin layer chromatography;
SelectFluor: 1-chloromethyl-4-fluoro-1, 4-azonia bicyclo [2.2.2] octane bis (tetrafluoroborate);
TEA: triethylamine;
THF: tetrahydrofuran;
TFA: trifluoroacetic acid;
xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
1 h NMR: nuclear magnetic resonance hydrogen spectrum
[ (R, R) -Ts-DPEN ] RuCl (p-cymene) ]: chloro { [ (1R, 2R) - (-) -2-amino-1, 2-diphenylethyl ] (4-toluenesulfonyl) amino } (P-isopropyltoluene) ruthenium (II).
Synthesis of intermediate M1 (5, 5-difluoro-3-iodo-1, 5,6, 7-tetrahydro-4H-indol-4-one)
Figure PCTCN2021119569-APPB-000008
Step 1 Synthesis of Compound M1-1
2-Pyrrolecarboxaldehyde (30 g) was dissolved in THF (300 mL) under nitrogen, 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 0deg.C for 3 hours, poured into a mixture of ice water (1000 mL), extracted with EA (500 mL. Times.3), washed with saturated brine (500 mL. Times.2), and dried over Na 2 SO 4 Drying and concentration gave a crude product, which was purified by column chromatography (EA/pe=1:10) to give the target compound M1-1 (68 g).
ESI-MS m/z:236.06[M+H + ] + 。
Step 2: synthesis of Compound M1-2
Diethylphosphonoacetic acid tert-butyl ester (73 g) was dissolved in THF (700 mL) under nitrogen, 60% NaH (17 g) was slowly added under ice-bath, and after stirring at room temperature for 1 hour, M1-1 (68 g) was added in portions. The reaction solution was stirred for 3 hours, and the reaction solution was poured into ice water (1000 mL) of the mixture, EA (1000 mL. Times.3) was extracted, washed with saturated saline (1000 mL. Times.2), and Na 2 SO 4 Drying and concentration gave crude M1-2 (95 g). The crude product was used directly in the next step.
ESI-MS m/z:276.05[M-t-Bu + ] - 。
Step 3: synthesis of Compound M1-3
M1-2 (95 g) was dissolved in MeOH (1000 mL) at room temperature, pd/C (10%, 10 g) was added to the reaction system at H 2 Stirring overnight under an atmosphere, filtering the reaction solution, and concentrating to obtain the target compound M1-3 (95 g), which was used directly in the next step.
ESI-MS m/z:278.06[M-t-Bu + ] - 。
Step 4: synthesis of Compounds M1-4
M1-3 (95 g) was dissolved in DCM (1000 mL) at room temperature, TFA (50 mL) was added to the reaction system under ice-bath, and stirred for 2 hours, and the reaction solution was concentrated to dryness to give the title compound M1-4 (80 g) which was used directly in the next step.
Step 5: synthesis of Compound M1-5
Oxalyl chloride (48 mL) was added dropwise to a solution of M1-4 (80 g) and DMF (1 mL) in DCM (800 mL) under ice, then stirred at room temperature for 2 hours and the reaction concentrated to dryness. The residue was dissolved in DCM (800 mL) and cooled to 0deg.C and AlCl was added in portions 3 (95g) Stirring was continued for 2 hours at room temperature. Pouring the reaction solution into an ice-water mixture for quenching, EA extraction and Na 2 SO 4 Drying, filtering and concentrating. The crude product was purified by column chromatography (EA/pe=1:10) to give the target compound M1-5 (33 g).
ESI-MS m/z:262.05[M+H + ] + 。
Step 6: synthesis of Compounds M1-6
NaOH (9.2 g) was added to M1-5 (33 g) MeOH (300 mL) in an ice bath, stirred at room temperature for 15 min, the reaction was freed from most of the solvent under reduced pressure, diluted with water, EA extract, na 2 SO 4 Drying, filtering, concentrating, and subjecting the crude product to column chromatography (EA/pe=)1:5) to give the target compound M1-6 (15 g).
ESI-MS m/z:122.09[M+H + ] + 。
Step 7: synthesis of Compound M1-7
M1-6 (15 g) was dissolved in THF (150 mL) under nitrogen, 60% NaH (7.4 g) was slowly added under ice-bath, and after stirring for half an hour, triisopropylchlorosilane (28.5 g) was added and the reaction mixture was stirred for 3 hours at 0 ℃. Pouring the reaction solution into ice water (500 mL) mixture, extracting with ethyl acetate (500 mL. Times.2), washing with saturated saline (500 mL. Times.2), and Na 2 SO 4 Drying and concentration gave a crude product which was purified by column chromatography (EA/pe=1:10) to give the target compound M1-7 (28 g).
ESI-MS m/z:278.23[M+H + ] + 。
Step 8: synthesis of Compounds M1-8
Compounds M1-7 (28 g) were dissolved in ACN (100 mL) under nitrogen, NIS (27 g) was added in portions, and the mixture was stirred at 60℃for 5 hours. The reaction mixture was then poured into ice water (500 mL), extracted with EA (500 mL x 2), washed with saturated brine (500 mL x 2), na 2 SO 4 Drying and concentration gave a crude product which was purified by column chromatography (EA/pe=1:10) to give the target compound M1-8 (18 g).
Step 9: synthesis of Compound M1
Compound M1-8 (2.5 g) was dissolved in THF (30 mL), cooled to-78deg.C, and LiHMDS tetrahydrofuran solution (1.0M, 17.5 mL) was slowly added dropwise, after stirring for half an hour, NFSI (4.1 g) tetrahydrofuran solution (10 mL) was added dropwise, and stirring was continued at-78deg.C for two hours. After the reaction was quenched with saturated ammonium chloride aqueous solution, the extract was extracted twice with ethyl acetate, washed twice with saturated brine, and dried over Na 2 SO 4 Drying and concentration gave a crude product, which was purified by column chromatography (EA/pe=1:10) to give the target compound M1 (700 mg).
ESI-MS m/z:283.97[M+H + ] + 。
Synthesis of intermediate M2 (5, 5-difluoro-3-iodo-1, 5,6, 7-tetrahydro-4H-indol-4-one)
Figure PCTCN2021119569-APPB-000009
Step 1: synthesis of Compound M2-1
Ethyl 4, 4-trifluoro-3-oxobutyrate (50 g) was dissolved in AcOH (80 mL), cooled in an ice water bath, and a solution of sodium nitrite (19 g) in water (50 mL) was added dropwise at 10℃or below, and after 2 hours, the mixture was concentrated, EA diluted, washed with water, and the organic phases were combined, and the target compound M2-1 (59 g) was concentrated by drying.
Step 2: synthesis of Compound M2
Cyclopentanedione (21 g) is dissolved in acetic acid (125 mL), heated to 60 ℃, then M2-1 water (65 mL) solution is added, stirring is carried out for 10 minutes at 60 ℃ after the addition, zinc powder (28 g) is added in batches, stirring is carried out for 0.5 hour at 60 ℃ after the addition, then the temperature is increased to 90 ℃ for reaction overnight, concentration, dilution by EA, pH adjustment by saturated sodium bicarbonate to about 8, filtration and liquid separation are carried out, the aqueous phase is extracted twice by EA, the organic phases are combined, dried, concentrated and purified by column chromatography to obtain the target compound M2 (12 g).
Example 1 5 Synthesis of- [5, 5-difluoro-4-hydroxy-3 (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1-yl ] -2-fluorobenzonitrile (Compound A1)
Figure PCTCN2021119569-APPB-000010
Step 1: synthesis of Compound 1-1
Compound M1 (200 mg) was dissolved in DCM (20 mL), copper acetate (60 mg), 3-cyano-4-fluorobenzeneboronic 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 give the crude product which was purified by column chromatography (EA/pe=1:5) to give the target compound 1-1 (110 mg).
ESI-MS m/z:403[M+H + ] + 。
Step 2: synthesis of Compounds 1-2
Compound 1-1 (50 mg) was dissolved in DMF (5 mL) under nitrogen, and Pd was added 2 (dba) 3 (23 mg), cuI (28 mg) and methyl fluorosulfonyl difluoroacetate (71 mg), stirring overnight at 100℃and EA extraction, washing the organic layer with brine, na 2 SO 4 Drying and concentrating to obtain crude product, and purifying the crude product by column chromatography (EA/PE=1:5) to obtain target compound 1-2 (30 mg).
ESI-MS m/z:345[M+H + ] + 。
Step 3: synthesis of Compound A1
Compound 1-2 (30 mg) was dissolved in THF (4 mL), naBH was added 4 (10 mg) after stirring at room temperature for 3 hours, quenching with saturated ammonium chloride solution, extraction with EA, washing the organic layer with brine, na 2 SO 4 Drying and concentration gave a crude product which was purified by Prep-TLC (EA/pe=1:5) to give the target compound A1 (10 mg).
ESI-MS m/z:328.95[M+H + -H 2 O] + 。
Example 2 1- (3-chloro-5-fluorophenyl) -5, 5-difluoro-4-hydroxy-1, 4,5, 6-tetrahydrocyclopenta [ b ] pyrrole-3-carbonitrile (Compound A2)
Figure PCTCN2021119569-APPB-000011
Step 1: synthesis of Compound 2-1
And (3) replacing boric acid with 3-chloro-5-fluorobenzeneboric acid, and obtaining the compound 2-1 by referring to the preparation method of the compound 1-1.
ESI-MS m/z:411.9[M+H + ] + 。
Step 2: synthesis of Compound 2-2
Compound 2-1 (212 mg) was dissolved in DMF (5 mL) under nitrogen, and Zn (CN) was added 2 (150 mg) and Pd (PPh) 3 ) 4 (80 mg), stirred overnight at 120 ℃, extracted with EA, the organic layer washed with brine,Na 2 SO 4 drying and concentrating to obtain crude product, and purifying the crude product by column chromatography (EA/PE=1:3) to obtain target compound 2-2 (120 mg).
ESI-MS m/z:311.0[M+H + ] + 。
Step 3: synthesis of Compound A2
Referring to the preparation method of the compound 1, the compound 2-2 is subjected to NaBH 4 And (3) reducing to obtain the target compound A2.
Example 3 2 Synthesis of chloro-5- (5, 5-difluoro-4-hydroxy-3- (methylsulfonyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A22)
Figure PCTCN2021119569-APPB-000012
Step 1: synthesis of Compound 22-1
The boric acid is replaced by 4-chloro-3-cyanobenzeneboric acid, and the compound 22-1 can be obtained by referring to the preparation method of the compound 1-1.
ESI-MS m/z:418.9[M+H + ] + 。
Step 2: synthesis of Compound 22-2
Compound 22-1 (380 mg), methyl 3-sulfanyl propionate (300 mg), xantphos (116 mg) and Pd 2 (dba) 3 The residue was purified by column chromatography to give 22-2 (200 mg) as the objective compound, which was added to toluene (10 mL), stirred overnight at 70 ℃.
ESI-MS m/z:411.0[M+H + ] + 。
Step 3: synthesis of Compound 22-3
Potassium tert-butoxide (50 mg) was added to a THF (10 mL) solution of compound 22-2 (120 mg) at-78deg.C, stirred at room temperature until the starting material disappeared, methyl iodide (100 mg) was added, stirred at room temperature for 5 hours, quenched with saturated ammonium chloride, extracted with EA, concentrated to give a crude product, which was purified by column chromatography to give the objective compound 22-3 (70 mg).
ESI-MS m/z:339.0[M+H + ] + 。
Step 4: synthesis of Compound 22-4
m-CPBA (300 mg) was added to a solution of compound 22-3 (130 mg) in dichloromethane (10 mL) at room temperature, stirred at room temperature for 10 hours, the reaction mixture extracted with aqueous sodium thiosulfate solution, DCM diluted, naHCO 3 Washing with water solution, washing with saturated saline, drying, concentrating to obtain crude product, and purifying by column chromatography to obtain target compound 22-4 (60 mg).
ESI-MS m/z:371.0[M+H + ] + 。
Step 5: synthesis of Compound A22
Reference compound 1 preparation method, compound 22-4 via NaBH 4 And (5) reducing to obtain the target compound A22.
LCMS：355.01[M+H + -H 2 O] + 。
Example 4 2 Synthesis of chloro-5- (2, 5-trifluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A24)
Figure PCTCN2021119569-APPB-000013
Step 1: synthesis of Compound 24-1
Compound 24-1 was prepared by substituting 3-cyano-4-fluorobenzeneboronic acid with 3-cyano-4-chlorobenzeneboronic acid and referring to the procedure of step 1 and step 2 of example 1.
ESI-MS m/z:361.0[M+H + ] + 。
Step 2: synthesis of Compound 24-2
Compound 24-1 (100 mg) was dissolved in acetonitrile (5 mL) under nitrogen, sele ctfluor (150 mg) was added, stirred overnight at 80℃and EA was extracted, the organic layer was washed with brine, na 2 SO 4 Drying and concentrating to obtain a crude product, and purifying the crude product by Prep-TLC (EA/PE=1:3) to obtain a target compound 24-2(20mg)。
ESI-MS m/z:379.0[M+H + ] + 。
Step 3: synthesis of Compound A24
Compound 24-2 (20 mg) was dissolved in THF (2 mL) and H 2 Adding NaBH into mixed solvent of O (1 mL) in ice bath 4 (20 mg) and stirred at 0℃for 1 hour. Ice water was added to the reaction solution, EA was extracted, the organic layer was washed with brine, na 2 SO 4 Drying and concentration gave the crude product, which was purified by Prep-TLC (EA/pe=1:3) to give the target compound a24 (15 mg).
ESI-MS m/z:363.01[M+H + -H 2 O] + 。
Example 5 1 Synthesis of- (3, 5-difluorobenzyl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol (Compound A25)
Figure PCTCN2021119569-APPB-000014
Step 1: synthesis of Compound 25-1
Intermediate M1 (300 mg) was dissolved in DMF (10 mL) and K was added 2 CO 3 (300 mg) and 3, 5-difluorobenzyl bromide (300 mg), 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 give a crude product, which was purified by column chromatography (EA/pe=1:7) to give the objective compound 25-1 (320 mg).
ESI-MS m/z:410.0[M+H + ] + 。
Step 2: synthesis of Compound 25-2
Compound 25-1 (320 mg) was dissolved in DMF (5 mL) under nitrogen, and Pd was added 2 (dba) 3 (192 mg), cuI (133 mg) and methyl fluorosulfonyl difluoroacetate (300 mg), stirring at 100℃for three hours, extracting the reaction solution with EA, washing the organic layer with brine, na 2 SO 4 Drying and concentrating to obtainThe crude product was purified by column chromatography (EA/pe=1:10) to give the target compound 25-2 (170 mg).
ESI-MS m/z:352.0[M+H + ] + 。
Step 3: synthesis of Compound A25
Compound 25-2 (170 mg) was dissolved in methanol (4 mL), and NaBH was added under ice-bath 4 (60 mg) after stirring at 0deg.C for 1 hr, ice water was added, EA was extracted, the organic layer was washed with brine, na 2 SO 4 The crude product was dried and concentrated and purified by Prep-TLC (EA/pe=1:5) to give the target compound a25 (120 mg).
ESI-MS m/z:[M+H + -H 2 O] + ：336.06。
Example 6 2 Synthesis of chloro-5- (5, 5-difluoro-4-hydroxy-3- (thiophen-2-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A26)
Figure PCTCN2021119569-APPB-000015
Step 1: synthesis of Compound 26-1
Pd (dppf) Cl at room temperature 2 (110mg)，K 2 CO 3 (270 mg), 2-thiopheneboronic acid (200 mg) was added to dioxane (10 mL)/H of Compound 22-1 (410 mg) 2 In O (1 mL) mixed solution, nitrogen is replaced for 3 times, the reaction is carried out for 3 hours at the temperature of 90 ℃ by microwaves, the reaction mixed solution is diluted by water, EA is used for extraction, na 2 SO 4 Drying and concentrating to obtain the target compound 26-1 (250 mg).
ESI-MS m/z:375.0[M+H + ] + 。
Step 1: synthesis of Compound A26
Referring to the preparation method of the compound 1, the compound 26-1 is subjected to NaBH 4 And reducing to obtain the target compound A26.
LCMS：[M+H + -H 2 O] + ：359.02。
Example 7 2 Synthesis of chloro-5- (3- (difluoromethyl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A27)
Figure PCTCN2021119569-APPB-000016
Step 1: synthesis of Compound 27-1
Compound 22-1 (400 mg) was dissolved in dioxane (5 mL)/H under nitrogen blanket 2 Pd (PPh) was added to the mixed solvent of O (5 mL) 3 ) 4 (110mg)，K 2 CO 3 (400 mg) and vinyl boronic acid pinacol ester (300 mg), reacted overnight at 90℃and EA extracted, the organic layer was washed with brine, na 2 SO 4 Drying and concentration gave a crude product, which was purified by column chromatography (EA/pe=1:5) to give the target compound 27-1 (200 mg).
ESI-MS m/z:319.0[M+H + ] + 。
Step 2: synthesis of Compound 27-2
Compound 27-1 (200 mg) was dissolved in THF (5 mL) and H 2 O (5 mL) in the mixed solvent, naIO was added 4 (500 mg) and potassium osmium (20 mg), were reacted at room temperature for 2 hours, EA was extracted, and the organic layer was washed with brine, na 2 SO 4 Drying and concentration gave a crude product, which was purified by Prep-TLC (EA/pe=1:4) to give the target compound 27-2 (80 mg).
ESI-MS m/z:321.0[M+H + ] + 。
Step 3: synthesis of Compound 27-3
Compound 27-2 (80 mg) was dissolved in DCM (4 mL) under nitrogen, DAST (98 mg) was added in an ice bath, and the mixture was stirred overnight at room temperature after the completion of the dropwise addition. Saturated sodium bicarbonate was quenched, extracted with EA, and the organic layer was washed with brine, dried over Na 2 SO 4 Drying and concentrating to obtain crude product, and purifying the crude product by Prep-TLC (EA/PE=1:4) to obtainTarget compound 27-3 (40 mg).
ESI-MS m/z:343.0[M+H + ] + 。
Step 4: synthesis of Compound A27
Compound 27-3 (40 mg) was dissolved in THF (5 mL) and H 2 Adding NaBH into mixed solvent of O (5 mL) in ice bath 4 (30 mg), reacted at room temperature for half an hour, extracted with EA, and the organic layer was washed with brine, followed by Na 2 SO 4 Drying and concentration gave a crude product which was purified by Prep-TLC (EA/pe=1:3) to give the target compound a27 (25 mg).
LCMS：[M+H + -H 2 O] + ：327.0。
Example 8 2 Synthesis of chloro-5- (3- (dimethylphosphoryl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A28)
Figure PCTCN2021119569-APPB-000017
Step 1: synthesis of Compound 28-1
Compound 22-1 (100 mg), dimethylphosphine (30 mg), palladium acetate (10 mg), potassium phosphate (70 mg) and Xantphos (30 mg) were added to dioxane (5 mL), nitrogen was replaced three times, reacted overnight at 100℃and then diluted with EA, washed with water and anhydrous Na 2 SO 4 Drying, filtration and concentration gave the crude product which was purified by Prep-TLC (DCM/meoh=20:1) to give the title compound 28-1 (80 mg).
ESI-MS m/z:369.0[M+H + ] + 。
Step 2: synthesis of Compound A28
Reference to the preparation of Compound 1, compound 28-1 was purified by NaBH 4 And (3) reducing to obtain the target compound A28.
LCMS：[M+H + -H 2 O] + ：353.0。
Example 9 2 Synthesis of 5- (5-fluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrazolo [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A45).
Figure PCTCN2021119569-APPB-000018
Step 1: synthesis of Compound 45-1
Compound M2 (650 mg), copper acetate (620 mg) and 4A molecular sieve (700 mg) were added to dichloromethane (7 mL), 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 dried, and column chromatography (PE/ea=5:1 to 1:1, eluent was added to 10% dcm) to give compound 45-1 (900 mg).
ESI-MS m/z:309.1[M+H + ] + 。
Step 2: synthesis of Compound 45-2
Compound 45-1 (200 mg) and SelectFluor (80 mg) were dissolved in methanol (10 mL), heated to 70℃and stirred overnight, EA diluted, washed with water, washed with saturated saline, dried and concentrated, and Prep-TLC gave compound 45-2 (100 mg).
ESI-MS m/z:327.0[M+H + ] + 。
Step 3: synthesis of Compound A45
Compound 45-2 (100 mg) was dissolved in methanol (3 mL) and THF (3 mL), cooled to 0℃and sodium borohydride (30 mg) was added thereto, and stirred at room temperature for 1 hour, H was added thereto 2 O and EA, separating, washing the organic phase with saturated saline, drying, concentrating to obtain a crude product, and preparing the target compound A45 by Prep-TLC.
LCMS：[M+H + -H 2 O] + ：311.1。
Example 10 Synthesis of 5- (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile (Compound A47)
Figure PCTCN2021119569-APPB-000019
Step 1: synthesis of Compound 47-1
Compound 45-2 (310 mg) and NBS (340 mg) were dissolved in 1, 2-dichloroethane (8 mL), AIBN (20 mg) was added, the mixture was stirred at 80℃for 3 hours, the residue was concentrated under reduced pressure, water and EA were added to the residue to dilute the residue, the organic phase was washed once with saturated brine, dried and concentrated to give a crude product, which was purified by column chromatography (PE/EA=19:1 to 13:1) to give the objective 47-1 (320 mg).
ESI-MS m/z:405/407[M+H + ] + 。
Step 2: synthesis of Compound 47-2
Compound 47-1 (320 mg) was dissolved in ethylene glycol dimethyl ether (4 mL) and water (0.8 mL), silver perchlorate (350 mg) was added, the mixture was stirred at 50℃for 1 hour, EA was diluted, saturated brine was washed, and the crude product was concentrated by drying to give the objective product 47-2 (260 mg) by Prep-TLC (PE/EA=2:1).
ESI-MS m/z:343.0[M+H + ] + 。
Step 3: synthesis of Compound 47-3
47-2 (260 mg) was dissolved in methylene chloride (4 mL), cooled to-78 ℃, DAST (0.2 mL) was added, the temperature was raised to 0℃and stirred for 1 hour, aqueous sodium bicarbonate and ethyl acetate were added for dilution, the solution was separated, the organic phase was washed with saturated brine, dried and concentrated to give a crude product, which was prepared by Prep-TLC (PE/EA=2:1) to give compound 47-3 (200 mg).
ESI-MS m/z:345.0[M+H + ] + 。
Step 4: synthesis of Compound A47
Compound 47-3 (130 mg) was dissolved in methanol (1 mL) and THF (1 mL), cooled to 0deg.C, sodium borohydride (40 mg) was added, stirred at room temperature for 1 hour, EA and water were added for dilution, the solution was separated, and the saturated brine was washed, and the crude product was dried and concentrated to give Compound A47 (70 mg) by Prep-TLC (2:1).
LCMS：[M+H + -H 2 O] + ：329。
Example 11: synthesis of (S) -2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile (Compound A11)
Figure PCTCN2021119569-APPB-000020
Compound 24-1 (50 mg) was dissolved in methylene chloride (5 mL), formic acid (0.03 mL) and triethylamine (1.05 mL) were added, the reaction mixture was bubbled with nitrogen, [ (R, R) -Ts-DPEN ] RuCl (p-cymene) ] (12 mg) was added, stirring overnight at room temperature under nitrogen, concentrated, and the crude product was purified by Prep-TLC (EA/PE=1:5) to give the objective compound A11 (30 mg, >98% ee).
LC-MS：344.92[M+H + -H 2 O] + 。
The following examples in Table 1 were prepared in a substantially similar manner to examples 1-11.
TABLE 1
Figure PCTCN2021119569-APPB-000021
Figure PCTCN2021119569-APPB-000022
Figure PCTCN2021119569-APPB-000023
Figure PCTCN2021119569-APPB-000024
Figure PCTCN2021119569-APPB-000025
Figure PCTCN2021119569-APPB-000026
Figure PCTCN2021119569-APPB-000027
Figure PCTCN2021119569-APPB-000028
Figure PCTCN2021119569-APPB-000029
Figure PCTCN2021119569-APPB-000030
Examples 10, 16, 19, 55, 58 1 The H NMR data are shown below:
1 h NMR (500 mhz, dmso) δ8.30 (dd, j=5.4, 2.9hz, 1H), 8.13 (s, 1H), 8.06 (ddd, j=9.0, 4.4,3.0hz, 1H), 7.80-7.71 (m, 1H), 6.37-6.19 (m, 2H), 5.42-5.21 (m, 1H), 4.96-4.82 (m, 1H). Example 10
1 H NMR(500MHz,CDCl 3 ) Delta 7.35-7.32 (m, 2H), 7.26-7.20 (m, 2H), 5.05 (dd, j=12.6, 4.0hz, 1H), 3.53-3.41 (m, 1H), 3.27 (td, j=16.0, 4.3hz, 1H), 2.36 (s, 1H). Example 16
1 H NMR(500MHz,CDCl 3 )δ7.69–7.64(m,1H),7.62(d,J＝2.6Hz,1H),7.49(dt,J＝7.7,3.9Hz,1H),7.25(s,1H),5.10(dt,J＝25.7,12.9Hz,1H),360-3.42 (m, 1H), 3.35-3.25 (m, 1H), 2.47-2.42 (m, 1H). Example 19
1 H NMR(500MHz,CDCl 3 ) Delta 7.53-7.46 (m, 2H), 7.28 (td, j=8.2, 1.0hz, 1H), 7.23 (dd, j=3.5, 1.2hz, 1H), 7.12 (dd, j=5.2, 1.1hz, 1H), 7.06 (s, 1H), 6.98 (dd, j=5.1, 3.5hz, 1H), 5.10 (dd, j=13.0, 6.0hz, 1H), 3.47 (td, j=15.4, 10.5hz, 1H), 3.23 (td, j=16.2, 4.1hz, 1H), 2.32 (dd, j=6.5, 2.2hz, 1H). Example 55
1 H NMR(500MHz,CDCl 3 ) Delta 7.61-7.49 (m, 1H), 7.43-7.35 (m, 1H), 7.26 (d, j=3.7 hz, 1H), 7.22 (s, 1H), 5.12 (dd, j=12.6, 5.2hz, 1H), 3.48 (td, j=15.2, 10.5hz, 1H), 3.27 (td, j=16.0, 4.2hz, 1H), 2.42 (dd, j=5.7, 2.2hz, 1H). Example 58
Pharmacological experiments
Experimental example 1 detection of Compound VEGFA ELISA of the present invention (IC 50 )
786-O cells grown in log phase were seeded in 96-well plates at a cell concentration of 65000 cells per ml of culture broth, 180ul per well. The compounds were diluted to the corresponding concentrations, and 20ul of the compound solutions of different concentrations were added to the corresponding cell wells so that the final concentrations of the compounds were (nM), respectively: 1.5, 4.6, 13.7, 41.2, 123.5, 370.4, 1111.1, 3333.3, 10000. Culturing for 24 hr, collecting cell culture supernatant, measuring VEGFA concentration with ELISA kit (purchased from abcam), stopping reaction, measuring light absorption value of each well at 450nm with enzyme labeling instrument, and calculating IC by GraphPadprism 50 . Cell viability was also determined using CellTiter-Glo reagent.
IC of the embodiment 50 The data are provided in Table 2, wherein A represents IC 50 Less than or equal to 0.5 mu M; b represents 0.5 μM nM < IC 50 Less than or equal to 1.0 mu M; c represents IC 50 ＞1.0μM。
TABLE 2
Examples numbering IC 50 (μM)
1 A
2 B
3 A
6 A
9 A
10 B
11 A
15 C
19 A
28 A
45 A
51 A
54 C
55 A
58 A
61 A
64 A
Luciferase assay
The luciferase LUC gene was stably transferred into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) and constructed as HIF 2. Alpha. Reporter cells (786-O-HIF 2. Alpha. -Luc cells). Experiments were performed with 786-O-hif2α -Luc cells in log phase, MEDIUM (RPMI media 1640, available from Invitrogen) was discarded and washed three times with PBS; cells were digested by trypsin (TrypLE, available from invitrogen) and the cells were washed with medium, 10% fetal bovine serum, 1% penicillin, streptomycin to terminate digestion. The cells are collected by centrifugation, the cells are purged twice by PBS, phenol red in the culture medium is removed, the cells are resuspended to proper concentration, the cell density and the activity rate are detected, and the cell activity rate is ensured to be above 90 percent and can be used for experiments.
Gradient concentration compounds were transferred into 384 wells, 25 nl/well, using Echo550 (non-contact sonicator, available from Labcyte); seeding cells to 384In the well plate, 4500 cells/well, 25 μl medium, give final concentrations of compound 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5nM, respectively. The cells were placed at 37℃with 5% CO 2 Culturing in the environment for 18-20h; adding Steady-Glo TM Luciferase assay systems (from Promega) to 384 well plates, 25 μl/well; the luminescence value was detected with Envision. The inhibition was calculated from RLU (Record Luminescence) signal values per well and then IC for the corresponding compound was calculated by Graphpad 8.0 fit 50 . Experiments show that the exemplary compound of the invention has better IC 50 。
In vivo PK
Compounds were formulated with 5% dmso, 5% solutol and 90% nacl. The animals are selected from SD rats and Balb/c mice for administration, the intravenous administration dosage is 1mg/kg, and blood is taken from the eyesockets of 5min, 15min, 30min, 1h, 2h, 4h, 7h and 24 h; the oral administration dose is 5mg/kg, and blood is taken from the eye sockets at 15min, 30min, 1h, 2h, 4h, 7h and 24 h. Centrifuging at 4000rpm for 10min after blood sampling, collecting supernatant, adding 200 μl of internal standard solution into 30 μl of supernatant for precipitation, centrifuging at 12000rpm for 10min after vortex oscillation, collecting 100 μl of supernatant, and mixing with purified water at a ratio of 1:1, and sampling. And detecting the concentration of the compound in the blood plasma by using a high-efficiency liquid chromatography-mass spectrometer, and quantitatively analyzing the concentration of the compound in the blood plasma sample by adopting an internal calibration method. After measuring the concentration of the compound, the content of CL and C is calculated by Winnoln software max AUC, etc. Experiments show that the exemplary compounds have better in vivo PK properties.

Claims (32)

  1. A compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,
    Figure PCTCN2021119569-APPB-100001
    wherein,
    l is a bond, -O-, NH-, -CR d R e -、-S-、-S(＝O)-、-S(＝O) 2 -, -c=c-, or-c≡c-;
    X 1 and X 2 Each independently selected from C or N;
    X 3 is CR (CR) 8 Or NR (NR) 8 ；
    X 4 Is CR (CR) 7 Or NR (NR) 7 ；
    And X is 1 、X 2 And X 4 At least one of which is N;
    R 1 selected from C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 6 -C 10 Aryl, 5-18 membered heteroaryl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl; wherein the 5-18 membered heteroaryl and 3-10 membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 6 -C 10 Aryl, 5-18 membered heteroaryl, C 3 -C 10 Cycloalkyl and 3-10 membered heterocyclyl groups may optionally be substituted with one or more H, halogen, hydroxy, cyano, oxo, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkenyl, C 3 -C 5 Cycloalkyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 C 6 Haloalkoxy, -C 1 -C 6 alkylene-OR c 、-C 1 -C 6 alkylene-c=o-R c 、-NO 2 、-SR c 、-NR a R b 、-C(＝O)R c 、-C(＝O)OR c 、-OC(＝O)R c 、-C(＝O)NR a R b 、-NC(＝O)R c 、-S(＝O)R c 、-S(＝O) 2 R c 、-S(＝O) 2 NR a R b 、-S(＝O)(＝NR a )R b 、-P(＝O)R a R b and/or-P (=s) R a R b Substituted;
    R 2 Selected from H, -OH, amino, C 1 -C 10 Alkoxy, -O-C (=o) -C 1-3 alkyl-NR a R b Deuterium, halogen, -CN, =n-OH, C 1 -C 5 Haloalkyl or-C (=o) -O-C 1-3 An alkyl group;
    R 3 selected from H, -OH, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Alkoxy, C 1 -C 10 Haloalkyl, -O-C (=o) -C 1-3 Alkyl, deuterium, halogen, -CN, =n-OH, -C (=o) -O-C 1-3 Alkyl, -O-C (=o) -C 1-3 Haloalkyl or-C (=o) -O-C 1-3 Haloalkyl, wherein the C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 1 -C 10 Alkoxy, -O-C (=o) -C 1-3 Alkyl, -C (=o) -O-C 1-3 Alkyl, -C (=o) -O-C 1-3 Alkyl, -O-C (=o) -C 1-3 Haloalkyl and-C (=o) -O-C 1-3 Haloalkyl can optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl;
    or R is 2 And R is 3 Together form an oxo group on the C atom to which they are attached;
    R 4 and R is 5 Are each independently selected from H, halogen, -OH, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl; wherein the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl may optionally be substituted with one or more H, halogen, -CN, -OH, oxo, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl; or R is 4 And R is 5 C being isomorphously substituted or unsubstituted with the C atom to which it is attached 3 -C 4 Cycloalkyl or C 3 -C 5 A heterocyclic group;
    R 6 selected from H, -CN, halogen, -OH, C 1 -C 6 Alkyl group、C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl, 3-6 membered heterocyclyl, -NO 2 、-NH 2 Or oxo; wherein the 3-6 membered heterocyclyl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 5 Cycloalkyl and 3-6 membered heterocyclyl may optionally be substituted with one or more H, halogen, -CN, -OH, amino, oxo, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl; or two
    R 6 Together with the C atom to which they are attached form a substituted or unsubstituted C 3 -C 5 Cycloalkyl or 3-5 membered heterocyclyl;
    or R is 6 And R is R 5 Together with the C atom to which they are attached form a substituted or unsubstituted C 3 -C 4 Cycloalkyl or 3-5 membered heterocyclyl;
    R d and R is e Are each independently selected from H, halogen, cyano, -NR a R b 、C 1 -C 10 Alkyl or C 3 -C 10 Cycloalkyl; or R is d And R is e Together form an oxo group on the C atom to which it is attached;
    R 7 selected from H, -NO 2 -CN, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, -OR c 、-SR c 、-NR a R b 、-C(＝O)R c 、-C(＝O)OR c 、-OC(＝O)R c 、-C(＝O)NR a R b 、-NC(＝O)R c 、-S(＝O)R c 、-S(＝O) 2 R c 、-S(＝O) 2 NR a R b 、-S(＝O)(＝NR a )R b 、-P(＝O)R a R b 、-P(＝S)R a R b or-C 1 -C 6 alkylene-OR c The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-10 membered heteroaryl and 3-10 membered heterocyclyl optionally contain 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl and 5-10 membered heteroaryl groups can optionally be substituted with one or more H, halogen, hydroxy, cyano, oxo, amino, C 1 -C 6 Alkyl, C 1-6 Alkoxy, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 5 Cycloalkyl, 3-6 membered heterocyclyl, P (=o) Me 2 、P(＝S)Me 2 、-S(＝O) 2 -C 13 Alkyl, -S (=o) 2 -C 3-5 Cycloalkyl, -S (=o) -C 1-3 Alkyl, -S (=o) -C 3-5 Cycloalkyl, -S (=o) -C 1-3 Haloalkyl or-S (=o) 2 -C 1-3 Haloalkyl;
    R 8 selected from the group consisting of absent, H, -CN, halogen, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, oxo and-NR a R b The method comprises the steps of carrying out a first treatment on the surface of the The C is 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl and C 3 -C 10 Cycloalkyl groups may optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Alkyl, C 2 -C 6 Alkenyl or C 1 -C 5 Haloalkyl;
    R a 、R b And R is c Are respectively and independently selected from H, C 1 -C 10 Alkyl, C 1 -C 10 Haloalkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl; wherein the 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S;
    m is 0, 1 or 2.
  2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein L is a bond, -CH 2 -、-S(＝O) 2 -, -C=C-, -C=O-, -C≡C-, or C 3 -C 5 Cycloalkyl groups.
  3. The compound of claim 1 or 2, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein L is a bond or-CR d R e -。
  4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein R is 4 And R is 5 Each independently is H, halogen or C 1 -C 6 Alkyl, wherein, the C 1 -C 6 The alkyl group may be optionally substituted with one or more H, halogen, -CN, -OH, amino or oxo groups.
  5. The compound of any one of claims 1-4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 4 And R is 5 Each independently is H or halogen.
  6. The compound of any one of claims 1-5, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 2 Halogen, -CN or-OH.
  7. The compound of any one of claims 1-6, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 2 is-OH.
  8. According to claimA compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein R 3 Is H, deuterium, C 1 -C 3 Alkyl or C 2 -C 5 Alkenyl group, wherein the C 1 -C 3 Alkyl and C 2 -C 5 Alkenyl groups may optionally be substituted with one or more H, halogen, -CN, -OH, amino, C 1 -C 5 Haloalkyl.
  9. The compound of any one of claims 1-8, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R 3 Is H, deuterium or C 1 -C 3 Alkyl, or said R 2 And R is R 3 Together form an oxo group on the C atom to which it is attached.
  10. The compound of any one of claims 1-9, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R 1 Is C 6 -C 8 Aryl or 5-8 membered heteroaryl, said 5-8 membered heteroaryl optionally containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, wherein said C 6 -C 8 Aryl and 5-8 membered heteroaryl groups may optionally be substituted with one or more halogen, -OH, -CN, oxo, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c 、-C 0 -C 6 alkylene-c=o-R c 、-NO 2 、-C(＝O)OR c Or-S(＝O) 2 R c Substituted.
  11. The compound of any one of claims 1-10, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 1 Is phenyl or 5-6 membered heteroaryl; wherein the 5-6 membered heteroaryl optionally contains a heteroatom selected from N, O and S, the phenyl and 5-6 membered heteroaryl optionally being substituted with one or more halogen, -OH, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c or-CN.
  12. The compound of any one of claims 1-11, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 1 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 are optionally substituted with one or more halogen, cyano or C 1 -C 6 Haloalkyl.
  13. The compound of any one of claims 1-12, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 1 Is phenyl or pyridinyl, which are optionally substituted with one or more halogen, -OH, amino, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -C 1 -C 6 alkylene-OR c or-CN.
  14. The compound of any one of claims 1-13, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 6 Is H, -CN, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkyl, wherein the C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkyl may be optionally substituted with one or more H, halogen, -CN, -OH, oxo, or amino.
  15. The compound of any one of claims 1-14, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 6 Is H, halogen or C 1 -C 6 An alkyl group.
  16. The compound of any one of claims 1-15, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 8 Is H, -CN, -NH 2 Halogen, C 1 -C 3 Alkyl or cyclopropyl.
  17. The compound of any one of claims 1-16, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 8 Is H or halogen.
  18. According to any one of claims 1 to 17The compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, is characterized in that R 7 Selected from H, -CN, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, -S (=o) R, a 5-10 membered heteroaryl c 、-C 1 -C 6 alkylene-OR c 、-S(＝O) 2 R c And P (=O) R a R b The method comprises the steps of carrying out a first treatment on the surface of the Wherein the 5-10 membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the C is 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Haloalkyl, C 3 -C 10 Cycloalkyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl may optionally be substituted with one or more halogen, hydroxy, P (=o) Me 2 、P(＝S)Me 2 、-S(＝O) 2 -C 1-3 Alkyl, -S (=o) 2 -C 3-5 Cycloalkyl, -S (=o) -C 1-3 Alkyl, -S (=o) -C 1-3 Haloalkyl, -S (=o) -C 3-5 Cycloalkyl, cyano, C 1 -C 6 Alkyl and/or C 1 -C 6 Haloalkyl.
  19. The compound of any one of claims 1-18, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 7 Selected from C 1 -C 6 Haloalkyl, cyano, -S (=o) 2 R c 、-P(＝O)Me 2 Or a 5-membered heteroaryl, wherein the 5-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the 5 membered heteroaryl may optionally be substituted with one or more H, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Haloalkyl.
  20. The compound of claims 1-19, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is 7 Selected from C 1 -C 6 Haloalkyl, -S (=o) 2 R c Or a 5-membered heteroaryl, wherein the 5-membered heteroaryl optionally contains 1, 2 or 3 heteroatoms each independently selected from N, O and S; the 5 membered heteroaryl may optionally be substituted with one or more H, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Haloalkyl.
  21. The compound of claims 1-20, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is a And R is b Each independently is H or C 1 -C 6 An alkyl group.
  22. The compound of claims 1-21, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R is c H, C of a shape of H, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
  23. The compound of claim 1-22, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is represented by formula (II-1), formula (II-2) or formula (II-3),
    Figure PCTCN2021119569-APPB-100002
  24. a compound according to claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from the group consisting of:
    1) 5- [5, 5-difluoro-4-hydroxy-3 (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    4) 2-chloro-5- (2, 5-trifluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    5) 1- (3, 5-difluorobenzyl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    6) 2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (thiophen-2-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    7) 2-chloro-5- (3- (difluoromethyl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    8) 2-chloro-5- (3- (dimethylphosphoryl) -5, 5-difluoro-4-hydroxy-5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    9) 2-fluoro-5- (5-fluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    10 5- (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    11 (S) -2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    12 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) phthalonitrile;
    13 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    14 2-chloro-4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    15 1- (3-chloro-5-fluorophenyl) -5, 5-difluoro-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-4 (1H) -one;
    16 3-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    17 3- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorobenzonitrile
    18 5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
    19 2-chloro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    20 2- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorobenzonitrile
    21 5-chloro-2- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    26 5- (5, 5-difluoro-4-hydroxy-3- (thiazol-4-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
    27 3- (5, 5-difluoro-3- (furan-3-yl) -4-hydroxy-5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    30 1- (3-chloro-5-fluorophenyl) -3- ((difluoromethyl) sulfonyl) -5, 5-difluoro-1, 4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    31 5- (5, 5-difluoro-4-hydroxy-3- (1-methyl-1H-pyrazol-5-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) isophthalonitrile;
    32 2-chloro-5- (5-fluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    33 2-chloro-5- (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    34 2-chloro-5- (5, 6-trifluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) benzonitrile;
    35 5- (3-chloro-5-fluorophenyl) -2, 2-difluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolidin-1-ol;
    36 1- (2-chloropyridin-4-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    37 1- (6-chloropyridin-3-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    38 1- (5-chloropyridin-2-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    39 1- (5-aminopyridin-2-yl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    40 5, 5-difluoro-1- (6-fluoropyridin-3-yl) -3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ b ] pyrrol-4-ol;
    41 5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -5-fluorophenyl) ethyl-1-one;
    44 4- (5, 5-difluoro-4-hydroxy-4-methyl-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-hydroxybenzonitrile;
    45 2-chloro-4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl-4-deuterium) benzonitrile;
    46 3-5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -5-fluorocyanophene;
    47 1- (3-chloro-5-fluorophenyl) -5, 5-difluoro-3- (trifluoromethyl) -1,4,5, 6-tetrahydrocyclopenta [ c ] pyrazol-4-ol;
    48 5- (3-chloro-5-fluorophenyl) -2, 3-difluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolidin-1-ol;
    49 3- (3-chloro-5-fluorophenyl) -6, 6-difluoro-1- (trifluoromethyl) -6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-7-ol;
    50 5- (3-chloro-5-fluorophenyl) -2-fluoro-7- (trifluoromethyl) -2, 3-dihydro-1H-pyrrolizin-1-ol;
    51 (S) -2-fluoro-5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    55 5- (5, 5-difluoro-4-hydroxy-3- (thiophen-2-yl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    56 4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ 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-dihydropyrrolo [ 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-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -3- (difluoromethyl) -2-fluorobenzonitrile;
    61 (S) -4- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ 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-dihydropyrrolo [ 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 (b)
    66 (S) -5- (5, 5-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydropyrrolo [ b ] pyrrol-1 (4H) -yl) -2, 3-difluorobenzonitrile;
    67 5- ((4S, 5S, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    68 5- ((4S, 5S, 6S) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile
    69 5- ((4S, 5R, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    70 5- ((4S, 5R, 6S) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    71 5- ((4 r,5r,6 s) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    72 5- ((4 r,5s,6 s) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile;
    73 5- ((4 r,5r,6 r) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile; or (b)
    74 5- ((4R, 5S, 6R) - (5, 6-difluoro-4-hydroxy-3- (trifluoromethyl) -5, 6-dihydro-cyclopenta [ b ] pyrrol-1 (4H) -yl) -2-fluorobenzonitrile).
  25. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, and at least one pharmaceutically acceptable adjuvant.
  26. Use of a compound according to any one of claims 1-24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, or a pharmaceutical composition according to claim 25, in the manufacture of a medicament for treating, delaying or preventing a disease mediated by HIF-2α.
  27. The use of claim 26, wherein the HIF-2α -mediated condition is VHL syndrome, an autoimmune disease, a metabolic disease, an inflammatory disease, and/or cancer.
  28. The use of claim 27, wherein the cancer is selected from the group consisting of hematological cancers and solid tumors.
  29. The use according to claim 28, wherein the cancer is selected from the group consisting of glioblastoma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, stomach cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neuroblastoma, glioblastoma, meningioma and medulloblastoma.
  30. A method of treating and/or preventing HIF-2α -mediated diseases, comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-24, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, or a pharmaceutical composition of claim 25.
  31. The method of claim 30, wherein the HIF-2α -mediated disease is VHL syndrome, autoimmune disease, metabolic disease, inflammatory disease, or cancer.
  32. The method of claim 31, wherein the cancer is selected from the group consisting of glioblastoma, pheochromocytoma, paraganglioma, colon cancer, rectal cancer, prostate cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, cervical cancer, uterine cancer, gastric cancer, ovarian cancer, breast cancer, skin cancer, brain cancer, meningioma, neuroblastoma, glioblastoma, meningioma, and medulloblastoma.
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