CYP11A1 inhibitor and application thereof

Abstract

The invention discloses a compound shown as a formula (I), or a stereoisomer, a deuterated compound, a solvate, a co-crystal or a pharmaceutically acceptable salt of the compound, a pharmaceutical composition of the stereoisomer, the deuterated compound, the solvate, the co-crystal or the pharmaceutically acceptable salt, and application of the stereoisomer, the deuterated compound, the solvate, the co-crystal or the pharmaceutically acceptable salt in preparation of drugs for treating / preventing CYP11A1-mediated diseases, and all groups in the formula (I) are defined as in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a small molecule compound having CYP11A1 selective inhibitory activity, its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, and use thereof in preparing medicines for treating related diseases. Background Art

[0002] Cytochrome p450 monooxygenase 11a1 (cyp11a1), also known as cholesterol side chain cleavage enzyme, is mainly involved in drug metabolism-related catalytic reactions and the synthesis of cholesterol, steroids and other lipids. CYP11A1 protein is located in the inner membrane of mitochondria and catalyzes the conversion of cholesterol to pregnenolone, which is the first and rate-limiting step in steroidogenesis. The reaction is carried out in the mitochondria of the adrenal cortex and is catalyzed by cytochrome CYP11A1 (also called P450scc). Together with CYP11A1, Adx and AdR also work together. CYP11A1, Adx and AdR belong to the cholesterol hydroxylase / lyase system (CH / L), which catalyzes the initial step of steroid synthesis in mammals, that is, the process of generating pregnenolone from cholesterol. Pregnenolone is an important precursor of steroid hormones. The reaction process includes three consecutive monooxygenation reactions, namely the formation of 22R-hydroxycholesterol (22HC), the formation of 20R, 22R-dihydroxycholesterol, and the cleavage of the C20-C22 bond. Each monooxygenation reaction requires the participation of two electrons and one molecular oxygen. The electrons are provided by NADPH and transferred to P450scc through NADPH-AdR and Adx. Adx forms a complex with P450scc and can act as a mobile electron transporter.

[0003] CYP11A1 is mainly expressed in the placenta, responding to the synthesis of placental hormones such as progesterone and testosterone, and is also highly expressed in the adrenal glands and testes, but is hardly expressed in other tissues. By inhibiting cyp11a1, which is a key enzyme in the steroid biosynthesis upstream of cyp17a1, complete blocking of the entire steroid biosynthesis can be achieved. Therefore, cyp11a1 inhibitors may have great potential for treating steroid hormone-dependent cancers such as prostate cancer, even in the late stages of the disease, especially in those patients who show hormone refractory. It has recently been demonstrated that compounds with cyp11a1 inhibition significantly inhibit tumor growth in vivo in a mouse crpc xenograft model.

[0004] CYP11A1 inhibitors with good activity, high safety and few side effects have been discovered, which have good clinical development prospects and can be used to treat cancer or other proliferative diseases or disorders. Summary of the invention

[0005] The present invention provides a small molecule compound having CYP11A1 inhibitory activity, a compound represented by formula (I), a stereoisomer, a deuterated substance, a solvate, a cocrystal or a pharmaceutically acceptable salt thereof,

[0006]

[0007] Ring A is selected from 6-membered heterocycloalkyl, 7-14-membered heterocycloalkyl, 4-6-membered heterocycloalkylene, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 Alkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, C 3-4 Cycloalkyl, 7-14-membered cycloalkyl or 4-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the 6-membered cycloalkyl, 6-membered heterocycloalkyl or 4-membered heterocycloalkyl is at least one R A Substituted, the heterocycloalkylene, 7-14 membered heterocycloalkyl, C 3-4 Cycloalkyl, 7-14 membered cycloalkyl, alkyl optionally substituted with 1-4 R A’ replace;

[0008] In some embodiments, Ring A is selected from C 3-4 Cycloalkyl, 6-membered monocyclic heterocycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 alkyl, cyclohexyl, 4-membered heterocycloalkylene or 4-membered heterocycloalkyl, wherein the 6-membered monocyclic heterocycloalkyl, cyclohexyl or 4-membered heterocycloalkyl is at least one R A Substitute, the C 3-4 Cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 Alkyl, 4-membered heterocycloalkyl group optionally 1-4 R A’ replace;

[0009] In some embodiments, the A ring is selected from 6-membered heterocycloalkyl, 7-14-membered heterocycloalkyl, 4-6-membered heterocycloalkylene, (C3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 alkyl, 6-membered cycloalkyl, 7-14-membered cycloalkyl or 4-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the 6-membered cycloalkyl, 6-membered heterocycloalkyl or 4-membered heterocycloalkyl is at least one R A The heterocycloalkylene, 7-14 membered heterocycloalkyl, 7-14 membered cycloalkyl, alkyl are optionally substituted by 1-4 R A’ replace;

[0010] In some embodiments, the A ring is selected from 6-membered monoheterocycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 alkyl, cyclohexyl, 4-membered heterocycloalkylene or 4-membered heterocycloalkyl, wherein the cyclohexyl, 6-membered heterocycloalkyl or 4-membered heterocycloalkyl is at least one R A The heterocycloalkylene, 7-14 membered heterocycloalkyl, 7-14 membered cycloalkyl, alkyl are optionally substituted by 1-4 R A’ replace;

[0011] In some embodiments, the A ring is selected from 6-membered azacycloalkyl, cyclohexyl, 5-6-membered heterocyclyl and 5-membered cycloalkyl, 5-6-membered heterocyclyl and 5-membered heterocyclyl, 4-5-membered heterocycloalkyl spiro 6-membered heterocycloalkyl, 5-membered cycloalkyl spiro 6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 Alkyl, azetidinyl or 4-membered azacycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S;

[0012] In some embodiments, Ring A is selected from one of the following structures:

[0013]

[0014]

[0015] Or selected from

[0016]

[0017] In some embodiments, Ring A is selected from one of the following structures:

[0018]

[0019]

[0020] Ring B is selected from The left side of the B ring is connected to L1;

[0021] The C ring is selected from

[0022] R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -O-HaloC 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-4 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl, C 2-6 radical substitution of alkynyl groups;

[0023] In some embodiments, R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3-R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl or selected from -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a 、-NH-C(O)-NH-R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl, C 2-6 radical substitution of alkynyl groups;

[0024] In some embodiments, R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-(CH2) 1-2 -O-HaloC 1-2 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-2 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R aThe alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl, C 2-4 radical substitution of alkynyl groups;

[0025] In some embodiments, R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl, C 2-4 radical substitution of alkynyl groups;

[0026] In some embodiments, R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 The alkyl, alkenyl, alkynyl group may be further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0027] In some embodiments, R A Each independently selected from CN, COOH, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC1-2 Alkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0028] In some embodiments, R A Each independently selected from COOH, -OC 1-2 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-C 1-2 Alkyl-R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-3 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 In some embodiments, R A Each is independently selected from: COOH, -S(O)2-CH3, -P(O)-(CH3)2, -CH2-C(O)-4-6 membered heterocycloalkyl, -C(O)-CH2-4-6 membered heterocycloalkyl, -C(O)-CH2-C 3-6 Cycloalkyl, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-OC 3-6 Cycloalkyl, -C(O)-OC 1-2 Alkyl-C 3-6 Cycloalkyl, -C(O)-O-halogenated C 1-3 alkyl, -S(O)2-CH2-4-6 membered heterocycloalkyl, -S(O)2-CH2-C 2-4 Alkynyl, -S(O)2-CH2-C3-5 Cycloalkyl, -S(O)2-CH2-5-6 membered heteroaryl, -S(O)2-CH2-O-halogenated C 1-2 alkyl, -S(O)2-CH2CH2-4-6 membered heterocycloalkyl, -S(O)2-CH2CH2-C 2-4 Alkynyl, -S(O)2-CH2CH2-C 3-5 Cycloalkyl, -S(O)2-CH2CH2-5-6 membered heteroaryl, -S(O)2-CH2CH2-O-halogenated C 1-2 alkyl;

[0029] In some embodiments, R A Each independently selected from COOH, -S(O)2-CH3, -P(O)-(CH3)2,

[0030]

[0031] Or selected from

[0032] In some embodiments, R A Each independently selected from COOH, -S(O)2-CH3, -P(O)-(CH3)2,

[0033]

[0034] R A’ Each independently selected from halogen, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a、-C(O)-O-halogenated C 1-4 The alkyl, alkenyl, alkynyl group may be further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0035] In some embodiments, R A’ Each independently selected from halogen, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-S(O)2-C 1-4 Alkyl, -CH2-NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 The alkyl, alkenyl, alkynyl group may be further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0036] In some embodiments, R A’ Each independently selected from halogen, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0037] In some embodiments, R A’ Each independently selected from halogen, OH, CN, COOH, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-2 Alkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-2 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0038] In some embodiments, R A’ Each independently selected from halogen, OH, COOH, C 1-2 Alkyl, -OC 1-2 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-C 1-2 Alkyl-R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-2 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0039] In some embodiments, R A’Each independently selected from halogen, OH, COOH, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH3-R a 、-S(O)2-CH2CH3-R a , -P(O)-(CH2CH3)2, -P(O)-(CH3)2, -C(O)-OR a 、-CH2-C(O)-R a 、-C(O)-CH2-R a ;

[0040] In some embodiments, R A’ Each is independently selected from F, Cl, OH, COOH, -CH3, -CH2CH3, -P(O)-(CH3)2, -S(O)2-CH3, -CH2-C(O)-4-6 membered heterocycloalkyl, -C(O)-CH2-4-6 membered heterocycloalkyl, -C(O)-CH2-C 3-6 Cycloalkyl, -C(O)-O-4-6 membered heterocycloalkyl, -C(O)-OC 3-6 Cycloalkyl, -C(O)-OC 1-2 Alkyl-C 3-6 Cycloalkyl, -C(O)-O-halogenated C 1-3 alkyl, -S(O)2-CH2-4-6 membered heterocycloalkyl, -S(O)2-CH2-C 2-4 Alkynyl, -S(O)2-CH2-C 3-5 Cycloalkyl, -S(O)2-CH2-5-6 membered heteroaryl, -S(O)2-CH2-O-halogenated C 1-2 Alkyl, -S(O)2-CH2CH2-4-6 membered heterocycloalkyl, -S(O)2-CH2CH2-C 2-4 Alkynyl, -S(O)2-CH2CH2-C 3-5 Cycloalkyl, -S(O)2-CH2CH2-5-6 membered heteroaryl, -S(O)2-CH2CH2-O-halogenated C 1-2 alkyl;

[0041] In some embodiments, R A’ Each independently selected from COOH, -CH3, -CH2CH3, -S(O)2-CH3, -P(O)-(CH3)2,

[0042]

[0043]

[0044] In some embodiments, RA’ Each independently selected from COOH, -CH3, -CH2CH3, -S(O)2-CH3, -P(O)-(CH3)2,

[0045]

[0046] R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl or 8-membered heterocycloalkyl, wherein the alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted by 1-4 alkyl radicals selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S;

[0047] In some embodiments, R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 5-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0048] In some embodiments, R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S;

[0049] In some embodiments, R a Selected from C 2-4 Alkynyl, cyclopropyl, 4-6 membered heterocycloalkyl, pyrazolyl, wherein the cyclopropyl, heterocycloalkyl, pyrazolyl may be further substituted with halogen, C 1-2 Alkyl, OH group substitution;

[0050] L1 is selected from W1-R L -W2, L2 is selected from -CH2-, the left side of L1 is connected to A, and the left side of L2 is connected to B;

[0051] In some embodiments, L1 is selected from a bond, C 1-2 Alkylene-O, C 1-2 Alkylene, C 1-2 Alkylene-S, C 1-2 Alkylene-Se, C 1-2 Alkylene-N(C 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene, -OC 1-3 Alkylene, C 2-4 Alkenylene, -N(C 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 alkylene), -O-, -C(=O)-O-, C 3-4 Cycloalkylene-O, wherein the alkylene, alkenylene, cycloalkylene is optionally further substituted by 1-3 R L1 replace;

[0052] In some embodiments, L1 is selected from a bond, C 1-2 Alkylene-O, C 1-2 Alkylene, C 1-2 Alkylene-S, C 1-2 Alkylene-Se, C 1-2 Alkylene-N(C 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene, -OC 1-3 Alkylene, C 2-4 Alkenylene, -N(C 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 alkylene), -O-, -C(=O)-O-, C 3-6 Cycloalkyl-O, the alkylene, alkenylene, cycloalkyl optionally further substituted by 1-3 R L1 replace;

[0053] R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, C 3-4 Cycloalkylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 replace;

[0054] In some embodiments, R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 replace;

[0055] In some embodiments, R L Select from key, C 1-2 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 replace;

[0056] In some embodiments, R L is selected from -CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH2CH2-CH=CH-, -CH(CH3)-CH=CH-, -CH2-CH=CH-CH2-, wherein the CH3, CH2, CH are optionally further replaced by 1-4 R L1 replace;

[0057] R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0058] In some embodiments, R L1 Each independently selected from halogen, =O, C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0059] In some embodiments, R L1 Each independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 3-6 Cycloalkyl;

[0060] In some embodiments, R L1 Each independently selected from F, Cl, Br, =O, -CH2-, -CH2CH2-, C 2-4 alkenyl, -O-CH2-, -O-CH2CH2-, cyclopropyl, wherein the CH2, alkenyl, cyclopropyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH and NH2;

[0061] W1 and W2 are each independently selected from a bond, -O-, -S-, -Se-, -NR W1 -;

[0062] In some embodiments, W1 and W2 are each independently selected from -O-, -S-, -Se-, -NH-, -N(CH3)-;

[0063] R W1 Selected from H, C 1-4 alkyl;

[0064] In some embodiments, R W1 Selected from H, C 1-2 alkyl;

[0065] In some embodiments, R W1 is selected from H, -CH3, -CH2CH3;

[0066] p is selected from 0, 1, 2, 3, 4;

[0067] In some embodiments, p is selected from 0, 1, 2, 3; in some embodiments, p is selected from 0, 1, 2; in some embodiments, p is selected from 0, 1; in some embodiments, p is selected from 0;

[0068] The condition is,

[0069] (1) When the A ring is selected from a 6-membered cycloalkyl group, R A Not selected from -S(O)2-CH3;

[0070] (2) When ring A is selected from And R A Selected from -S(O)2-C 1-3 When alkyl, L1 is not selected from -(CH2) 1-3 -O-;

[0071] (3) Ring A is not selected from

[0072] As a specific technical solution 1 of the present invention, a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0073]

[0074] Ring A is selected from 6-membered heterocycloalkyl, 7-14-membered heterocycloalkyl, 4-6-membered heterocycloalkylene, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 Alkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, C 3-4Cycloalkyl, 7-14-membered cycloalkyl or 4-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the 5-membered cycloalkyl, 6-membered cycloalkyl, 6-membered heterocycloalkyl or 4-membered heterocycloalkyl is at least one R A Substituted, the heterocycloalkylene, 7-14 membered heterocycloalkyl, C 3-4 Cycloalkyl, C 3-4 Cycloalkyl, 7-14 membered cycloalkyl, alkyl optionally substituted with 1-4 R A’ replace;

[0075] Ring B is selected from The left side of the B ring is connected to L1;

[0076] The C ring is selected from

[0077] L1 is selected from W1-R L -W2, L2 is selected from -CH2-, the left side of L1 is connected to A, and the left side of L2 is connected to B;

[0078] R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, C 3-4 Cycloalkylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0079] In some embodiments, R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0080] W1 and W2 are each independently selected from a bond, -O-, -S-, -Se-, -NR W1 -;

[0081] RW1 Selected from H, C 1-4 alkyl;

[0082] R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -O-HaloC 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-4 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl, C 2-6 radical substitution of alkynyl groups;

[0083] In some embodiments, R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2)1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl or -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a 、-NH-C(O)-NH-R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl, C 2-6 radical substitution of alkynyl groups;

[0084] R A’ Each independently selected from halogen, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0085] R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl or 8-membered heterocycloalkyl, wherein the alkynyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted by 1-4 alkyl radicals selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4Alkyl, -S(O)2-CH3, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S;

[0086] p is selected from 0, 1, 2, 3, 4;

[0087] The condition is,

[0088] (1) When the A ring is selected from a 6-membered cycloalkyl group, R A Not selected from -S(O)2-CH3;

[0089] (2) When ring A is selected from And R A Selected from -S(O)2-C 1-3 When alkyl, L1 is not selected from -(CH2) 1-3 -O-;

[0090] (3) Ring A is not selected from

[0091] Further, a compound represented by formula (I), a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof is provided.

[0092]

[0093] Ring A is selected from 6-membered heterocycloalkyl, 7-14-membered heterocycloalkyl, 4-6-membered heterocycloalkylene, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 alkyl, 6-membered cycloalkyl, 7-14-membered cycloalkyl, the heterocycloalkyl containing 1-3 heteroatoms selected from N, O, S; the 6-membered cycloalkyl, 6-membered heterocycloalkyl is at least 1 R A The heterocycloalkylene, 7-14 membered heterocycloalkyl, 7-14 membered cycloalkyl, alkyl are optionally substituted by 1-4 R A’ replace;

[0094] Ring B is selected from

[0095] The C ring is selected from

[0096] L1 is selected from W1-R L -W2, L2 is selected from -CH2-, the left side of L1 is connected to A, and the left side of L2 is connected to B;

[0097] R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2;

[0098] W1 and W2 are each independently selected from a bond, -O-, -S-, -Se-, -NR W1 -;

[0099] R W1 Selected from H, C 1-4 alkyl;

[0100] R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 The alkyl, alkenyl, alkynyl group may be further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0101] R A’ Each independently selected from halogen, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2)1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0102] R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 groups selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S;

[0103] p is selected from 0, 1, 2, 3, 4;

[0104] The condition is,

[0105] (1) When the A ring is selected from a 6-membered cycloalkyl group, R A Not selected from -S(O)2-CH3;

[0106] (2) When ring A is selected from And R A Selected from -S(O)2-C 1-3 When alkyl, L1 is not selected from -(CH2) 1-3 -O-;

[0107] (3) Ring A is not selected from

[0108] As a specific technical solution 2 of the present invention, a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0109] Among them, the A ring is selected from C 3-4 Cycloalkyl, 6-membered monocyclic heterocycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2alkyl, cyclohexyl, 4-membered heterocycloalkylene or 4-membered heterocycloalkyl, wherein the 6-membered monocyclic heterocycloalkyl, cyclohexyl or 4-membered heterocycloalkyl is at least one R A Substitute, the C 3-4 Cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 Alkyl, 4-membered heterocycloalkyl group optionally 1-4 R A’ replace;

[0110] R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-(CH2) 1-2 -O-HaloC 1-2 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-2 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R a The alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl, C 2-4 radical substitution of alkynyl groups;

[0111] In some embodiments, R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl or -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a 、-NH-C(O)-NH-R a The alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl, C 2-4 radical substitution of alkynyl groups;

[0112] R A’ Each independently selected from halogen, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-S(O)2-C 1-4 Alkyl, -CH2-NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0113] R a Selected from C 2-4 Alkynyl, C 3-5Cycloalkyl, 6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 5-membered heteroaryl or 8-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted by halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0114] p is selected from 0, 1 or 2;

[0115] The definitions of the remaining groups are the same as those in the above technical solution.

[0116] Further, a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein:

[0117] Ring A is selected from 6-membered monoheterocycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocyclyl spiro 5-6-membered heterocyclyl, 5-6-membered cycloalkyl and 5-6-membered heterocyclyl, 5-6-membered cycloalkyl and 5-6-membered heterocyclyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocyclyl, 10-14-membered partially unsaturated tricyclic heterocyclyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 Alkyl, cyclohexyl, 4-membered heterocycloalkylene, wherein the cycloalkyl, heterocycloalkyl, heterocyclic group is optionally substituted by 1-4 R A replace;

[0118] R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl radical substitution;

[0119] R A’ Each independently selected from halogen, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2)p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 The alkyl, alkenyl, alkynyl group may be further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution;

[0120] R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl, 5 membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution;

[0121] p is selected from 0, 1 or 2;

[0122] The definitions of the remaining groups are the same as those in the above technical solution.

[0123] As a specific technical solution 3 of the present invention, a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein the A ring is selected from one of the following structures:

[0124]

[0125]

[0126] Or the A ring is selected from one of the following structures: Or the A ring is selected from one of the following structures:

[0127] Or the A ring is selected from the following structures

[0128] one:

[0129] The remaining groups are defined the same as in any of the above technical solutions.

[0130] As a specific technical solution 4 of the present invention, a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt,

[0131] Wherein L1 is selected from a bond, C 1-2 Alkylene-O, C 1-2 Alkylene, C 1-2 Alkylene-S, C 1-2 Alkylene-Se, C 1-2 Alkylene-N(C 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene, -OC 1-3 Alkylene, C 2-4 Alkenylene, -N(C 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 alkylene), -O-, -C(=O)-O-, C 3-4 Cycloalkylene-O, wherein the alkylene, alkenylene, cycloalkylene is optionally further substituted by 1-3 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 3-6 Cycloalkyl;

[0132] In some embodiments, L1 is selected from a bond, C 1-2 Alkylene-O, C 1-2 Alkylene, C 1-2 Alkylene-S, C 1-2 Alkylene-Se, C 1-2 Alkylene-N(C 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene, -OC 1-3 Alkylene, C 2-4 Alkenylene, -N(C 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 alkylene), -O-, -C(=O)-O-, C 3-6 Cycloalkyl-O, the alkylene, alkenylene, cycloalkyl optionally further substituted by 1-3 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 3-6 Cycloalkyl;

[0133] The remaining groups are defined the same as in any of the above technical solutions.

[0134] The present invention also provides a pharmaceutical composition or pharmaceutical preparation, which contains the compound described in any one of the aforementioned schemes, its stereoisomers, deuterated substances, solvates, cocrystals or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0135] Furthermore, the composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the aforementioned schemes, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt and a carrier and / or excipient.

[0136] The present invention also provides the use of the compound described in any of the aforementioned schemes, its stereoisomers, deuterated forms, solvates, cocrystals or pharmaceutically acceptable salts, or the composition described in any of the aforementioned schemes in the preparation of a medicament for treating / preventing a disease mediated by CYP11A1. Furthermore, the disease mediated by CYP11A1 is a steroid hormone-dependent cancer, and the more preferred cancer is prostate cancer.

[0137] The present invention also provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound described in any one of the foregoing schemes or a stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably prostate cancer. In some embodiments, the mammal described in the present invention does not include a human.

[0138] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0139] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, a deuterated substance or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or a stereoisomer, a deuterated substance or a pharmaceutically acceptable salt thereof is the same as that in the above-mentioned pharmaceutical composition.

[0140] The amount of the compound according to the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0141] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0142] Synthetic route

[0143] Patent documents such as WO2018115591A1 introduce the preparation method of CYP11A1 inhibitors. Those skilled in the art can combine the document and known organic synthesis techniques to prepare the compounds of the present invention, and the starting materials are commercially available chemicals and (or) compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0144] the term

[0145] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0146] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0147] "Halo" or "halogen substituted" means that a hydrogen atom is replaced by one or more halogens selected from F, Cl, Br, I, or isotopes thereof, and the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they may be substituted by the same or different halogens.

[0148] "Deuterated" or "deuterated substance" refers to the situation where hydrogen atoms on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. are replaced by at least one isotope deuterium, and the upper limit of the number of deuterations is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms are replaced, more preferably 1-10 deuterium atoms are replaced, more preferably 1-6 deuterium atoms are replaced, and further preferably 1-3 deuterium atoms are replaced.

[0149] "Alkyl" refers to a monovalent straight or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, is an alkyl 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, further preferably an alkyl group of 1 to 4 carbon atoms, and further preferably an alkyl group of 1-2 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.

[0150] "Alkylene" refers to a divalent straight chain or branched chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

[0151] "Cycloalkyl" refers to a partially unsaturated or fully saturated, substituted or unsubstituted non-aromatic carbocyclic hydrocarbon group, and unless otherwise specified, usually has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and further preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Or cycloheptyl, etc.

[0152] "Cycloalkylene" refers to a divalent radical of "cycloalkyl", and non-limiting examples include cyclopropylene, cyclobutylene, and the like.

[0153] "Heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which contains 1 to 3 heteroatoms selected from N, O or S when not specifically defined, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles, etc., and is 3 to 12-membered heterocycles, more preferably 4-12-membered heterocycles, more preferably 4-10-membered heterocycles, and further preferably 4-7-membered heterocycles when not specifically defined. Its definition includes heterocycloalkyl and heteroaryl. N and S in the heterocyclic ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dithio ... ]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, wait.

[0154] "Heterocyclylene" is a divalent group corresponding to "heterocyclyl", and non-limiting examples include imidazolyl, piperidinyl, aziridinyl, and the like.

[0155] "Carbocycle" or "carbocyclic group" refers to substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic groups, including monocyclic carbocycles, bicyclic bridged rings, bicyclic cyclic rings and bicyclic spirocycles, etc., and unless otherwise specified, has 3 to 12 carbon atoms, preferably 3-10 carbon atoms, and more preferably 3-6 carbon atoms. Its definition includes cycloalkyl and aryl. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc., the bicyclic bridge ring includes etc., double ring and ring include etc., bicyclic spiro ring includes wait.

[0156] "Aryl" refers to a carbon ring having aromatic properties. Non-limiting examples include phenyl, naphthyl, and the like.

[0157] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propargyl, etc.

[0158] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, the alkynyl group contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples are ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0159] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, -OC 1-8 Alkyl, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl, more preferably -OC 1-2 Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, and the like.

[0160] "Haloalkoxy" refers to -O-haloalkyl, and unless otherwise specified, is -O-haloC 1-8 Alkyl, preferably -O-halogenated C 1-6 Alkyl, more preferably -O-halogenated C 1-4 Alkyl, more preferably -O-halogenated C 1-2 Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0161] “C 1-4 "Alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, propionyl.

[0162] “C 1-4 "Alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methylsulfonyl, ethylsulfonyl, propanesulfonyl.

[0163] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring having aromatic properties. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furanyl, pyrone, pyridone, and the like.

[0164] "Heterocycloalkyl" refers to a non-aromatic, partially unsaturated or fully saturated heterocycle, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and further preferably 5 or 6 ring members. In addition to carbon atoms, heterocycloalkyl also contains 1-3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, etc.

[0165] "Alkyl NH2" or "alkane NH2" refers to NH2 substituted with a single or double alkyl group, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkyl NH2. Non-limiting examples include dimethyl NH2, monomethyl NH2, diethyl NH2, monoethyl NH2, etc.

[0166] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0167] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which 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.

[0168] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0169] "Carrier" refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0170] "Excipient" refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and / or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other nontoxic compatible substances used in pharmaceutical preparations.

[0171] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0172] "Solvate" refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0173] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates. DETAILED DESCRIPTION

[0174] The content of the present invention will be described in detail below through examples. If no specific conditions are specified in the examples, the experimental method according to conventional conditions is carried out. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Those skilled in the art can make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still belongs to the protection scope of the present invention.

[0175] Dess-Martin reagent; 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3-(1H)-one

[0176] DIPEA: N,N-diisopropylethylamine

[0177] NMP; N-methylpyrrolidone

[0178] TBDMSCl: tert-butyldimethylsilyl chloride

[0179] DMAP: 4-dimethyl NH2pyridine

[0180] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0181] T3P: Propylphosphonic acid tricyclic anhydride

[0182] Intermediate 1: 2-(Chloromethyl)-5-hydroxy-(4H)-pyran-4-one (Intermediate 1)

[0183] 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one(intermediate 1)

[0184]

[0185] Kojic acid (20.0 g, 140.7 mmol) was dissolved in 40 ml of thionyl chloride and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, the filter cake was slurried with 100 mL of petroleum ether, filtered, and the filter cake was dried to obtain intermediate 1 (29.8 g, 90%).

[0186] LCMS (ESI): m / z = 161.2 [M+H]

[0187] 1 H NMR (400MHz, DMSO) δ8.12(s,1H),6.57(s,1H),4.66(s,2H).

[0188] Intermediate 2: Methyl 1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (Intermediate 2)

[0189] (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate(intermediate 2)

[0190]

[0191] 4-Hydroxymethylpiperidine (20.0 g, 175.4 mmol) was dissolved in 200 ml of acetonitrile, potassium carbonate (53.6 g, 386.0 mmol) was added, and the mixture was stirred mechanically at room temperature for 16 h. After the reaction, the reaction solution was filtered, the filtrate was concentrated, and then slurried with 100 mL of a mixed solvent of ethyl acetate: petroleum ether = 1:1, filtered, and the filter cake was washed with water and dried to obtain intermediate 2 (47 g, 40%).

[0192] LCMS (ESI): m / z = 272.3 [M+H]

[0193] 1 H NMR (400MHz, CDCl3) δ4.10(d,2H),3.95–3.78(m,2H),3.03(s,3H),2.79(s,3H),2.71-2.67(m,2H),1.95–1.80(m,3H),1.51–1.34(m,2H).

[0194] Intermediate 3: 5-Hydroxy-2-(isoindol-2-ylmethyl)-4H-pyran-4-one (Intermediate 3)

[0195] 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(intermediate 3)

[0196]

[0197] Intermediate 1 (9.8 g, 61.0 mmol) and isoindole hydrochloride (19.0 g, 122.1 mmol) were dissolved in 200 ml of acetonitrile, and DIPEA (30.8 g, 244.2 mmol) was added and reacted at room temperature with mechanical stirring for 16 h. After the reaction was completed, the reaction solution was filtered, and the filter cake was slurried with 100 mL of water and 50 mL of ethyl acetate in turn, filtered, and the filter cake was dried to obtain Intermediate 3 (47 g, 40%).

[0198] LCMS (ESI): m / z = 244.1 [M+H]

[0199] 1H NMR (400MHz, DMSO) δ9.06(s,1H),8.06(s,1H),7.39–7.04(m,4H),6.41(s,1H),3.95(s,4H),3.78(s,2H).

[0200] Intermediate 4: 6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate

[0201] 6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yltrifluoromethanesulfonate

[0202]

[0203] Step 1: Dissolve the raw substrate intermediate 3 (1.0 g, 4.12 mmol) and triethylamine (1.26 g, 12.36 mmol) in ultra-dry DCM (10 mL) at room temperature, cool to 0°C under nitrogen protection, then dropwise add a solution of trifluoromethanesulfonic anhydride (1.75 g, 6.18 mmol) in ultra-dry DCM (10 mL), and naturally warm to room temperature to react for 1 h after the dropwise addition. Add 30 mL of saturated sodium bicarbonate to quench the reaction, extract with DCM (50 mL × 3), combine the organic phases, wash with water (50 mL × 3), wash with saturated sodium chloride (50 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain intermediate 4 (1.0 g, 65%).

[0204] LC-MS (ESI): m / z = 376.1 [M+H] + .

[0205] Example 1: 5-(difluoro(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-(isoindol-2-ylmethyl)-4H-pyran-4-one (Compound 1)

[0206] 5-(difluoro(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-(isoin dolin-2-ylmethyl)-4H-pyran-4one(compound 1)

[0207]

[0208] Step 1: Add raw material 1A (4.35 g, 24.54 mmol, 1.0 eq.) to dry THF (200 mL), add dibromodifluoromethane (9.63 mL, 4.5 eq.) and HMPA (18.69 mL, 4.5 eq.) under ice bath. Then slowly warm to room temperature and stir for 30 minutes, add zinc powder (6.42 g, 4.5 eq.) and HMPA (1.78 mL 0.4 eq.), and heat to reflux for 5 hours. Cool, filter, wash the filtrate with saturated anhydrous copper sulfate solution, dry and filter with anhydrous sodium sulfate, concentrate, and purify and separate the target compound 1B (2.9 g, yield 56%) by silica gel column chromatography (PE:EA (v / v) = 1:0-10:1).

[0209] LCMS m / z=212.1[M+1]

[0210] Step 2: Dissolve the raw material 1B (2.0 g, 9.47 mmol, 1.0 eq.) in TCM (30 mL) solvent, slowly add bromine (2.27 g, 14.21 mmol, 1.5 eq.) under ice bath, continue stirring for 1 hour after addition, then wash with saturated sodium sulfite solution, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the target compound 1C (2.8 g, yield 80%).

[0211] Step 3: Add raw material 1C (1.0 g, 2.70 mmol), intermediate 3 (0.79 g, 3.24 mmol), KI (0.45 g, 2.70 mmol), and potassium carbonate (0.75 g, 5.40 mmol) into DMF (20 ml) successively, heat to 75 ° C for 4 hours, filter, dilute the filtrate with water, extract with EA, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify and separate the target compound 1 (75 mg, yield 7%) by silica gel column chromatography (PE: EA (v / v) = 1:0 to 1:6).

[0212] LCMS m / z=453.7[M+1]

[0213] 1 H NMR (400MHz, CD3OD) δ7.98-7.99(m,1H),7.19-7.24(m,4H),6.58(s,1H),6.41-6.44(m,1H),4. 09-4.12(m,4H),3.92-3.94(m,2H),3.83(s,2H),3.47(t,2H),2.85(s,3H),2.53-2.55(m,2H).

[0214] Example 2: 6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl-4-(methylsulfonyl)piperazine-1-carboxylate (Compound 2)

[0215] 6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl 4-(methylsulfonyl)piperazine-1-carboxylate(compound 2)

[0216]

[0217] Step 1: N-Boc piperazine (0.1 g, 0.54 mmol), intermediate 3 (0.13 g, 0.54 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in DCM (10 mL), cooled to 0°C and triphosgene (0.16 g, 0.54 mmol) was added. The mixture was reacted at room temperature for 1 h. LCMS detected that the reaction of the raw materials was complete. The system was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 1:1 to 1:0) to obtain the target compound 2A (0.17 g, 71%).

[0218] LC-MS (ESI): m / z = 456.1 [M+H] + .

[0219] Step 2: 2A (170 mg, 0.37 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. LCMS showed that the reaction of the raw material was complete. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 2B, which was directly used for the next step without purification (130 mg, 99%).

[0220] LC-MS (ESI): m / z = 356.1 [M+H] + .

[0221] Step 3: 2B (130 mg, 0.37 mmol) and DIPEA (239 mg, 1.85 mmol) were dissolved in DCM (5 mL), and methylsulfonyl chloride (63 mg, 0.55 mmol) was added. The mixture was reacted at room temperature for 3 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was concentrated and the residue was separated by column chromatography (DCM: MeOH = 1:0 to 20:1) to obtain compound 2 (100 mg, 62.5%).

[0222] LC-MS (ESI): m / z = 434.1 [M+H] + .

[0223] 1H NMR(400MHz, CDCl3)δ7.93(s,1H),7.22–7.19(m,4H),6.56(s,1H),4.07(s, 4H),3.81-3.79(m,4H),3.71–3.68(m,2H),3.36-3.32(m,4H),2.82(s,3H).

[0224] Example 3: 2-(isoindolin-2-ylmethyl)-5-(2-(methylsulfonyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-4H-pyran-4-one (Compound 3)

[0225] 2-(isoindolin-2-ylmethyl)-5-(2-(methylsulfonyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-4H-pyran-4-one(compound 3)

[0226]

[0227] Step 1: Dissolve the raw material substrate 3A (1.0 g, 4.45 mmol) in ultra-dry THF (50 mL) at room temperature, cool to -78 ° C under nitrogen protection, then add LiHMDS (5.34 mL, 5.34 mmol) dropwise, continue stirring at -78 ° C for 1 h after the dropwise addition, then add N-phenylbis(trifluoromethanesulfonyl)imide (3.18 g, 8.9 mmol) in ultra-dry THF (50 mL) dropwise, and naturally warm to room temperature for 2 h after the dropwise addition. Add 20 mL of water to quench the reaction, extract with EA (200 mL × 3), combine the organic phases and wash with water (200 mL × 3), wash with saturated sodium chloride (200 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound 3B (1.35 g, 85%).

[0228] LC-MS (ESI): m / z = 358.1 [M+H] + .

[0229] Step 2: Dissolve the raw material substrate 3B (1.35 g, 3.78 mmol), biboronic acid pinacol ester (1.25 g, 4.91 mmol), potassium acetate (0.74 g, 7.56 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.28 g, 0.38 mmol) in ultra-dry 1,4-dioxane (50 mL) at room temperature, and heat to 80°C under nitrogen protection for 16 h. Add 50 mL of water to quench the reaction, extract with EA (100 mL × 3), combine the organic phases, wash with water (100 mL × 3), wash with saturated sodium chloride (100 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound 3C (0.78 g, 60%).

[0230] LC-MS (ESI): m / z = 336.2 [M+H] + .

[0231] Step 3: Dissolve the raw material substrate 3C (375 mg, 1.05 mmol), intermediate 4 (394 mg, 1.05 mmol), potassium carbonate (434 mg, 3.15 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (72 mg, 0.1 mmol) in 1,4-dioxane (10 mL) at room temperature, add water (2 mL), and heat to 80°C under nitrogen protection for 16 h. Add 10 mL of water to quench the reaction, extract with EA (30 mL × 3), combine the organic phases, wash with water (30 mL × 3), wash with saturated sodium chloride (30 mL × 1), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain compound 3D (200 mg, 46%).

[0232] LC-MS (ESI): m / z = 435.2 [M + H] + .

[0233] Step 4: 3D (100 mg, 0.23 mmol) was dissolved in DCM (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 h. LCMS showed that the reaction of the raw material was complete. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 3E, which was directly used for the next step without purification (70 mg, 90%).

[0234] LC-MS (ESI): m / z = 335.2 [M+H] + .

[0235] Step 5: 3E (70 mg, 0.21 mmol) and DIPEA (136 mg, 1.05 mmol) were dissolved in DCM (5 mL), and methylsulfonyl chloride (35 mg, 0.31 mmol) was added. The mixture was reacted at room temperature for 3 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was concentrated and the residue was separated by column chromatography (DCM:MeOH=1:0-20:1) to obtain compound 3 (30 mg, 34.6%).

[0236] LC-MS (ESI): m / z = 413.2 [M + H] + .

[0237] 1 H NMR(400MHz, CDCl3)δ7.76(s,1H),7.24–7.19(m,4H),6.44(s,1H),4.08(s,4H),3.79(s,2H),3.71–3 .68(m,2H),3.49-3.48(m,3H),3.09-2.93(m,2H),2.81-2.76(m,1H),2.42-2.38(m,1H),2.82(s,3H).

[0238] Example 4: 5-((1-((cyclopropylmethyl)sulfonyl)piperidin-4-methoxy)-2-isoindolin-2-ylmethyl-4H-pyran-4-one (Compound 4)

[0239] 5-((1-((cyclopropylmethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(compound 4)

[0240]

[0241] Step 1: Dissolve compound 4A (2g, 9.30mmol) and triethylamine (2.82g, 27.9mmol) in dichloromethane (8mL), slowly add methylsulfonyl chloride (1.28, 11.16mmol) dropwise under ice bath, and naturally warm to room temperature after the addition is complete. After 3h, TLC detection shows that the reaction is complete, add 50mL of water to the reaction solution, extract with dichloromethane (20mL×3), combine the organic layers, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude target compound 4B (2.74g).

[0242] LC-MS (ESI): m / z = 294.1 [M+H] + .

[0243] Step 2: Compound 4B (1.0 g, 3.4 mmol) and intermediate 3 (0.83 g, 3.4 mmol) were dissolved in DMF (8 mL), triethylamine (1.03 g, 10.2 mmol) was added, and the mixture was reacted at 60°C for 3 h. The reaction was completed after TLC detection. Water (20 mL) was poured into the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 6:1) to obtain compound 4C (1.01 g, 68%).

[0244] LC-MS (ESI): m / z = 441.3 [M + H] + .

[0245] Step 3: Dissolve compound 4C (1.01 g, 2.30 mmol) in dichloromethane (8 mL), add dioxane hydrochloride solution (4 mL), and stir at room temperature for 2 hours. Concentrate the reaction solution, remove excess hydrochloric acid, add dichloromethane (4 mL), and adjust the pH to 6-7 with triethylamine, and concentrate to obtain a brown crude target compound 4D. No purification is required, and proceed directly to the next step.

[0246] LC-MS (ESI): m / z = 341.5 [M+H] + .

[0247] Step 4: Dissolve compound 4D (200 mg, 0.59 mmol) and triethylamine (178 mg, 1.76 mmol) in anhydrous dichloromethane (10 mL). Add cyclopropylmethanesulfonamide (118 mg, 0.77 mmol) at room temperature and react for 4 hours. TLC monitors the disappearance of the raw material. Add water (50 mL) to the reaction solution for extraction, extract with dichloromethane (20 mL × 3), combine the organic layers, wash with saturated brine (15 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product is purified by high-performance liquid phase preparation to obtain the target compound 4 (148 mg, yield 55%). Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19 mm × 250 mm). The sample is dissolved in DMF and filtered with a 0.45 μm filter to prepare a sample solution. Preparative chromatographic conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 1% ammonium acetate), gradient elution, mobile phase A content from 10% to 55%, flow rate 12 mL / min. Elution time 15 min.

[0248] 1H NMR(400MHz,Methanol-d4)δ7.96(s,1H),7.30-7.00(m,4H),6.45(s,1H),3.94(s,4H),3.86-3.59(m,6H),3.0 0-2.68(m,4H),2.10-1.71(m,3H),1.42-1.20(m,2H),1.10-0.91(m,1H),0.73-0.51(m,2H),0.29-0.21(m,2H).

[0249] LC-MS (ESI): m / z = 459.2 [M+H] + .

[0250] Example 5: Oxetane-3-yl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-oxy)methyl)piperidine-1-carboxylate (Compound 5)

[0251] oxetan-3-yl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate(compound 5)

[0252]

[0253] Step 1: Dissolve compound 4D (200 mg, 0.59 mmol) and triethylamine (178 mg, 1.76 mmol) in dichloromethane (8 mL), slowly add p-nitrophenyl chloroformate (143 mg, 0.71 mmol) dropwise under ice bath, and naturally warm to room temperature after the addition is complete. After 3 h, TLC detection shows that the reaction is complete, add 50 mL of water to the reaction solution, extract with dichloromethane (20 mL × 3), combine the organic layers, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, and concentrate to obtain a crude product, which is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 6:1) to obtain the target compound 5A (152 mg, yield 51%).

[0254] LC-MS (ESI): m / z = 506.5 [M+H] + .

[0255] Step 2: Dissolve oxacyclobutane-3-ol in anhydrous DMF (10 mL), add sodium hydride (18 mg, 60%, 0.45 mmol) under ice bath, stir for 0.5 hour, add compound 5A (152 mg, 0.3 mmol). Stir under ice bath for 1 hour, warm to room temperature and stir for 1 hour. TLC detection shows that the reaction is complete, add 50 mL of ice water to the reaction solution to quench, extract with ethyl acetate (20 mL×3), wash the organic phase with saturated brine several times, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a brown crude product, which is purified using a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-10% MeOH / DCM) to obtain the target compound 5 (74 mg, two-step yield 56%).

[0256] 1 H NMR(400MHz, Methanol-d4)δ8.05(s,1H),7.42-7.12(m,4H),6.55(s,1H),5.34-5.31(m,1H),4.87-4.84(m,2H),4.62-4.59(m,2H),4 .17(s,2H),4.04(s,4H),3.87(s,2H),3.77-3.74(m,2H),2.91-2.88(m,2H),2.24-1.98(m,1H),1.95-1.77(m,2H),1.30-1.27(m,2H).

[0257] LC-MS (ESI): m / z = 441.3 [M + H] + .

[0258] Example 6: 3,3-difluorocyclobutyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (compound 6)

[0259]

[0260] At room temperature, 3,3-difluorocyclobutanol (134 mg, 1.25 mmol) was dissolved in dry DMF (5 mL). Under an ice-water bath, NaH (50 mg, 1.25 mmol) was added, and after stirring for 10 min, a DMF solution of intermediate 5A (210 mg, 0.41 mmol) was added dropwise to the reaction system, and the temperature was slowly raised to room temperature, and the reaction was continued for 5 h. The reaction solution was poured into ice water to quench, extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by a medium pressure preparation instrument Biotage Isolera One (12 g silica gel column, eluent: 0-5% MeOH / DCM) to obtain compound 6 (50 mg, yield 25.37%).

[0261] LC-MS (ESI): m / z = 475.5 [M + H] + .

[0262] 1 H NMR (400MHz, CDCl3): δ7.26(s,1H),7.24–7.19(m,4H),6.49(s,1H),4.91–4.86(m,1H),4.25–4.24(m,2H),4.09–4.06(m,4H),3.80(s ,2H),3.74–3.72(m,2H),3.02–2.99(m,2H),2.68(s,2H),2.68–2.63(m,2H),2.07–2.05(m,1H),1.89–1.86(m,2H),1.29–1.23(m,2H).

[0263] Example 7: Cyclobutyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (compound 7)

[0264]

[0265] Using 5A and cyclobutanol as raw materials, referring to the synthesis steps of Example 14, compound 7 was synthesized.

[0266] 1H NMR(400 MHz, CD3Cl) δ7.33(s,1H),7.24-7.18(m,4H),6.50(s,1H),4.94-4.90(m,1H),4.23-4.21(m,2H),3.98-3.95(m,4H),3.76(s,2H),3. 56-3.50(m,2H),3.38-3.32(m,2H),2.66-2.61(m,2H),2.28-2.21(m,4H),2.06-2.03(m,1H),1.86-1.81(m,2H),1.28-1.22(m,2H).

[0267] LC-MS (ESI): m / z = 439.5 [M+H] +.

[0268] Example 8: 5-(1-((cyclobutylmethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (compound 8)

[0269]

[0270] Compound 4D (400 mg, 1.2 mmol) and triethylamine (360.0 mg, 3.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and cyclobutylmethanesulfonyl chloride (140.0 mg, 1.5 mmol) was added at room temperature and reacted for 2 hours. The disappearance of the raw material was monitored by TLC, and the mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain the target compound 8 (150 mg, 55%).

[0271] LC-MS (ESI): m / z = 473.1 [M+H] + .

[0272] 1 H NMR(400 MHz, DMSO) δ8.14(s,1H),7.32–7.11(m,4H),6.38(s,1H),3.95(s,4H),3.78(s,2H),3.71(d,2H), 3.59(d,2H),3.12(d,2H),2.85–2.61(m,3H),2.16–1.97(m,2H),1.86(d,7H),1.29–1.21(m,2H).

[0273] Example 9: 5-(1-((cyclopentylmethylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindol-2-ylmethyl)-4H-pyran-4-one (Compound 9)

[0274] 5-((1-((cyclopentylmethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(compound 9)

[0275]

[0276] Compound 4D (400 mg, 1.2 mmol) and triethylamine (360.0 mg, 3.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and cyclopentylmethanesulfonyl chloride (149.0 mg, 1.5 mmol) was added at room temperature and reacted for 2 hours. The disappearance of the raw material was monitored by TLC, and the product was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain the target compound 9 (200 mg, 71%).

[0277] LC-MS (ESI): m / z = 487.1 [M+H] + .

[0278] 1 H NMR(400 MHz, DMSO) δ8.14(s,1H),7.30–7.11(m,4H),6.38(s,1H),3.95(s,4H),3.78(s,2H),3.72(d,2H),3.60(d,2H) ,3.01(d,2H),2.81–2.75(m,2H),2.28–2.12(m,1H),1.92–1.70(m,5H),1.66–1.40(m,4H),1.32–1.21(m,4H).

[0279] Example 10: (E)-2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-4H-pyran-4-one (Compound 10) (E)-2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-4H-pyran-4-one (Compound 10)

[0280]

[0281] Step 1: Dissolve the raw material substrate 10A (0.9 g, 2.66 mmol), intermediate 4 (1.0 g, 2.66 mmol), potassium carbonate (1.10 g, 7.98 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.19 mg, 0.27 mmol) in 1,4-dioxane (20 mL) and water (4 mL) at room temperature, and heat to 90 ° C for 4 h under nitrogen protection. After the reaction, add 20 mL of water to quench the reaction, extract with EA (30 mL × 3), combine the organic phases, wash with saturated brine (40 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:1) to obtain compound 10B (1.1 g, 86%).

[0282] LC-MS (ESI): m / z = 437.2 [M+H] + .

[0283] Step 2: Compound 10B (1.1 g, 2.52 mmol) was dissolved in DCM (15 mL), trifluoroacetic acid (3 mL) was added, and the mixture was reacted at room temperature for 2 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was concentrated to obtain compound 10C (750 mg, 88%), which was directly used for the next step without purification.

[0284] LC-MS (ESI): m / z = 337.1 [M+H] + .

[0285] Step 3: Dissolve compound 10C (750 mg, 2.23 mmol) and TEA (910 mg, 8.95 mmol) in DCM (15 mL), add methylsulfonyl chloride (510 mg, 4.52 mmol), and react at room temperature for 3 h. LCMS detected that the reaction of the raw material was complete. After concentrating the reaction solution, the residue was purified by column chromatography (DCM:MeOH=1:0-20:1) to obtain compound 10 (600 mg, 65%).

[0286] LC-MS (ESI): m / z = 415.1 [M+H] + .

[0287] 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.27-7.18(m,4H),6.72-6.65(m,1H),6.36(s,1H),6.16(d,1H),3.98(s,2H),3.85-3.77(m,2 H),3.61-3.53(m,2H),3.35-3.25(m,2H),2.86(s,3H),2.80-2.71(m,2H),2.26-2.15(m,1H),1.85-1.75(m,2H),1.45-1.30(m,2H).

[0288] Example 11: 2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-4H-pyran-4-one (Compound 11)

[0289] 2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-4H-pyran-4-one(compound 11)

[0290]

[0291] Compound 10 (300 mg, 0.72 mmol) was dissolved in methanol (10 mL), and Pd / C (77 mg, 0.072 mmol) was added. The reaction solution was reacted under a hydrogen atmosphere for 2 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was concentrated and the residue was purified by column chromatography (DCM:MeOH=1:0~20:1) to obtain compound 11 (180 mg, 60%).

[0292] LC-MS (ESI): m / z = 417.1 [M+H] + .

[0293] Example 12: 1-methylpiperidin-4-yl 4-((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (compound 12)

[0294]

[0295] 1-Methyl-4-piperidinol (203 mg, 1.76 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in dichloromethane (15 mL), cooled to 0 degrees Celsius in an ice bath, triphosgene (350 mg, 1.18 mmol) was added, stirred for 30 minutes, and compound 4D (200 mg, 0.59 mmol) was slowly added. Stirring was continued in an ice bath for 2 hours, and the reaction was completed by TLC detection. The crude product was directly concentrated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1) to obtain the target compound 12 (30 mg, yield 10.56%).

[0296] LC-MS (ESI): m / z = 482.60 [M+H] + .

[0297] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.24–7.18(m,4H),6.49(s,1H),4.81–4.73(m,1H),4.04(s,4H),3.77(s,2H),3.75–3 .70(m,2H),2.85–2.68(m,4H),2.37(s,3H),2.10–2.04(m,1H),2.04–1.96(m,4H),1.91–1.75(m,4H),1.35–1.17(m,4H).

[0298] Example 13: 1,1,1-trifluoropropane-2-yl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 13)

[0299] 1,1,1-trifluoropropan-2-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0300]

[0301] 1,1,1-Trifluoroisopropanol (46 mg, 0.40 mmol) was dissolved in dry tetrahydrofuran (6 mL), 60% NaH (32 mg, 0.80 mmol) was added under ice-water bath, and after stirring for 10 min, 5A (200 mg, 0.40 mmol) in DMF solution (2 mL) was added dropwise to the reaction solution, and the temperature was slowly raised to room temperature, and the reaction was continued for 3 h. The reaction solution was poured into ice water to quench, extracted with ethyl acetate (15 mL × 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 20:1) after concentration to obtain compound 13 (88 mg, 46%).

[0302] 1 H NMR(400MHz,CD3Cl)δ7.60(s,1H),7.25-7.17(m,4H),6.49(s,1H),5.30-5.19(m,1H),4.27-4.11(m,2H),4.05(s,4H),3.77(s,2 H),3.75-3.71(m,2H),2.92-2.77(m,2H),2.13-2.01(m,1H),1.91-1.87(m,2H),1.41-1.39(d,J=6.4Hz,3H),1.32-1.21(m,2H).

[0303] LC-MS (ESI): m / z = 481.2 [M+H] + .

[0304] Example 14: 5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methoxy)-2-isoindol-2-ylmethyl)-4(1H)-one (Compound 14)

[0305] 5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(compound 14)

[0306]

[0307] 4D (400 mg, 1.06 mmol, synthesized according to patent WO2018115591) and triethylamine (324 mg, 3.18 mmol) were dissolved in 5 ml of dichloromethane, and cyclohexylsulfonyl chloride (250 mg, 1.27 mmol) was added under ice bath, and the reaction was carried out for 1 h. The excess solvent was removed by concentration under reduced pressure, and the target compound 14 (81 mg, 16.53 min, 15%) was obtained by HPLC purification.

[0308] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm). The sample was dissolved in DMSO and filtered with a 0.45μm filter to prepare a sample solution. Preparative chromatography conditions: Mobile phase A, B composition: Mobile phase A: acetonitrile Mobile phase B: water (containing 1% ammonium acetate), gradient elution, mobile phase A content from 30% to 80%, flow rate 12mL / min, elution time 30min.

[0309] LCMS (ESI): m / z = 501.1 [M+H] +

[0310] 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.29–7.11(m,4H),6.39(s,1H),3.96(s,4H),3.79(s,2H),3.72(d,,2H),3.65–3.56( m,2H),2.89-2.85(m,2H),2.80-2.74(m,2H),1.91–1.76(m,6H),1.70–1.57(m,3H),1.30–1.16(m,4H),1.16–0.99(m,3H).

[0311] Example 15: 2-(isoindolin-2-ylmethyl)-5-((1-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (Compound 15)

[0312] 2-(isoindolin-2-ylmethyl)-5-((1-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one

[0313]

[0314] Compound 4D (200 mg, 0.59 mmol) was added to a 100 mL single-necked bottle and dissolved in dichloromethane (10 mL). Compound 15a (140 mg, 0.70 mmol) and triethylamine (0.24 g, 2.37 mmol) were then added. The mixture was reacted at room temperature for 2 h. LCMS detected that the reaction of the raw materials was complete. The crude target compound was obtained after concentration under reduced pressure. The title compound 15 (100 mg, 33.7%) was separated by preparative HPLC.

[0315] Preparation method: Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm; The sample was dissolved in DMF and filtered with a 0.45μm filter to prepare a sample solution; Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 5mM ammonia water); b. Gradient elution, mobile phase A content from 40% to 80%; c. Flow rate 15mL / min. d. Elution time 20min; Retention time: 12.20min.

[0316] LCMS m / z=503.2[M+1] +

[0317] 1 H NMR(400MHZ,DMSO)δ8.14(s,1H),7.18-7.25(m,4H),6.39(s,1H),3.95(m,4H),3.76-3.85(m,4H),3.72(d,2H),3.61(d,2H),3 .34-3.35(m,1H),3.28-3.32(m,1H),2.95(d,2H),2.76-2.82(m,2H),2.00-2.12(m,1H),1.73-1.91(m,5H),1.21-1.39(m,4H).

[0318] Example 16: Tetrahydropyran-4-yl-4-(((6-(isoindoline-2-methylene)-4-oxo-4H-pyran-3-yl)oxa)methyl)piperidine-1-carbonate (Compound 16)

[0319] tetrahydro-2H-pyran-4-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0320]

[0321] Using tetrahydropyran-4-ol and compound 4D as raw materials, compound 16 was synthesized by referring to the first step of compound example 14.

[0322] LC-MS (ESI): m / z = 469.2 [M+H]

[0323] 1 H NMR(400MHz, CDCl3)δ7.61(s,1H),7.23–7.19(m,4H),6.49(s,1H),4.90-4.84(m,1H),4.19(s,2H),4.08(s,4H),3.92–3.87(m,2H),3 .80(s,2H),3.72(d,2H),3.58–3.53(m,2H),2.80(t,2H),2.10–2.00(m,1H),1.97–1.85(m,4H),1.72–1.63(m,2H),1.30–1.20(m,2H).

[0324] Example 17: Tetrahydrofuran-3-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 17)

[0325] tetrahydrofuran-3-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0326]

[0327] Using 4D (170 mg, 0.5 mmol) and 3-hydroxytetrahydrofuran (88 mg, 1.0 mmol) as raw materials, referring to the synthesis method of the first step of Example 14, compound 17 (22 mg, 9.68%) was synthesized.

[0328] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.22-7.21(d,4H),6.49(s,1H),5.27-5.24(m,1H),4.08(s,6H),3.94-3.89(m,2H),3.87-3.82(m, 2H),3.79(s,2H),3.73-3.71(d,2H),2.82-2.76(t,2H),2.21-2.12(m,1H),2.05-2.00(m,2H),1.88-1.85(d,2H),1.29-1.19(m,2H).

[0329] LC-MS (ESI): m / z = 455.1 [M+H] + .

[0330] Example 18: Cyclopropyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 18)

[0331]

[0332] Using 5A (200 mg, 0.4 mmol) and cyclopropylmethanol (120 mg, 2.07 mmol) as raw materials, referring to the synthesis method of the second step of Example 5, compound 18 (20 mg, 11.78%) was synthesized.

[0333] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.22(d,4H),6.49(s,1H),4.24-4.06(m,7H),3.81(s,2H),3.72-3.70 (d,2H),2.80-2.74(t,2H),2.07-2.00(m,1H),1.87-1.83(d,2H),1.26-1.21(t,2H),0.68-0.67(d,4H).

[0334] LC-MS (ESI): m / z = 425.2 [M + H] + .

[0335] Example 19: 1-Methylcyclopropyl-4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylic acid (Compound 19)

[0336] 1-methylcyclopropyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0337]

[0338] Using 4D (170 mg, 0.5 mmol) and 1-methylcyclopropanol (72 mg, 1.0 mmol) as raw materials, referring to the synthesis method of the first step of Example 14, compound 19 (40 mg, 18.24%) was synthesized.

[0339] 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.22-7.21(d,4H),6.49(s,1H),4.08(s,6H),3.79(s,2H),3.72-3.70(d,2H),2.77-2 .71(t,2H),2.09-2.00(m,1H),1.85-1.82(d,2H),1.54(s,3H),1.25-1.16(m,2H),0.88-0.85(t,2H),0.63-0.60(t,2H).

[0340] LC-MS (ESI): m / z = 439.3 [M + H] + .

[0341] Example 20: 2,2,2-trifluoroethyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 20)

[0342]

[0343] Using 5A and trifluoroethanol as raw materials, referring to the synthesis procedure of the second step of Example 5, compound 20 was obtained.

[0344] LC-MS (ESI): m / z = 467.2 [M+H] + .

[0345] 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),7.23–7.18(m,4H),6.49(s,1H),4.51–4.45(m,2H),4.21–4.14(m,2H),4.06(s ,4H),3.78(s,2H),3.74–3.73(m,2H),2.89–2.84(m,2H),2.10–2.06(m,1H),1.92–1.88(m,2H),1.29–1.26(m,2H).

[0346] Example 21: 1-(Methylsulfonyl)piperidin-4-yl 4-(((6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 21)

[0347] 1-(methylsulfonyl)piperidin-4-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0348]

[0349] Using 4D and 21A as raw materials and referring to the first step of the synthesis procedure of Example 14, compound 21 was obtained.

[0350] LC-MS (ESI): m / z = 546.7 [M+H] + .

[0351] 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),7.24–7.19(m,4H),6.49(s,1H),4.87–4.93(m,1H),4.21–4.08(m,6H),3.79(s,2H),3.74–3 .73(m,2H),3.42–3.39(m,2H),3.22–3.17(m,2H),2.89–2.79(m,5H),2.09–2.06(m,3H),1.87–1.84(m,4H),1.30–1.24(m,2H).

[0352] Example 22: 1-(Methylsulfonyl)azetidin-4-yl 4-(((6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate (Compound 22)

[0353] 1-(methylsulfonyl)azetidin-3-yl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0354]

[0355] Using 4D and 22A as raw materials, refer to the first step of the synthesis procedure in Example 14 to obtain compound 22.

[0356] LC-MS (ESI): m / z = 518.6 [M + H] + .

[0357] 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),7.25-7.16(m,4H),6.49(s,1H),5.16-5.08(m,1H),4.25-4.12(m,4H),4.07(s,4H),4 .02-3.97(m,2H),3.79(s,2H),3.75-3.71(m,2H),2.89(s,5H),2.09-2.02(m,1H),1.93-7.84(m,2H),1.33-1.21(m,2H).

[0358] Example 23: N-(1-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopropyl)methane sulfonamide (Compound 23)

[0359]

[0360] Step 1: Using compound 23A as raw material, refer to the first step of compound Example 4 to synthesize compound 23B.

[0361] 1 H NMR (400MHz, CDCl3) δ5.08(s,1H),4.24(s,2H),3.02(s,3H),1.45(s,9H),0.97–0.89(m,4H).

[0362] Step 2: Using compound 23B and intermediate 3 as raw materials, refer to the second step of compound example 4 to synthesize compound 23C.

[0363] LC-MS (ESI): m / z = 413.4 [M+H] + .

[0364] Step 3: Using compound 23C as raw material, refer to the third step of compound Example 4 to synthesize compound 23D.

[0365] LC-MS (ESI): m / z = 313.1 [M+H] + .

[0366] Step 4: Using compound 23D as raw material, refer to the fourth step of compound Example 4 to synthesize compound 23.

[0367] LC-MS (ESI): m / z = 391.1 [M+H]

[0368] 1 H NMR(400MHz, CDCl3)δ7.76(s,1H),7.24–7.19(m,4H),6.52(s,1H),5.86(s,1H),4.07 (s,4H),3.99(s,2H),3.79(s,2H),3.05(s,3H),1.14–1.12(t,2H),0.88–0.86(t,2H).

[0369] Example 24: N-(1-((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopropyl)cyclopropanesulfonamide

[0370]

[0371] Using 23D and cyclopropylcarbonyl chloride as raw materials, referring to the synthesis procedure of the third step of Example 4, compound 24 was obtained.

[0372] LC-MS (ESI): m / z = 417.2 [M+H] + .

[0373] 1 H NMR (400MHz, CDCl3): δ7.70(s,1H),7.24-7.16(m,4H),6.51(s,1H),6.34(s,1H),4.05(s,4H),3.97(s ,2H),3.78(s,2H),2.53-2.44m,1H),1.21-1.16(m,4H),1.00-0.95(m,3.5Hz,2H),0.90-0.79(m,2H).

[0374] Example 25: N-((1-((6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide

[0375]

[0376] Step 1: Using 25A (320 mg, 1.59 mmol) as starting material, refer to the operation of Example 4 (step 1) to obtain compound 25B (380 mg, 85%).

[0377] LC-MS(ESI): m / z=255.2[M+H-56]+.

[0378] Step 2: Using 25B (380 mg, 1.36 mmol) as starting material, refer to the operation of Example 4 (step 2) to obtain crude compound 25C (300 mg, 51%).

[0379] LC-MS(ESI): m / z=427.40[M+H]+.

[0380] Step 3: Using 25C (300 mg, 0.70 mmol) as raw material, refer to the operation of Example 4 (step 3) to obtain compound 25D (143 mg, 40%) hydrochloride.

[0381] LC-MS(ESI): m / z=327.50[M+H]+.

[0382] Step 4: Using 25D (143 mg, 0.40 mmol) as starting material, the operation was carried out according to Example 4 (Step 4) to obtain compound 25 (32 mg, 19%).

[0383] 1 H NMR(400MHz, CDCl3)δ7.80(s,1H),7.24–7.18(m,4H),6.59–6.55(m,1H),6.54(s,1H),4.06(s, 4H),3.82–3.78(m,4H),3.26–3.22(m,2H),3.00(s,3H),0.74–0.69(m,2H),0.64–0.60(m,2H).

[0384] Example 26: Cyclopropylmethyl-4-(((6-(isoindolin-2-methylene)-4-oxo-4H-pyran-3-yl)oxa)methyl)piperidine-1-carbonate (Compound 26)

[0385] cyclopropylmethyl 4-(((6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)oxy)methyl)piperidine-1-carboxylate

[0386]

[0387] Carbonyldiimidazole (0.22 g, 1.36 mmol) and cyclopropylmethanol (0.11 g, 1.48 mmol) were added to dry tetrahydrofuran in sequence. After the addition was completed, the mixture was stirred at room temperature for 30 minutes. Compound 4D (281.06 mg, 0.68 mmol) and N-methylmorpholine (0.34 g, 3.36 mmol) were then added to the reaction solution in sequence. After the addition was completed, the mixture was heated to 60°C and reacted for 16 hours. The reaction solution was cooled to room temperature, tap water (10 mL) and ethyl acetate (30 mL) were added and stirred for 5 minutes. The organic phase was separated, dried, and concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM: MeOH = 1: 0 to 20: 1) to obtain compound 26 (54 mg, 19.1%).

[0388] LC-MS (ESI): m / z = 439.7 [M+H] +

[0389] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.23–7.18(m,4H),6.49(s,1H),4.23-4.19(m,2H),4.04(s,4H),3.91(d,2H),3.77(s,2H),3.73 (d,2H),2.80(t,2H),2.10–2.00(m,1H),1.87(d,2H),1.30–1.19(m,2H),1.16–1.09(m,1H),0.56–0.52(m,2H),0.29–0.26(m,2H).

[0390] Example 27: 5-((1-((Butyl-3-yne)sulfonyl)piperidin-4-yl)methoxy)-2-isoindol-2-ylmethyl)-4(1H)-one (Compound 27)

[0391] 5-((1-(but-3-yn-1-ylsulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one(compound 27)

[0392]

[0393] 4D (250 mg, 0.73 mmol) and triethylamine (184 mg, 1.83 mmol) were dissolved in 5 ml of dichloromethane, and 3-butyne-1-sulfonyl chloride (167 mg, 1.10 mmol) was added under ice bath and reacted for 1 h. After the reaction, the excess solvent was removed by rotary evaporator, and the target compound 27 (59 mg, 18%) was purified by silica gel column chromatography (DCM: MeOH-20:1).

[0394] LCMS (ESI): m / z = 457.3 [M+H] +

[0395] 1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.28–7.16(m,4H),6.39(s,1H),3.95(s,4H),3.79(s,2H),3.71(d,2H),3.62(d,2H ),3.28-3.20(m,2H),3.04-2.98(m,1H),2.93-2.81(m,2H),2.61-2.52(m,2H),1.90-1.78(m,3H),1.33–1.20(m,2H).

[0396] Example 28: 2-(isoindolin-2-ylmethyl)-5-(((1-(methylsulfonyl)piperidin-4-yl)oxy)methyl)-4H-pyran-4-one (Compound 28)

[0397] 2-(isoindolin-2-ylmethyl)-5-(((1-(methylsulfonyl)piperidin-4-yl)oxy)methyl)-4H-pyran-4-one

[0398]

[0399] Step 1: Dissolve compound 28A (15.2 g, 39.1 mmol) in 1.4-dioxane (100 mL), add tributyltin methanol (32.1 g, 100 mmol), X-Phos-Pd-G2 (2.36 g, 3 mmol) and lithium chloride (5.09 g, 120 mmol) in sequence, replace the system with nitrogen three times, and react at 90 ° C for 3 hours. After the reaction is completed, cool to room temperature, add water (200 mL), extract with ethyl acetate (250 mL × 2), combine the organic phases, wash with saturated sodium chloride aqueous solution (300 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated by silica gel column chromatography (PE: EA (v / v) = 3: 1 to 1: 2) to obtain compound 28B (2.3 g, yield 22%).

[0400] LCMS m / z=271.3[M+H] + .

[0401] Step 2: Compound 28B (0.83 g, 3.1 mmol) was dissolved in DCM (20 ml), triphenylphosphine (0.94 g, 3.6 mmol) was added, and the mixture was cooled to 0°C. Carbon tetrabromide (1.19 g, 3.6 mmol) was added to the system in batches. After the addition was complete, the mixture was reacted at room temperature for 30 min. After the reaction was completed, the system was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain the target compound 28C (0.66 g, yield 64%).

[0402] LC-MS(ESI):m / z=333.0 / 335.1[M+H] +

[0403] Step 3: Sodium hydride (96 mg, 2.4 mmol, 60% wt) was dissolved in THF (20 mL), and compound N-Boc-4-hydroxypiperidine (0.48 g, 2.4 mmol) was added at 0°C. After the addition was complete, the mixture was stirred at room temperature for 20 minutes, and then a solution of compound 28C (0.66 g, 1.98 mmol) in THF (5 mL) was added dropwise at 0°C. After the addition was complete, the reaction was continued for 4 hours under this condition. The reaction was quenched with saturated sodium bicarbonate (40 mL), and extracted with ethyl acetate (60 mL × 2). Drying was performed over anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE: EA (v / v) = 3:1) to obtain compound 28D (98 mg, yield 9%).

[0404] LC-MS(ESI):m / z=354.4[M-Boc+H] +

[0405] Step 4: Dissolve compound 28D (98 mg, 0.22 mmol) in THF (10 mL), add tetrabutylammonium fluoride (0.3 mL, 0.3 mmol, 1 M THF solution), react at room temperature for 10 min, concentrate under reduced pressure, and separate by silica gel column chromatography (EA) to obtain the target compound 28E (56 mg, yield 76%).

[0406] LC-MS(ESI):m / z=240.3[M-Boc+H] +

[0407] Step 5: Dissolve compound 28E (56 mg, 0.16 mmol) in dichloromethane (5 mL), add triethylamine (32 mg, 0.32 mmol). Then add methylsulfonyl chloride (23 mg, 0.20 mmol) at 0°C, and react for 10 minutes after the addition. After reduced pressure concentration, column chromatography (PE:EA (v / v) = 4:1) was performed to obtain compound 28F (58 mg, yield 84%).

[0408] LC-MS(ESI):m / z=318.2[M-Boc+H] + .

[0409] Step 6: Compound 28F (58 mg, 0.14 mmol) and 2,3-dihydroisoindole hydrochloride (31 mg, 0.20 mmol) were dissolved in DMSO (5 mL), and N,N-diisopropylethylamine (40 mg, 0.30 mmol) was added, and the mixture was reacted at 50° C. for 1 h. After the reaction was complete, the system was directly concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:2) to obtain the target compound 28G (42 mg, yield 69%).

[0410] LCMS m / z=441.3[M+1] +

[0411] Step 7: Dissolve compound 28G (42 mg, 0.095 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), react at room temperature for 30 minutes and then concentrate under reduced pressure. Dissolve the residue in dichloromethane (5 mL), add triethylamine (40 mg, 0.40 mmol). Then add methylsulfonyl chloride (17 mg, 0.15 mmol) at 0°C, and react for 10 minutes after the addition. After the reaction is completed, the system is concentrated under reduced pressure and then subjected to silica gel column chromatography (EA) to obtain compound 28 (21 mg, yield 53%).

[0412] LC-MS (ESI): m / z = 419.2 [M+H] + .

[0413] 1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.25-7.19(m,4H),6.44(s,1H),4.39(d,2H),4.12(s,4H),3.84(s,2 H),3.72-3.62(m,1H),3.42-3.32(m,2H),3.23-3.16(m,2H),2.78(s,3H),2.01-1.92(m,2H),1.89-1.79(m,2H).

[0414] Biological Testing:

[0415] 1. The purpose of this study is to use the enzyme linked immunosorbent assay (ELISA) method to detect the testosterone level in NCI-H295R cells, so as to evaluate the inhibitory effect of the compound on the levels of pregnenolone and testosterone in NCI-H295R cells.

[0416] H295R cells were purchased from ATCC, and the complete cell culture medium was DMEM:F12+10% FBS+0.00625mg / ml insulin+0.00625mg / ml transferrin+6.25ng / ml selenium+1.25mg / ml BSA+0.00535mg / ml linoleic acid, and cultured in an incubator at 37°C, 5% CO2. Cells in the exponential growth phase were collected and cultured in hormone deprivation medium (phenol red-free 1640+1% PS+10% css FBS+1.25mg / ml BSA+0.00625mg / ml insulin+0.00625mg / ml transferrin+6.25ng / ml selenium+0.00535mg / ml linoleic acid) for 3 days. On the third day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration plate with hormone deprivation medium, so that the cells were 60000 / well, and the volume was 90 μL per well, and 10 μL of compounds of different concentrations were subsequently added, and the cells were placed in a CO2 incubator and cultured for 3 days. After the culture was completed, according to the testosterone detection Elisa kit (Biyuntian, PT872) operating instructions, 50 μL of cell culture supernatants were taken from each well, centrifuged at 500g, 5min room temperature, and the supernatant was subsequently collected. The sample was added to the corresponding well according to 25 μl / well, and then the prepared horseradish peroxidase-labeled testosterone was added according to 75 μl / well, and the reaction wells were sealed with a sealing film (white), and the room temperature was incubated in dark for 120min. Then wash the plate 3 times with 300 μl per well, and after the last wash, place it on thick absorbent paper and pat it dry, add 100 μl / well of the colorimetric reagent TMB solution, seal the reaction wells with a sealing film (white), incubate at room temperature in the dark for 15-20 minutes, then add 50 μl / well of the stop solution, mix well and measure the OD immediately. 450 Absorbance value. The absorbance readings were used with Graphpad Prim 8.0 software to draw a S-shaped concentration curve using a four-parameter nonlinear regression model and calculate the IC 50 The results were processed according to formula (1) to calculate the inhibition rate of each concentration of the compound, and the concentration IC of the compound when the inhibition rate was 50% was calculated using Graphpad Prim 8.0 software. 50 Value. Among them, RLU compound The readings for the drug treatment groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0417] Inhibition rate % = 100-RLU compound / RLU control ×100 Formula (1)

[0418] Table 1 Inhibitory activity of test compounds on testosterone levels in NCI-H295R cells

[0419]

[0420] NA: Not detected

[0421] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the testosterone level in NCI-H295R cells.

[0422] 2. Pharmacokinetics test in rats

[0423] 2.1 Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0424] 2.2 Experimental design: On the day of the experiment, 6 SD rats were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0425] Table 2 Dosage information

[0426]

[0427] Dosing vehicle: 0.5% MC

[0428] Before and after drug administration, 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The time points for blood collection in the venous group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; the time points for blood collection in the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and testing.

[0429] Table 3 Pharmacokinetic parameters of test compounds in rat plasma

[0430] Test compound Dosage CL(mL / min / kg) <![CDATA[Vd ss (L / kg)]]> <![CDATA[AUC 0-t (hr*ng / mL)]]> <![CDATA[T 1 / 2 (h)]]> Compound 10 Intravenous. (2.5mg / kg) 22.6 2.19 1943 4.43 Compound 10 Oral administration. (10 mg / kg) - - 5298 1.76

[0431] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good bioavailability and pharmacokinetic characteristics.

Claims

1. A compound represented by formula (I), its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, Ring A is selected from 6-membered heterocycloalkyl, 7-14-membered heterocycloalkyl, 4-6-membered heterocycloalkylene, (C 3-4 Cycloalkyl) 0-1 -NHSO2-C 1-4 Alkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, C 3-4 Cycloalkyl, 7-14-membered cycloalkyl, 4-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, and S; the 5-membered cycloalkyl, 6-membered cycloalkyl, 6-membered heterocycloalkyl, and 4-membered heterocycloalkyl are at least one R A Substituted, the heterocycloalkylene, 7-14 membered heterocycloalkyl, C 3-4 Cycloalkyl, 7-14 membered cycloalkyl, alkyl optionally substituted with 1-4 R A’ replace; Ring B is selected from The left side of the B ring is connected to L1; The C ring is selected from L1 is selected from W1-R L -W2, L2 is selected from -CH2-, the left side of L1 is connected to A, and the left side of L2 is connected to B; R L Select from key, C 1-4 Alkylene, C 2-4 Alkenylene, C 3-4 Cycloalkylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen, CN, OH and NH2; W1 and W2 are each independently selected from a bond, -O-, -S-, -Se-, -NR W1 -; R W1 Selected from H, C 1-4 alkyl; R A Each independently selected from CN, NO2, COOH, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) 1-3 -O-HaloC 1-4 Alkyl, -S(O)2-(CH2) 1-3 -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-4 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R a The alkyl, alkenyl, and alkynyl groups are optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl, C 2-6 radical substitution of alkynyl groups; R A’ Each independently selected from halogen, OH, CN, NO2, COOH, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-4 Alkyl, -(CH2) p -NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution; R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, 8-membered heterocycloalkyl, the alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted by 1-4 alkyl radicals selected from halogen, OH, C 1-4 Alkyl, C 2-4 Alkynyl, -O-halogenated C 1-4 Alkyl, -S(O)2-CH3, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, O, and S; p is selected from 0, 1, 2, 3, 4; The condition is, (1) When the A ring is selected from a 6-membered cycloalkyl group, R A Not selected from -S(O)2-CH3; (2) When ring A is selected from And R A Selected from -S(O)2-C 1-4 When alkyl, L1 is not selected from -(CH2) 1-3 -O-; (3) Ring A is not selected from 2. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein: A ring is selected from C 3-4 Cycloalkyl, 6-membered monocyclic heterocycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 alkyl, cyclohexyl, 4-membered heterocycloalkylene, 4-membered heterocycloalkyl, wherein the 6-membered monocyclic heterocycloalkyl, cyclohexyl, 4-membered heterocycloalkyl is at least one R A Substitute, the C 3-4 Cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl spiro 5-6-membered cycloalkyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkyl, 4-6-membered heterocycloalkyl spiro 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl and 5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl spiro 5-6-membered heterocycloalkyl, 10-14-membered partially unsaturated tricyclic heterocycloalkyl, cyclopropyl-NHSO2-C 1-2 Alkyl, -NHSO2-C 1-2 Alkyl, 4-membered heterocycloalkyl group optionally 1-4 R A’ replace; R A Each independently selected from COOH, -OC 1-4 Alkyl, -S(O)2-C 1-2 Alkyl, -S(O)2-(CH2) 1-2 -O-HaloC 1-2 Alkyl, -S(O)2-(CH2) 1-2 -R a 、-P(O)-(C 1-2 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, -C(O)-NH-S(O)2-C 1-2 Alkyl, -C(O)-R a 、-C(O)-NH-R a 、-NH-C(O)-C 1-4 Alkyl, -NH-C(O)-R a 、-NH-C(O)-OR a or -NH-C(O)-NH-R a The alkyl group is optionally further substituted with 1 to 4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-2 Alkyl, C 2-4 radical substitution of alkynyl groups; R A’ Each independently selected from halogen, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH-S(O)2-C 1-4 Alkyl, -CH2-NH-S(O)2-C 1-4 Alkyl, -NH-S(O)2-R a 、-S(O)2-C 1-4 Alkyl, -S(O)2-(CH2) p -R a 、-P(O)-(C 1-4 Alkyl)2, -C(O)-O-(CH2) p -R a 、-(CH2) 1-2 -C(O)-R a 、-C(O)-(CH2) 1-2 -R a 、-C(O)-O-halogenated C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl may be further substituted by 1-4 groups selected from halogen, OH, NH2, CN, -O-halogenated C 1-4 Alkyl radical substitution; R a Selected from C 2-4 Alkynyl, C 3-5 Cycloalkyl, 6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 5-membered heteroaryl, 8-membered heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl may be further substituted with halogen, C 1-2 Alkyl, OH, -S(O)2-CH3 group substitution; p is selected from 0, 1 or 2.

3. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, Ring A is selected from one of the following structures:

4. The compound of formula (I) according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein L1 is selected from a bond, C 1-2 Alkylene-O, C 1-2 Alkylene, C 1-2 Alkylene-S, C 1-2 Alkylene-Se, C 1-2 Alkylene-N(C 1-2 Alkylene), N(C 1-2 Alkylene)-C 1-2 Alkylene, -OC 1-3 Alkylene, C 2-4 Alkenylene, -N(C 1-2 Alkylene)-C(=O), -C(=O)-N(C 1-2 alkylene), -O-, -C(=O)-O-, C 3-4 Cycloalkylene-O, wherein the alkylene, alkenylene, cycloalkylene is optionally further substituted by 1-3 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 3-6 Cycloalkyl.

5. The compound according to claim 1, its stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt, wherein the compound is selected from one of the following structures:

6. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 5, or a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. A pharmaceutical composition or pharmaceutical preparation according to claim 1, comprising 1-1500 mg of a compound according to any one of claims 1-5 or a stereoisomer, deuterated substance, solvate, cocrystal or pharmaceutically acceptable salt thereof and a carrier and / or excipient.

8. Use of the compound according to any one of claims 1 to 5, its stereoisomer, deuterated form, solvate, cocrystal or pharmaceutically acceptable salt, or the composition according to claims 6 to 7 in the preparation of a medicament for treating / preventing a disease mediated by CYP11A1.

9. The use according to claim 8, wherein the CYP11A1-mediated disease is selected from the group consisting of treating steroid hormone-dependent cancers.

10. A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 5 or a stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1 to 1500 mg, and the disease preferably being prostate cancer.

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