Sulfonamide cyp11a1 inhibitors

Abstract

The present application belongs to the technical field of medicine. In particular, the present application relates to a kind of fused ring sulfamide compounds that can be used as CYP11A1 inhibitor, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof, pharmaceutical composition and preparation containing the compound, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof, and the use of the compound, pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology. In particular, this invention relates to a class of sulfonamide compounds that can be used as CYP11A1 inhibitors, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, and the use of said compounds, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof. Background Technology

[0002] Prostate cancer is the most common cancer among men worldwide, with a higher incidence rate in Europe and America than in China. In the Chinese population, metastatic castration-resistant prostate cancer (mCRPC) accounts for 54% of new prostate cancer cases. Patients with castration-resistant prostate cancer (CRPC) have a generally poor prognosis, and the overall incidence rate, especially the detection rate of mCRPC, is high.

[0003] Androgen receptor (AR) signaling is crucial at all stages of prostate cancer. Current treatments for advanced prostate cancer include androgen deprivation therapy (ADT), which involves gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, as well as AR antagonists or CYP17A1 inhibitors (such as abiraterone acetate in combination with prednisone). The main reason for drug resistance in prostate cancer, especially CRPC, is dependence on AR pathway activation. Increased progesterone levels in patients using CYP17A1 inhibitors (abiraterone acetate) are one resistance mechanism. Studies show that enzymes catalyzing steroid biosynthesis are upregulated in advanced CRPC, and data demonstrate that cortisol, progesterone, and testosterone can effectively activate the AR signaling pathway.

[0004] Cytochrome P450 monooxygenase 11A1 (CYP11A1), also known as cholesterol side-chain cleavage enzyme, is the first step in the conversion of cholesterol into various glucocorticoids, mineralocorticoids, and sex hormones. It is a key upstream enzyme in steroid biosynthesis, converting cholesterol into pregnenolone. It is widely found in the adrenal glands, testes, ovaries, placenta, etc., located in the inner membrane of mitochondria. Inhibiting CYP11A1 can completely block the entire steroid biosynthesis process. Therefore, CYP11A1 inhibitors can treat steroid hormone-dependent diseases, including but not limited to prostate and breast cancer, and are effective in patients resistant to existing treatments. In particular, CYP11A1 inhibitors can be used to treat androgen receptor-dependent diseases and conditions. Therefore, using small molecule inhibitors to inhibit CYP11A1 shows great potential for cancer treatment. Summary of the Invention

[0005] The technical problem to be solved by this invention is to provide a novel compound with good inhibitory activity against CYP11A1. Furthermore, this type of compound can be used to prepare drugs for the treatment and / or prevention of steroid hormone-dependent conditions and diseases requiring inhibition of CYP11A1.

[0006] The technical solution of the present invention is as follows:

[0007] In one aspect, the present invention provides compounds represented by the following general formula (I), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof.

[0008]

[0009] in,

[0010] X1 is selected from C(O), S(O) or S(O)2;

[0011] X2 and X3 are each independently selected from CR or N;

[0012] L1 does not exist or is selected from -CR 1a R 1b -、-O-、-S-、-NR 1a -、-CR 1a R 1b -CR 1a’ R 1b’ -、-CR 1a R 1b -NR 1c -、-C(O)-CR 1a R 1b -、-CR 1a R 1b -O-;

[0013] L2 does not exist or is selected from -CR2a R 2b -、-CR 2a R 2b -CR 2a’ R 2b’ -、-CR 2a R 2b -CR 2a’ R 2b’ -CR 2a” R 2b” -;

[0014] X is selected from O, S, or NR. 3a ;

[0015] Ring A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl or 6-15 membered aryl;

[0016] Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0017] R is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -NR 4a R 4b -OR 4a -SR 4a -NR 4a -C(O)-R 4b -、-C(O)R 4a -C(O)NR 4a R 4b -C(O)OR 4a ;

[0018] R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, oxo, and C, respectively, each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -NR 5a R 5b -OR 5a -SR 5a -NR 5a -C(O)-R 5b , -C(O)R 5a , -C(O)NR 5a R5b -C(S)NR 5a R 5b -C(O)OR 5a , -S(O)NR 5a R 5b -S(O)2NR 5a R 5b -S(O)2R 5a Alternatively, the following groups may be optionally substituted with 1 to 4 substituents: -(CH2) t -3-10 membered cycloalkyl groups, -(CH2) t -3-10 heterocyclic group, -(CH2) t -5-10 heteroaryl groups, -(CH2) t -6-10 aryl group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0019] R 1a R 1a’ R 1b R 1b’ R 1c R 2a R 2b R 2a’ R 2b’ R 2a” R 2b” R 3a R 4a R 4b R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0020] m, n, and t are each independently selected from 0, 1, 2, 3, or 4;

[0021] p is selected from 0, 1, 2 or 3.

[0022] In some implementations, X1 is selected from C(O), S(O) or S(O)2;

[0023] X2 and X3 are each independently selected from CH or N;

[0024] L1 does not exist or is selected from -CHR 1a -、-CHR 1a -CHR 1a’ -;

[0025] L2 does not exist or is selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -;

[0026] X is selected from O or S;

[0027] Ring A is selected from 8-10 member nitrogen-containing fused heterocyclic groups or 8-10 member nitrogen-containing fused heteroaryl groups;

[0028] Ring B is selected from 5-6 membered monocyclic alkyl groups or 5-6 membered monoheterocyclic groups;

[0029] R1 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, oxo, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0030] R2 is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, oxo, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR 5a R 5b -OR 5a -NR 5a -C(O)-R 5b -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0031] R 1a R 1a’ R 2a R 2a’ R 2a” Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0032] R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0033] m and n are independently selected from 0, 1, 2 or 3 respectively;

[0034] p is selected from 0, 1, or 2.

[0035] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, its ester, or its stereoisomer further has a structure of general formula (II-1) or general formula (II-2).

[0036]

[0037] The definitions of L1, L2, X, X2, X3, R1, R2, ring A, ring B, m, and n are as described in any embodiment of the present invention.

[0038] In some implementations, L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0039] L2 is selected from -CHR 2a -or-CHR2a -CHR 2a’ -;

[0040] X2 and X3 are each independently selected from CH or N;

[0041] Ring A is selected from Preferably, ring A is

[0042] Ring B is selected from pyrrolidinyl, pyrazolyl, piperidinyl, or piperazinyl; preferably, ring B is piperidinyl.

[0043] R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0044] R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0045] R 1a R 1a’ R 2a R 2a’ Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; preferably, R a R c R a’ R 1a R 1a’ R2a R 2a’ R 4a Each time it appears, it is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0046] R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy;

[0047] m and n are independently selected from 0, 1, 2 or 3 respectively.

[0048] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, its ester, or its stereoisomer further has a structure of general formula (III-1) or general formula (III-2).

[0049]

[0050]

[0051] The definitions of L1, L2, X2, R1, R2, m, and n are as described in any embodiment of the present invention.

[0052] In some embodiments, the compound of formula (I), its pharmaceutically acceptable salt, its ester, or its stereoisomer further has a structure of general formula (III-3) or general formula (III-4).

[0053]

[0054] The definitions of L1, L2, X2, R1, R2, m, and n are as described in any embodiment of the present invention.

[0055] In some implementations, X2 is selected from CH or N;

[0056] L1 is selected from -CH2- or -CH2-CH2-;

[0057] L2 is selected from -CH2- or -CH2-CH2-;

[0058] R1 is independently selected from hydrogen, halogen, cyano, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a Preferably, each R1 is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ;

[0059] R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a Preferably, each R2 is independently selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0060] R 5a Each time it appears, it is independently selected from hydrogen, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 Alkyl; preferably, R 5aEach time it appears, it is independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, cyanomethyl, cyanoethyl, or cyanopropyl.

[0061] R 5b Each time it appears, it is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 5b Each time it appears, it is independently selected from hydrogen, methyl, ethyl, propyl, or isopropyl;

[0062] m and n are independently selected from 0, 1, or 2, respectively.

[0063] In some embodiments, X1 is selected from C(O) or S(O). In some embodiments, X1 is C(O).

[0064] In some embodiments, X2 and X3 are independently selected from CH or N. In some embodiments, X3 is CH, and X2 is selected from CH or N. In some embodiments, X2 is CH, and X3 is CH.

[0065] In some embodiments, L1 is absent or selected from -CH2-, -O-, -S-, -NH-, -CH2-CH2-, -CH2-NH-, -C(O)-CH2-, and -CH2-O-. In some embodiments, L1 is absent or selected from -CH2-, -O-, -S-, -NH-, and -CH2-CH2-. In some embodiments, L1 is selected from -CH2- or -CH2-CH2-. In some embodiments, L1 is -CH2-.

[0066] In some implementations, L1 is selected from -CR 1a R 1b -or-CR 1a R 1b -CR 1a’ R 1b’ - Preferably, L1 is selected from -CR 1a R 1b -;R 1a R 1a’ R 1b R 1b’ Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkyl group.

[0067] In some implementations, L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ - Preferably, L1 is selected from -CHR 1a ;R 1a R 1a’ Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group.

[0068] In some implementations, L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ - Preferably, L1 is selected from -CHR 1a ;R 1a R 1a’ Each time it appears, it is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0069] In some embodiments, L2 is absent or selected from -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In some embodiments, L2 is absent or selected from -CH2- or -CH2-CH2-. In some embodiments, L2 is selected from -CH2- or -CH2-CH2-. In some embodiments, L2 is selected from -CH2-.

[0070] In some implementations, L2 is absent or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” - Preferably, L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;R 2a R 2a’ R 2a” Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6alkoxy or halogenated C 1-6 Alkyl group.

[0071] In some implementations, L2 is absent or selected from -CHR 2a -、-CHR 2a -CHR 2a’ - Preferably, L2 is selected from -CHR 2a -;R 2a R 2a’ Each time it appears, it is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0072] In some embodiments, X is selected from O or S. In some embodiments, X is selected from O.

[0073] In some embodiments, ring A is selected from 8-10 member nitrogen-containing fused heterocyclic groups or 8-10 member nitrogen-containing fused aryl groups. In some embodiments, ring A is selected from... In some implementations, ring A is

[0074] In some embodiments, ring B is selected from 5-6 membered monocyclic alkyl or 5-6 membered monoheterocyclic groups. In some embodiments, ring B is selected from pyrrolidinyl, pyrazolyl, piperidinyl, or piperazinyl. In some embodiments, ring B is selected from piperidinyl. In some embodiments, ring B is...

[0075] In some embodiments, R is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl or cyano C 1-6 Alkyl group. In some embodiments, R is independently selected from hydrogen, halogen, hydroxyl, amino, C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 Alkyl group. In some embodiments, R is independently selected from hydrogen, halogen, hydroxyl, amino, C each time it appears. 1-6 Alkyl or halogenated C 1-6 alkyl.

[0076] In some embodiments, R1 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, oxo, C, each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a In some embodiments, R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, C, and so on, each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a In some implementations, R1 is independently selected from hydrogen, halogen, cyano, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a In some embodiments, each R1 is independently selected from hydrogen, halogen, cyano, C, 1-4 Alkyl, Halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b In some embodiments, each R1 is independently selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, or -C(O)NH2.

[0077] In some embodiments, R2 is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, oxo, C, each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR 5a R5b -OR 5a -NR 5a -C(O)-R 5b -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a In some embodiments, R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, C, and so on, each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a In some embodiments, R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, C, and so on, each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a In some implementations, each R2 is independently selected from hydrogen, C, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a In some embodiments, each R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, -C(O)R 5a -C(O)NHR5a -C(O)OR 5a -S(O)2NHR 5a or -S(O)2R 5a In some embodiments, each R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, -C(O)R 5a -S(O)2NHR 5a or -S(O)2R 5a In some embodiments, each R2 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, -S(O)2NHR 5a or -S(O)2R 5a In some embodiments, each R2 is independently selected from hydrogen, methyl, ethyl, -S(O)2NHR 5a or -S(O)2R 5a .

[0078] In some implementations, R 3a Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl group. In some embodiments, R 3a Selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl group. In some embodiments, R 3a Selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl group. In some embodiments, R 3a Selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl group. In some embodiments, R 3a Selected from hydrogen or C 1-4 alkyl.

[0079] In some implementations, R 4a R 4b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl group. In some embodiments, R 4aR 4b Selected independently from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl group. In some embodiments, R 4a R 4b Selected independently from hydrogen and C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl group. In some embodiments, R 4a R 4b Selected independently from hydrogen and C 1-4 Alkyl or halogenated C 1-4 Alkyl group. In some embodiments, R 4a R 4b Each is independently selected from hydrogen or C. 1-4 alkyl.

[0080] In some implementations, R 5a Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkyl group. In some embodiments, R 5a Each time it appears, it is independently selected from hydrogen, hydroxyl, amino, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl or cyano C 1-4 Alkyl group. In some embodiments, R 5a Each time it appears, it is independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, cyanomethyl, cyanoethyl, or cyanopropyl. In some embodiments, R 5a Each time it appears, it is independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, or hydroxypropyl.

[0081] In some implementations, R 5bEach time it appears, it is independently selected from hydrogen and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl or cyano C 1-4 Alkyl group. In some embodiments, R 5b Each time it appears, it is independently selected from hydrogen or C. 1-4 Alkyl group. In some embodiments, R 5b Each time it appears, it is independently selected from hydrogen, methyl, ethyl, propyl, or isopropyl.

[0082] In some implementations, m is selected from 0, 1, 2, or 3. In some implementations, m is selected from 0, 1, or 2. In some implementations, m is selected from 0 or 1.

[0083] In some implementations, n is selected from 0, 1, 2, or 3. In some implementations, n is selected from 0, 1, or 2. In some implementations, n is selected from 1 or 2.

[0084] In some implementations, t is selected from 0, 1, or 2.

[0085] In some implementations, p is selected from 0, 1, or 2.

[0086] In some embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its ester, or its stereoisomer is selected from the following compounds:

[0087]

[0088] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical composition may be formulated into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalers or sprays, etc.

[0089] In some embodiments of the present invention, the above-described pharmaceutical preparations can be administered to patients or subjects requiring such treatment via oral, parenteral, rectal, or pulmonary administration. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid dosage forms like tablets, capsules, pills, granules, etc.; or into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When formulating oral preparations, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the above-described pharmaceutical preparations can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectable preparations, conventional methods in the existing pharmaceutical field can be used. When preparing injectable preparations, excipients may not be added, or suitable excipients may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays, etc.

[0090] The pharmaceutical carriers and / or diluents used in the pharmaceutical compositions or formulations of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical formulations. The choice of a specific carrier and / or diluent will depend on the route of administration or the type and state of disease for treating a particular patient. Methods for preparing suitable pharmaceutical compositions for a specific route of administration are entirely within the knowledge of those skilled in the art of pharmaceutical work.

[0091] In another aspect, the present invention also relates to the use of the aforementioned compounds, their pharmaceutically acceptable salts, their esters, or their stereoisomers in the preparation of medicaments for the prevention and / or treatment of CYP11A1-mediated diseases and related conditions, said medicaments being used in combination with one or more other drugs to prevent or treat CYP11A1-mediated diseases and related conditions. The CYP11A1-mediated diseases and related conditions are steroid hormone-dependent conditions and diseases requiring inhibition of CYP11A1; particularly, the CYP11A1-mediated diseases and related conditions are androgen receptor-dependent conditions and diseases requiring inhibition of CYP11A1. The diseases and related conditions are cancers, including carcinoma in situ and metastatic cancer.

[0092] In some embodiments, the cancer is selected from prostate cancer or breast cancer. In some embodiments, the cancer is selected from castration-resistant prostate cancer or breast cancer.

[0093] Furthermore, the present invention also relates to the use of pharmaceutical formulations of the aforementioned compounds, their pharmaceutically acceptable salts, their esters or stereoisomers in the preparation of pharmaceuticals, said pharmaceuticals being used in combination with one or more pharmaceuticals to treat and / or prevent diseases and related conditions mediated by CYP11A1.

[0094] On the other hand, the pharmaceuticals relating to the aforementioned compounds, their pharmaceutically acceptable salts, their esters, or their stereoisomers can be administered alone or in combination with one or more second therapeutic agents, which, in combination with the CYP11A1 inhibitor compounds of this application, are used to treat and / or prevent diseases and related conditions mediated by CYP11A1. Therefore, in some embodiments, the pharmaceutical composition further comprises one or more second therapeutic agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutical carriers and / or diluents.

[0095] The second therapeutic active agent is selected from glucocorticoids, mineralocorticoids, or anticancer drugs. The glucocorticoids include, but are not limited to, hydrocortisone, prednisone, betamethasone, prednisolone, beclomethasone dipropionate, methylprednisolone, and dexamethasone; the mineralocorticoids include, but are not limited to, fludrocortisone acetate and deoxycorticosterone; the anticancer drugs include, but are not limited to, nonsteroidal androgen receptor antagonists (e.g., enzalutamide, apalutamide, and darauroutamide), steroid synthesis inhibitors (e.g., CYP17A1 inhibitors, such as abiraterone acetate), chemotherapeutic agents (e.g., paclitaxel), anti-estrogens (e.g., tamoxifen, fulvestrant), targeted therapies (e.g., CDK4 / 6 inhibitors, PI3K inhibitors, AKT inhibitors, BET inhibitors, HDAC inhibitors, etc.), and radiopharmaceuticals.

[0096] In some embodiments, the components to be combined (e.g., the compounds of the present invention, their pharmaceutically acceptable salts, their esters, their stereoisomers, and the second therapeutic agent) may be administered simultaneously or sequentially. For example, the second therapeutic agent may be administered before, simultaneously with, or after the administration of the compounds of the present invention, their pharmaceutically acceptable salts, their esters, or their stereoisomers. Furthermore, the components to be combined may be administered in combination in the same formulation or in separate, different formulations.

[0097] In another aspect, the present invention also provides a method for treating diseases and related conditions mediated by CYP11A1, the method comprising administering to a patient in need an effective amount of the aforementioned compound, its pharmaceutically acceptable salt, its ester or stereoisomer, the aforementioned formulation or pharmaceutical composition; the diseases and related conditions mediated by CYP11A1 are as defined above.

[0098] The term "effective dose" refers to the dosage of a drug that can alleviate, delay, suppress, or cure the subject's symptoms. The dosage is determined based on factors such as the route of administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual characteristics (gender, weight, height, age).

[0099] [Definitions and General Terminology]

[0100] In the specification and claims of this application, compounds are named according to their chemical structural formulas. If the name of the compound and its chemical structural formula do not match when referring to the same compound, the chemical structural formula shall prevail.

[0101] In this application, unless otherwise stated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided in this application differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations provided in this application shall prevail.

[0102] The "halogen" mentioned in this invention refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0103] In this invention, "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 Alkyl groups, preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C14, C24, C34, C44, C44, C54, C64, C74, C84, C9 ... 1-12 Alkyl groups, more preferably alkyl groups containing 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The "C" described in this invention... 1-4 "Alkyl" refers to specific examples of alkyl groups containing 1 to 4 carbon atoms.

[0104] The "C" described in this invention 1-6 "Alkoxy" refers to "C 1-6 alkyl-O-”, the “C” 1-6 "alkyl" is as defined above. The "C" in this invention... 1-4 "Alkoxy" refers to "C 1-4 alkyl-O-”, the “C” 1-4 "Alkyl" is as defined above.

[0105] The "hydroxyl C" of this invention 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, carboxyl C 1-6 "alkyl" refers to C 1-6 One or more hydrogen atoms in the alkyl group are replaced by one or more hydroxyl, amino, cyano, halogen, or carboxyl groups. The "C" group...1-6 "Alkyl" is as defined above.

[0106] The "hydroxyl C" of this invention 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy, halogenated C 1-6 "Alkoxy" refers to "C 1-6 One or more hydrogen atoms in the "alkoxy" group are replaced by one or more hydroxyl, amino, cyano, or halogen groups.

[0107] The "C" described in this invention 1-6 Alkylamino, C 1-6 Alkoxyamino, C 1-6 alkyl carbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylthiocarbonyl, C 1-6 alkylsulfonyl, C 1-6 Alkylamide group, di(C 1-6 alkyl)amino, di(C) 1-6 "alkyl)aminocarbonyl" refers to C 1-6 Alkyl-NH-, C 1-6 Alkyl-O-NH-, C 1-6 Alkyl-C(O)-, C 1-6 Alkoxy-C(O)-, C 1-6 Alkylthio-C(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-C(O)-NH-,

[0108] The "-NR" of this invention 5a -C(O)-R 5b -C(O)R 5a -C(O)NR 5a R 5b -C(S)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b -S(O)2R 5a "respectively refers to"

[0109] The term "cycloalkyl" as used in this invention refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably comprising 3 to 15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, ...). The cycloalkyl group comprises 13, 14, or 15 carbon atoms (i.e., 3 to 15-membered cycloalkyl groups), preferably 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10), more preferably 3 to 7 carbon atoms (e.g., 3, 4, 5, 6, and 7), and more preferably 3 to 6 carbon atoms (e.g., 3 to 6-membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. The cycloalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any usable linker.

[0110] The term "spirocycloalkyl" as used in this invention refers to a polycyclic group consisting of 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, i.e., 5 to 20-membered spirocycloalkyl), where the monocyclic rings share a single carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6 to 14-membered (i.e., 6 to 14-membered spirocycloalkyl), more preferably 7 to 9-membered (e.g., 7, 8, or 9-membered, i.e., 7 to 9-membered spirocycloalkyl). Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0111] The term "fused cycloalkyl" as used in this invention refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, i.e., 5- to 20-membered fused cycloalkyl), wherein each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7- to 9-membered (e.g., 7, 8, or 9-membered, i.e., 7- to 9-membered fused cycloalkyl). Based on the number of rings, alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups, preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused-ring alkyl groups. Non-limiting examples of fused-ring alkyl groups include: wait.

[0112] The term "bridged cycloalkyl" as used in this invention refers to a polycyclic aromatic hydrocarbon group consisting of 5 to 20 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, i.e., 5 to 20-membered bridged cycloalkyl), wherein any two rings share two non-directly connected carbon atoms, and may contain one or more double bonds. Preferably, it is 6 to 14-membered (i.e., 6 to 14-membered bridged cycloalkyl), more preferably 7 to 9-membered (e.g., 7, 8, or 9-membered, i.e., 7 to 9-membered bridged cycloalkyl). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0113] The cycloalkyl ring includes cycloalkyl groups (including monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... wait.

[0114] The "heterocyclic group" as described in this invention refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, i.e., 3 to 20 membered heterocyclic groups), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) ring atoms (i.e., 3 to 15-membered heterocyclic groups), wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 10 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, and 10, i.e., 3 to 10-membered heterocyclic groups), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; further... Preferably, it comprises 4 to 7 ring atoms (e.g., 4, 5, 6, and 7, i.e., 4 to 7-membered heterocyclic groups), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, it comprises 3 to 6 ring atoms (e.g., 3, 4, 5, and 6, i.e., 3 to 6-membered heterocyclic groups), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; most preferably, it comprises 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups), wherein 1 to 2 (e.g., 1 and 2) are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. The heterocyclic group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point.

[0115] The "spiroheterocyclic group" described in this invention refers to a polycyclic heterocyclic group with 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, i.e., 5 to 20-membered spiroheterocyclic groups), in which the single rings share a single atom (called a spiroatom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered (i.e., 6 to 14-membered spiroheterocyclic groups), more preferably 7 to 9-membered (e.g., 7, 8, 9-membered, i.e., 7 to 9-membered spiroheterocyclic groups). Spiroheterocyclic groups are classified into monospirocyclic groups, bispirocyclic groups, or polyspirocyclic groups according to the number of shared spiroatoms between the rings, with monospirocyclic groups and bispirocyclic groups being preferred. More preferably, it is a 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic heterocyclic group. Non-limiting examples of spirocyclic groups include:

[0116] The "fused heterocyclic group" described in this invention refers to a polycyclic heterocyclic group consisting of 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, i.e., a 5 to 20 fused heterocyclic group). Each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is a 6 to 14 fused heterocyclic group (i.e., a 6 to 14 fused heterocyclic group), more preferably a 7 to 9 fused heterocyclic group (e.g., 7, 8, or 9 fused heterocyclic groups, i.e., a 7 to 9 fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic, tricyclic, tetracyclic, or multicyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably ternary / quadricyclic, ternary / pentacyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentacyclic, quadricyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / hexacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, pentacyclic / pentacyclic, and pentacyclic / pentacyclic bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include...

[0117] The "bridged heterocyclic group" described in this invention refers to a polycyclic heterocyclic group with 5 to 15 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, i.e., a 5 to 15-membered bridged heterocyclic group), in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 ring atoms (i.e., a 6 to 14-membered bridged heterocyclic group), more preferably 7 to 9 ring atoms (e.g., 7, 8, or 9 ring atoms, i.e., a 7 to 9-membered bridged heterocyclic group). Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0118] The heterocyclic ring comprises a heterocyclic group (including monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0119] The "aryl" in this invention refers to a 6 to 15-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring atoms, i.e., 6 to 15-membered aryl) all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10-membered (i.e. 6 to 10-membered aryl), such as phenyl and naphthyl.

[0120] The term "heteroaryl" as used in this invention refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 15 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, i.e., 5 to 15-membered heteroaryl), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered, i.e., 5 to 10-membered heteroaryl), more preferably 5 or 6-membered (i.e., 5 or 6-membered heteroaryl), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0121] The “cycloalkyl”, “heterocyclic”, “aryl” and “heteroaryl” mentioned in this invention include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely “divalent cycloalkyl”, “divalent heterocyclic”, aryl and heteroaryl.

[0122] The ring atoms described in this invention can optionally form a structure of C=O, N=O, S=O, or SO2.

[0123] The term "optionally substituted" in this invention refers to two situations in which one or more atoms on the substituted group can be "substituted" or "not substituted" by one or more substituents.

[0124] The "L1 does not exist" mentioned in this invention refers to ring A being directly connected to the aromatic ring structure.

[0125] The "L2 does not exist" mentioned in this invention refers to the fact that ring B is directly connected to O.

[0126] The "pharmaceutically acceptable salt" as described in this invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.) present in the compound and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and a salt formed by a basic functional group (e.g., -NH2, etc.) present in the compound and a suitable inorganic or organic anion (acid), including salts formed with inorganic acids or organic acids (e.g., carboxylic acids, etc.).

[0127] The term "ester" as used in this invention refers to a pharmaceutically acceptable ester, particularly esters that are hydrolyzed in vivo and include esters that readily decompose in the human body, leaving behind a parent compound (the compound of general formula (I)) or its salt. The term "ester" as used in this invention may, for example, be selected from the following group: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (1) Alkoxy or amino substituted); (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valine or L-isoleucyl); and (4) mono-, di-, or triphosphate esters, etc.; (4) esters obtained by esterification with alcohols, wherein the non-hydroxyl portion of the alcohol is selected from, for example, C 1-20 Straight-chain or branched alkyl groups, C 1-12 Straight-chain or branched alkyl groups, C 1-8 Straight-chain or branched alkyl groups, C 1-6 Straight-chain or branched alkyl groups (e.g., methyl, ethyl, n-propyl, tert-butyl, or n-butyl), C 1-6 Alkoxy C 1-6 Alkyl (e.g., methoxymethyl), C 6-10 Aryl C 1-6 Alkyl (e.g., benzyl), C 6-10 Aryloxy C 1-6 Alkyl (e.g., phenoxymethyl), C 6-10 Aryl (e.g., phenyl, optionally replaced by, for example, halogen, C) 1-4 Alkyl or C 1-4 (alkoxy or amino substitution).

[0128] The term "stereoisomer" as used in this invention refers to compounds containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Compounds of this invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of this invention includes all possible optical isomers and mixtures thereof. If the compounds of this invention contain an alkene double bond, unless otherwise specified, they include cis and trans isomers. Compounds of this invention may exist as tautomers (a type of functional group isomer) having different hydrogen connection points through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are included within the scope of this invention. All enantiomers, diastereomers, racemic mixtures, mesomixes, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of this invention.

[0129] The term "dosage form" as used in this invention refers to a form in which a drug is prepared for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), sprays, aerosols, powder inhalers, lotions, liniments, ointments, plasters, pastes, patches, mouthwashes, or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, mouthwashes, or suppositories.

[0130] Beneficial effects of the invention

[0131] (1) The compounds of the present invention, their pharmaceutically acceptable salts, their esters or their stereoisomers have excellent inhibitory activity against CYP11A1 and can treat diseases mediated by CYP11A1 and related diseases.

[0132] (2) The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good pharmacokinetic properties, longer duration of action and high bioavailability;

[0133] (3) The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good safety;

[0134] (4) The compound preparation process of the present invention is simple, the drug has high purity and stable quality, and it is easy to carry out large-scale industrial production. Detailed Implementation

[0135] The present invention will be further described in detail below through specific embodiments. However, this should not be construed as limiting the scope of the invention to the following embodiments. All technologies that can be implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0136] 1. Examples of preparation of compounds of the present invention

[0137] DIBAL-H: Diisobutylaluminum hydride; DCM: Dichloromethane; THF: Tetrahydrofuran

[0138] DMF: N,N-dimethylformamide; MsCl: methanesulfonyl chloride; m-CPBA: m-chloroperoxybenzoic acid 1,4-Dioxane: 1,4-dioxane; K2CO3: potassium carbonate; SOCl2: thionyl chloride

[0139] Xphos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0140] Preparation Example 1: Preparation of 4-(isoindoline-2-ylmethyl)-2-(methanesulfonyl)-7-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[d]isothiazolium 1-oxide (Compound 3)

[0141] 1. Preparation of methyl 6-bromo-2,3-difluorobenzoate

[0142]

[0143] 6-Bromo-2,3-difluorobenzoic acid (7.7 g, 32.5 mmol) was dissolved in N,N-dimethylformamide (80 mL), and potassium carbonate (6.7 g, 48.6 mmol) and iodomethane (22.8 g, 160.7 mmol) were added. The reaction was continued at 28 °C for 3 hours. The system was then poured into water and extracted with ethyl acetate. The organic phase was obtained by separation. After drying with anhydrous sodium sulfate, the mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product (8.1 g, yield 99.3%).

[0144] 2. Preparation of methyl 6-bromo-3-fluoro-2-(methylthio)benzoate

[0145]

[0146] Methyl 6-bromo-2,3-difluorobenzoate (7.4 g, 29.5 mmol) was dissolved in 1,4-dioxane (100 mL), and sodium methyl mercaptan (3.1 g, 44.2 mmol) was added. After reacting at 40 °C for 16 hours, the reaction mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-10%) to give the target compound (7.2 g, yield: 87.5%).

[0147] 3. Preparation of methyl 6-bromo-3-fluoro-2-(methylsulfinyl)benzoate

[0148]

[0149] Methyl 6-bromo-3-fluoro-2-(methylthio)benzoate (5.8 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and m-chloroperoxybenzoic acid (4.3 g, 85%, 21.2 mmol) was added. After reacting at 25 °C for 3 hours, saturated sodium bicarbonate solution was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with dichloromethane and then separated. The organic phases were combined, concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-35%) to give the target compound (5.2 g, yield: 84.8%).

[0150] 4. Preparation of tert-butyl 4-((4-bromo-3-(methoxycarbonyl)-2-(methylsulfinyl)phenoxy)methyl)piperidine-1-carboxylic acid

[0151]

[0152] Methyl 6-bromo-3-fluoro-2-(methylsulfinyl)benzoate (2.2 g, 7.5 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.9 g, 8.8 mmol) were dissolved in tetrahydrofuran (70 mL), and sodium hydride (560 mg, 60%, 14 mmol) was added. After reacting at 15 °C for 2 hours, a saturated ammonium chloride solution was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with ethyl acetate and then separated again. The organic phases were combined, concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-50%) to give the target compound (2.4 g, yield: 65.6%).

[0153] 5. Preparation of methyl 6-bromo-2-(methylsulfinyl)-3-(piperidin-4-ylmethoxy)benzoate hydrochloride

[0154]

[0155] 4-((4-bromo-3-(methoxycarbonyl)-2-(methylsulfinyl)phenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 4.9 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (40 mL, 4 M), and the reaction was carried out at 15 °C for 1.5 hours. The solvent was removed from the system under reduced pressure to obtain the crude product, which was directly added to the next reaction step.

[0156] 6. Preparation of methyl 6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate

[0157]

[0158] The crude methyl 6-bromo-2-(methylsulfinyl)-3-(piperidin-4-ylmethoxy)benzoate hydrochloride obtained in the previous step was dissolved in dichloromethane (30 mL), and methanesulfonyl chloride (660 mg, 5.8 mmol) and N,N-diisopropylethylamine (1.8 g, 13.9 mmol) were added. After reacting at 20 °C for 2 hours, the system was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain the crude compound (1.2 g). This crude product was directly added to the next reaction step.

[0159] 7. Preparation of (6-bromo-3-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-2-(methylthio)phenyl)methanol

[0160]

[0161] The crude product (1.2 g) of methyl 6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate obtained in the previous step was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, a toluene solution (10 mL, 1.5 M) of diisobutylaluminum hydride was added dropwise. After reacting at 45 °C for 8 hours, the system was quenched with methanol, filtered, the filtrate was concentrated, and the residue was used to prepare the compound (230 mg, three-step yield 11.1%) under reverse phase medium pressure (water:acetonitrile = 0-30%).

[0162] 8. Preparation of (6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)methanol

[0163]

[0164] (6-bromo-3-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-2-(methylthio)phenyl)methanol (230 mg, 0.54 mmol) was dissolved in dichloromethane (15 mL), and m-chloroperoxybenzoic acid (125 mg, 85%, 0.62 mmol) was added. After reacting at 15 °C for 3 hours, saturated sodium bicarbonate solution was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with dichloromethane and then separated. The organic phases were combined and concentrated to obtain the crude product of the target compound, which was directly fed into the next reaction step.

[0165] 9. Preparation of 6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl methanesulfonate

[0166]

[0167] The crude (6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)methanol obtained in the previous step was dissolved in dichloromethane (15 mL), and methanesulfonyl chloride (93 mg, 0.81 mmol) and N,N-diisopropylethylamine (210 mg, 1.6 mmol) were added to the solution. After reacting at 20 °C for 2 hours, the system was concentrated to obtain the crude compound. This crude compound was directly added to the next reaction step.

[0168] 10. Preparation of 4-((3-(azidomethyl)-4-bromo-2-(methylsulfinyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine

[0169]

[0170] The crude 6-bromo-2-(methylsulfinyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzyl methanesulfonate obtained in the previous step was dissolved in N,N-dimethylformamide (8 mL), and sodium azide (70 mg, 1.1 mmol) was added. After reacting at 20 °C for 4 hours, water and ethyl acetate were added, and the mixture was separated to obtain the organic phase. The residue was concentrated and purified by column chromatography (MeOH:DCM = 1:12) to obtain the target compound (110 mg, three-step yield 43.6%).

[0171] 11. 4-Bromo-1-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3H-1λ 4 Preparation of 1-oxide of benzo[d]isothiazolium

[0172]

[0173] 4-((3-(azidomethyl)-4-bromo-2-(methylsulfinyl)phenoxy)methyl)-1-(methylsulfonyl)piperidine (110 mg, 0.23 mmol) was dissolved in toluene (8 mL), and iron phthalocyanine (40 mg, 0.070 mmol) was added. After reacting at 100 °C for 4 hours, the residue was concentrated and purified by column chromatography (MeOH:DCM = 1:12) to obtain the target compound (100 mg, yield 96.7%).

[0174] 12, 4-(hydroxymethyl)-1-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3H-1λ 4 Preparation of 1-oxide of benzo[d]isothiazolium

[0175]

[0176] 4-Bromo-1-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3H-1l4-benzo[d]isothiazolium 1-oxide (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (10 mL), and tributyltin methanol (110 mg, 0.34 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (20 mg, 0.025 mmol) were added. After reacting at 100 °C for 14 hours, the residue was concentrated and purified by column chromatography (MeOH:DCM = 1:10) to give the target compound (22 mg, yield 24.8%).

[0177] 13. (1-Methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxo-3H-1λ 4 Preparation of benzo[d]isothiazolyl-4-yl)methylmethanesulfonate

[0178]

[0179] 4-(hydroxymethyl)-1-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-3H-1λ 4 1-Benzo[d]isothiazolium 1-oxide (22 mg, 0.057 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of methanesulfonyl chloride (10 mg, 0.087 mmol) and N,N-diisopropylethylamine (20 mg, 0.15 mmol). The mixture was reacted at 20 °C for 3 hours, and then the system was concentrated to obtain the crude compound. This crude compound was directly added to the next reaction step.

[0180] 14. Preparation of 4-(isoindoline-2-ylmethyl)-2-(methanesulfonyl)-7-((1-(methanesulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[d]isothiazolium 1-oxide

[0181]

[0182] (1-Methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxidation-3H-1λ 4 Crude benzo[d]isothiazolyl-4-yl)methylmethanesulfonate was dissolved in acetonitrile (5 mL), and isoindoline hydrochloride (17 mg, 0.11 mmol) and N,N-diisopropylethylamine (28 mg, 0.22 mmol) were added. The mixture was reacted at 80 °C for 3 hours. The solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol).

[0183] =10:1), yielding the product (6 mg, two-step yield: 19.1%).

[0184] LC-MS (m / z): 554.2 (M+H) + )

[0185] 1 H-NMR(400MHz, CDCl3)δ:7.53(d,J=8.2Hz,1H),7.30-7.12(m,4H),6.92(d,J=8.2Hz,1H),5.29(d,J=15Hz,1H),5.11(d ,J=15Hz,1H),4.10-3.70(m,8H),3.21(s,3H),2.83(s,3H),2.75(t,J=11Hz,2H),2.21-1.95(m,4H),1.60-1.40(m,3H).

[0186] The compounds shown in the following table were prepared using the same or similar methods as those used in the preparation examples above:

[0187]

[0188] 2. Pharmacological activity tests of the compounds of this invention

[0189] The following pharmacological experimental examples further illustrate the beneficial effects of the compounds of the present invention, but should not be construed as the compounds of the present invention having only the following beneficial effects.

[0190] Experimental Example 1: In vitro enzymatic activity of the compounds of the present invention

[0191] This experiment assesses the inhibitory effect of the invented compound on CYP11A1 by detecting the biosynthesis of pregnenolone.

[0192] Test sample: The compound of the present invention, the structural formula and preparation method of which are given in the preparation examples.

[0193] Experimental method (ELISA assay):

[0194] 1. Cell preparation

[0195] Cells adhered and grew in NCI-H295R culture medium. Cells in the logarithmic growth phase were harvested, and cell viability was assessed using the trypan blue rejection assay to ensure it was above 90%. Cells were counted using an automated cell counter, and the cell suspension was adjusted to an appropriate concentration. 90 μL of cell suspension was added to each well of a 96-well plate, and the plates were incubated overnight at 37°C with 5% CO2.

[0196] 2. Compound dilution

[0197] 1) Prepare the compound of the present invention and the positive control drug to 10 mM using DMSO as the test stock solution.

[0198] 2) Dilute the test stock solution 100 times to 100 μM to prepare the test working solution.

[0199] 3) Dilute the test working solution 4 times to 6 concentrations, with the highest concentration being 100 μM.

[0200] 4) The final concentrations of the tested compounds were 100 nM, 25 nM, 6.25 nM, 1.56 nM, 0.39 nM, 0.098 nM, and 0 nM.

[0201] 3. Detection of pregnenolone biosynthesis

[0202] 1) Add 10 μL of the compound to the 96-well plate containing the cell suspension and incubate at 37°C and 5% CO2 for 24 hours.

[0203] 2) Centrifuge the supernatant and transfer 10 μL of the supernatant into a new 96-well plate. Dilute the supernatant 8 times with culture medium.

[0204] 3) Prepare the working solution and washing buffer for the pregnenolone-HRP conjugate.

[0205] 4) Take out the required number of enzyme-labeled strips.

[0206] 5) Add 50 μL each of the standard, positive control, and sample to the corresponding label wells, in duplicate.

[0207] 6) Add 100 μL of pregnenolone-HRP conjugate working solution to each well.

[0208] 7) Incubate at room temperature on a fixed-orbit shaker at approximately 200 rpm for 1 hour.

[0209] 8) Wash each well three times with 300 μL of diluted washing buffer and pat dry on clean absorbent paper.

[0210] 9) Add 150 μL of TMB substrate to each well.

[0211] 10) Incubate on a fixed-orbit shaker at room temperature for 10-15 minutes.

[0212] 11) At the same time interval as in step 10, add 50 μL of the stop solution to each well.

[0213] 3. Result Detection

[0214] 1) Within 20 minutes of adding the stop solution, read the OD value at a wavelength of 450 nm using a multi-functional microplate reader.

[0215] 2) Collect data.

[0216] 4. Data Processing

[0217] 1) Inhibition rate (%) = 1 - (concentration of test substance in well – concentration of blank control well) / (concentration of DMSO solvent in well – concentration of blank control well) × 100%;

[0218] 2) Input the data into GraphPad Prism to plot the curve and obtain the IC. 50 .

[0219] Experimental results:

[0220] Table 1. Inhibitory activity of the compounds of the present invention against CYP11A1

[0221] compound <![CDATA[IC 50 (nM)]]> Compound 3 179.39

[0222] The experimental results above show that the compound of the present invention can effectively inhibit the enzyme activity of CYP11A1 and is an effective CYP11A1 inhibitor.

Claims

1. Compounds of general formula (I), their pharmaceutically acceptable salts, their esters or stereoisomers thereof, in, X1 is selected from C(O), S(O) or S(O)2; X2 and X3 are each independently selected from CR or N; L1 does not exist or is selected from -CR 1a R 1b -、-O-、-S-、-NR 1a -、-CR 1a R 1b -CR 1a’ R 1b’ -、-CR 1a R 1b -NR 1c -、-C(O)-CR 1a R 1b -、-CR 1a R 1b -O-; L2 does not exist or is selected from -CR 2a R 2b -、-CR 2a R 2b -CR 2a’ R 2b’ -、-CR 2a R 2b -CR 2a’ R 2b’ -CR 2a” R 2b” -; X is selected from O, S, or NR. 3a ; Ring A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl or 6-15 membered aryl; Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl; R is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -NR 4a R 4b -OR 4a -SR 4a -NR 4a -C(O)-R 4b -、-C(O)R 4a -C(O)NR 4a R 4b -C(O)OR 4a ; R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, oxo, and C, respectively, each time they appear. 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -NR 5a R 5b -OR 5a -SR 5a -NR 5a -C(O)-R 5b , -C(O)R 5a , -C(O)NR 5a R 5b -C(S)NR 5a R 5b -C(O)OR 5a , -S(O)NR 5a R 5b -S(O)2NR 5a R 5b -S(O)2R 5a Alternatively, the following groups may be optionally substituted with 1 to 4 substituents: -(CH2) t -3-10 membered cycloalkyl groups, -(CH2) t -3-10 heterocyclic group, -(CH2) t -5-10 heteroaryl groups, -(CH2) t -6-10 aryl group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R 1a R 1a’ R 1b R 1b’ R 1c R 2a R 2b R 2a’ R 2b’ R 2a” R 2b” R 3a R 4a R 4b R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy; m, n, and t are each independently selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2 or 3.

2. The compound of claim 1, its pharmaceutically acceptable salt, its ester, or its stereoisomer, wherein, X1 is selected from C(O), S(O) or S(O)2; X2 and X3 are each independently selected from CH or N; L1 does not exist or is selected from -CHR 1a -、-CHR 1a -CHR 1a’ -; L2 does not exist or is selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -; X is selected from O or S; Ring A is selected from 8-10 member nitrogen-containing fused heterocyclic groups or 8-10 member nitrogen-containing fused heteroaryl groups; Ring B is selected from 5-6 membered monocyclic alkyl groups or 5-6 membered monoheterocyclic groups; R1 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, oxo, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a ; R2 is independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, oxo, and C each time it appears. 1-6 Alkyl, Halogenated C 1-6 Alkyl, -NR 5a R 5b -OR 5a -NR 5a -C(O)-R 5b -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)NR 5a R 5b -S(O)2NR 5a R 5b or -S(O)2R 5a ; R 1a R 1a’ R 2a R 2a’ R 2a” Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy; R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy; m and n are independently selected from 0, 1, 2 or 3 respectively; p is selected from 0, 1, or 2.

3. The compound of claim 1 or 2, its pharmaceutically acceptable salt, its ester, or its stereoisomer, having a structure of general formula (II-1) or general formula (II-2), in, The definitions of L1, L2, X, X2, X3, R1, R2, ring A, ring B, m, and n are as described in any one of claims 1 or 2.

4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, its ester, or its stereoisomer, wherein, L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -; L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -; X2 and X3 are each independently selected from CH or N; Ring A is selected from Preferably, ring A is Ring B is selected from pyrrolidinyl, pyrazolyl, piperidinyl, or piperazinyl; preferably, ring B is piperidinyl. R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ; R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, oxo, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ; R 1a R 1a’ R 2a R 2a’ Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; preferably, R a R c R a’ R 1a R 1a’ R 2a R 2a’ R 4a Each time it appears, it is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. R 5a R 5b Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy; m and n are independently selected from 0, 1, 2 or 3 respectively.

5. The compound according to any one of claims 1-4, its pharmaceutically acceptable salt, its ester, or its stereoisomer, having the structure shown in general formula (III-1) or general formula (III-2), in, The definitions of L1, L2, X2, R1, R2, m, and n are as described in any one of claims 1-4.

6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, its ester, or its stereoisomer, wherein, X2 is selected from CH or N; L1 is selected from -CH2- or -CH2-CH2-; L2 is selected from -CH2- or -CH2-CH2-; R1 is independently selected from hydrogen, halogen, cyano, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a Preferably, each R1 is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ; R2 is independently selected from hydrogen, halogen, hydroxyl, cyano, and C each time it appears. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -NR 5a R 5b -OR 5a -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a Preferably, R2 is independently selected from hydrogen and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, -C(O)R 5a -C(O)NR 5a R 5b -C(O)OR 5a -S(O)2NR 5a R 5b or -S(O)2R 5a ; R 5a Each time it appears, it is independently selected from hydrogen, amino, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 Alkyl; preferably, R 5a Each time it appears, it is independently selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, cyanomethyl, cyanoethyl, or cyanopropyl. R 5b Each time it appears, it is independently selected from hydrogen or C. 1-4 Alkyl; preferably, R 5b Each time it appears, it is independently selected from hydrogen, methyl, ethyl, propyl, or isopropyl; m and n are independently selected from 0, 1, or 2, respectively.

7. The compound of claim 1, its pharmaceutically acceptable salt, its ester, or its stereoisomer, wherein the compound is selected from:

8. A pharmaceutical preparation containing the compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, characterized in that, It contains one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation is any pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising the compound of any one of claims 1-7, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, characterized in that, The pharmaceutical composition contains one or more second therapeutic agents; optionally, it further contains one or more pharmaceutical carriers and / or diluents.

10. The use of the compound of any one of claims 1-7, its pharmaceutically acceptable salt, its ester or stereoisomer, the pharmaceutical formulation of claim 8, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating and / or preventing diseases and related conditions mediated by CYP11A1, wherein the diseases and related conditions mediated by CYP11A1 are steroid hormone-dependent diseases and conditions; preferably, the diseases and related conditions mediated by CYP11A1 are androgen receptor-dependent diseases and conditions; preferably, the diseases and related conditions mediated by CYP11A1 are cancer.

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