A compound capable of inhibiting and degrading androgen receptor, its pharmaceutical composition and pharmaceutical application

Abstract

Provided are a compound of the general formula B-L-K(I) or its stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates thereof, as well as uses thereof in AR-related diseases such as prostate cancer.

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and uses thereof in AR-related diseases such as prostate cancer. Background Art

[0002] Prostate cancer is often diagnosed at an early stage, with its causes often linked to genetic factors, a high-fat diet, and endocrine factors. Generally speaking, the incidence of prostate cancer is higher in developed countries than in developing countries. In 2016, there were 120,000 new cases of prostate cancer in China, and by 2030, the number of new cases is expected to reach 237,000, with a market share of US$4.8 billion. For patients with early-stage prostate cancer, radical treatment is available, resulting in longer survival. However, for patients with advanced metastatic disease, castration combined with anti-androgen therapy is recommended, and the disease can progress to castration-resistant prostate cancer. Clinical studies have shown that most patients with castration-resistant prostate cancer overexpress the androgen receptor (AR). Inhibiting AR signaling has significant therapeutic effects in patients with hormone-refractory prostate disease, making AR inhibition an effective means of directly blocking this pathway.

[0003] The androgen receptor (AR) is a nuclear hormone receptor structurally divided into an N-terminal activation domain (NTD), a DNA-binding domain (DBD), and a ligand-binding domain (LBD). It regulates the expression of genes that drive prostate cancer, making AR inhibition an effective treatment for prostate cancer. Currently available AR inhibitors, such as enzalutamide and bicalutamide, primarily exert their inhibitory effects by interacting with the AR ligand-binding domain (LBD). However, some patients develop resistance to AR splice variants (AR-Vs) during treatment due to LBD deletions. Preclinical studies have shown that AR splice variants can accelerate the progression of enzalutamide-resistant prostate cancer, making addressing AR resistance a key concern in clinical medicine.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0005] Therefore, it is necessary to develop novel androgen receptor (AR) or / and AR splicing mutant inhibitors and PROTAC drugs for E3 ubiquitin ligases for the treatment of androgen receptor-related tumor diseases. Summary of the Invention

[0006] The present invention develops an AR or / and AR splice mutant inhibitor with novel structure, good efficacy, high bioavailability and greater safety, which is used to treat AR-related diseases such as prostate cancer.

[0007] The present invention provides a compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compound represented by general formula (I),

[0008] BLK(I);

[0009] In certain embodiments, B is selected from

[0010] B1 is selected from one of the following groups, substituted or unsubstituted: 6-membered aryl or 6-membered heteroaryl, when substituted, optionally further substituted by 0 to 4 R b1 substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0011] B2 is selected from one of the following groups: substituted or unsubstituted: 5-10 membered heterocyclyl or -NHC(=O)-, when substituted, optionally further substituted by 0 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0012] B3 is selected from substituted or unsubstituted 5-6 membered aryl or a bond, when the 5-6 membered aryl is substituted, optionally further substituted by 0 to 4 R b2 replaced by;

[0013] R b1 、R b2Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, -C(=O)NH2, -C(=O)NH-C 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

[0014] R b3 、R b4 Each independently selected from H or C 1-6 Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0015] or R b3 、R b4 The carbon atoms connected to it together form C 3-6 Cycloalkyl or C 3-6 Heteromonocyclic ring, wherein the cycloalkyl or heteromonocyclic ring is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 is substituted by an alkoxy substituent, and the heteromonocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0016] In certain embodiments, B is selected from

[0017] B1 is selected from one of the following groups, substituted or unsubstituted: 6-membered aryl or 6-membered heteroaryl, when substituted, optionally further substituted by 0 to 4 R b1 substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0018] B2 is selected from one of the following groups: substituted or unsubstituted: 5-10 membered heterocyclyl or -NHC(=O)-, when substituted, optionally further substituted by 0 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0019] B3 is selected from substituted or unsubstituted phenyl or a bond, when the phenyl is substituted, optionally further substituted by 0 to 4 R b2 replaced by;

[0020] R b1 、R b2Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy or ethoxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

[0021] R b3 、R b4 Each independently selected from H or C 1-3 Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0022] or R b3 、R b4 The carbon atoms connected to it together form C 3-6 Cycloalkyl or C 3-6 Heteromonocyclic ring, wherein the cycloalkyl or heteromonocyclic ring is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 is substituted by an alkoxy substituent, and the heteromonocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0023] In certain embodiments, B is selected from

[0024] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0025] Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, O, C≡C or a bond;

[0026] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4-7 membered heteromonocycle, a 5-10 membered heterocyclic ring, a 6-12 membered heterospirocycle, a 7-10 membered heterobridged ring, a 4-7 membered monocycloalkyl, a 5-10 membered cycloalkyl, a 6-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocycle, heterocyclic ring, heterospirocycle, or heterobridged ring is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C1-4 The alkyloxy group is substituted by a substituent, wherein the heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N;

[0027] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0028] Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, O, C≡C or a bond;

[0029] Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 5-10 membered nitrogen-containing heterocyclic ring, a 7-10 membered heterobridged ring or a 6-12 membered nitrogen-containing heterospirocycle, wherein the heteromonocycle, heterocyclic ring, heterobridged ring or heterospirocycle is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 The alkyl group is substituted by an alkoxy substituent, wherein the heteromonocyclic ring, heterocyclic ring, heterobridged ring or heterospirocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;

[0030] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0031] Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, O, C≡C or a bond;

[0032] Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: azetidinyl, azepentyl, azehexyl, piperidine, morpholine, piperazine, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclopentyl ... Butyl, cyclopentylazacyclopentyl, cyclopentylazacyclohexyl, cyclopentylpiperidine, cyclohexylazetidinyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azo Heterocyclopentylpiperidine, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and piperidine, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, Azetidinyl, azetidinyl spiroazetyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, When substituted, it is optionally further substituted with 0 to 4 moieties selected from H, F, Cl, Br, I, OH, NH2, COOH, CN, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0033] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0034] Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, O, C≡C or a bond;

[0035] Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, CF3, methyl, oxo, hydroxymethyl, COOH, CN or NH2;

[0036] In certain embodiments, L is selected from The left side of L is connected to B, and Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, CF3, methyl, oxo, hydroxymethyl, COOH, CN or NH2;

[0037] In certain embodiments, L is selected from The left side of L is connected to B, and Cy1 and Cy2 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, CF3, methyl, oxo, hydroxymethyl, COOH, CN or NH2;

[0038] In certain embodiments, L is selected from a bond, The left side is connected to B;

[0039] Or L is selected from The left side is connected to B;

[0040] Or L is selected from The left side is connected to B;

[0041] Or L is selected from The left side is connected to B;

[0042] In certain embodiments, K is selected from

[0043] Ring E or F is independently selected from a benzene ring or a 5-6 membered heteroaromatic ring, wherein the heteroaromatic ring contains 1 to 2 heteroatoms selected from O, S, and N;

[0044] R k2 Each independently selected from CH2, C=O, S=O, SO2;

[0045] R k1 、R k3 or R k4 Each independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, COOH, C 1-4 Alkyl or C 1-4 alkoxy;

[0046] R k5 Selected from C=O or

[0047] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0048] M2 is selected from -NHC(=O)-C 1-6 Alkyl or -NHC(=O)-C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0049] M3 is selected from -NH- or -O-;

[0050] R k6 Selected from C 1-6 Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0051] R k7 Each independently selected from H, F, Cl, Br, I, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylformyloxy, wherein the alkyl, alkoxy or alkylthio group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0052] R k8 、R k9 Each independently selected from H, C 1-6 Alkyl or C 3-6Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0053] R k10 5-6 membered heteroaryl, wherein the heteroaryl is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent;

[0054] G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent;

[0055] p1 or p2 are each independently selected from 0, 1, 2, 3 or 4;

[0056] In certain embodiments, K is selected from

[0057] In certain embodiments, K is selected from

[0058] R k2 Each independently selected from CH2 or C=O;

[0059] R k1 、R k3 or R k4 Each independently selected from H, CH3, F, Cl, Br, I, OH or NH2;

[0060] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0061] M2 is selected from -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl or -NHC(=O)-cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0062] R k6 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl;

[0063] R k7 Each is independently selected from H, F, OH, SH, methyl, methoxy or -SCH3;

[0064] R k8 、R k9 Each is independently selected from H, methyl, ethyl, cyclopropyl or cyclobutyl;

[0065] p1 or p2 are each independently selected from 0, 1 or 2;

[0066] In certain embodiments, K is selected from

[0067] In certain embodiments, K is selected from

[0068] In certain embodiments, K is selected from

[0069] As a first embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0070] BLK(I);

[0071] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0072] Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, O, C≡C or a bond;

[0073] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4-7 membered heteromonocycle, a 5-10 membered heterocyclic ring, a 6-12 membered heterospirocycle, a 7-10 membered heterobridged ring, a 4-7 membered monocycloalkyl, a 5-10 membered cycloalkyl, a 6-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocycle, heterocyclic ring, heterospirocycle, or heterobridged ring is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 The alkyloxy group is substituted by a substituent, wherein the heteroaryl group, heteromonocyclic group, heterocyclic group, heterospirocyclic group or heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N;

[0074] B is selected from

[0075] B1 is selected from one of the following groups, substituted or unsubstituted: 6-membered aryl or 6-membered heteroaryl, when substituted, optionally further substituted by 0 to 4 R b1 substituted, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

[0076] B2 is selected from one of the following groups: substituted or unsubstituted: 5-10 membered heterocyclyl or -NHC(=O)-, when substituted, optionally further substituted by 0 to 4 R b2 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

[0077] B3 is selected from substituted or unsubstituted 5-6 membered aryl or a bond, when the 5-6 membered aryl is substituted, optionally further substituted by 0 to 4 R b2 replaced by;

[0078] R b1 、R b2 Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, -C(=O)NH2, -C(=O)NH-C 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

[0079] R b3 、R b4 Each independently selected from H or C 1-6Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0080] or R b3 、R b4 The carbon atoms connected to it together form C 3-6 Cycloalkyl or C 3-6 Heteromonocyclic ring, wherein the cycloalkyl or heteromonocyclic ring is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 is substituted by an alkoxy substituent, and the heteromonocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

[0081] K is selected from

[0082] Ring E or F is independently selected from a benzene ring or a 5-6 membered heteroaromatic ring, wherein the heteroaromatic ring contains 1 to 2 heteroatoms selected from O, S, and N;

[0083] R k2 Each independently selected from CH2, C=O, S=O, SO2;

[0084] R k1 、R k3 or R k4 Each independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, COOH, C 1-4 Alkyl or C 1-4 alkoxy;

[0085] R k5 Selected from C=O or

[0086] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0087] M2 is selected from -NHC(=O)-C 1-6 Alkyl or -NHC(=O)-C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0088] M3 is selected from -NH- or -O-;

[0089] R k6 Selected from C1-6 Alkyl, wherein the alkyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, C 1-6 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0090] R k7 Each independently selected from H, F, Cl, Br, I, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio, C 1-6 Alkylformyloxy, wherein the alkyl, alkoxy or alkylthio group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0091] R k8 、R k9 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0092] R k10 5-6 membered heteroaryl, wherein the heteroaryl is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent;

[0093] G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, CF3, CN, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 substituted by a cycloalkyl substituent;

[0094] p1 and p2 are each independently selected from 0, 1, 2, 3 or 4.

[0095] As a second embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0096] Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 5-10 membered nitrogen-containing heterocyclic ring, a 7-10 membered heterobridged ring or a 6-12 membered nitrogen-containing heterospirocycle, wherein the heteromonocycle, heterocyclic ring, heterobridged ring or heterospirocycle is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, COOH, CN, NH2, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 The alkyl group is substituted by an alkoxy substituent, wherein the heteromonocyclic ring, heterocyclic ring, heterobridged ring or heterospirocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;

[0097] K is selected from

[0098] The definitions of other groups are the same as those of the first scheme.

[0099] As a third embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0100] Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following groups which are substituted or unsubstituted: azetidinyl, azepentyl, azehexyl, piperidine, morpholine, piperazine, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclopropyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclobutyl azetidinyl, cyclopentyl ... Butyl, cyclopentylazacyclopentyl, cyclopentylazacyclohexyl, cyclopentylpiperidine, cyclohexylazetidinyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azetidinylpiperidine, azetidinylazetidinyl, azetidinylazacyclopentyl, azetidinylazacyclohexyl, azo Heterocyclopentylpiperidine, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and piperidine, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, Azetidinyl, azetidinyl spiroazetyl, azetidinyl spiroazahexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, azetidinyl spiroazetyl, cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, azetidinyl spiropiperidine, When substituted, it is optionally further substituted with 0 to 4 moieties selected from H, F, Cl, Br, I, OH, NH2, COOH, CN, oxo, C 1-4 Alkyl, halogen-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Alkoxy substituents substituted

[0101] R b1 、R b2 Each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CF3, -C(=O)NH2, -C(=O)NH-CH3, -C(=O)N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy or ethoxy group is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I or OH;

[0102] K is selected from

[0103] R k2 Each independently selected from CH2 or C=O;

[0104] R k1 、R k3 or R k4 Each independently selected from H, CH3, F, Cl, Br, I, OH or NH2;

[0105] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0106] M2 is selected from -NHC(=O)-methyl, -NHC(=O)-ethyl, -NHC(=O)-cyclopropyl, -NHC(=O)-cyclobutyl, -NHC(=O)-cyclopentyl or -NHC(=O)-cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally further substituted by 0 to 4 groups selected from H, F, Cl, Br, I, OH, NH2, C 1-4 Alkyl or C 1-4 substituted by an alkoxy substituent;

[0107] R k6 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl or sec-butyl;

[0108] R k7 Each is independently selected from H, F, OH, SH, methyl, methoxy or -SCH3;

[0109] R k8 、R k9 Each is independently selected from H, methyl, ethyl, cyclopropyl or cyclobutyl;

[0110] p1 or p2 are each independently selected from 0, 1 or 2;

[0111] The definitions of other groups are the same as those of the second scheme.

[0112] As a fourth embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0113] Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, CF3, methyl, oxo, hydroxymethyl, COOH, CN or NH2;

[0114] B is selected from

[0115] K is selected from

[0116] Other definitions are the same as the third option.

[0117] As a fifth embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0118] L is selected from a bond, The left side is connected to B;

[0119] Or L is selected from The left side is connected to B;

[0120] Or L is selected from The left side is connected to B;

[0121] Or L is selected from The left side is connected to B;

[0122] The definitions of other groups are the same as those of the fourth scheme.

[0123] As a sixth embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0124] K is selected from

[0125] The definitions of other groups are the same as those of the fifth scheme.

[0126] As a seventh embodiment of the present invention, the general formula (I) or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0127] K is selected from

[0128] The definitions of other groups are the same as those of the sixth scheme.

[0129] As one embodiment of the present invention, the compound represented by general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from one of the following structures:

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0136] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to AR activity or expression.

[0137] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating and inhibiting or degrading AR-related diseases.

[0138] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to the activity or expression of AR or AR splicing mutants.

[0139] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to the inhibition or degradation of AR or AR splicing mutants.

[0140] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, characterized in that the disease is selected from prostate cancer.

[0141] Synthesis method:

[0142]

[0143]

[0144] General formula (Z-1) and general formula (Z-2) undergo a nucleophilic substitution reaction to generate general formula (Z-3), i.e., general formula (Z-3′). When R1 is an amino protecting group, general formula (Z-3′) is deprotected to generate the corresponding general formula (Z-4). General formula (Z-4) then undergoes a nucleophilic substitution reaction with general formula (Z-5) to generate general formula (Z-6), i.e., general formula (I). General formula (Z-4) and general formula (Z-7) undergo a nucleophilic substitution or reductive amination reaction to generate general formula (Z-8). When R4 is an amino protecting group, general formula (Z-8) is deprotected to generate the corresponding general formula (Z-9). General formula (Z-9) then undergoes a nucleophilic substitution reaction with general formula (Z-5) to generate general formula (Z-10), i.e., general formula (I).

[0145] General formula (Z-9) and general formula (Z-11) undergo nucleophilic substitution or reductive amination reaction to produce general formula (Z-12). When R6 is an amino protecting group, general formula (Z-12) is deprotected to produce the corresponding general formula (Z-13). General formula (Z-13) then undergoes nucleophilic substitution reaction with general formula (Z-5) to produce general formula (Z-14), i.e., general formula (I);

[0146] The general formula (Z-13) and the general formula (Z-15) undergo nucleophilic substitution or reductive amination reaction to produce the general formula (Z-16). When R8 is an amino protecting group, the general formula (Z-16) is deprotected to produce the corresponding general formula (Z-17). The general formula (Z-17) then undergoes a nucleophilic substitution reaction with the general formula (Z-5) to produce the general formula (Z-18), i.e., the general formula (I).

[0147] The synthesis method of general formula (Z-5) is described in WO2017197056;

[0148] R1 is selected from H, (=O), -CHO, F, Cl, Br, I or an amino protecting group (preferably Boc);

[0149] R2 is selected from NH2, F, Cl, Br, I, OTf, OH;

[0150] R3, R4, R5, R6, R7, and R8 are each independently selected from H, (=O), -CHO, H, F, Cl, Br, I, OTf, or an amino protecting group (preferably Boc).

[0151] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0152] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0153] "Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; the alkyl group may be optionally further substituted by 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 The alkyl group appearing in this article is substituted by an alkoxy group, a 3- to 8-membered carbocyclyl group, a 3- to 8-membered heterocyclyl group, a 3- to 8-membered carbocyclyloxy group, a 3- to 8-membered heterocyclyloxy group, a carboxyl group or a carboxylate group. Its definition is consistent with this definition.

[0154] "Alkoxy" refers to an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The alkoxy group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Alkoxy groups appearing herein are defined in accordance with this definition.

[0155] "Cycloalkyl" refers to a straight or branched saturated cyclic aliphatic hydrocarbon group of 3 to 20 carbon atoms, preferably a cycloalkyl group of 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Cycloalkyl groups appearing herein are defined in accordance with this definition.

[0156] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S. Preferably, the heterocyclyl is a 3-8 membered group. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl group can be attached to a heteroatom or a carbon atom. The heterocyclyl group can be connected to a bridged ring or a spirocyclic ring. Non-limiting examples include oxiranyl, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, morpholino ... The heterocyclic group may be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, =O, hydroxyl, thiol, nitro, cyano, amino, alkylamino, amide, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl or carboxylate. The heterocyclic groups appearing herein have the same definition as this one.

[0157] "Spirocycle" refers to a 5- to 20-membered polycyclic group in which substituted or unsubstituted monocyclic rings share a carbon atom (called a spiro atom), which may contain 0 to 5 double bonds and 0 to 5 atoms selected from N, O or S (=O). n Preferably, it is 6 to 14-membered, more preferably 6 to 12-membered, and more preferably 6 to 10-membered. Non-limiting examples thereof include:

[0158] When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m-C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or cyclized group. The spiro ring appearing in this article has the same definition as this one.

[0159] "Parallel ring" refers to a polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain zero or more double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain zero to five atoms selected from N, S(=O), n or O heteroatom (n is selected from 0, 1 or 2). Preferably 5 to 20 members, more preferably 5 to 14 members, more preferably 5 to 12 members, and even more preferably 5 to 10 members. Non-limiting examples include:

[0160] When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O)n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spirocyclic group or cycloalkyl. The cycloalkyl group appearing herein has the same definition as this one.

[0161] "Bridged ring" refers to a polycyclic group of any two carbon atoms that are not directly connected, which may contain zero or more double bonds and may be substituted or unsubstituted, and any ring in the ring system may contain zero to five atoms selected from N, S(=O), n or O heteroatoms or groups (wherein n is 0, 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, and even more preferably 5 to 10 atoms. Non-limiting examples include When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, paracyclyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m-alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or cyclized group. The definition of bridged ring appearing in this article is consistent with this definition.

[0162] "Heteromonocycle" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system. The heteromonocycle appearing herein has the same definition as this one.

[0163] "Heterocyclic ring" refers to a "cyclic ring" containing a heteroatom. The definition of heterocyclic ring appearing in this article is consistent with this definition.

[0164] "Heterospirocycle" refers to a spirocycle containing a heteroatom. The definition of heterospirocycle appearing herein is consistent with this definition.

[0165] "Heterobridged ring" refers to a "bridged ring" containing a heteroatom. The definition of heterobridged ring appearing herein is consistent with this definition.

[0166] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted 5- to 14-membered aromatic ring containing 1 to 5 groups selected from N, O, or S(=O). n Heteroatoms or groups, preferably 5 to 10-membered heteroaromatic rings, more preferably 5 to 6-membered. Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzimidazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include

[0167] When substituted, the substituents may be 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-Ra 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spirocyclic group or cyclized group. The heteroaryl or heteroaromatic ring appearing herein has the same definition as this definition.

[0168] "Replaced by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, where X is selected from any integer between 1 and 10. For example, "replaced by 0 to 4 substituents" means substituted by 0, 1, 2, 3, or 4 substituents. For example, "replaced by 0 to 5 substituents" means substituted by 0, 1, 2, 3, 4, or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3, or 4 substituents selected from H or F.

[0169] XY-membered rings (X is an integer, 3≤X<Y, and Y is any integer between 4 and 12) include rings with X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocyclic rings, heterospirocycles, or heterobridged rings. For example, "4-7-membered heteromonocycle" refers to a 4-, 5-, 6-, or 7-membered heteromonocycle, and "5-10-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0170] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0171] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0172] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0173] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0174] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0175] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0176] “DC 50 ” refers to the dose that degrades 50% of the protein.

[0177] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0178] The technical solutions of the present invention are described in detail below in conjunction with the embodiments, but the protection scope of the present invention includes but is not limited to them.

[0179] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0180] Reference books and monographs in the field detailing the synthesis of reactants that can be used to prepare the compounds described herein, or articles describing such preparations, are provided for reference. These reference books and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4thEdition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModernCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2ndEdition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial OrganicChemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes;and“Chemistry of FunctionalGroups”John Wiley&Sons,in 73volumes.

[0181] Specific and similar reactants can be selectively identified by indexing known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog can alternatively be prepared by custom chemical synthesis facilities, many of which standard chemical supply houses (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0182] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0183] The compounds used in the reactions described herein were prepared using organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0184] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0185] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0186] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0187] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0188] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0189] DMSO: dimethyl sulfoxide; DIPEA: N,N'-diisopropylethylamine; DCE: dichloroethane; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine.

[0190] Synthesis of intermediate A:

[0191] tert-Butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A)

[0192] tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate

[0193]

[0194] Step 1: tert-Butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (A2)

[0195] tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate

[0196]

[0197] Dissolve N-Boc-4-piperidone (A1) (5.21 g, 26.1 mmol) in 26 mL of tetrahydrofuran, cool to -78 ° C under nitrogen protection, and slowly add 1 mol / L lithium bistrimethylsilylamide in tetrahydrofuran solution (28.5 mL) dropwise. After the addition, the reaction is continued to stir at -78 ° C for 1 h, followed by the dropwise addition of N-phenylbis(trifluoromethanesulfonyl)imide (10.2 g, 28.6 mmol) in tetrahydrofuran solution (26 mL). After the addition is complete, the temperature is naturally raised to room temperature and the reaction is carried out for 3 h. 20 mL of saturated sodium bicarbonate solution was added dropwise to quench the reaction, 50 mL of ethyl acetate was added, the layers were separated, the organic layer was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0-9 / 1) to give tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (A2) (7.80 g, yield: 90%).

[0198] Step 2: tert-Butyl 4-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (A3)

[0199] tert-butyl 4-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0200]

[0201] Tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (A2) (1.00 g, 3.02 mmol) was dissolved in 5 mL of acetonitrile, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (0.761 g, 3.92 mmol), 5 mL of saturated aqueous sodium bicarbonate solution and Pd(dppf)Cl2·CH2Cl2 (122 mg, 0.16 mmol) were added in sequence, and the reaction was carried out by microwave reaction at 110 °C for 30 min. The reaction was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic layers were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1-1 / 1) to obtain tert-butyl 4-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (A3) (0.420 g, yield: 56%).

[0202] 1 H NMR (400MHz, CDCl3) δ7.61(s,2H),5.92(s,1H),4.07–4.00(m,2H),3.62(t,2H),2.46–2.37(m,2H),1.48(s,9H).

[0203] LCMS m / z=250.3[M+1] +

[0204] Step 3: tert-Butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A)

[0205] tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate

[0206]

[0207] tert-Butyl 4-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (A3) (0.400 g, 1.60 mmol) was dissolved in 10 mL of anhydrous ethanol. 200 mg of 10% palladium on carbon was added, and the hydrogen atmosphere was replaced three times. The mixture was reacted at 40°C under a hydrogen balloon atmosphere for 5 h. The reaction solution was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A) (0.4 g, yield: >99%).

[0208] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),7.43(s,2H),4.30–4.00(m,2H),2.83(t,2H),2.74–2.63(m,1H),1.96–1.84(m,2H),1.60–1.39(m,11H).

[0209] Synthesis of intermediate B:

[0210] tert-Butyl 3-ethynyl-[1,3'-bicyclobutane]-1'-carboxylate (Intermediate B)

[0211] tert-butyl 3-ethynyl-[1,3'-biazetidine]-1'-carboxylate

[0212]

[0213]

[0214] Step 1: Hydrochloride of 3-ethynylazetidine (B2)

[0215] 3-ethynylazetidine hydrochloride

[0216]

[0217] 3-Ethynylazetidine-carboxylic acid tert-butyl ester (B1) (2.77 g, 15.28 mmol) was added to 40 mL of 3 mol / L hydrochloric acid in ethyl acetate in a 250 mL single-necked round-bottom flask and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride salt of 3-ethynylazetidine (B2) (1.74 g).

[0218] LCMS m / z=82.2[M+1] +

[0219] Step 2: tert-Butyl 3-ethynyl-[1,3'-bicyclobutane]-1'-carboxylate (Intermediate B)

[0220] tert-butyl 3-ethynyl-[1,3'-biazetidine]-1'-carboxylate

[0221]

[0222] The crude 3-ethynylazetidine (B2) hydrochloride (1.74 g) was weighed into a 250 mL single-necked round-bottom flask and dissolved in 100 mL of 1,2-dichloroethane. Then, 3 mL of triethylamine was added, followed by tert-butyl 3-oxoazetidine-1-carboxylate (6.33 g, 37.00 mmol), acetic acid (3.11 g, 51.80 mmol), and 6 g of anhydrous sodium sulfate. The mixture was heated to 60°C and reacted for 2 h. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (18.82 g, 88.79 mmol) was added in batches. The reaction mixture was allowed to react at room temperature for 16 h. After the reaction was completed, 50 mL of water was added to the reaction solution, the layers were separated, and the organic phase was washed once with 50 mL of saturated sodium bicarbonate solution, 50 mL of water, and 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1) to obtain tert-butyl 3-ethynyl-[1,3'-bicyclobutane]-1'-carboxylate (intermediate B) (3.33 g, two-step yield based on compound B1: 92%).

[0223] LCMS m / z=237.2[M+1] +

[0224] Synthesis of intermediate 1:

[0225] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (Intermediate 1)

[0226] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide

[0227]

[0228] Step 1: tert-Butyl 4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate (1A)

[0229] tert-butyl 4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0230]

[0231] 2-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (synthesis method, see WO2020063407) (4.0 g, 11.9 mmol) was dissolved in 50 mL of acetonitrile, and tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A) (2.5 g, 9.9 mmol) and cesium carbonate (6.5 g, 19.9 mmol) were added, and the reaction was stirred at 50 ° C for 1 h. The reaction solution was concentrated under reduced pressure, diluted with 100 mL of ethyl acetate, washed with 100 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to give tert-butyl 4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate (1A) (3.7 g, yield: 74%).

[0232] Step 2: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propionamide (Intermediate 1)

[0233] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide

[0234]

[0235] Tert-Butyl 4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate (1A) (3.7 g, 7.3 mmol) was dissolved in 50 mL of DCM, and 15 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, diluted with 50 mL of dichloromethane, and the pH was adjusted to 9.0 by adding saturated sodium bicarbonate solution. The organic phase was separated, washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (Intermediate 1) (2.9 g, yield: 98%).

[0236] LCMS m / z=406.3[M+1] +

[0237] Synthesis of intermediate 2:

[0238] N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide (Intermediate 2)

[0239] N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide

[0240]

[0241]

[0242] Step 1: tert-Butyl 4-[1-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]piperidine-1-carboxylate (2A)

[0243] tert-butyl 4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]piperidine-1-carboxylate

[0244]

[0245] Tert-butyl 4-(1H-pyrazol-4-yl)piperidine-1-carboxylate (Intermediate A) (0.145 g, 0.576 mmol) was dissolved in 5 mL of acetonitrile, and 1-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide (synthesis method see WO2020063407) (0.200 g, 0.576 mmol) and cesium carbonate (0.207 g, 0.635 mmol) were added in sequence, and the reaction was stirred at 80 ° C for 3 h. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate and 10 mL of water were added, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl 4-[1-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]piperidine-1-carboxylate (2A) (0.060 g, yield: 20%).

[0246] 1 H NMR(400MHz, CDCl3)δ9.14(s,1H),8.00–7.96(m,1H),7.81–7.70(m,2H),7.60(s,1H),7.39(s,1H),4.23–4.12(m,2H) ,3.10–2.99(m,2H),2.87–2.61(m,5H),2.27–2.14(m,1H),2.14–2.04(m,1H),1.94–1.85(m,2H),1.58–1.40(m,11H).

[0247] Step 2: N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide (Intermediate 2)

[0248] N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide

[0249]

[0250] Tert-butyl 4-[1-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]piperidine-1-carboxylate (2A) (1.50 g, 2.90 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 20 min. The reaction solution was concentrated under reduced pressure, and 50 mL of dichloromethane was added to the residue. The pH was adjusted to 9 with saturated sodium bicarbonate solution. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide (Intermediate 2) (1.20 g, yield: >99%).

[0251] LCMS m / z=418.2[M+1] +

[0252] Example 1:

[0253] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 1)

[0254] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxois oindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0255]

[0256] Step 1: (3aR,6aS)-5-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1a)

[0257] tert-butyl(3aR,6aS)-5-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0258]

[0259] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (Intermediate 1) (202 mg, 0.50 mmol) was dissolved in 15 mL of DCE, and tert-butyl (3aR, 6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (225 mg, 1.00 mmol) was added. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride (318 mg, 1.50 mmol) was added and stirred at room temperature for 16 h. To the reaction solution was slowly added 20 mL of saturated aqueous sodium bicarbonate solution, extracted with DCM (40 mL×3), the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give (3aR,6aS)-5-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1a) (0.25 g, yield: 81%).

[0260] LCMS m / z=615.4[M+1] +

[0261] Step 2: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (1b)

[0262] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide

[0263]

[0264] tert-Butyl (3aR,6aS)-5-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1a) (0.25 g, 0.41 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction system was concentrated under reduced pressure, and the residue was dissolved with 30 mL of 4 mol / L NaOH aqueous solution, extracted with DCM (40 mL×3), and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (1b) (0.18 g).

[0265] LCMS m / z=515.3[M+1] +

[0266] Step 3: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 1)

[0267] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxois oindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0268]

[0269] The above crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (1b) (0.18 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (145 mg, 0.53 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid. The solid was washed with 10 mL of water, dissolved in 50 mL of dichloromethane, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((3aR,6aS)-2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)octahydrocyclopenta[c]pyrrol-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 1) (140 mg, two-step yield based on Compound 1a: 44%).

[0270] 1 H NMR(400MHz, CDCl3)δ9.78(s,1H),8.57(br.s,1H),7.99–7.90(m,1H),7.80–7.68(m,2H),7. 64(d,1H),7.60(s,1H),7.45(s,1H),7.00–6.95(m,1H),6.69(dd,1H),4.92(dd,1H),3.66–3 .52(m,2H),3.44–3.32(m,2H),3.19–3.03(m,2H),2.92–2.63(m,6H),2.59–2.45(m,1H),2.3 5–2.21(m,2H),2.18–2.01(m,3H),1.97–1.85(m,8H),1.84–1.62(m,2H),1.60–1.47(m,2H).

[0271] LCMS m / z=771.3[M+1] +

[0272] Example 2:

[0273] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)pyrrol-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 2)

[0274] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0275]

[0276] Step 1: tert-Butyl 3-((4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)pyrrole-1-carboxylate (2a)

[0277] tert-butyl 3-((4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate

[0278]

[0279] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propionamide (Intermediate 1) (202 mg, 0.50 mmol) was dissolved in 15 mL of DCE, and tert-butyl 3-formylpyrrole-1-carboxylate (200 mg, 1.00 mmol) was added. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added and stirred at room temperature for 16 h. To the reaction solution was slowly added 20 mL of saturated aqueous sodium bicarbonate solution, extracted with DCM (40 mL×3), the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give tert-butyl 3-((4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)pyrrole-1-carboxylate (2a) (260 mg, yield: 88%).

[0280] LCMS m / z=589.2[M+1] +

[0281] Step 2: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-(pyrrol-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-1-yl)propionamide (2b)

[0282] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide

[0283]

[0284] Tert-butyl 3-((4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)pyrrole-1-carboxylate (2a) (0.26 g, 0.44 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction, the reaction system was directly dried by rotary evaporation, the residue was dissolved with 30 mL of 4 mol / L NaOH aqueous solution, extracted with DCM (40 mL×3), and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-(pyrrol-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (2b) (0.20 g).

[0285] LCMS m / z=489.2[M+1] +

[0286] Step 3: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)pyrrol-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 2)

[0287] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0288]

[0289] The above crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(1-(pyrrol-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-1-yl)propanamide (2b) (0.18 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (153 mg, 0.55 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid, which was washed with 10 mL of water. The solid was dissolved in 50 mL of dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)pyrrol-3-yl)methyl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 2) (150 mg, two-step yield based on Compound 2a: 51%).

[0290] 1 H NMR(400MHz, CDCl3)δ9.79(s,1H),8.22(s,1H),7.99–7.93(m,1H),7.81– 7.69(m,2H),7.68–7.60(m,2H),7.48(s,1H),6.95(d,1H),6.68(dd,1H),4 .93(dd,1H),3.65–3.35(m,3H),3.30–3.15(m,1H),3.12–2.59(m,6H),2. 59–2.32(m,3H),2.30–2.05(m,3H),1.98–1.80(m,9H),1.76–1.52(m,3H).

[0291] LCMS m / z=745.3[M+1] +

[0292] Example 3:

[0293] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 3)

[0294] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0295]

[0296] Step 1: tert-Butyl 7-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (3a)

[0297] tert-butyl 7-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate

[0298]

[0299] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propionamide (Intermediate 1) (202 mg, 0.50 mmol) was dissolved in 15 mL of DCE, and tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (240 mg, 1.00 mmol) was added. After stirring at room temperature for 0.5 h, sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added and stirred at room temperature for 16 h. To the reaction solution was slowly added 20 mL of saturated aqueous sodium bicarbonate solution, extracted with DCM (40 mL×3), the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to give tert-butyl 7-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (3a) (200 mg, yield: 64%).

[0300] LCMS m / z=629.4[M+1] +

[0301] Step 2: 2-(4-(1-(2-azaspiro[3.5]non-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (3b)

[0302] 2-(4-(1-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide

[0303]

[0304] tert-Butyl 7-(4-(1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)piperidin-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate (3a) (0.20 g, 0.32 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction system was directly concentrated under reduced pressure. The residue was dissolved with 30 mL of 4 mol / L NaOH aqueous solution and extracted with DCM (40 mL×3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 2-(4-(1-(2-azaspiro[3.5]non-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (3b) (0.15 g).

[0305] LCMS m / z=529.3[M+1] +

[0306] Step 3: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]non-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 3)

[0307] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0308]

[0309] The above crude product 2-(4-(1-(2-azaspiro[3.5]non-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (3b) (0.15 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (118 mg, 0.43 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid, which was washed with 10 mL of water. The solid was dissolved in 50 mL of dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]non-7-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 3) (120 mg, two-step yield based on Compound 3a: 48%).

[0310] 1H NMR(400MHz, CDCl3)δ9.78(s,1H),8.22(br.s,1H),7.97–7.93(m,1H),7.81–7.69(m,2 H),7.66–7.59(m,2H),7.46(s,1H),6.76(d,1H),6.49(dd,1H),4.93(dd,1H),3.73(s, 2H),3.68(s,2H),3.16–2.95(m,2H),2.93–2.67(m,3H),2.59–2.46(m,1H),2.44–2.24 (m,2H),2.16–2.02(m,3H),2.00–1.84(m,10H),1.80–1.52(m,5H),1.45–1.31(m,2H).

[0311] LCMS m / z=785.3[M+1] +

[0312] Example 4:

[0313] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]pyrrol-3-yl]methyl]-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 4)

[0314] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pyrrolidin-3-yl]methyl]-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide

[0315]

[0316] Step 1: tert-Butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]-1-piperidinyl]methyl]pyrrole-1-carboxylate (4a)

[0317] tert-butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]-1-piperidyl]methyl]pyrrolidine-1-carboxylate

[0318]

[0319] N-(4-cyano-3-(trifluoromethyl)phenyl)-1-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carboxamide (Intermediate 2) (0.100 g, 0.240 mmol) was dissolved in 3 mL of 1,2-dichloroethane, and N-Boc-3-pyrrolecarboxaldehyde (0.0955 g, 0.479 mmol), glacial acetic acid (0.036 g, 0.599 mmol) and sodium triacetoxyborohydride (0.102 g, 0.481 mmol) were added in sequence. After the addition was complete, the reaction was carried out at room temperature for 16 hours. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 9. The mixture was separated and the aqueous layer was extracted with 20 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 100 / 0-97 / 3) to give tert-butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]-1-piperidinyl]methyl]pyrrole-1-carboxylate (4a) (0.08 g, yield: 56%).

[0320] LCMS m / z=601.3[M+1] +

[0321] Step 2: N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-(pyrrol-3-ylmethyl)-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (4b)

[0322] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-(pyrrolidin-3-ylmethyl)-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide

[0323]

[0324] Tert-butyl 3-[[4-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]-1-piperidinyl]methyl]pyrrole-1-carboxylate (4a) (0.08 g, 0.133 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue. The pH was adjusted to 9 with saturated sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with 10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-(pyrrol-3-ylmethyl)-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (4b) (0.0667 g).

[0325] LCMS m / z=501.3[M+1] +

[0326] Step 3: N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]pyrrol-3-yl]methyl]-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 4)

[0327] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pyrrolidin-3-yl]methyl]-4-piperidyl]pyrazol-1-yl]cyclobutanecarboxamide

[0328]

[0329] The above crude N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-(pyrrol-3-ylmethyl)-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (4b) (0.060 g, 0.12 mmol) was dissolved in 3 mL of dimethyl sulfoxide, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (0.036 g, 0.13 mmol) and diisopropylethylamine (0.031 g, 0.24 mmol) were added, and the reaction was stirred at 90 ° C for 2 h. The reaction solution was cooled to room temperature, 5 mL of water was added, stirred for 2 minutes, filtered, and the filter cake was washed with 10 mL of water. The filter cake was collected and dissolved in dichloromethane (30 mL), washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:19) to give N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]pyrrol-3-yl]methyl]-4-piperidinyl]pyrazol-1-yl]cyclobutanecarboxamide (compound 4) (0.040 g, yield: 44%).

[0330] 1 H NMR(400MHz, CDCl3)δ9.01(s,1H),8.17(s,1H),7.98–7.92(m,1H),7.79–7.68(m,2H ),7.68–7.57(m,2H),7.41(s,1H),6.95(d,1H),6.72–6.65(m,1H),4.94(dd,1H),3.6 6–3.46(m,2H),3.45–3.37(m,1H),3.28–3.15(m,1H),3.09–2.97(m,3H),2.95–2.65 (m,6H),2.60–2.32(m,3H),2.30–1.76(m,9H),1.75–1.60(m,1H),1.37–1.20(m,2H).

[0331] LCMS m / z=757.3[M+1] +

[0332] Example 5:

[0333] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 5)

[0334] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0335]

[0336] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-yl)-1H-pyrazol-1-yl)propionamide (Intermediate 1) (0.1 g, 0.25 mmol) was dissolved in 5 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (90 mg, 0.33 mmol) were added, and the reaction was stirred at 85 ° C for 3 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was filtered to collect the solid. The solid was washed with 10 mL of water, dissolved in 50 mL of dichloromethane, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 5) (90 mg, yield: 54%).

[0337] 1 H NMR(400MHz, CDCl3)δ9.82(s,1H),8.12(br.s,1H),7.96–7.93(m,1H),7.82–7.66(m,3H),7.63(s,1H),7.48(s,1H),7.31(d,1H),7.0 8(dd,1H),4.94(dd,1H),4.08–3.98(m,2H),3.16–3.04(m,2H),2.94–2.67(m,4H),2.19–2.01(m,3H),1.92(s,6H),1.78–1.65(m,2H).

[0338] LCMS m / z=662.2[M+1] +

[0339] Example 6:

[0340] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 6)

[0341] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide

[0342]

[0343]

[0344] Step 1: N-[4-cyano-3-(trifluoromethyl)phenyl]-1-(4-iodopyrazol-1-yl)cyclobutanecarboxamide (6b)

[0345] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-(4-iodopyrazol-1-yl)cyclobutanecarboxamide

[0346]

[0347] 4-Iodo-1H-pyrazole (6a) (0.559 g, 2.88 mmol) was dissolved in 10 mL of acetonitrile, and 1-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide (synthesis method, see WO2020063407) (1.00 g, 2.88 mmol) and cesium carbonate (1.03 g, 3.16 mmol) were added sequentially. The mixture was microwaved at 80°C for 1 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 10 mL of water were added. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 9 / 1) to obtain N-[4-cyano-3-(trifluoromethyl)phenyl]-1-(4-iodopyrazol-1-yl)cyclobutanecarboxamide (6b) (0.130 g, yield: 10%).

[0348] Step 2: tert-Butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate (6c)

[0349] tert-butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate

[0350]

[0351] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-(4-iodopyrazol-1-yl)cyclobutanecarboxamide (6b) (0.100 g, 0.217 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (0.0660 g, 0.652 mmol) was added. Under nitrogen protection, PdCl2(PPh3)2 (0.0150 g, 0.0213 mmol) and cuprous iodide (0.0062 g, 0.0326 mmol) were added in sequence. Then, a dichloromethane solution (1 mL) of tert-butyl 3-ethynyl-[1,3'-bicyclobutane]-1'-carboxylate (Intermediate B) (0.0770 g, 0.326 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 16 h. 5 mL of water and 10 mL of dichloromethane were added, the layers were separated, the organic layer was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate) to give tert-butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidin-1-carboxylate (6c) (0.0350 g, 28% yield).

[0352] Step 3: 1-[4-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (6d)

[0353] 1-[4-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide

[0354]

[0355] Tert-butyl 3-[3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidin-1-yl]azetidine-1-carboxylate (6c) (0.030 g, 0.053 mmol) was dissolved in 5 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue. The pH was adjusted to 9 with saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with 10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 1-[4-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (6d) (0.020 g).

[0356] LCMS m / z=469.2[M+1] +

[0357] Step 4: N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 6)

[0358] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide

[0359]

[0360] The above crude product 1-[4-[2-[1-(azetidin-3-yl)azetidin-3-yl]ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (6d) (0.020 g) was dissolved in dimethyl sulfoxide (3 mL), and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (0.013 g, 0.047 mmol) and diisopropylethylamine (0.011 g, 0.085 mmol) were added, and the reaction was stirred at 90 ° C for 2 h. The reaction solution was cooled to room temperature, 5 mL of water was added, stirred for 2 min, and filtered. The filter cake was washed with 10 mL of water, the filter cake was collected, dissolved in dichloromethane (30 mL), washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:19) to give N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 6) (0.020 g, two-step yield based on Compound 6c: 52%).

[0361] 1 H NMR (400MHz, CDCl3) δ8.11–7.97(m,2H),7.95–7.87(m,1H),7.80–7.74(m,1 H),7.72–7.64(m,2H),7.58–7.50(m,1H),6.83–6.77(m,1H),6.58–6.51(m,1 H),4.93(dd,1H),4.20–3.26(m,10H),2.94–2.67(m,4H),2.56–2.45(m,1H), 2.44–2.28(m,2H),2.28–2.17(m,1H),2.17–2.08(m,1H),2.06–1.96(m,1H).

[0362] LCMS m / z=725.2[M+1] +

[0363] Example 7:

[0364] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 7)

[0365] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide

[0366]

[0367] Step 1: tert-Butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7b)

[0368] tert-butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate

[0369]

[0370] 1-Acetyl-4-iodo-1H-pyrazole (7a) (0.200 g, 0.847 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (0.257 g, 2.54 mmol) was added. PdCl2(PPh3)2 (0.06 g, 0.0855 mmol) and cuprous iodide (0.0242 g, 0.127 mmol) were added in sequence under nitrogen protection, and then a dichloromethane solution (1 mL) of tert-butyl 3-ethynyl-1-azetidinecarboxylate (0.200 g, 1.10 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 16 h. 5 mL of water and 10 mL of dichloromethane were added to the reaction system, the layers were separated, the organic layer was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give tert-butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7b) (0.190 g, yield: 78%).

[0371] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.69(s,1H),4.23–4.16(m,2H),4.04–3.96(m,2H),3.56–3.45(m,1H),2.69(s,3H),1.45(s,9H).

[0372] Step 2: tert-Butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7c)

[0373] tert-butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate

[0374]

[0375] tert-Butyl 3-[2-(1-acetylpyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7b) (0.190 g, 0.657 mmol) was dissolved in 5 mL of anhydrous methanol, potassium carbonate (0.182 g, 1.32 mmol) was added, and the mixture was stirred at room temperature for 5 min. 10 mL of water and 20 mL of ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude tert-butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7c) (0.150 g).

[0376] Step 3: tert-Butyl 3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate (7d)

[0377] tert-butyl 3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate

[0378]

[0379] The above crude product tert-butyl 3-[2-(1H-pyrazol-4-yl)ethynyl]azetidine-1-carboxylate (7c) (0.142 g) was dissolved in 10 mL of acetonitrile, and 1-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide (synthesis method see WO2020063407) (0.200 g, 0.576 mmol) and cesium carbonate (0.207 g, 0.635 mmol) were added, and the mixture was reacted at 80 ° C. by microwave for 1 h. The reaction solution was cooled to room temperature, and 5 mL of water and 10 mL of ethyl acetate were added. The layers were separated, and the organic layer was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 9 / 1) to give tert-butyl 3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate (7d) (0.130 g, two-step yield based on compound 7b: 41%).

[0380] Step 4: 1-[4-[2-(azetidin-3-yl)ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (7e)

[0381] 1-[4-[2-(azetidin-3-yl)ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide

[0382]

[0383] Tert-butyl 3-[2-[1-[1-[[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl]cyclobutyl]pyrazol-4-yl]ethynyl]azetidine-1-carboxylate (7d) (0.050 g, 0.097 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and 20 mL of dichloromethane was added to the residue. The pH was adjusted to 10 with saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with 10 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 1-[4-[2-(azetidin-3-yl)ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (7e) (0.040 g).

[0384] LCMS m / z=414.1[M+1] +

[0385] Step 5: N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 7)

[0386] N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide

[0387]

[0388] The above crude product 1-[4-[2-(azetidin-3-yl)ethynyl]pyrazol-1-yl]-N-[4-cyano-3-(trifluoromethyl)phenyl]cyclobutanecarboxamide (7e) (0.030 g) was dissolved in dimethyl sulfoxide (3 mL), and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method see WO2017197056) (0.022 g, 0.080 mmol) and diisopropylethylamine (0.019 g, 0.15 mmol) were added, and the reaction was stirred at 90 ° C for 2 h. The reaction solution was cooled to room temperature, 5 mL of water was added, stirred for 2 min, and filtered. The filter cake was washed with 10 mL of water, the filter cake was collected, and the filter cake was dissolved with dichloromethane (30 mL). The organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3 / 7) to give N-[4-cyano-3-(trifluoromethyl)phenyl]-1-[4-[2-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]azetidin-3-yl]ethynyl]pyrazol-1-yl]cyclobutanecarboxamide (Compound 7) (0.010 g, two-step yield based on Compound 7d: 21%).

[0389] 1H NMR(400MHz, CDCl3)δ8.83(s,1H),8.23(s,1H),7.97–7.91(m,1H),7.83–7.61(m,5H),6.80(d,1H),6.55(dd,1H),4.94(d d,1H),4.40–4.31(m,2H),4.11–4.00(m,2H),3.87–3.74(m,1H),3.11–2.99(m,2H),2.96–2.67(m,5H),2.26–1.96(m,3H).

[0390] LCMS m / z=670.3[M+1] +

[0391] Example 8:

[0392] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-[1,3'-diazetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 8)

[0393] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0394]

[0395]

[0396] Step 1: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionamide (8a)

[0397] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanamide

[0398]

[0399] 2-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (synthesis method, see WO2020063407) (1.72 g, 5.13 mmol) was dissolved in 35 mL of acetonitrile, and 4-iodo-1H-pyrazole (6a) (1.0 g, 5.15 mmol) and cesium carbonate (3.36 g, 10.30 mmol) were added. The reaction was stirred at 50°C for 3 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with DCM (40 mL × 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionamide (8a) (1.5 g, yield: 65%).

[0400] 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.26(d,1H),8.18(s,1H),8.15(dd,1H),8.08(d,1H),7.62(s,1H),1.81(s,6H).

[0401] LCMS m / z=449.0[M+1] +

[0402] Step 2: tert-Butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)-[1,3'-diazetidine]-1'-carboxylate (8b)

[0403] tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)-[1,3'-biazetidine]-1'-carboxylate

[0404]

[0405] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionamide (8a) (224 mg, 0.50 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (150 mg, 1.48 mmol) was added. Under nitrogen protection, PdCl2(PPh3)2 (35 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) were added in sequence, and then a dichloromethane solution (2 mL) of tert-butyl 3-ethynyl-[1,3'-bicyclobutane]-1'-carboxylate (Intermediate B) (178 mg, 0.75 mmol) was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 16 h. To the reaction solution were added 15 mL of water and 10 mL of dichloromethane, the layers were separated, the organic layer was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)-[1,3'-diazetidine]-1'-carboxylate (8b) (260 mg, yield: 93%).

[0406] LCMS m / z=557.3[M+1] +

[0407] Step 3: 2-(4-([1,3'-diazetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (8c)

[0408] 2-(4-([1,3'-biazetidin]-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide

[0409]

[0410] tert-Butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)-[1,3'-diazetidine]-1'-carboxylate (8b) (0.24 g, 0.43 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction system was directly concentrated under reduced pressure. The residue was dissolved with 20 mL of 4 mol / L NaOH aqueous solution and extracted with DCM (40 ml × 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 2-(4-([1,3'-diazetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide (8c) (0.18 g).

[0411] LCMS m / z=457.1[M+1] +

[0412] Step 4: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-[1,3'-diazetidine]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 8)

[0413] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[1,3'-biazetidin]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0414]

[0415] The above crude product 2-(4-([1,3'-diazetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (8c) (0.18 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (181 mg, 0.66 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid, which was washed with 20 mL of water. The solid was dissolved in 50 mL of dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-[1,3'-diazetidine]-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 8) (18 mg, two-step yield based on Compound 8b: 6%).

[0416] 1 H NMR(400MHz, CDCl3)δ9.47(s,1H),8.31(s,1H),7.96–7.90(m,1H),7.84–7.70(m,4H),7.64(d,1H),6.78(d,1H),6.52(dd,1H),4.92(dd,1H),4. 11–4.01(m,2H),3.96–3.84(m,2H),3.83–3.63(m,3H),3.58–3.47(m,1H ),3.39–3.25(m,2H),2.94–2.64(m,3H),2.17–2.07(m,1H),1.92(s,6H).

[0417] LCMS m / z=713.3[M+1] +

[0418] Example 9:

[0419] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 9)

[0420] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0421]

[0422] Step 1: tert-Butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate (9a)

[0423] tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate

[0424]

[0425] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionamide (8a) (224 mg, 0.50 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (150 mg, 1.48 mmol) was added. Under nitrogen protection, PdCl2(PPh3)2 (35 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) were added in sequence, and then a dichloromethane solution (2 mL) of tert-butyl 3-ethynylazetidine-1-carboxylate (136 mg, 0.75 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 16 h. To the reaction solution were added 15 mL of water and 10 mL of dichloromethane, the mixture was separated, the organic layer was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate (9a) (230 mg, yield: 92%).

[0426] Step 2: 2-(4-(azetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (9b)

[0427] 2-(4-(azetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide

[0428]

[0429] Tert-butyl 3-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate (9a) (0.23 g, 0.46 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the system was directly concentrated under reduced pressure. The residue was dissolved in 20 mL of 4 mol / L aqueous NaOH solution and extracted with DCM (40 mL×3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 2-(4-(azetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide (9b) (0.18 g).

[0430] LCMS m / z=402.1[M+1] +

[0431] Step 3: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 9)

[0432] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0433]

[0434] The above crude product 2-(4-(azetidin-3-ylethynyl)-1H-pyrazol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropionamide (9b) (0.17 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (180 mg, 0.65 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid, which was washed with 20 mL of water. The solid was dissolved in 50 mL of dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 9) (80 mg, two-step yield based on Compound 9a: 28%).

[0435] 1 H NMR(400MHz, CDCl3)δ9.49(s,1H),8.04(s,1H),7.95–7.90(m,1H),7.84–7.70(m,4H),7.67(d,1H),6.80(d,1H),6.56(dd,1H ),4.94(dd,1H),4.40–4.32(m,2H),4.10–4.02(m,2H),3.86–3.75(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.92(s,6H).

[0436] LCMS m / z=658.2[M+1] +

[0437] Example 10:

[0438] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 10)

[0439] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0440]

[0441] Step 1: tert-Butyl 4-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)piperidine-1-carboxylate (10a)

[0442] tert-butyl 4-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)piperidine-1-carboxylate

[0443]

[0444] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionamide (8a) (224 mg, 0.50 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (150 mg, 1.48 mmol) was added. Under nitrogen protection, PdCl2(PPh3)2 (35 mg, 0.05 mmol) and cuprous iodide (10 mg, 0.05 mmol) were added in sequence, and then a dichloromethane solution (2 mL) of tert-butyl 4-ethynylpiperidine-1-carboxylate (170 mg, 0.81 mmol) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 16 h. To the reaction solution were added 15 mL of water and 10 mL of dichloromethane, the mixture was separated, the organic layer was washed with 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl 4-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)piperidine-1-carboxylate (10a) (200 mg, yield: 76%).

[0445] Step 2: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-ylethynyl)-1H-pyrazol-1-yl)propionamide (10b)

[0446] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-ylethynyl)-1H-pyrazol-1-yl)propanamide

[0447]

[0448] Tert-butyl 4-((1-(1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)-1H-pyrazol-4-yl)ethynyl)piperidine-1-carboxylate (10a) (0.20 g, 0.38 mmol) was dissolved in 10 mL of DCM, 6 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction system was directly concentrated under reduced pressure. The residue was dissolved in 20 mL of 4 mol / L aqueous NaOH solution and extracted with DCM (40 mL×3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-ylethynyl)-1H-pyrazol-1-yl)propanamide (10b) (0.16 g).

[0449] LCMS m / z=430.2[M+1] +

[0450] Step 3: N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 10)

[0451] N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide

[0452]

[0453] The above crude N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyl-2-(4-(piperidin-4-ylethynyl)-1H-pyrazol-1-yl)propionamide (10b) (0.15 g) was dissolved in 10 mL of DMSO, and 0.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (synthesis method, see WO2017197056) (145 mg, 0.53 mmol) were added, and the reaction was stirred at 80 ° C for 5 h. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was filtered to collect the solid, which was washed with 20 mL of water. The solid was dissolved in 50 mL of dichloromethane and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to give N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethynyl)-1H-pyrazol-1-yl)-2-methylpropanamide (Compound 10) (45 mg, two-step yield based on Compound 10a: 18%).

[0454] 1 H NMR(400MHz, CDCl3)δ9.49(s,1H),8.13(s,1H),7.96–7.90(m,1H),7.82–7.65(m,5H),7.30(d,1H),7.10(dd,1H),4.94 (dd,1H),3.78–3.68(m,2H),3.39–3.28(m,2H),2.96–2.66(m,4H),2.18–1.99(m,3H),1.92(s,6H),1.88–1.78(m,2H).

[0455] LCMS m / z=686.2[M+1] +

[0456] Biological test cases

[0457] 1. Inhibition of VCaP cell proliferation experiment

[0458] Prostate cancer cells (VCaP) were purchased from ATCC and cultured in a 37°C, 5% CO2 incubator using 1640 medium supplemented with 10% FBS. On the first day, cells were harvested from the exponential growth phase and the cell suspension was adjusted to a cell density of 7,500 cells per well in 1% css-FBS-phenol red-free medium. The cells were plated simultaneously with the T0 well and incubated for 3 days. Following the incubation period, R1881 was added to a final concentration of 0.1 nM and various concentrations of the compounds were added. The cells were then incubated in the incubator for an additional 7 days. On the day of drug addition, the T0 plate was assayed using the CellTiter-Glo assay kit and recorded as RLU0. After the incubation period, 100 μL of culture medium was aspirated from each well. 50 μL of pre-melted and room temperature CellTiter-Glo reagent was added to each well according to the instructions of the CellTiter-Glo kit (Promega, G7573). The mixture was mixed for 2 minutes using a microplate shaker. After standing at room temperature for 10 minutes, the fluorescence signal value was measured using a microplate reader (PHERAstar FSX). The results were processed according to formula (1) to calculate the inhibition rate of each concentration of the compound. The concentration GI of the compound at which the inhibition rate was 50% was calculated using origin9.2 software. 50 Value. Among them, RLU compound The readings for the drug-treated groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0459] Inhibition % = [1-(RLU compound -RLU0) / (RLU control -RLU0)]×100% Formula (1)

[0460] GI inhibition of VCaP cell proliferation 50 The results are shown in Table 1.

[0461] Table 1 The compounds of the present invention inhibit GI of VCaP cells 50 value

[0462] Serial number Compound number <![CDATA[GI 50 (μM)]]> 1 Compound 2 4.79 2 Compound 3 3.09 3 Compound 4 1.81 4 Compound 5 1.91 5 Compound 6 1.69 6 Compound 7 0.47 7 Compound 8 3.96 8 Compound 9 0.18 9 Compound 10 0.33

[0463] Conclusion: The compounds of the present invention have inhibitory effects on prostate cells VCaP.

[0464] 2. Pharmacokinetic Test in Rat

[0465] Experimental purpose: This study administered the test substance to SD rats by single-dose intravenous and oral gavage, determined the concentration of the test substance in rat plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in rats.

[0466] Experimental animals: Male SD rats, 200-250 g, 6-8 weeks old, 6 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0467] Experimental method: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0468] Table 2

[0469]

[0470] *Dosage is based on free base.

[0471] Sampling: Before and after drug administration, 0.1 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0472] The time points for plasma collection in G1 and G2 groups were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, and 24 h.

[0473] All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0474] Table 3 Pharmacokinetic parameters of the compounds of the present invention in rat plasma

[0475] Test compound Dosage* <![CDATA[AUC 0-t (ng / mL h)]]> <![CDATA[T 1 / 2 (h)]]> Is it orally bioavailable? Compound 9 ig (20 mg / kg) 45604±3725 24.0±10 yes

[0476] *Note: Compounds were administered ig (orally);

[0477] Conclusion: The compound of the present invention has a certain oral bioavailability in rats.

[0478] 3. Inhibition of 22RV1 Cell Proliferation Experiment

[0479] Prostate cancer cells 22RV1 were purchased from ATCC, and the cell culture medium was RPMI 1640 + 10% FBS, and cultured in a 37°C, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration using 1% css-FBS phenol red-free culture medium for plating, so that the cells were 2000 / well, and incubated overnight. On the second day, different concentrations of compounds were added, and the cells were placed in the incubator and cultured for another 7 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CellTiter-Glo reagent that had been pre-melted and equilibrated to room temperature was added to each well, mixed for 2 minutes using a microplate shaker, and placed at room temperature for 10 minutes before measuring the fluorescence signal value using a microplate reader (PHERAstar FSX). The results were processed according to formula (2), and the inhibition rate of each concentration of the compound was calculated. The IC of the compound inhibition rate of 50% was calculated using the DoseResp function using origin9.2 software.50 Value. Among them, RLU compound The readings for the drug-treated groups, RLU control The values ​​are the average values ​​of the DMSO solvent control group.

[0480] Inhibition % = [1-RLU compound / RLU control ]×100% Formula (2)

[0481] IC that inhibits 22RV1 cell proliferation 50 The results are shown in Table 4.

[0482] Table 4 IC50 values ​​of the compounds of the present invention for inhibiting 22RV1 cells

[0483] Serial number Compound number <![CDATA[IC 50 (μM)]]> 1 Compound 9 0.078

[0484] Conclusion: The compounds of the present invention have inhibitory effects on prostate cells 22RV1.

[0485] 4.2 Degradation of full-length AR (AR-FL) and AR splice mutants (AR-Vs) in 2RV1 cells

[0486] Prostate cancer cells 22RV1 were purchased from ATCC and cultured in 1640 medium supplemented with 10% FBS at 37°C in a 5% CO2 incubator. On the first day, cells were harvested from the exponential growth phase and plated with 1% css-FBS-free phenol red-free medium at the appropriate concentrations. 1 mL of cell suspension was plated per well of a 6-well plate at a density of 100,000 cells. The next day, 1% css-FBS-free phenol red-free medium containing the test compound was added. One well was treated with 0.2% DMSO in 1% css-FBS-free phenol red-free medium as a DMSO vehicle control. The 6-well plate was incubated at 37°C in a 5% CO2 incubator. After 24 hours, cells were trypsinized and collected in a 1.5 mL centrifuge tube. 15 μL of RIPA lysis buffer (containing 1X protease inhibitor cocktail) was added to each well. Lysis was performed on ice for 15 minutes, followed by centrifugation at 12,000 g at 4°C for 10 minutes. Supernatant protein samples were collected and quantified using the BCA assay. AR-FL and AR-Vs were detected using an automated protein expression quantitative assay. The assay procedure was as follows: The protein to be assayed was diluted to 1 mg / mL. 4 μL of the diluted protein sample was added to 1 μL of 5× Master Mix (provided with the kit). The prepared sample was denatured at 95°C for 5 minutes and placed on ice until ready to use. The primary antibodies, AR (CST, 5153S) and β-actin (CST, 3700), were diluted in Antibody Diluent II (provided with the kit) at a dilution ratio of 1:20 and 1:200, respectively. A 1:1 mixture of goat anti-mouse and goat anti-rabbit secondary antibodies was used as the secondary antibody. The color development solution was a 1:1 mixture of Lumino-S and Peroxide. The prepared reagents were added sequentially to the assay plate according to the kit instructions, and the assay was performed on the assay. Western blot analysis was performed using the automated protein expression quantitative analysis software "Compass for SW," which automatically simulated western blots based on signal values. The degradation rate of AR-FL (1) or AR-Vs (2) relative to the vehicle control at different drug concentrations was calculated according to formula (1) (2). compound is the relative peak area of ​​AR-FL in the drug-treated group, AR-FL solvent is the relative peak area of ​​AR-FL in the vehicle control group. compound is the relative peak area of ​​AR-Vs in the drug-treated group, AR-Vs solvent is the relative peak area of ​​AR-Vs in the vehicle control group.

[0487] AR-FL degradation rate = (1-AR-FL compound / AR-FL solvent )×100% Formula (1)

[0488] AR-Vs degradation rate = (1-AR-Vs compound / AR-Vs solvent )×100% Formula (2)

[0489] DC 50 Calculation: According to formula (1) or (2), the compound concentration DC at which the degradation rate of AR-FL or AR-Vs is 50% was calculated using OriginPro2015 software and analyzed using the DoseResp function. 50 value.

[0490] Conclusion: The compounds of the present invention have a certain degradation effect on AR-FL or AR-Vs in prostate cells 22RV1.

Claims

1. A compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK(I); L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1 was selected from C≡C; Ak2, Ak3, Ak4 and Ak5 are selected from a bond; B is selected from B1 is selected from substituted or unsubstituted 6-membered aryl or 6-membered heteroaryl, when substituted, optionally further substituted by 0 to 4 R b1 replaced by; B2 is selected from a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from N; B3 is selected from a bond; R b1 、R b2 Each independently selected from H, F, Cl, Br, I, CN or CF3; R b3 、R b4 Each independently selected from H or C 1-6 alkyl; or R b3 、R b4 The carbon atoms connected to it together form C 3-6 Cycloalkyl or C 3-6 Heteromonocyclic ring, the cycloalkyl group or heteromonocyclic ring is optionally further C 1-4 Alkyl substituted, Cy1 and Cy2 are each independently selected from one of the following groups: substituted or unsubstituted: a bond, When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, CF3, methyl, oxo, hydroxymethyl, COOH, CN or NH2; and Cy1 and Cy2 are not simultaneously bonds; Cy3 and Cy4 are selected from the bond; K is selected from 2. The compound according to claim 1, or its stereoisomer, or pharmaceutically acceptable salt, wherein B is selected from 3. The compound according to claim 1 or its stereoisomer, or pharmaceutically acceptable salt, wherein Or L is selected from The left side is connected to B; Or L is selected from The left side is connected to B.

4. The compound according to claim 3, or its stereoisomer, or pharmaceutically acceptable salt, wherein K is selected from 5. The compound according to claim 1 or its stereoisomer, or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. Use of the compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating diseases associated with AR activity or expression.

8. Use of the compound according to any one of claims 1 to 5, or a stereoisomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating, inhibiting or degrading AR-related diseases.

9. The use according to claim 8, characterized in that The disease is selected from prostate cancer.

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