CYP11A1 inhibitor and application thereof

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular to a small molecule compound with CYP11A1 selective inhibitory activity, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, and use thereof in the preparation of a drug for treating related diseases. BACKGROUND

[0002] Cytochrome p450 monooxygenase 11a1 (CYP11A1), also known as cholesterol side chain cleavage enzyme, is mainly involved in catalytic reactions related to drug metabolism, as well as synthesis of cholesterol, steroids and other lipids. CYP11A1 protein is located in the inner membrane of mitochondria, catalyzing the conversion of cholesterol to pregnenolone, which is the first step and rate-limiting step of steroid synthesis. The reaction is carried out in adrenal cortical mitochondria, catalyzed by cytochrome CYP11A1 (also known as P450scc), and CYP11A1 also plays a role together with Adx and AdR. CYP11A1, Adx and AdR belong to the cholesterol hydroxylase / cleavage enzyme system (CH / L), which catalyzes the initial step of steroid synthesis in mammals, i.e. the process of generating pregnenolone from cholesterol. Pregnenolone is an important precursor of steroid hormones. The reaction process includes three consecutive monooxygenation reactions, i.e. the generation of 22R-hydroxycholesterol (22HC), the generation of 20R, 22R-dihydroxycholesterol, and the cleavage of C20-C22 bond. In each monooxygenation reaction process, two electrons and one molecule of oxygen are required. The electrons are provided by NADPH, which is 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 in response to the synthesis of placental hormones such as progesterone and testosterone, and is also highly expressed in the adrenal gland and testis, and is almost not expressed in other tissues. By inhibiting cyp11a1, which is a key enzyme upstream of steroid biosynthesis of cyp17a1, complete blockade of the entire steroid biosynthesis can be achieved. Therefore, cyp11a1 inhibitors can have great potential for treating steroid hormone-dependent cancers such as prostate cancer, even in the late stage of the disease, especially in patients who show hormone refractory. It has been recently demonstrated that compounds with cyp11a1 inhibitory effect significantly inhibit tumor growth in vivo in a mouse crpc xenograft model.

[0004] It is found that CYP11A1 inhibitors with good activity, high safety and small side effects have good clinical development prospects and can be used for treating cancer or other proliferative diseases or conditions. SUMMARY

[0005] The compound provided by the application and stereoisomers, deuterium compounds or pharmaceutically acceptable salts thereof have good activity, excellent physical and chemical properties, are convenient for preparation, have excellent pharmacokinetic properties, high bioavailability and low toxicity and side effects.

[0006] The application provides a compound represented by formula (I-1), (I), (I-a), (II) and (II-a), a stereoisomer, deuterium compound or pharmaceutically acceptable salt thereof, wherein,

[0007]

[0008] B ring is selected from In some embodiments, B ring is selected from wherein the left end is connected to the double bond, and the right end is connected to the methylene group;

[0009] In some embodiments, B ring is selected from wherein the left end is connected to the double bond, and the right end is connected to the methylene group;

[0010] X is selected from CH or N; in some embodiments, X is selected from CH; in some embodiments, X is selected from N;

[0011] X1 is selected from CH or N; in some embodiments, X1 is selected from CH; in some embodiments, X1 is selected from N;

[0012] represents a single bond or a double bond;

[0013] L1 is selected from a bond, ethenyl, -C 1-6 alkyl-O-; in some embodiments, L1 is selected from a bond, ethenyl, -CH2CH2-O-;

[0014] R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -N(CH3)-C(O)-(CH2) p -R a , -NH-SO2-(CH2) p -R a , -NH-C(O)-O-R a , -NH-C(O)-NHR a , -NHR a , -(CH2) p -C(O)-R a , -C(O)-(CH2)p -R a , -C(O)-O-(CH2) p -R a , -C(O)-NHR a or -C(O)-NH-S(O)2-R a ; in some embodiments, R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -N(CH3)-C(O)-(CH2) p -R a , -NH-SO2-(CH2) p -R a , -NH-C(O)-O-R a , -NHR a , -(CH2) p -C(O)-R a , -C(O)-(CH2) p -R a , -C(O)-O(CH2) p -R a , -C(O)-NHR a or -C(O)-NH-S(O)2-R a ; in some embodiments, R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -N(CH3)-C(O)-(CH2) p -R a , -NH-SO2-(CH2) p -R a , -NH-C(O)-O-R a , -NHR a , -(CH2) p -C(O)-R a , -C(O)-(CH2) p -R a , -C(O)-NHR a or -C(O)-NH-S(O)2-R a ; in some embodiments, R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -C(O)-(CH2) p -R a , -C(O)-O-(CH2) p -Ra ; in some embodiments, R is selected from -S(O)2-R a , -NH-C(O)-R a , -C(O)-R a , -C(O)-CH2-R a , -C(O)-O-R a ; in some embodiments, R is selected from -S(O)2-R a or -NH-C(O)-R a ;

[0015] In some embodiments, R is selected from -S(O)2-CH3, -S(O)2-NH2, -NHC(O)CD3, -NHC(O)CF2CH3, -S(O)2-CH2CH2OH, -S(O)2-CH2CN, -C(O)N(CH3)2, -S(O)2-N(CH3)2;

[0016] R a is selected from H, D, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =O, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, -S(O)2-C 1-4 alkyl;

[0017] In some embodiments, R a is selected from H, D, NH2, C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-2 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 membered heteroaryl, 6 membered heteroaryl, said NH2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, =O, C 1-2 alkyl, C 1-2 deuteroalkyl, C1-2 Haloalkyl, C 1-2 Alkoxy, -OC 1-2 Halogenated alkyl groups, -S(O)2-C 1-2 Alkyl group substitution; in some embodiments, R a Selected from NH2, methyl, CD3, -CF2CH3, ethyl, cyclopropyl, cyclobutyl, oxacyclobutyl, 3,3-difluorocyclobutyl, 1-methylpyrazolyl, -CH2CH2OH, -CH2CN, -N(CH3)2; in some embodiments, R a Selected from NH2, methyl, ethyl, cyclopropyl, or cyclobutyl;

[0018] R1 is independently selected from H, D, halogen, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further selected from 1-4 elements selected from D, halogen, CN, OH, =O, NH2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkyl or -OC 1-4 Substituents of haloalkyl groups, or any two R1 groups and their connecting atoms together to form 3-6 membered cycloalkyl groups;

[0019] In some implementations, R1 is independently selected from H, D, halogen, C. 1-2 Alkyl, C 1-2 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally further selected from 1-4 elements selected from D, halogen, OH, =O, NH2, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 1-2 Alkyl or -OC 1-2 Substituents of haloalkyl groups, or any two R1 groups and their connecting atoms together to form 3-6 membered cycloalkyl groups;

[0020] In some embodiments, R1 is independently selected from H, F, Cl, methyl, methoxy, cyclopropyl, and trifluoromethyl;

[0021] In some implementations, R1 is selected from H;

[0022] In some implementation schemes, Selected from:

[0023] In some embodiments, selected from:

[0024] R2is selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl being optionally further substituted with 1-4 substituents selected from the group consisting of D, halogen, CN, OH, =0, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy or -0-C 1-4 haloalkyl, -0-C

[0025] In some embodiments, R2is selected from H, D, C 1-4 alkyl, 3-4 membered cycloalkyl, said alkyl, cycloalkyl being optionally further substituted with 1-4 substituents selected from the group consisting of D, halogen, OH, =0, NH2, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 deuteroalkyl, C 1-2 alkoxy or -0-C 1-2 haloalkyl, -0-C

[0026] In some embodiments, R2is selected from H, D, methyl, ethyl, cyclopropyl or cyclobutyl;

[0027] In some embodiments, R2is selected from methyl, ethyl or cyclopropyl;

[0028] R3is each independently selected from H, D, CN, halogen, OH, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, -0-C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-4 alkyl, -0-(CH2) p -C 3-6 cycloalkyl or -(CH2) p -O-C 3-6 cycloalkyl, or any two R3and the atoms to which they are attached together form a 3-8 membered cycloalkyl;

[0029] In some embodiments, each R3is independently selected from H, D, CN, halogen, OH, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2 haloalkyl, C 1-2 alkoxy, -O-haloC 1-2 alkyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-2 alkyl, -O-(CH2) p -C 3-6 cycloalkyl or -(CH2) p -O-C 3-6 cycloalkyl, or any two R 3 and their connecting atoms together form a 4-6 membered cycloalkyl;

[0030] In some embodiments, R3is selected from H, D, F, Cl, methyl, ethyl, trifluoromethyl, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, or -O-cyclobutyl;

[0031] In some embodiments, R3is selected from H, D, F, trifluoromethyl, cyclopropyl;

[0032] R4is selected from -S(O)2-R B ;

[0033] R B is selected from NH2, C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =O, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, C 3-6 cycloalkyl;

[0034] In some embodiments, R B is selected from NH2, C 1-2 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, F, Cl, OH, NH2, CN, =O, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2Haloalkyl, C 1-2 Alkoxy, -OC 1-2 Haloalkyl, C 3-6 Substitution of cycloalkyl groups;

[0035] In some implementation schemes, R B Selected from NH2, -NH(CH3), -N(CH3)2, -NH(cyclopropyl),

[0036] In some implementation schemes, R B The group is selected from NH2, azircyclobutyl, and azircyclohexyl, wherein the NH2, azircyclobutyl, and azircyclohexyl are optionally further substituted by 1-4 groups selected from D, F, Cl, OH, NH2, CN, =O, methyl, ethyl, and cyclopropyl.

[0037] In some embodiments, R4 is selected from -S(O)2-NH2, -S(O)2-NH(CH3), -S(O)2-N(CH3)2, -S(O)2-NH (cyclopropyl), -S(O)2- (4-6 membered heterocyclic alkyl);

[0038] In some implementations, R4 is selected from

[0039] R5 is selected from H, D, and C. 1-4 Alkyl, C 3-4 cycloalkyl;

[0040] In some implementations, R5 is selected from H and D;

[0041] Alternatively, R4 and R5 together with the carbon atom they are attached to form a 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally further surrounded by 1-4 atoms selected from D, halogen, OH, NH2, CN, =O, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Haloalkyl, C 3-6 Cycloalkyl group substitution;

[0042] In some embodiments, R4 and R5 together with the carbon atom they are attached to form a 5-membered heterocyclic alkyl group or a 5-membered heteroaryl group, wherein the heterocyclic alkyl group or heteroaryl group is optionally further composed of 1-3 atoms selected from D, halogen, OH, NH2, CN, =O, C. 1-2 Alkyl, C 3-4 Cycloalkyl group substitution;

[0043] In some embodiments, R4and R5together with the carbon atom to which they are attached form

[0044] In some embodiments, selected from:

[0045] In some embodiments, selected from:

[0046] selected from:

[0047] In some embodiments, selected from:

[0048] n is selected from 1 or 2;

[0049] In some embodiments, n is selected from 1;

[0050] m is selected from 1 or 2;

[0051] In some embodiments, m is selected from 1;

[0052] p is selected from 0, 1 or 2;

[0053] In some embodiments, p is selected from 0 or 1;

[0054] In some embodiments, p is selected from 0;

[0055] In some embodiments, p is selected from 1.

[0056] As a more specific first technical solution of the present application, there is provided a compound represented by formula (I), (I-1), (I-a), a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein,

[0057]

[0058] B ring is selected from the end connected with the left double bond, and the * end connected with the right methylene;

[0059] X is selected from CH or N;

[0060] X1is selected from CH or N;

[0061] represents a single bond or a double bond;

[0062] L1is selected from a bond, ethenyl, -C 1-6 alkyl-O-;

[0063] R is selected from -S(O)2-R a -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) p -R a -NH-C(O)-O-R a -NH-C(O)-NHR a -NHR a -(CH2) p -C(O)-R a -C(O)-(CH2) p -R a -C(O)-O-(CH2) p -R a -C(O)-NHR a or -C(O)-NH-S(O)2-R a ;

[0064] R a is selected from H, D, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =O, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, -S(O)2-C 1-4 alkyl;

[0065] each R1is independently selected from H, D, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally further substituted with 1-4 groups selected from D, halogen, CN, OH, =O, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C1-4 alkyl, C 1-4 haloalkyl, or any two R1and the atom(s) to which they are attached together form a 3-6 membered cycloalkyl;

[0066] R2is selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl being optionally further substituted with 1-4 substituents selected from D, halogen, CN, OH, =0, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy, or -O-C 1-4 haloalkyl substituted;

[0067] R3is each independently selected from H, D, CN, halogen, OH, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, -O-C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-4 alkyl, -O-(CH2) p -C 3-6 cycloalkyl, or -(CH2) p -O-C 3-6 cycloalkyl, or any two R 3 and the atom(s) to which they are attached together form a 3-8 membered cycloalkyl;

[0068] R4is selected from -S(O)2-R B ;

[0069] R B is selected from NH2, C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 substituents selected from D, halogen, OH, NH2, CN, =0, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, C 3-6Cycloalkyl group substitution;

[0070] R5 is selected from H, D, and C. 1-4 Alkyl, C 3-4 cycloalkyl;

[0071] Alternatively, R4 and R5 together with the carbon atom they are attached to form a 5-6 membered heterocyclic group, wherein the heterocyclic group is optionally further surrounded by 1-4 atoms selected from D, halogen, OH, NH2, CN, =O, C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Haloalkyl, C 3-6 Cycloalkyl group substitution;

[0072] n is selected from 1 or 2;

[0073] m is selected from 1 or 2;

[0074] p can be selected from 0, 1, or 2.

[0075] As a more specific second technical solution of the present invention, a compound of formula (I), its stereoisomer, deuterated product, or pharmaceutically acceptable salt, wherein,

[0076]

[0077] Ring B is selected from The * end is connected to the left double bond, and the * end is connected to the right methylene group;

[0078] X is selected from CH or N;

[0079] R is selected from -S(O)2-R a -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) p -R a -NH-C(O)-OR a -NH-C(O)-NHR a -NHR a -(CH2) p -C(O)-R a -C(O)-(CH2) p -R a -C(O)-O-(CH2)p -R a , -C(O)-NHR a , -C(O)-NH-S(O)2-R a ;

[0080] R a is selected from H, D, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 substituents selected from the group consisting of D, halogen, OH, NH2, CN, =O, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl or -O-C 1-4 haloalkyl;

[0081] each R1is independently selected from H, D, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally further substituted with 1-4 substituents selected from the group consisting of D, halogen, CN, OH, =O, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy or -O-C 1-4 haloalkyl, or any two R1and the atoms to which they are attached together form a 3-6 membered cycloalkyl;

[0082] R2is selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl being optionally further substituted with 1-4 substituents selected from the group consisting of D, halogen, CN, OH, =O, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy or -O-C 1-4 haloalkyl;

[0083] each R3is independently selected from H, D, CN, halogen, OH, C1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, -SCF3, -SF5, -(CH2) p -OC 1-4 Alkyl group, -O-(CH2) p -C 3-6 Cycloalkyl or -(CH2) p -OC 3-6 cycloalkyl, or any two R 3 Together with their connecting atoms, they form 3-8 membered cycloalkyl groups;

[0084] n is selected from 1 or 2;

[0085] m is selected from 1 or 2;

[0086] p can be selected from 0, 1, or 2.

[0087] As a more specific third technical solution of the present invention, a compound of formula (I), its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, wherein the compound has the structures of formula (II) and (II-a), wherein,

[0088]

[0089] X is selected from CH or N;

[0090] R is selected from -S(O)2-R a -NH-C(O)-(CH2) p -R a -N(CH3)-C(O)-(CH2) p -R a -NH-SO2-(CH2) p -R a -NH-C(O)-OR a -NHR a -(CH2) p -C(O)-R a -C(O)-(CH2) p -R a -C(O)-O(CH2) p -R a -C(O)-NHR a or -C(O)-NH-S(O)2-R a ;

[0091] R a selected from H, D, NH2, C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-2 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 membered heteroaryl, 6 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted with 1-4 substituents selected from D, halogen, OH, NH2, =0, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2 haloalkyl, C 1-2 alkoxy, -O-C 1-2 haloalkyl, -S(O)2-C 1-2 alkyl;

[0092] each R1is independently selected from H, D, halogen, C 1-2 alkyl, C 1-2 alkoxy, 3-6 membered cycloalkyl, said alkyl, alkoxy, cycloalkyl are optionally further substituted with 1-4 substituents selected from D, halogen, OH, =0, NH2, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 deuteroalkyl, C 1-2 alkoxy or -O-C 1-2 haloalkyl, or any two R1and their connecting atoms together form a 3-6 membered cycloalkyl;

[0093] R2is selected from H, D, C 1-4 alkyl, 3-4 membered cycloalkyl, said alkyl, cycloalkyl are optionally further substituted with 1-4 substituents selected from D, halogen, OH, =0, NH2, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 deuteroalkyl, C 1-2 alkoxy or -O-C 1-2 haloalkyl;

[0094] each R3is independently selected from H, D, CN, halogen, OH, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2 haloalkyl, C 1-2 alkoxy, -O-haloC 1-2 alkyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-2 alkyl, -O-(CH2)p -C 3-6 cycloalkyl or -(CH2) p -O-C 3-6 cycloalkyl, or any two R3and the atoms that they connect together form a 4-6 membered cycloalkyl;

[0095] n is selected from 1 or 2;

[0096] m is selected from 1 or 2;

[0097] p is selected from 0 or 1.

[0098] the remaining groups are as described in the first or second technical solution.

[0099] As a more specific fourth technical solution of the present application, a compound of formula (I-1), (I), (II), a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein,

[0100] R is selected from -S(O)2-R a , -NH-C(O)-R a , -C(O)-R a , -C(O)-CH2-R a , -C(O)-O-R a ;

[0101] R a is selected from D, NH2, methyl, CD3, -CF2CH3, ethyl, cyclopropyl, cyclobutyl, oxetanyl, 3,3-difluorocyclobutyl, 1-methylpyrazolyl, -CH2CH2OH, -CH2CN, -N(CH3)2;

[0102] R2is selected from H, D, methyl, ethyl, cyclopropyl or cyclobutyl;

[0103] R3is selected from H, D, F, Cl, methyl, ethyl, trifluoromethyl, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl or -O-cyclobutyl;

[0104] R4is selected from -S(O)2-NH2, -S(O)2-NH(CH3), -S(O)2-N(CH3)2, -S(O)2-(4-6 membered heterocycloalkyl), -S(O)2-NH(cyclopropyl);

[0105] R5is selected from H, D;

[0106] or R4and R5together with the carbon atom to which they are attached form a 5 membered heterocycloalkyl, 5 membered heteroaryl, wherein said heterocycloalkyl, heteroaryl is optionally further substituted with 1-3 groups selected from D, halogen, OH, NH2, CN, =O, C 1-2 alkyl, C3-4 Cycloalkyl groups are substituted.

[0107] The remaining groups are as described in any of the aforementioned technical solutions.

[0108] As a more specific fifth technical solution of the present invention, a compound represented by formulas (I-1), (I), and (II), its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, wherein,

[0109] R is selected from -S(O)2-R a or -NH-C(O)-R a ;

[0110] R a Selected from NH2, methyl, ethyl, cyclopropyl, or cyclobutyl;

[0111] R2 is selected from H, D, methyl, ethyl, cyclopropyl, or cyclobutyl;

[0112] R3 is selected from H, D, F, Cl, methyl, ethyl, trifluoromethyl, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, or -O-cyclobutyl;

[0113] The remaining groups are as described in any of the aforementioned technical solutions.

[0114] As a more specific sixth technical solution of the present invention, a compound represented by formulas (I-1), (I), and (II), its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, wherein,

[0115] Selected from:

[0116] R2 is selected from methyl, ethyl, or cyclopropyl;

[0117] Selected from:

[0118] Selected from:

[0119] Selected from:

[0120] Ring B is selected from in The * end is connected to the left double bond, and the * end is connected to the right methylene group;

[0121] The remaining groups are as described in any of the aforementioned technical solutions.

[0122] As a specific technical scheme of the present application, the compound, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to the present application is selected from one of the following structures:

[0123] Table I:

[0124]

[0125]

[0126]

[0127] The present application also provides a pharmaceutical composition or a pharmaceutical preparation containing the compound, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of the preceding schemes, and a pharmaceutically acceptable carrier and / or excipient.

[0128] Further, the present application provides a composition or a pharmaceutical preparation containing 1-1500 mg of the compound, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of the preceding schemes, and a carrier and / or excipient.

[0129] The present application also provides the use of the compound, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of the preceding schemes, or the composition according to any one of the preceding schemes in the preparation of a medicament for treating / preventing a CYP11A1-mediated disease, further preferably a steroid hormone-dependent cancer, and further preferably a prostate cancer.

[0130] The present application also provides a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of the compound, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of the preceding schemes, and the disease is preferably a prostate cancer. In some embodiments, the mammal according to the present application includes a human.

[0131] An "effective amount" or "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein that is needed to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount 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, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg.

[0132] The present application relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present application, or a stereoisomer, deuterated isotope, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition can be in the form of a unit formulation (the amount of the drug in the unit formulation is also referred to as the "formulation strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present application, or a stereoisomer, deuterated isotope, or pharmaceutically acceptable salt thereof.

[0133] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of a compound of the present application, or a stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, the disease preferably being prostate cancer.

[0134] A method for treating a disease in a mammal, the method comprising administering to the subject a compound of the present application, or a stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, in a daily dose of 1-1500 mg per day, which can be in a single dose or in divided doses, in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg per day, 20-1500 mg per day, 25-1500 mg per day, 50-1500 mg per day, 75-1500 mg per day, 100-1500 mg per day, 200-1500 mg per day, 10-1000 mg per day, 20-1000 mg per day, 25-1000 mg per day, 50-1000 mg per day, 75-1000 mg per day, 100-1000 mg per day, 200-1000 mg per day, 25-800 mg per day, 50-800 mg per day, 100-800 mg per day, 200-800 mg per day, 25-400 mg per day, 50-400 mg per day, 100-400 mg per day, 200-400 mg per day, in some embodiments, the daily dose includes, but is not limited to, 1 mg per day, 5 mg per day, 10 mg per day, 20 mg per day, 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 200 mg per day, 400 mg per day, 600 mg per day, 800 mg per day, 1000 mg per day, 1200 mg per day, 1400 mg per day, 1500 mg per day.

[0135] The present application relates to a kit which can include a composition in single or multiple dose form, the kit comprising a compound of the present application, or a stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, in an amount equivalent to that in the above pharmaceutical composition.

[0136] The amount of a compound of the present application, or a stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, in the present application is in each case calculated as the free base.

[0137] "Formulation strength" means the weight of the principal drug contained in each unit of a preparation.

[0138] Synthetic route

[0139] WO2018115591A1 and other patent documents describe the preparation of CYP11A1 inhibitors, and one skilled in the art can prepare the compounds of the present application in combination with these documents and known techniques of organic synthesis, starting from commercially available chemicals and / or compounds described in the chemical literature. “Commercially available chemicals” are obtained from regular commercial sources, including suppliers such as Titan Chemicals, Anpel Chemicals, Shanghai Dema, Chengdu Kelong Chemicals, Shaoyuan Chemical Technology, Nanjing Yushi, WuXi AppTec, and Bailingwei Technology.

[0140] Specific and analogous reactants can be identified selectively by the use of the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and on-line. Chemicals that are known but not commercially available can alternatively be prepared by custom chemical synthesis houses, many of which (such as those listed above) offer custom synthesis services.

[0141] The terms

[0142] The terms of the present application have the following meanings, unless specifically stated otherwise:

[0143] “Halogen” means F, Cl, Br, I, or isotopes thereof.

[0144] “Halo” or “halogen substitution” means substitution of one or more hydrogens with one or more halogens selected from F, Cl, Br, I, or isotopes thereof, the upper limit of the number of halogen substituents being equal to the sum of the number of hydrogens that the substituted group can have, and unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit, and when the number of halogen substituents is greater than one, the substituents can be the same or different halogens.

[0145] “Deuterium” means the isotope of hydrogen (H) and is synonymous with “D”.

[0146] “Deuterated” or “deuterium substitution” means substitution of one or more hydrogens on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. group with at least one isotope of deuterium, the upper limit of the number of deuterium substitutions being equal to the sum of the number of hydrogens that the substituted group can have, and unless otherwise specified, the number of deuterium substitutions is any integer between 1 and this upper limit, preferably 1-20 deuterium substitutions, more preferably 1-10 deuterium substitutions, more preferably 1-6 deuterium substitutions, and further more preferably 1-3 deuterium substitutions.

[0147] “C x-y ” means a group containing x to y carbons, such as “C 1-6 “Alkyl” means an alkyl group containing 1-6 carbons.

[0148] "alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, it is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, further preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 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 their various branched isomers.

[0149] "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0150] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group. Unless otherwise specified, it typically has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Or cycloheptyl, etc.

[0151] "Cycloalkylene" refers to the divalent group of "cycloalkyl", and non-limiting examples include cyclopropylene, cyclobutylene, etc.

[0152] "Heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring. Unless otherwise specified, it contains 1 to 4 heteroatoms selected from N, O, or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles. Unless otherwise specified, it is a 3- to 14-membered heterocycle, more preferably a 4- to 12-membered heterocycle, even more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl and heteroaryl groups. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithial, and dihydrofuranyl. nylonyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, etc.

[0153] "Heterocyclyl" refers to a saturated or unsaturated, partially or fully aromatic ring having 3 to 12 ring atoms, preferably 3 to 10 ring atoms, and further preferably 3 to 6 ring atoms, which contains at least one ring atom that is not carbon, i.e., a heteroatom. Non-limiting examples of heteroatoms include nitrogen, oxygen, and sulfur. Non-limiting examples of heterocyclyl groups include imidazolyl, pyridinyl, pyranyl, furanyl, thienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0154] "Carbocyclo" or "carbocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or nonaromatic carbocyclic ring group, including monocyclic rings, bicyclic bridged rings, bicyclic fused rings, and bicyclic spiro rings, unless otherwise specified, having 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and further preferably 3 to 6 carbon atoms. The definition includes cycloalkyl and aryl groups. Non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc., bicyclic bridged rings include etc., bicyclic fused rings include etc., and bicyclic spiro rings include etc.

[0155] "Aryl" refers to a carbocyclic ring having aromaticity. Non-limiting examples include phenyl, naphthyl, and the like.

[0156] "Akynyl" refers to a straight-chained or branched, monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds, unless otherwise specified, akynyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples are ethynyl, propynyl, propargyl, and the like.

[0157] "Alkenyl" refers to a straight-chained or branched, monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds, unless otherwise specified, akynyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples are ethenyl, propenyl, allyl, 2-butenyl, 1-butenyl, and the like.

[0158] "Alkoxy" or "alkyloxy" refers to -O-alkyl, unless otherwise specified, -O-C 1-8 alkyl, preferably -O-C 1-6 alkyl, more preferably -O-C 1-4 alkyl, further preferably -O-C 1-2 alkyl. Non-limiting examples include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like.

[0159] "Haloalkoxy" refers to -O-haloalkyl, unless otherwise specified, -O-haloC 1-8 alkyl, preferably -O-haloC 1-6 alkyl, more preferably -O-haloC 1-4alkyl, further preferred -O-haloC 1-2 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0160] "C 1-4 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like. 1-4 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0161] "C 1-4 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like. 1-4 alkyl. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0162] "Heteroaromatic" or "heteroaryl" means a heterocycle that is aromatic. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridyl, furanyl, pyranyl, pyridonyl, and the like.

[0163] "Heterocycloalkyl" means 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, further preferably 5 or 6 ring members. In addition to carbon atoms, a heterocycloalkyl group contains 1 to 3 heteroatoms as ring members, selected from N, S, O. Non-limiting examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, and the like.

[0164] "AlkylNH2" or "alkNH2" means NH2substituted by one or two alkyl groups, also written as -N-(alkyl)2or -NH-alkyl, the latter also written as monoalkylNH2. Non-limiting examples include dimethylNH2, monomethylNH2, diethylNH2, monoethylNH2, and the like.

[0165] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group can or can not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0166] Any hydrogen atom described herein can be replaced by its isotope deuterium, and any hydrogen atom in the compounds of the embodiments described herein can be replaced by deuterium.

[0167] The compounds of the present application include all suitable isotopic variations of the compounds. The term "isotopic variations" refers to compounds having at least one atom replaced by an atom having the same atomic number but an atomic mass different from the dominant natural mass. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine and iodine, such as3H,3C,13C,14C,15N,18F,31P,32P,35S,18O,17O,75Se,74As,76As, and125I, respectively. Certain isotopic variations of the compounds of the present application, for example, those into which radioactive isotopes are incorporated, are useful in drug and / or substrate tissue distribution studies ranging from in vitro to in vivo. 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, respectively.

[0168] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each of the available hydrogen atoms attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0169] In the compounds of the present application, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% incorporation of deuterium).

[0170] "Pharmaceutically acceptable salt" refers to salts of a compound of the present application which retain the biological effectiveness and properties of the free acids or bases, and which are not biologically or otherwise undesirable. The free acids are salts derived from

[0171] “Pharmaceutical composition” means a mixture of one or more compounds described herein or stereoisomers, deuterated forms, pharmaceutically acceptable salts thereof, with other ingredients

[0172] “Carrier” refers to a system that does not cause significant irritation to an 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 target organ, non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0173] “Excipient” refers to an agent that is not itself a therapeutic agent, used as a diluent, adjuvant, binder, and / or vehicle, for addition 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. Pharmaceutical excipients can serve various functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners, as known to those skilled in the art. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses, their derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and crosscarmellose (e.g., crosscarmellose sodium); (4) powdered tragacanth; (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 glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0174] The compounds of this invention can exist in specific geometric or stereoisomeric forms. Stereoisomers are isomers that exist in molecules with the same order of interconnection of atoms or groups of atoms, but different spatial arrangements. All such compounds of this invention include cis-trans isomers, optical isomers, and racemic mixtures and other mixtures thereof, such as cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers; all such mixtures are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. The purification and separation of such substances can be achieved using standard techniques known in the art. Detailed Implementation

[0175] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0176] Detection methods

[0177] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0178] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0179] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0180] Thin layer chromatography silica gel plate Yuhai HSGF254 or Qingdao GF254 silica gel plate was used. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.20mm. The specification of silica gel plate used in thin layer chromatography separation and purification of products was 0.4mm-0.5mm.

[0181] Column chromatography generally used Yuhai silica gel 200-300 mesh silica gel as carrier.

[0182] Example 1

[0183]

[0184] First step:

[0185] 1A (4.50g, 19.39mmol) was dissolved in N,N-dimethylformamide (45mL), and sodium hydride (0.93g, 23.27mmol) was added at 0-5℃. After the addition, the reaction was carried out at room temperature for 30min, and iodomethane (3.03g, 21.33mmol) was added at 0-5℃. After the addition, the reaction was carried out at room temperature overnight. After the reaction was completed, water (100mL) was added to quench the reaction, and extraction was carried out with ethyl acetate (100mL*2). The organic phase was combined, washed with water (100mL) and saturated brine (100mL) once, and dried with anhydrous sodium sulfate. After drying, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=5 / 1, (v / v)) to obtain compound 1B (3.1g, 64%).

[0186] 1 H NMR (400MHz, CDCl3) δ 7.76-7.74 (m, 1H), 6.70-6.67 (m, 1H), 3.93 (s, 3H), 3.78 (s, 3H).

[0187] Second step:

[0188] 1B (3.10g, 12.6mmol) was dissolved in isopropyl alcohol (77.5mL), and sodium borohydride (1.43g, 37.8mmol) was added at 0-5℃. After the addition, the reaction was carried out at 60℃ for 1hr, and then methanol (4mL) was added. The reaction was carried out at 60℃ for 3hrs. After the reaction was completed, the reaction liquid was concentrated, and the residue was dissolved in water (100mL) and ethyl acetate (100mL). Extraction was carried out with ethyl acetate (100mL*2). The organic phase was combined, washed with water (100mL) and saturated brine (100mL) once, and dried with anhydrous sodium sulfate. After drying, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate= / 1, (v / v)) to obtain compound 1C (2.00g, 72%).

[0189] LC-MS (ESI): m / z = 218.0 [M+H] + .

[0190] Third step:

[0191] Compound 1C (1.80 g, 8.25 mmol) was dissolved in dichloromethane (20 mL), triethylamine (3.34 g, 32.96 mmol), methylsulfonyl chloride (1.13 g, 9.90 mmol) were added at 0-5 °C. After the addition was completed, the reaction was carried out at room temperature for 30 min, then 5-trifluoromethylisoindoline (1.85 g, 9.89 mmol) was added at room temperature, and the reaction was carried out at room temperature overnight. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to obtain compound 1D (2.3 g, 72%).

[0192] LC-MS (ESI): m / z = 387.0 [M+H] + .

[0193] Fourth step:

[0194] Compound 1D (1.00 g, 2.58 mmol) and (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl) tert-butyl-1-carboxylate (1.04 g, 3.10 mmol, synthesis reference: WO2020160333A1) were dissolved in 1,4-dioxane (10 mL), and then potassium carbonate (1.07 g, 7.74 mmol) and water (2 mL) were added in turn, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.19 g, 0.26 mmol) was added, and then the reaction was carried out at 100 °C for 5 hrs after being replaced with nitrogen for 3 times. After the reaction was completed, water (20 mL) was added, and the organic phase was extracted with ethyl acetate (20 mL*2), and then the combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 1E (0.70 g, yield: 52%).

[0195] LC-MS (ESI): m / z = 518.3 [M+H] + .

[0196] Fifth step:

[0197] Compound 1E (400 mg, 0.77 mmol) was dissolved in 1,4-dioxane (2 mL), and hydrochloric acid dioxane solution (10 mL) was added, and the reaction was carried out at room temperature for 2 hrs. After the reaction was completed, the compound 1F (322 mg, crude product) was obtained by concentration, and was directly used in the next step without purification.

[0198] LC-MS (ESI): m / z = 418.2 [M+H] + .

[0199] Sixth step:

[0200] Dissolve 1F (322 mg, 0.77 mmol) in dichloromethane (10 mL), add triethylamine (233.75 mg, 2.31 mmol) and methylsulfonyl chloride (105.84 mg, 0.92 mmol) at 0-5 °C, after adding, react overnight at room temperature. After the reaction is complete, the reaction solution is concentrated, and the crude product is purified by HPLC to obtain compound 1 (55.00 mg, yield: 14%).

[0201] LC-MS (ESI): m / z = 496.2 [M+H] + .

[0202] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.58-7.56 (d, 1H), 7.49-7.45 (m, 2H), 6.61-6.55 (m, 1H), 6.47-6.43 (d, 1H), 6.36-6.34 (d, 1H), 3.97 (s, 3H), 3.89 (s, 2H), 3.61-3.55 (m, 5H), 3.25-3.33 (m, 1H), 2.86 (s, 3H), 2.79-2.74 (m, 2H), 2.28-2.18 (m, 1H), 1.83-1.80 (d, 2H), 1.46-1.35 (m, 2H).

[0203] Example 2

[0204]

[0205] First step:

[0206] To a solution of 1A (5.00 g, 21.55 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.03 g, 25.86 mmol) at 0-5 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 30 min, and then iodoe thane (3.70 g, 23.71 mmol) was added at 0-5 °C. After the addition was completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (100 mL*2). The organic phase was combined and washed with water (150 mL), saturated brine (100 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1, (v / v)) to give compound 2B (2.0 g, 35%).

[0207] 1 H NMR (400 MHz, CDCl3) δ 7.68-7.66 (d, 1H), 6.60-6.58 (d, 1H), 4.29-4.23 (m, 2H), 3.86 (s, 3H), 1.32-1.29 (t, 3H).

[0208] Second step:

[0209] To a solution of 2B (2.00 g, 7.69 mmol) in isopropanol (50 mL) was added sodium borohydride (0.87 g, 23.07 mmol) at 0-5 °C. After the addition was completed, the reaction mixture was stirred at 60 °C for 1 hr, and then methanol (2.5 mL) was added. After the addition was completed, the reaction mixture was stirred at 60 °C for 3 hrs. After the reaction was completed, the reaction mixture was concentrated. The residue was dissolved in water (50 mL) and ethyl acetate (50 mL), and extracted with ethyl acetate (50 mL*2). The organic phase was combined and washed with water (50 mL), saturated brine (50 mL) and dried over anhydrous sodium sulfate. After drying, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2, (v / v)) to give compound 2C (2.00 g, 100%).

[0210] Third step:

[0211] To a solution of 2C (1.80 g, 7.76 mmol) in dichloromethane (20 mL) was added triethylamine (3.13 g, 30.96 mmol), methylsulfonyl chloride (1.07 g, 9.31 mmol) at 0-5 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 30 min, and then 5-trifluoromethylisoindoline (1.74 g, 9.29 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, (v / v)) to give compound 2D (2.2 g, 70%).

[0212] LC-MS (ESI): m / z = 401 [M+H] + .

[0213] Fourth step:

[0214] Compound 2D (1.00 g, 2.49 mmol) and (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)vinyl)tert-butyl-1-carboxylate (1.01 g, 2.99 mmol, synthesis reference: WO2020160333A1) were dissolved in 1,4-dioxane (10 mL), and then potassium carbonate (1.03 g, 7.47 mmol) and water (2 mL) were added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.25 mmol). After the addition, the reaction was stirred at 100 °C for 5 h after being replaced with nitrogen for 3 times. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 2E (1.30 g, yield: 98%).

[0215] LC-MS (ESI): m / z = 532.3 [M+H] + .

[0216] Fifth step:

[0217] Compound 2E (550 mg, 1.03 mmol) was dissolved in 1,4-dioxane (2 mL), and hydrochloric acid dioxane solution (10 mL) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated to obtain compound 2F (446 mg, crude product), which was used directly in the next step without purification.

[0218] LC-MS (ESI): m / z = 432.3 [M+H] + .

[0219] Sixth step:

[0220] Compound 2F (446 mg, 1.03 mmol) was dissolved in 1,4-dioxane (10 mL), and N,N- diisopropylethylamine (266.23 mg, 2.06 mmol) and sulfonamide (197.99 mg, 2.06 mmol) were added at room temperature. After the addition, the reaction was carried out at 100 °C overnight. After the reaction was completed, the reaction mixture was concentrated, and the crude product was purified by HPLC to obtain compound 2 (66.00 mg, yield: 12%).

[0221] LC-MS (ESI): m / z = 511.1 [M+H] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.58-7.56 (d, 1H), 7.48-7.46 (d, 2H), 6.70 (s, 2H), 6.61-6.56 (m, 1H), 6.47-6.43 (d, 1H), 6.36-6.34 (d, 1H), 4.18-4.12 (m, 2H), 3.97-3.89 (m, 6H), 3.49-3.47 (d, 2H), 2.61-2.56 (m, 2H), 2.20-2.12 (m, 1H), 1.81-1.79 (d, 2H), 1.46-1.38 (m, 2H), 1.24-1.19 (t, 3H).

[0223] Example 3

[0224]

[0225] First step:

[0226] Compound 3A (1.00 g, 4.48 mmol) was dissolved in dry toluene (30 mL), pinacolborane (2.00 g, 15.61 mmol) was added dropwise, and bis(cyclopentadienyl)zirconium chloride hydride (0.23 g, 0.89 mmol) was added. After the addition was completed, the nitrogen was replaced, and the reaction was stirred at 65 °C for 18 h. TLC monitoring (petroleum ether: ethyl acetate = 5:1 (v / v)) showed that the reaction was complete. The reaction solution was concentrated, and the crude product was directly used in the next step.

[0227] Second step:

[0228] Compound 3B (1.57 g, 4.47 mmol) and 1D (1.0 g, 2.58 mmol) were dissolved in 1,4-dioxane (20 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.19 g, 0.26 mmol), potassium carbonate (1.07 g, 7.74 mmol), and water (4 mL) were added in sequence. After the addition was completed, the nitrogen was replaced for 3 times, and the reaction was stirred at 100 °C for 5 h. After the reaction was completed, water (30 mL) was added, and extraction was performed with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1 (v / v)) to obtain compound 3C (0.5 g, yield: 37%).

[0229] LC-MS (ESI): m / z = 532.30 [M+H]+ .

[0230] Third Step:

[0231] Compound 3C (500 mg, 0.94 mmol) was dissolved in dichloromethane (10 mL), hydrochloric acid dioxane solution (3 mL) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, compound 3D (410 mg, crude product) was obtained by concentration, which was directly used in the next step without purification.

[0232] LC-MS (ESI): m / z = 432.20 [M+H] + .

[0233] Fourth Step:

[0234] Compound 3D (410 mg, 0.93 mmol) and cyclopropylformic acid (160 mg, 1.86 mmol) were dissolved in DMF (10 mL), and then N-methylimidazole (310 mg, 3.72 mmol) and TCFH (520 mg, 1.86 mmol) were added in sequence. The reaction was carried out at room temperature for 3 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and extraction was carried out with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to obtain compound 3 (100 mg, 22%).

[0235] LC-MS (ESI): m / z = 500.20 [M+H] + .

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.49-7.42 (m, 2H), 6.56-6.47 (m, 1H), 6.41 (d, 1H), 6.32 (d, 1H), 3.96 (s, 4H), 3.88 (s, 2H), 3.56 (s, 3H), 3.52-3.45 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.70 (m, 4H), 1.55-1.45 (m, 1H), 1.27-1.17 (m, 4H), 0.67-0.57 (m, 4H).

[0237] Example 4

[0238]

[0239] First Step:

[0240] Compound 4A (486 mg, 1.0 mmol, synthesis reference: WO2024199262A1) was dissolved in dry 1,4-dioxane (5 mL) and stirred at 85 °C for 12 h. The reaction was monitored by TLC and was complete. The reaction was concentrated and the residue was purified by HPLC prep to give compound 4 (15 mg, 6%).

[0241] LC-MS (ESI): m / z = 485.1 [M+H] + .

[0242] 1 H NMR (400 MHz, DMSO) d 8.27 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.68 (d, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 7.00 (d, 1H), 6.60 (dd, 1H), 6.20 (s, 1H), 6.06 (d, 1H), 5.50 (s, 2H), 3.51 - 3.42 (m, 1H), 2.02 - 1.92 (m, 1H), 1.85 - 1.76 (m, 2H), 1.72 (dd, 2H), 1.48 (dt, 1H), 1.18 (q, 4H), 0.61 (dd, 4H).

[0243] Biological test:

[0244] 1. The purpose of this experiment is to detect the level of Testosterone in NCI-H295R cells by enzyme linked immunosorbent assay (ELISA) method, so as to evaluate the inhibitory effect of the compound on the level of Testosterone in NCI-H295R cells.

[0245] H295R cells were purchased from ATCC, the cell complete 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 the cells were cultured in a 37°C, 5% CO2 incubator. Cells in the exponential growth phase were collected and cultured in hormone deprivation medium (without phenol red 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 for plating, so that the cells were 60000 per well, and the volume was 90μL per well, then 10μL of different concentrations of compounds were added, and placed in a CO2 incubator for incubation for 3 days. After the end of the culture, according to the operation instruction of the testosterone detection Elisa kit (Bi Yun Tian, PT872), 50μL of cell culture supernatant was taken from each well, centrifuged at 500g, 5min at room temperature, and then the supernatant was collected. The samples were added to the corresponding wells according to 25μl / well, then 75μl / well of prepared horseradish peroxidase-labeled testosterone was added, mixed thoroughly for 10 seconds, the reaction wells were covered with sealing film (white), and incubated at room temperature for 120min. Then wash the plate 3 times with a volume of 300μl per well, and after the last time, dry with thick absorbent paper, add color developing agent TMB solution 100μl / well, cover the reaction wells with sealing film (white), incubate at room temperature for 15-20min, then add stop solution 50μl / well, mix immediately after measuring the OD 450 absorbance value. The absorbance value reading was plotted using a four-parameter nonlinear regression model using Graphpad Prim 8.0 software to draw an S-shaped concentration curve and calculate the IC 50 value. The results were processed according to formula (1), the inhibition rate of each concentration of the compound was calculated, and the concentration of the compound when the inhibition rate was 50% was calculated using Graphpad Prim 8.0 software. 50 RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group.

[0246] Inhibition rate % = 100-RLU compound / RLU control x 100 formula (1)

[0247] Table 1 Inhibition of Testosterone levels in NCI-H295R cells by compounds

[0248]

[0249] Conclusion: The compound of the present application, such as the compound of the example, has a significant inhibitory effect on the level of Testosterone in NCI-H295R cells

[0250] 2. The purpose of this experiment is to detect the level of Pregnenolone in NCI-H295R cells by using the method of Enzyme linked immunosorbent assay (ELISA), so as to evaluate the inhibitory effect of the compound on the level of Pregnenolone in NCI-H295R cells.

[0251] H295R cells were purchased from ATCC (CRL-2128), and the complete 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 the culture was carried out in a 37℃, 5%CO2 incubator. Cells in the exponential growth phase were collected, and the cells were 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 for plating, so that the cells were 60000 per well, and the volume was 90μL per well, then 10μL of different concentrations of compounds were added, and the cells were incubated in a CO2 incubator for 3 days. After the culture was completed, the cell culture supernatant was centrifuged at 800xg for 10min at 2-8℃, and the supernatant was collected and determined according to the operation instruction of the Pregnenolone detection Elisa kit (Antibodies-A73791), and the OD 450 signal was read.

[0252] Data processing:

[0253] 2.1 Draw the standard curve. The standard concentration is taken as the abscissa, the OD 450 value is taken as the ordinate, the coordinate points of each standard are connected with a smooth line, and the curve is fitted according to the 4-PL (four parameter logistic) method.

[0254] 2.2 Sample quantification: The corresponding concentration of testosterone / pregnenolone in the sample CONC was calculated by the absorbance value of the sample and the standard curve, and was processed according to formula (2), the inhibition rate of each concentration of the compound was calculated, and the S-shaped concentration curve was drawn and the IC value, that is, the concentration of the compound when the inhibition rate was 50%, was calculated using the three-parameter nonlinear regression model in the Graphpad Prim 8.0 software. Wherein CONC 50 is the concentration of the drug treatment group, CONC cpd is the average concentration of the solvent control group. ctrl

[0255] Inhibition rate % = 100% - CONC cpd / CONC ctrl × 100% formula (2)

[0256] Table 2 Inhibition of the compound on the level of Pregnenolone in NCI-H295R cells

[0257]

[0258] Conclusion: The compound of the present application, for example, the compound of the examples, has obvious inhibitory effect on the level of Pregnenolone in NCI-H295R cells.​

Claims

1. A compound of Formula (I), (I-1), (I-a), a stereoisomer, deuterated form, or a pharmaceutically acceptable salt thereof, wherein, B ring is selected from the left end of the double bond, the right end of the methylene group; X is selected from CH or N; X1is selected from CH or N; represents a single or double bond; L1is selected from a bond, ethenyl, -C 1-6 alkyl-O-; R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -N(CH3)-C(O)-(CH2) p -R a , -NH-SO2-(CH2) p -R a , -NH-C(O)-O-R a , -NH-C(O)-NHR a , -NHR a , -(CH2) p -C(O)-R a , -C(O)-(CH2) p -R a , -C(O)-O-(CH2) p -R a , -C(O)-NHR a or -C(O)-NH-S(O)2-R a ; R a selected from H, D, NH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =0, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, -S(O)2-C 1-4 alkyl; each R1is independently selected from H, D, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl groups are optionally further substituted with 1-4 substituents selected from D, halogen, CN, OH, =0, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy or -O-C 1-4 haloalkyl, or any two R1and their incident atoms together form a 3-6 membered cycloalkyl; R2is selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl, which alkyl, alkenyl, alkynyl, cycloalkyl is optionally further substituted with 1 to 4 substituents selected from the group consisting of D, halogen, CN, OH, =0, NH2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, C 1-4 alkoxy or -O-C 1-4 haloalkyl; R3is each independently selected from H, D, CN, halogen, OH, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, -O-C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-4 alkyl, -O-(CH2) p -C 3-6 cycloalkyl or -(CH2) p -O-C 3-6 cycloalkyl, or any two R 3 and their connecting atoms form a 3-8 membered cycloalkyl; R4is selected from -S(O)2-R B ; R B selected from NH2, C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, said NH2, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =0, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkynyl, -O-C 1-4 haloalkyl, C 3-6 cycloalkyl; R5is selected from H, D, C 1-4 alkyl, C 3-4 cycloalkyl; or R4and R5together with the carbon atom to which they are attached form a 5-6 membered heterocyclyl group, wherein said heterocyclyl group is optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, CN, =0, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -O-C 1-4 haloalkyl, C 3-6 cycloalkyl; n is selected from 1 or 2; m is selected from 1 or 2; p is selected from 0, 1 or 2.

2. The compound of claim 1, a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein, said compound has the structure of Formula (II), (II-a), wherein, X is selected from CH or N; R is selected from -S(O)2-R a , -NH-C(O)-(CH2) p -R a , -N(CH3)-C(O)-(CH2) p -R a , -NH-SO2-(CH2) p -R a , -NH-C(O)-O-R a , -NHR a , -(CH2) p -C(O)-R a , -C(O)-(CH2) p -R a , -C(O)-O(CH2) p -R a , -C(O)-NHR a or -C(O)-NH-S(O)2-R a ; R a selected from H, D, NH2, C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-2 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5 membered heteroaryl, 6 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl groups are optionally further substituted with 1-4 groups selected from D, halogen, OH, NH2, =0, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2 haloalkyl, C 1-2 alkoxy, -O-C 1-2 haloalkyl, -S(O)2-C 1-2 alkyl; R1is each independently selected from H, D, halogen, C 1-2 alkyl, C 1-2 alkoxy, 3-6 membered cycloalkyl, said alkyl, alkoxy, cycloalkyl are optionally further substituted with 1-4 substituents selected from D, halogen, OH, =0, NH2, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 deuteroalkyl, C 1-2 alkoxy or -O-C 1-2 haloalkyl, or any two R1and their incident atoms together form a 3-6 membered cycloalkyl; R2is selected from H, D, C 1-4 alkyl, 3-4 membered cycloalkyl, said alkyl, cycloalkyl optionally further substituted with 1-4 substituents selected from D, halogen, OH, =0, NH2, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 deuteroalkyl, C 1-2 alkoxy or -O-C 1-2 haloalkyl substituted; R3is each independently selected from H, D, CN, halogen, OH, C 1-2 alkyl, C 1-2 deuteroalkyl, C 1-2 haloalkyl, C 1-2 alkoxy, -O-haloC 1-2 alkyl, C 3-6 cycloalkyl, -SCF3, -SF5, -(CH2) p -O-C 1-2 alkyl, -O-(CH2) p -C 3-6 cycloalkyl or -(CH2) p -O-C 3-6 cycloalkyl, or any two R3together with their connecting atoms form a 4-6 membered cycloalkyl; n is selected from 1 or 2; m is selected from 1 or 2; p is selected from 0 or 1.

3. The compound of claim 1 or 2, stereoisomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein which satisfies one or more of the following conditions: (1) R is selected from -S(O)2-R a , -NH-C(O)-R a , -C(O)-R a , -C(O)-CH2-R a , -C(O)-O-R a ; (2) R a selected from D, NH2, methyl, CD3, -CF2CH3, ethyl, cyclopropyl, cyclobutyl, oxetanyl, 3,3-difluorocyclobutyl, 1-methylpyrazolyl, -CH2CH2OH, -CH2CN, -N(CH3)2; (3) R2is selected from H, D, methyl, ethyl, cyclopropyl or cyclobutyl; (4) R3is selected from H, D, F, Cl, methyl, ethyl, trifluoromethyl, ethynyl, cyclopropyl, cyclobutyl, -O-cyclopropyl or -O-cyclobutyl; (5) R4is selected from -S(O)2-NH2, -S(O)2-NH(CH3), -S(O)2-N(CH3)2, -S(O)2-NH(cyclopropyl), -S(O)2-(4-6 membered heterocycloalkyl); (6) R5is selected from H, D; or R4and R5together with the carbon atom to which they are attached form a 5-membered heterocycloalkyl, 5-membered heteroaryl, wherein said heterocycloalkyl, heteroaryl is optionally further substituted with 1 to 3 groups selected from the group consisting of D, halogen, OH, NH2, CN, =0, C 1-2 alkyl, C 3-4 cycloalkyl.

4. The compound of claim 3, a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein, which satisfies one or more of the following conditions: (1) selected from the group consisting of: (2) R2is selected from methyl, ethyl or cyclopropyl; (3) selected from the group consisting of: (4) selected from the group consisting of: (5) selected from the group consisting of: (6) the B ring is selected from wherein the left end is attached to the left double bond and the right end is attached to the right methylene group.

5. The compound of claim 1, a stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the following structures:

6. A pharmaceutical composition or a pharmaceutical preparation comprising a compound of any one of claims 1-5, a stereoisomer, deuterated form, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition or the pharmaceutical preparation of claim 6, comprising 1-1500 mg of a compound of any one of claims 1-5, a stereoisomer, deuterated form, or a pharmaceutically acceptable salt thereof, and a carrier and / or excipient.

8. Use of a compound of any one of claims 1-5, or a stereoisomer, deuterated form, or a pharmaceutically acceptable salt thereof, or a composition of claims 6-7, for the manufacture of a medicament for the prevention and / or treatment of a CYP11A1 mediated disease.

9. The use of claim 8, wherein the CYP11A1 mediated disease is selected from treating a steroid hormone dependent cancer.

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

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