Condensed ring CYP11A1 inhibitor

Abstract

The invention belongs to the technical field of medicine. In particular, the invention relates to a fused ring compound capable of being used as a CYP11A1 inhibitor, a pharmaceutically acceptable salt, an ester or a stereoisomer of the fused ring compound, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer of the fused ring compound, and a preparation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer of the fused ring compound. And uses of the compounds, pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology. In particular, the present invention relates to a class of compounds that can be used as CYP11A1 inhibitors, pharmaceutically acceptable salts, esters and stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts, esters and stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts, esters and stereoisomers thereof. Background Art

[0002] Prostate cancer is the most common cancer in men worldwide. The incidence rate in European and American patients is higher than that in China. In 2015, the number of new prostate cancer patients in China was 72,000, ranking sixth among male malignant tumors, and the mortality rate was about 10th among male malignant tumors. Among the Chinese population, metastatic castration-resistant prostate cancer (mCRPC) accounts for 54% of new prostate cancers. The overall prognosis of patients with castration-resistant prostate cancer (CRPC) is poor, and the overall incidence rate, especially the detection rate of mCRPC, is high.

[0003] The conduction of androgen receptor (AR) signaling is critical in all stages of prostate cancer. Existing treatments for advanced prostate cancer include androgen deprivation therapy (ADT), which is hormonal treatment with gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, as well as AR antagonists or CYP17A1 inhibitors (such as abiraterone acetate combined with prednisone). The main cause of drug resistance in prostate cancer, especially CRPC, is dependent on the activation of the AR pathway, among which increased progesterone levels in patients using CYP17A1 inhibitors (abiraterone acetate) is one of the resistance mechanisms. Studies have shown that enzymes that catalyze steroid biosynthesis are upregulated in advanced CRPC, and there is data demonstrating that adrenal cortisol and progesterone can effectively activate the AR signaling pathway just like testosterone.

[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 enzyme upstream of steroid biosynthesis, converting cholesterol into pregnenolone. It is widely present in the adrenal glands, testicles, ovaries, placenta, etc., and is located in the inner membrane of mitochondria. By inhibiting CYP11A1, complete blocking of the entire steroid biosynthesis can be achieved. Therefore, CYP11A1 inhibitors can treat steroid hormone-dependent diseases, including but not limited to prostate cancer and breast cancer, and play a role in patients who are resistant to existing treatments. In particular, CYP11A1 inhibitors can be used to treat androgen receptor-dependent diseases and disorders. Therefore, the use of small molecule inhibitors to inhibit CYP11A1 has great potential for the treatment of cancer. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a novel compound having a good inhibitory effect on CYP11A1. Furthermore, the compound can be used to prepare drugs for treating and / or preventing 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 a compound represented by the following general formula (I-1), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof,

[0008]

[0009] in,

[0010] When "---" is a single key, When it is a single bond, X 1 Selected from C(O), S(O) or S(O) 2 , X 2 Selected from CR a R b or NR c , X 3 Selected from CR a’ R b’ ;

[0011] When "---" is a single key, When it is a double bond, X 1 Selected from C(O), S(O) or S(O) 2 , X 2 Selected from CR a or N, X 3 Selected from CR a’ ;

[0012] When "---" is a double bond, When it is a single bond, X 1 S(O)R c’ , X 2 Selected from CR a or N, X 3 Selected from CR a’ R b’ ;

[0013] X 4 and X 5 are independently selected from CR or N;

[0014] L 1 Not present or 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-;

[0015] L 2 Not present or 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” -;

[0016] X is selected from O, S or NR 3a ;

[0017] Ring A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl or 6-15 membered aryl;

[0018] Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0019] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, halogenated C 1-6Alkyl, 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 ;

[0020] R 1 , R 2 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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) 2 NR 5a R 5b , -S(O) 2 R 5a Or the following groups optionally substituted by 1 to 4 substituents: -(CH 2 ) t -3-10 membered cycloalkyl, -(CH 2 ) t -3-10 membered heterocyclic group, -(CH 2 ) t -5-10 membered heteroaryl, -(CH 2 ) t -6-10 membered aromatic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0021] R a , R b , R c , R a’ , R b’ , R c’ , 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 occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0022] Or, R 5a , R 5b Together with the N to which it is attached, it forms a 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl group optionally substituted by 1-2 Q; the substituent Q is independently selected from 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy or cyano C 1-6 Alkoxy;

[0023] m, n, t are independently selected from 0, 1, 2, 3 or 4;

[0024] p is selected from 0, 1, 2 or 3.

[0025] In certain embodiments, the compound represented by the general formula (I-1), its pharmaceutically acceptable salt, its ester, or its stereoisomer has the structure represented by the general formula (I),

[0026]

[0027] in,

[0028] X 1 Selected from C(O), S(O) or S(O) 2 ;

[0029] when When it is a single bond, X 2 Selected from CR a R b or NR c , X 3 Selected from CR a’ R b’ ;

[0030] when When it is a double bond, X 2 Selected from CR a or N, X 3 Selected from CR a’ ;

[0031] X 4 and X 5 are independently selected from CR or N;

[0032] L 1 Not present or 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-;

[0033] L 2 Not present or 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” -;

[0034] X is selected from O, S or NR 3a ;

[0035] Ring A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl or 6-15 membered aryl;

[0036] Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0037] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, 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, -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 ;

[0038] R 1 , R 2 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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)OR5a , -S(O)NR 5a R 5b , -S(O) 2 NR 5a R 5b , -S(O) 2 R 5a Or the following groups optionally substituted by 1 to 4 substituents: -(CH 2 ) t -3-10 membered cycloalkyl, -(CH 2 ) t -3-10 membered heterocyclic group, -(CH 2 ) t -5-10 membered heteroaryl, -(CH 2 ) t -6-10 membered aromatic 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;

[0039] R a , R b , R c , R a’ , R b’ , 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 occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0040] m, n, t are independently selected from 0, 1, 2, 3 or 4;

[0041] p is selected from 0, 1, 2 or 3.

[0042] In certain embodiments, the compound represented by the general formula (I-1), its pharmaceutically acceptable salt, its ester, or its stereoisomer has the structure represented by the general formula (I'),

[0043]

[0044] in,

[0045] X 1 S(O)R c’ ;X 2 Selected from CR a or N;X 3 Selected from CR a’ R b’ ;

[0046] X 4 and X 5 are independently selected from CR or N;

[0047] L 1 Not present or 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-;

[0048] L 2 Not present or 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” -;

[0049] X is selected from O, S or NR 3a ;

[0050] Ring A is selected from 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl or 6-15 membered aryl;

[0051] Ring B is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0052] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, 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, -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 ;

[0053] R 1 , R 2 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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) 2 NR 5a R 5b , -S(O) 2 R 5a Or the following groups optionally substituted by 1 to 4 substituents: -(CH 2 )t -3-10 membered cycloalkyl, -(CH 2 ) t -3-10 membered heterocyclic group, -(CH 2 ) t -5-10 membered heteroaryl, -(CH 2 ) t -6-10 membered aromatic 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;

[0054] R a , R a’ , R b’ , R c’ , 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 occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0055] m, n, t are independently selected from 0, 1, 2, 3 or 4;

[0056] p is selected from 0, 1, 2 or 3.

[0057] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X is selected from O, S or NH.

[0058] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X is selected from O or S.

[0059] In certain embodiments, the aforementioned compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, wherein Ring A is selected from a 5-12-membered cycloalkyl, a 5-12-membered heterocyclyl, a 6-12-membered aryl or a 5-12-membered heteroaryl; preferably, Ring A is selected from a 5-6-membered monocycloalkyl, a 7-12-membered fused cyclyl, a 7-12-membered spirocyclyl, a 7-12-membered bridged cyclyl, a 5-6-membered monoheterocyclyl, a 7-12-membered fused heterocyclyl, a 7-12-membered spiroheterocyclyl, a 7-12-membered bridged heterocyclyl, a 5-6-membered monoheteroaryl, a 7-12-membered fused heteroaryl, a 7-12-membered spiroheteroaryl, a 7-12-membered bridged heterocyclyl, a 5-6-membered monoheteroaryl, a 7-12-membered fused heteroaryl, a 7-12-membered spiroheteroaryl, a 7-12-membered bridged heteroaryl or a phenyl; preferably, Ring A is selected from an 8-10-membered fused heterocyclyl or an 8-10-membered fused heteroaryl; more preferably, Ring A is selected from an 8-10-membered nitrogen-containing fused heterocyclyl or an 8-10-membered nitrogen-containing fused heteroaryl.

[0060] In certain embodiments, Ring A is selected from

[0061] In certain embodiments, ring B is selected from a 5-6-membered monocycloalkyl, a 7-10-membered fused cyclyl, a 7-10-membered spirocyclyl, a 7-10-membered bridged cyclyl, a 5-6-membered monoheterocyclyl, a 7-10-membered fused heterocyclyl, a 7-10-membered spiroheterocyclyl, a 7-10-membered bridged heterocyclyl, a 5-6-membered monoheteroaryl, a 7-10-membered fused heteroaryl, a 7-10-membered spiroheteroaryl, a 7-10-membered bridged heteroaryl, or a phenyl group; preferably, ring B is selected from a 5-6-membered monocycloalkyl, a 5-6-membered monoheterocyclyl, a 5-6-membered monoheteroaryl, or a phenyl group; more preferably, ring B is selected from a 5-6-membered monoheterocyclyl or a 5-6-membered monocycloalkyl.

[0062] In certain embodiments, Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, or piperazinyl.

[0063] In certain embodiments, R at each occurrence is independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, 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, -NR 4a R 4b OR 4a .

[0064] In certain embodiments, R at each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl or -OR 4a .

[0065] In certain embodiments, R at each occurrence is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Preferably, R at each occurrence is independently selected from hydrogen or C 1-4 alkyl.

[0066] In certain embodiments, R 1 , R 2 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 , -C(O)R 5a , -C(O)NR 5a R 5b , -C(O)OR 5a , -S(O)NR 5a R 5b , -S(O) 2 NR 5a R 5b , -S(O) 2 R 5a Or the following groups optionally substituted by 1 to 4 substituents: -(CH 2 ) t -3-6 membered cycloalkyl, -(CH 2 ) t -3-6 membered heterocyclic group, -(CH 2 ) t -5-6 membered heteroaryl, -(CH 2 ) t -phenyl; 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.

[0067] In certain embodiments, R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C1-6 Alkyl, -NR 5a R 5b 、-OR 5a 、-SR 5a 、-C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O)NR 5a R 5b 、-S(O) 2 NR 5a R 5b or -S(O) 2 R 5a .

[0068] In certain embodiments, R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, halogenated 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) 2 NR 5a R 5b or -S(O) 2 R 5a .

[0069] In certain embodiments, R a , R b , R c , R a’ , R b’ , R c’ , R 1a , R 1a’ , R 1b , R 1b’ , R 1c , R 2a , R 2b , R 2a’ , R 2b’ , R 2a” , R2b” , R 3a , R 4a , R 4b Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0070] In certain embodiments, R a , R b , R c , R a’ , R b’ , R c’ , 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 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0071] In certain embodiments, R a , R b , R c , R a’ , R b’ , R c’ , 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 are independently selected at each occurrence from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0072] In certain embodiments, R 5a Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0073] R 5b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0074] In certain embodiments, R 5a Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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;

[0075] R 5b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0076] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein:

[0077] X 1 Selected from C(O), S(O) or S(O) 2 ;

[0078] when When it is a single bond, X 2 Selected from CR a R b or NR c , X 3 Selected from CR a’ R b’ ;

[0079] when When it is a double bond, X 2 Selected from CR aor N, X 3 Selected from CR a’ ;

[0080] X 4 and X 5 are independently selected from CR or N;

[0081] L 1 Not present or selected from -CHR 1a -、-CHR 1a -CHR 1a’ -;

[0082] L 2 Not present or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -;

[0083] X is selected from O, S or NH;

[0084] Ring A is selected from an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group;

[0085] Ring B is selected from a 5-6 membered monocycloalkyl group or a 5-6 membered monoheterocyclic group;

[0086] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 4a R 4b 、-OR 4a ;

[0087] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0088] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0089] R a , R b , R c , R a’ , R b’ , R 1a , R 1a’ , R 2a , R 2a’ , R 2a” , R 4a , R 4b is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0090] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0091] m and n are independently selected from 0, 1, 2 or 3;

[0092] p is selected from 0, 1 or 2.

[0093] In certain embodiments, the compound of the aforementioned general formula (I-1) or general formula (I'), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein:

[0094] L 1 Not present or selected from -CHR 1a -、-CHR 1a -CHR 1a’ -;

[0095] L 2 Not present or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -;

[0096] X is selected from O, S or NH;

[0097] Ring A is selected from an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group;

[0098] Ring B is selected from a 5-6 membered monocycloalkyl group or a 5-6 membered monoheterocyclic group;

[0099] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 4a R 4b 、-OR 4a ;

[0100] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0101] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0102] R a , R b , R c , R a’ , R b’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ , R 2a” , R 4a , R 4b is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0103] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0104] m and n are independently selected from 0, 1, 2 or 3;

[0105] p is selected from 0, 1 or 2.

[0106] In certain embodiments, X 1 Selected from C(O), S(O) or S(O) 2 ;

[0107] when When it is a single bond, X 2 Selected from CR a R b or NR c , X 3 Selected from CR a’ R b’ ;

[0108] when When it is a double bond, X 2 Selected from CR a or N, X 3 Selected from CR a’ ;

[0109] X 4 and X 5 are independently selected from CR or N;

[0110] L 1 Not present or selected from -CHR 1a -、-CHR 1a -CHR 1a’ -;

[0111] L 2 Not present or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -;

[0112] X is selected from O, S or NH;

[0113] Ring A is selected from an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group;

[0114] Ring B is selected from a 5-6 membered monocycloalkyl group or a 5-6 membered monoheterocyclic group;

[0115] R is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 4a R 4b 、-OR 4a ;

[0116] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0117] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0118] R a , R b , R c , R a’ , R b’ , R 1a , R 1a’ , R 2a , R 2a’ , R 2a” , R 4a , R 4b is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0119] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy; or, R 5a , R 5b Together with the N to which it is attached, it forms a 4-6 membered heterocycloalkyl optionally substituted by 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy or amino C 1-6 Alkoxy;

[0120] m and n are independently selected from 0, 1, 2 or 3;

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

[0122] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure shown in the general formula (II-1) or the general formula (II-2),

[0123]

[0124]

[0125] Among them, L 1 , L 2 ,X,X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , Ring A, Ring B, m, n, p, is defined as in any of the previous schemes.

[0126] In certain embodiments, the compound of the aforementioned general formula (I'), its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure shown in the general formula (II-3),

[0127]

[0128] Among them, L 1 , L 2 ,X,X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R c’ , Ring A, Ring B, m, n, and p are defined as described in any of the above schemes.

[0129] In certain embodiments, the compound of the aforementioned general formula (I), general formula (II-1), general formula (II-2), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein:

[0130] when When it is a single bond, X 2 Selected from CHR a or NR c , X 3 Selected from CHR a’ ;

[0131] when When it is a double bond, X 2 Selected from CR a or N, X 3 Selected from CR a’ ;

[0132] L 1 Selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0133] L 2 Selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0134] X 4 and X 5 are independently selected from CR or N;

[0135] Ring A is selected from Preferably, ring A is

[0136] Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; Ring B is piperidinyl;

[0137] R is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -OR 4a ;

[0138] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0139] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0140] R a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, 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 c’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0141] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy;

[0142] m and n are independently selected from 0, 1, 2 or 3;

[0143] p is selected from 0, 1 or 2.

[0144] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I') or general formula (II-3), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein:

[0145] L 1 Selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0146] L 2 Selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0147] X 4 and X 5 are independently selected from CR or N;

[0148] Ring A is selected from Preferably, ring A is

[0149] Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; Ring B is piperidinyl;

[0150] R is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -OR 4a ;

[0151] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0152] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0153] R a , R c , R a’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4Alkoxy; preferably, R a , R c , R a’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0154] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy;

[0155] m and n are independently selected from 0, 1, 2 or 3;

[0156] p is selected from 0, 1 or 2.

[0157] In certain embodiments, X 5 is CH. In certain embodiments, when When it is a single bond, X 2 Selected from CHR a or NR c , X 3 Selected from CHR a’ ;

[0158] when When it is a double bond, X 2 Selected from CR a or N, X 3 Selected from CR a’ ;

[0159] L 1 Selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0160] L 2 Selected from -CHR 2a-or-CHR 2a -CHR 2a’ -;

[0161] X 4 and X 5 are independently selected from CR or N;

[0162] Ring A is selected from Preferably, ring A is

[0163] Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; preferably, ring B is piperidinyl;

[0164] R is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -OR 4a ;

[0165] R 1 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0166] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0167] R a , R c, R a’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, 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 is independently selected at each occurrence from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0168] R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy; or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl;

[0169] m and n are independently selected from 0, 1, 2 or 3;

[0170] p is selected from 0, 1 or 2.

[0171] In certain embodiments, X 4 is selected from CH or N;

[0172] L 1Selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0173] L 2 Selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0174] R 1 is independently selected at each occurrence from hydrogen, halogen, cyano, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a Preferably, each R 1 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ;

[0175] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a Preferably, R 2 are independently selected from -C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O) 2 NR 5a R5b or -S(O) 2 R 5a ;

[0176] R a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0177] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 Alkyl; preferably, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl or cyanopropyl;

[0178] R 5b Each occurrence is independently selected from hydrogen or C 1-4 Alkyl; preferably, R 5b is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl or isopropyl;

[0179] Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from hydroxyl, C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0180] In certain embodiments, the compound of the aforementioned general formula (I-1), general formula (I), general formula (II-1), its pharmaceutically acceptable salt, its ester or its stereoisomer, which has the structure shown in general formula (III-1),

[0181]

[0182] Among them, L 1 , L 2 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 ,m,n,p, is defined as in any of the previous schemes.

[0183] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-1), general formula (III-1), its pharmaceutically acceptable salt, its ester or its stereoisomer, which has the structure shown in general formula (IV-1),

[0184]

[0185] Among them, X 2 Selected from CHR a or NR c ;X 3 Selected from CHR a’ ;

[0186] L 1 , L 2 , X 4 , R 1 , R 2 , m, n, R a , R c , R a’ is defined as in any of the previous schemes.

[0187] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-1), general formula (III-1), general formula (IV-1), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure represented by general formula (V-1),

[0188]

[0189] Among them, X 2 Selected from CHR a or NR c ;X 3 Selected from CHR a’ ;

[0190] L 1 , L 2 , X 4 , R 1 , R 2 ,m,Ra , R c , R a’ is defined as in any of the previous schemes.

[0191] In certain embodiments, the compound of the aforementioned general formula (I), general formula (II-1), general formula (III-1), general formula (IV-1), general formula (V-1), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein X 2 Selected from NR c ; R c Selected from hydrogen or C 1-4 Alkyl; X 3 CH 2 .

[0192] In certain embodiments, the compound of the aforementioned general formula (I-1), general formula (I), general formula (II-1), general formula (III-1), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure represented by general formula (IV-1').

[0193]

[0194] Among them, X 2 Selected from CR a or N;X 3 Selected from CR a’ ;

[0195] L 1 , L 2 , X 4 , R 1 , R 2 , m, n, R a , R c , R a’ is defined as in any of the previous schemes.

[0196] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-1), general formula (III-1), general formula (IV-1), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure shown in general formula (V-1').

[0197]

[0198] Among them, X 2 Selected from CR a or N;X 3 Selected from CR a’ ;

[0199] L 1 , L 2 , X 4 , R1 , R 2 ,m,R a , R c , R a’ is defined as in any of the previous schemes.

[0200] In certain embodiments, the compound of the aforementioned general formula (I), general formula (II-2), its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in general formula (III-2),

[0201]

[0202] Among them, L 1 , L 2 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 ,m,n,p, is defined as in any of the previous schemes.

[0203] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-2), general formula (III-2), its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in general formula (IV-2),

[0204]

[0205] Among them, X 2 Selected from CHR a or NR c ;X 3 Selected from CHR a’ ;

[0206] L 1 , L 2 , X 4 , R 1 , R 2 , m, n, R a , R c , R a’ is defined as in any of the previous schemes.

[0207] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-2), general formula (III-2), general formula (IV-2), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure shown in general formula (V-2),

[0208]

[0209] Among them, X 2 Selected from CHR a or NR c ;X 3 Selected from CHR a’ ;

[0210] L 1 , L 2 , X 4 , R 1 , R 2 ,m,R a , R c , R a’ is defined as in any of the previous schemes.

[0211] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-2), general formula (III-2), its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in general formula (IV-2'),

[0212]

[0213] Among them, X 2 Selected from CR a or N;X 3 Selected from CR a’ ;

[0214] L 1 , L 2 , X 4 , R 1 , R 2 , m, n, R a , R c , R a’ is defined as in any of the previous schemes.

[0215] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I), general formula (II-2), general formula (III-2), general formula (IV-2), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure shown in general formula (V-2').

[0216]

[0217] Among them, X 2 Selected from CR a or N;X 3 Selected from CR a’ ;

[0218] L 1 , L 2 , X 4 , R1 , R 2 ,m,R a , R c , R a’ is defined as in any of the previous schemes.

[0219] In certain embodiments, the compound of the aforementioned general formula (I-1), general formula (I'), general formula (II-3), its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in general formula (III-3),

[0220]

[0221] Among them, L 1 , L 2 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R c’ The definitions of , m, n, and p are as described in any of the previous schemes.

[0222] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I'), general formula (II-3), general formula (III-3), its pharmaceutically acceptable salt, its ester or its stereoisomer, has the structure shown in general formula (IV-3),

[0223]

[0224] Among them, X 2 Selected from CR a or N;X 3 Selected from CHR a’ ;

[0225] L 1 , L 2 , X 4 , R 1 , R 2 , m, n, R a , R c , R c’ , R a’ is defined as in any of the previous schemes.

[0226] In certain embodiments, the compound described in the aforementioned general formula (I-1), general formula (I'), general formula (II-3), general formula (III-3), general formula (IV-3), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof has a structure shown in general formula (V-3),

[0227]

[0228] Among them, X 2 Selected from CR a or N;X 3 Selected from CHR a’ ;

[0229] L 1 , L 2 , X 4 , R 1 , R 2 ,m,R a , R c , R a’ , R c’ is defined as in any of the previous schemes.

[0230] In certain embodiments, the compounds of the aforementioned general formula (I'), general formula (II-3), general formula (III-3), general formula (IV-3), general formula (V-3), their pharmaceutically acceptable salts, esters or stereoisomers thereof, wherein X 2 is N.

[0231] In certain embodiments, the compounds described in the aforementioned general formula (I-1), general formula (I), general formula (I'), general formula (II-1), general formula (II-2), general formula (II-3), general formula (III-1), general formula (III-2), general formula (III-3), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (V-1), general formula (V-2), general formula (V-3), general formula (IV-1'), general formula (IV-2'), general formula (V-1'), general formula (V-2'), pharmaceutically acceptable salts thereof, esters thereof, or stereoisomers thereof, wherein,

[0232] X 4 is selected from CH or N;

[0233] L 1 Selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0234] L 2 Selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0235] R 1 is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -NR 5a R 5b 、-OR5a 、-C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O) 2 NR 5a R 5b or -S(O) 2 R 5a Preferably, each R 1 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ;

[0236] R 2 Each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C 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) 2 NR 5a R 5b or -S(O) 2 R 5a Preferably, R 2 are independently selected from -C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O) 2 NR 5a R 5b or -S(O) 2 R 5a ;

[0237] R a , R c , R a’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R a , R c , Ra’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0238] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 Alkyl; preferably, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl or cyanopropyl;

[0239] R 5b Each occurrence is independently selected from hydrogen or C 1-4 Alkyl; preferably, R 5b Each occurrence is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0240] In certain embodiments, R a , R c , R a’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ is independently hydrogen at each occurrence.

[0241] In certain embodiments, R a , R c , R a’ , R c’ , R 1a , R 1a’ , R 2a , R 2a’ Each occurrence is independently methyl.

[0242] In certain embodiments, R 1a , R 1a’ , R 2a , R 2a’ Each occurrence is independently selected from hydrogen or methyl.

[0243] In certain embodiments, R a’ For hydrogen.

[0244] In certain embodiments, R c’ It is hydrogen or methyl.

[0245] In certain embodiments, R a is hydrogen; R c It is hydrogen or methyl.

[0246] In certain embodiments, L 1 -CH 2 -.

[0247] In certain embodiments, L 2 Selected from -CH 2 -or-CH 2 -CH 2 -.

[0248] In certain embodiments, X is O.

[0249] In certain embodiments, "---" is a single bond, is a double bond, X 2 is selected from N or CH; X 3 For CH.

[0250] In certain embodiments, m is selected from 0 or 1.

[0251] In certain embodiments, n is selected from 0 or 1.

[0252] In certain embodiments, p is selected from 0 or 1; preferably, p is 0.

[0253] In certain embodiments, R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0254] Or, R 5a , R 5b Together with the N to which it is attached, it forms a 4-6 membered heterocycloalkyl optionally substituted by 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy or amino C 1-6 Alkoxy.

[0255] In certain embodiments, R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy;

[0256] Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl.

[0257] In certain embodiments, R 5a Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy;

[0258] R 5b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0259] Or, R5a , R 5b Together with the N to which it is attached, it forms a 4-6 membered heterocycloalkyl optionally substituted by 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy or amino C 1-6 Alkoxy.

[0260] In certain embodiments, R 5a Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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;

[0261] R 5b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0262] Or, R 5a , R 5b Together with the N to which it is attached, it forms a 4-6 membered heterocycloalkyl optionally substituted by 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy or amino C 1-6 Alkoxy.

[0263] In certain embodiments, R 5a Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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;

[0264] R 5b are independently selected at each occurrence from hydrogen, C 1-6Alkyl or halogenated C 1-6 alkyl;

[0265] Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl.

[0266] In certain embodiments, R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 alkyl;

[0267] R 5b Each occurrence is independently selected from hydrogen or C 1-4 alkyl;

[0268] Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from hydroxyl, C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

[0269] In certain embodiments, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl or cyanopropyl;

[0270] R 5b is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl or isopropyl;

[0271] Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl group optionally substituted with 1-2 Qs; the substituent Q is independently selected at each occurrence from hydroxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl or hydroxyethyl.

[0272] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer is selected from the following compounds:

[0273]

[0274] The present invention also provides a pharmaceutical composition comprising the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical composition can be prepared 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, inhalants or sprays, etc.

[0275] In certain embodiments of the present invention, the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or transpulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When made into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives can be omitted or appropriate additives can be added according to the properties of the drugs. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for transpulmonary administration, the pharmaceutical composition can be made into inhalants or sprays, etc.

[0276] The pharmaceutically acceptable carrier and / or diluent used in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carrier and / or diluent in the field of pharmaceutical preparations, and the selection of a specific carrier and / or diluent will depend on the mode of administration or the type and state of disease used to treat a specific patient. The preparation method of a suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of a person skilled in the art of medicine.

[0277] In another aspect, the present invention also relates to the use of the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer in the preparation of a drug for preventing and / or treating diseases mediated by CYP11A1 and related diseases, and the drug can be used in combination with one or more other drugs to prevent or treat diseases mediated by CYP11A1 and related conditions. The diseases and related conditions mediated by CYP11A1 are steroid hormone-dependent conditions and diseases that require inhibition of CYP11A1; in particular, the diseases and related conditions mediated by CYP11A1 are androgen receptor-dependent conditions and diseases that require inhibition of CYP11A1. The diseases and related conditions are cancers, including carcinoma in situ and metastatic cancers.

[0278] In certain embodiments, the cancer is selected from prostate cancer or breast cancer. In certain embodiments, the cancer is selected from castration-resistant prostate cancer or breast cancer.

[0279] Furthermore, 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 drugs, which can be used in combination with one or more drugs to treat and / or prevent diseases and related conditions mediated by CYP11A1.

[0280] On the other hand, the present invention relates to the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, which can be administered alone or used in combination with one or more second therapeutic agents, which are combined with the CYP11A1 inhibitor compound of the present application for the treatment and / or prevention of diseases and related conditions mediated by CYP11A1. Therefore, in certain embodiments, the pharmaceutical composition further contains one or more second therapeutic agents. Optionally, the pharmaceutical composition also contains one or more pharmaceutically acceptable carriers and / or diluents.

[0281] The second therapeutic agent is selected from glucocorticoids, mineralocorticoids or anticancer drugs. The glucocorticoid drugs include but are not limited to hydrocortisone, prednisone, betamethasone, prednisolone, beclomethasone propionate, methylprednisone and dexamethasone; the mineralocorticoids include but are not limited to fludrocortisone acetate, deoxycorticosterone, etc.; the anticancer drugs include but are not limited to non-steroidal androgen receptor antagonists (such as enzalutamide, apalutamide and darolutamide), steroidogenesis inhibitors (such as CYP17A1 inhibitors, such as abiraterone acetate), chemotherapeutic agents (such as paclitaxel), antiestrogens (such as tamoxifen, fulvestrant), targeted drugs (such as CDK4 / 6 inhibitors, PI3K inhibitors, AKT inhibitors, BET inhibitors, HDAC inhibitors, etc.), radiopharmaceuticals.

[0282] In certain embodiments, the components to be combined (e.g., a compound of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof and a second therapeutically active agent) can be administered simultaneously or separately in sequence. For example, the second therapeutically active agent can be administered before, simultaneously with, or after the administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof. In addition, the components to be combined can also be administered in combination in the form of the same preparation or in the form of separate different preparations.

[0283] In another aspect, the present invention also provides a method for treating diseases and related conditions mediated by CYP11A1, the method comprising administering an effective amount of the aforementioned compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, the aforementioned preparation or pharmaceutical composition to a patient in need thereof; the diseases and related conditions mediated by CYP11A1 are as defined above.

[0284] The "effective amount" is a dose of a drug that can alleviate, delay, inhibit or cure the condition of a subject. The size of the dose is determined by the drug administration method, the pharmacokinetics of the drug, the severity of the disease, the individual characteristics of the subject (gender, weight, height, age), etc.

[0285]

Definitions and general terms

[0286] In the specification and claims of the present application, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structure shall prevail.

[0287] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

[0288] The "halogen" described in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0289] The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon group, which is a straight chain or branched chain group (i.e., C 20 or C 20) 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), preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C 1-6alkyl). 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 various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available connection point. The substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl. 1-4 The term "alkyl" refers to a specific example of an alkyl group containing 1 to 4 carbon atoms.

[0290] The "C 1-6 "Alkoxy" refers to "C 1-6 Alkyl-O-", the "C 1-6 "C alkyl" is as defined above. 1-4 "Alkoxy" refers to "C 1-4 Alkyl-O-", the "C 1-4 "Alkyl" is as defined above.

[0291] The "hydroxy C 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 groups, amino groups, cyano groups, halogen groups or carboxyl groups.1-6 "Alkyl" is as defined above.

[0292] The "hydroxy C 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 groups, amino groups, cyano groups or halogen groups.

[0293] The "C 1-6 Alkylamino, C 1-6 Alkoxyamino, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylthiocarbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylamide, 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-,

[0294] The "-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) 2 NR 5a R 5b 、-S(O) 2 R 5a ” refers to

[0295] The "cycloalkyl" of the present invention refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 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., a 3 to 20-membered cycloalkyl), preferably 3 to 15 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, The cycloalkyl group may be a cycloalkyl group having 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., 3 to 10-membered cycloalkyl groups), preferably 3 to 7 (e.g., 3, 4, 5, 6 and 7) carbon atoms (i.e., 3 to 7-membered cycloalkyl groups), more preferably 3 to 6 (e.g., 3, 4, 5 and 6) carbon atoms (i.e., 3 to 6-membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any usable point of attachment.

[0296] "Spirocycloalkyl" of the present invention refers to 5 to 20 yuan (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 yuan spirocycloalkyl), a polycyclic group sharing a carbon atom (called spiral atom) between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan (i.e., 6 to 14 yuan spirocycloalkyl), more preferably 7 to 9 yuan (e.g., 7, 8 or 9 yuan, i.e., 7 to 9 yuan spirocycloalkyl). According to the number of spiral atoms shared between rings, spirocycloalkyl is divided into single spirocycloalkyl, double spirocycloalkyl or multiple spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0297] The "condensed cycloalkyl" of the present invention refers to a full-carbon polycyclic group of 5 to 20 members (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 condensed cycloalkyl), each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14 members (i.e., 6 to 14-membered condensed cycloalkyl), and more preferably, it is 7 to 9 members (e.g., 7, 8, 9 members, i.e., 7 to 9-membered condensed cycloalkyl). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, 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 condensed cycloalkyl. Non-limiting examples of condensed cycloalkyl include: wait.

[0298] The "bridged cycloalkyl" of the present invention refers to a full-carbon polycyclic group of 5 to 20 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, i.e., a 5 to 20-membered bridged cycloalkyl), any two rings sharing two carbon atoms that are not directly connected, which may contain one or more double bonds. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered bridged cycloalkyl), and more preferably, it is 7 to 9 members (e.g., 7, 8, 9 members, i.e., a 7 to 9-membered bridged cycloalkyl). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0299] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include wait.

[0300] The "heterocyclyl" described in the present 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., a 3 to 20-membered heterocyclyl), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxidized (i.e., to form a sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 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 heterocyclyl), of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 10 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9 and 10, i.e., 3 to 10-membered heterocyclyl), of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; further Preferably, 4 to 7 ring atoms (e.g., 4, 5, 6 and 7, i.e., 4 to 7-membered heterocyclic radicals) are included, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, 3 to 6 ring atoms (e.g., 3, 4, 5 and 6, i.e., 3 to 6-membered heterocyclic radicals) are included, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; most preferably, 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic radicals) are included, of which 1-2 (e.g., 1, 2) are heteroatoms. Non-limiting examples of monocyclic heterocyclic radicals include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic radicals include spiro heterocyclic radicals, condensed heterocyclic radicals and bridged heterocyclic radicals. Heterocyclic radicals may be substituted or unsubstituted, and when substituted, they may be substituted at any usable point of attachment.

[0301] The "spiro heterocyclic group" of the present invention refers to a polycyclic heterocyclic group with 5 to 20 members (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-membered spiro heterocyclic group), wherein one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members (i.e., a 6 to 14-membered spiro heterocyclic group), and more preferably 7 to 9 members (e.g., 7, 8, 9 members, i.e., a 7 to 9-membered spiro heterocyclic group). According to the number of spiro atoms shared between rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a bispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a bispiro heterocyclic group. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0302] The "fused heterocyclic group" of the present invention refers to a polycyclic heterocyclic group of 5 to 20 members (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-membered 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, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably, it is 7 to 9 members (e.g., 7, 8 or 9 members, i.e., a 7 to 9-membered fused heterocyclic group). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, 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 heterocyclic groups. Non-limiting examples of fused heterocyclic groups include

[0303] The "bridged heterocyclic group" of the present invention refers to a polycyclic heterocyclic group of 5 to 15 members (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms, i.e., a 5 to 15-membered bridged heterocyclic group), any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (i.e., a 6 to 14-membered bridged heterocyclic group), and more preferably, it is 7 to 9 members (e.g., 7, 8, 9 members, i.e., a 7 to 9-membered bridged heterocyclic group). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0304] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic heterocyclic group, a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0305] The "aryl" described in the present 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., a 6- to 15-membered aryl) all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably a 6- to 10-membered (i.e., a 6- to 10-membered aryl) group, such as phenyl and naphthyl.

[0306] The "heteroaryl" of the present invention refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 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 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan, i.e., 5 to 10-membered heteroaryl), more preferably 5 or 6 yuan (i.e., 5 or 6-membered heteroaryl), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0307] The "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" described in the present invention include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", arylene and heteroarylene.

[0308] The ring atoms described in the present invention may optionally form C=O, N=O, S=O or SO 2 structure.

[0309] The term "optionally substituted" used in the present invention refers to two situations in which one or more atoms on the substituted group may be "substituted" or "unsubstituted" by one or more substituents.

[0310] The "L 1 "Absent" means that ring A is directly attached to the aromatic ring structure.

[0311] The "L 2 "Absent" means that ring B is directly connected to O.

[0312] The term "pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO 3 H, etc.) with an appropriate inorganic or organic cation (base), including salts with alkali metals or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups (e.g., -NH 2 The invention also includes salts formed with suitable inorganic or organic anions (acids), including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).

[0313] The "ester" of the present invention refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes an ester that is easily decomposed in the human body to leave the parent compound (the compound of general formula (I)) or its salt. The "ester" of the present invention can be selected from the following groups: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl part of the carboxylic acid compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight or branched alkyl, C 1-6 Straight-chain or branched alkyl (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 substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 (2) sulfonates, such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); and (4) mono-, di- or triphosphates, etc.; (5) esters obtained by esterification with alcohol compounds, wherein the non-hydroxyl portion of the alcohol compound is selected from, for example, C 1-20 Straight or branched alkyl, C 1-12 Straight or branched alkyl, C 1-8 Straight or branched alkyl, C 1-6 Straight-chain or branched alkyl (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 substituted with, for example, halogen, C 1-4 Alkyl or C 1-4 substituted with alkoxy or amino groups).

[0314] The "stereoisomer" of the present invention refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, unless otherwise specified, cis isomers and trans isomers are included. The compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. Each tautomer and its mixture are included in the scope of the present invention. Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds are included in the scope of the present invention.

[0315] The "dosage form" mentioned in the present invention refers to a form of a drug suitable 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 mists, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.

[0316] Advantageous Effects of the Invention

[0317] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have excellent inhibitory activity against CYP11A1 and can treat diseases mediated by CYP11A1 and related diseases;

[0318] (2) The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good pharmacokinetic properties, longer-lasting effects and high bioavailability;

[0319] (3) The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has good safety;

[0320] (4) The compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production. DETAILED DESCRIPTION

[0321] The present invention is further described in detail below through specific examples. However, this should not be understood as limiting the scope of the present invention to the following examples. All technologies that can be implemented based on the above content of the present invention belong to the scope of the present invention.

[0322] 1. Preparation Examples of Compounds of the Present Invention

[0323] NBS: bromosuccinimide DCM: dichloromethane THF: tetrahydrofuran

[0324] DMF: N,N-dimethylformamideSOCl 2 :Thionyl chloride TEA:Triethylamine

[0325] CCl 4 :Carbon Tetrachloride K 2 CO 3 :Potassium carbonate MsCl:Methanesulfonyl chloride

[0326] Br 2 :Bromide BBr 3 :Boron tribromide m-CPBA:Meta-chloroperbenzoic acid 1,4-dioxane: 1,4-dioxane SOCl 2 :Thionyl chloride AIBN:Azobisisobutyronitrile Xphos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Preparation Example 1: Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)isoindolin-1-one hydrochloride (hydrochloride salt of compound 1)

[0327]

[0328]

[0329] 1. Preparation of ethyl 3-bromo-6-methoxy-2-methylbenzoate (Int-2)

[0330] Dissolve ethyl 2-methoxy-6-methylbenzoate (Int-1) (5.0 g, 25.7 mmol) in DCM (200 mL), cool to 0°C, add bromine (5.3 g, 33.2 mmol), and react at 30°C for 2 hours. After the reaction is complete, add 5% sodium thiosulfate solution and stir for 20 minutes, extract, concentrate, and purify by silica gel column chromatography (n-heptane: ethyl acetate = 8:1) to obtain 5.0 g of the product, with a yield of 71.1%.

[0331] 2. Preparation of ethyl 3-bromo-2-(bromomethyl)-6-methoxybenzoate (Int-3)

[0332] Int-2 (4.5 g, 16.5 mmol) and NBS (4.4 g, 24.7 mmol) were dissolved in CCl 4 (100 mL), add benzoyl peroxide (400 mg, 1.7 mmol), react at 80°C for 3 hours, concentrate, and purify by silica gel column chromatography (n-heptane: ethyl acetate = 6:1) to obtain 4.0 g of the product, with a yield of 69.0%.

[0333] 3. Preparation of 4-bromo-7-methoxyisoindolin-1-one (Int-4)

[0334] Int-3 (1.1 g, 3.1 mmol) was dissolved in THF (35 mL), and aqueous ammonia (25%, 5.5 mL) was added, and the mixture was reacted at 25°C for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM: methanol = 10:1) to obtain 700 mg of the product with a yield of 92.5%.

[0335] 4. Preparation of 4-bromo-7-hydroxyisoindolin-1-one (Int-5)

[0336] Int-4 (700 mg, 2.9 mmol) and hydrobromic acid (48%) (35 mL) were added to the sealed tube and reacted at 100°C for 16 hours until the reaction was complete. The mixture was concentrated to obtain 660 mg of a crude product, which was used directly in the next step.

[0337] 5. Preparation of 4-bromo-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)isoindolin-1-one (Int-7)

[0338] Int-5 (660 mg, crude) and (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (Int-6) (2.3 g, 8.5 mmol) were dissolved in DMF (35 mL) and K 2 CO 3 (2.4 g, 17.4 mmol), react at 60 ° C for 24 hours. After the reaction is completed, extract with water and ethyl acetate. The organic phase is washed with water, concentrated, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 0-100%, ethyl acetate: DCM: methanol = 7:2:1) to obtain 300 mg of the product. The two-step yield is 25.7%.

[0339] 6. Preparation of tert-butyl 4-bromo-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxoisoindoline-2-carboxylate (Int-8)

[0340] Int-7 (100 mg, 0.25 mmol) and di-tert-butyl dicarbonate (110 mg, 0.50 mmol) were dissolved in DCM (10 mL), 4-dimethylaminopyridine (130 mg, 1.1 mmol) was added, and the reaction was carried out at 25°C for 1 h. The reaction was completed. The product was concentrated and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:3) to obtain 85 mg of the product, with a yield of 68.1%.

[0341] 7. Preparation of tert-butyl 4-(hydroxymethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxoisoindoline-2-carboxylate (Int-10)

[0342] Int-8 (85 mg, 0.17 mmol) and (tributyltin)methanol (Int-9) (109 g, 0.34 mmol) were dissolved in 1,4-dioxane (8 mL), Xphos Pd G2 (27 mg, 0.034 mmol) was added, purged with nitrogen, and reacted at 80°C for 16 hours under nitrogen. After concentration, the crude product was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 40 mg of the product, with a yield of 52.1%.

[0343] 8. Preparation of tert-butyl 4-(chloromethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxoisoindoline-2-carboxylate (Int-11)

[0344] Int-10 (40 mg, 0.088 mmol) was dissolved in DCM (10 mL) and SOCl was added 2 (32 mg, 0.27 mmol), react at 25°C for 0.5 h, the reaction is complete, concentrate, and the crude product is used directly in the next step.

[0345] 9. Preparation of tert-butyl 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1-oxoisoindolin-2-carboxylate (Int-13)

[0346] Int-11 (the crude product from the previous step) and isoindoline hydrochloride (Int-12) (28 mg, 0.18 mmol) were dissolved in acetonitrile (10 mL) and K 2 CO 3 (52 mg, 0.38 mmol) and potassium iodide (4 mg, 0.024 mmol) were reacted at 70°C for 1 h. After the reaction was completed, the solid was removed by filtration. Prep-TLC (DCM: methanol = 15: 1) was used to obtain 25 mg of the product. The two-step yield was 51.1%.

[0347] 10. Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)isoindolin-1-one hydrochloride

[0348] Int-13 (25 mg, 0.045 mmol) was dissolved in DCM (13 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 1.3 mL) was added. The mixture was reacted at 25°C for 2 h and concentrated to obtain 22 mg of the product. The yield was 99.4%.

[0349] Molecular formula: C 24 H 29 N 3 O 4 S molecular weight: 455.6 LC-MS (M / e): 456.2 (M+H + )

[0350] 1 H-NMR (400MHz, CD 3 OD)δ:7.78(d,J=8.4Hz,1H),7.45-7.35(m,4H),7.19(d,J=8.4Hz,1H),4.79-4.65(m,4H),4.64(s,2H),4.55 (s,2H),4.06(d,J=6.2Hz,2H),3.80-3.75(m,2H),2.89-2.75(m,5H),2.19-2.00(m,3H),1.50-1.44(m,2H).

[0351] Preparation Example 2: Preparation of 4-(isoindolin-2-ylmethyl)-2-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)isoindolin-1-one (Compound 2)

[0352]

[0353] Using the same or similar method as Preparation Example 1, the compound 4-(isoindolin-2-ylmethyl)-2-methyl-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)isoindolin-1-one (Compound 2) was prepared according to the above route.

[0354] Molecular formula: C 25 H 31 N 3 O 4 S molecular weight: 469.6 LC-MS (M / e): 470.2 (M+H + )

[0355] 1 H-NMR (400MHz, CDCl 3)δ:7.41(d,J=8.4Hz,1H),7.21-7.15(m,4H),6.82(d,J=8.4Hz,1H),4.41(s,2H),3.96(d,J=6.2Hz,2H) ,3.90-3.85(m,8H),3.11(s,3H),3.28(s,3H),2.77-2.71(m,2H),2.19-2.00(m,3H),1.57-1.50(m,2H).

[0356] Preparation Example 3: Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzo[b]thiophene 1,1-dioxide (Compound 5)

[0357]

[0358] 1. Preparation of 4-bromo-7-methoxybenzo[b]thiophene (Int-20)

[0359] At 0℃, Br 2 (472 mg, 3.0 mmol) was added dropwise with 7-methoxybenzo[b]thiophene (Int-19) (485 mg, 3.0 mmol) in CCl 4 The crude product was directly mixed with silica gel and purified by silica gel column chromatography (n-heptane: ethyl acetate = 10:1) to obtain 690 mg of the product with a yield of 96.1%.

[0360] 2. Preparation of 4-bromobenzo[b]thiophene-7-ol (Int-21)

[0361] At 0℃, BBr 3 (1.4 g, 5.6 mmol) was added dropwise to DCM (20 mL) containing Int-20 (690 mg, 2.8 mmol) and the reaction was continued for 10 hours. After the reaction was completed, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 3:1) to obtain 600 mg of the product with a yield of 92.3%.

[0362] 3. Preparation of 4-(((4-bromobenzo[b]thiophen-7-yl)oxy)methyl)-1-(methylsulfonyl)piperidine (Int-22)

[0363] K 2 CO 3(995 mg, 7.2 mmol) was added to acetonitrile (30 mL) containing Int-21 (540 mg, 2.4 mmol) and Int-6 (1.3 g, 4.8 mmol) and reacted at 85°C for 3 hours. After the reaction was completed, the sample was directly mixed with silica gel and purified by silica gel column chromatography (n-heptane: ethyl acetate = 3:1) to obtain 650 mg of the product with a yield of 68.2%.

[0364] 4. Preparation of 4-bromo-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzo[b]thiophene 1,1-dioxide (Int-23)

[0365] A DCM (10 mL) solution containing Int-22 (130 mg, 0.32 mmol) and m-CPBA (173 mg, 1.0 mmol) was reacted at 30°C for 3 hours. After the reaction was completed, the sample was directly mixed with silica gel, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:3) to obtain 100 mg of the product with a yield of 71.3%.

[0366] 5. Preparation of 4-(hydroxymethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzo[b]thiophene 1,1-dioxide (Int-24)

[0367] N 2 Under protection, 1,4-dioxane (8 mL) containing Int-23 (100 mg, 0.23 mmol), Int-9 (148 mg, 0.46 mmol) and XphosPdG2 (36 mg, 0.046 mmol) was reacted at 90°C for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (pure ethyl acetate) to obtain 60 mg of the product with a yield of 67.6%.

[0368] 6. Preparation of 4-(chloromethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzo[b]thiophene 1,1-dioxide (Int-25)

[0369] At 30°C, SOCl 2 (115 mg, 1.0 mmol) was added dropwise to DCM (5 mL) containing Int-24 (60 mg, 0.15 mmol) and the reaction was continued for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure and the crude product was directly used for the next step reaction.

[0370] 7. Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzo[b]thiophene 1,1-dioxide (Compound 5)

[0371] N 2Under protection, containing Int-25 (the crude product of the previous step), Int-12 (30 mg, 0.19 mmol), K 2 CO 3 (138 mg, 1.0 mmol) and potassium iodide (166 mg, 1.0 mmol) in acetonitrile (10 mL) were reacted at 80°C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified on a silica gel plate (pure ethyl acetate) to obtain 35 mg of the product, with a two-step yield of 46.3%.

[0372] Molecular formula: C 24 H 28 N 2 O 5 S 2 Molecular weight: 488.6 LC-MS (m / z): 489.2 (M+H + )

[0373] 1 H-NMR (400 MHz, DMSO-d 6 )δ: 7.75(m,1H),7.58(m,1H),7.24-7.14(m,6H),4.07(m,2H),3.94(s,2H),3.81(s ,4H),3.58(m,2H),2.84(s,3H),2.75(m,2H),1.88-1.86(m,3H),1.40-1.21(m,2H).

[0374] Preparation Example 4: Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 6)

[0375]

[0376] 1. Preparation of 6-bromo-2,3-difluorobenzaldehyde (Int-27)

[0377] -78°C, add lithium diisopropylamide (2M, 57ml, 114mmol) to a solution of 4-bromo-1,2-difluorobenzene (Int-26) (20.0g, 103.6mmol) in THF (100mL), react for 40 minutes, add DMF (9.1g, 124.5mmol) and continue to react for 30 minutes, raise the temperature to 20°C, add acetic acid and water and react for 5 minutes. Add dilute hydrochloric acid to quench the reaction, extract the organic phase with ethyl acetate, remove the solvent under reduced pressure, and purify the normal phase (ethyl acetate: petroleum ether = 1:5) to obtain 19.8g of the target compound with a yield of 86.5%.

[0378] 2. Preparation of methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (Int-28)

[0379] To a solution of Int-27 (19.8 g, 89.6 mmol) in DMF (100 mL) were added methyl thioglycolate (11.4 g, 107.4 mmol) and K 2 CO 3 (24.8 g, 179.5 mmol), react at 60°C for 3 hours, add water to the system, extract the organic phase with ethyl acetate, remove the solvent under reduced pressure to obtain the crude target compound which is directly used in the next step.

[0380] 3. Preparation of 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (Int-29)

[0381] Int-28 (N / A, 89.6 mmol) was dissolved in a mixed solution of THF (80 mL), methanol (80 mL) and water (80 mL), and lithium hydroxide monohydrate (11.3 g, 269.0 mmol) was added, and the mixture was reacted at 25°C for 1 hour. Water was added to the system, and the pH was adjusted to acidity with 4 M dilute hydrochloric acid. The organic phase was extracted with ethyl acetate, and the solvent was removed under reduced pressure to obtain 20 g of the target compound, with a two-step yield of 96.6%.

[0382] 4. Preparation of 4-bromo-7-fluorobenzo[b]thiophene (Int-30)

[0383] To a solution of Int-29 (6.0 g, 21.8 mmol) in N,N-dimethylacetamide (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 g, 21.7 mmol). The mixture was reacted at 200 °C in a microwave oven for 1 hour. Water was added to the system, and the organic phase was extracted with ethyl acetate. The solvent was removed under reduced pressure and purified by normal phase (ethyl acetate: petroleum ether = 1:20) to obtain 3.0 g of the target compound in a yield of 59.5%.

[0384] 5. Preparation of 4-bromo-7-fluorobenzo[b]thiophene 1,1-dioxide (Int-31)

[0385] m-CPBA (80%) (1.2 g, 5.9 mmol) was added to a solution of Int-30 (450 mg, 1.9 mmol) in DCM (20 mL), and then the mixture was allowed to react at 25°C for 16 hours. The reaction was quenched with saturated aqueous thiosulfate and aqueous sodium bicarbonate, and the organic phase was extracted with DCM, dried, concentrated and spin-dried to obtain 450 mg of the crude target compound, which was used directly in the next step.

[0386] 6. Preparation of 4-bromo-7-fluoro-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Int-32)

[0387] Sodium borohydride (129 mg, 3.4 mmol) was added to Int-31 (450 mg, 1.7 mmol) at 0°C, and then reacted at 25°C for 16 hours. Water was added to the system to quench, and the organic phase was extracted with ethyl acetate, dried, and the solvent was removed under reduced pressure and purified by normal phase (ethyl acetate: petroleum ether = 1:2) to obtain 400 mg of the target compound, with a two-step yield of 77.5%.

[0388] 7. Preparation of tert-butyl 4-(((4-bromo-1,1-dioxo-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-33)

[0389] Int-32 (430 mg, 1.2 mmol) was dissolved in THF (20 mL), and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (310 mg, 1.4 mmol) and potassium tert-butoxide (162 mg, 1.4 mmol) were added at 25°C, and reacted for 1 hour at 25°C. Water was added to the system to quench, and the organic phase was extracted with ethyl acetate, dried, and the solvent was removed under reduced pressure. The target compound was purified by normal phase purification (ethyl acetate: petroleum ether = 3:7) to obtain 260 mg of the target compound with a yield of 17.0%.

[0390] 8. Preparation of tert-butyl 4-(((4-(hydroxymethyl)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-34)

[0391] Int-33 (235 mg, 0.51 mmol) was dissolved in 1,4-dioxane (10 mL) solution, tri-tert-butyl (hydroxymethyl) tin (819 mg, 2.6 mmol) and Xphos Pd G2 (100 mg, 0.13 mmol) were added, and the mixture was reacted at 80°C for 24 hours under nitrogen protection. The solvent was removed under reduced pressure and the reaction solution was purified by normal phase purification (ethyl acetate: petroleum ether = 9:1) to obtain 80 mg of the target compound with a yield of 38.1%.

[0392] 9. Preparation of tert-butyl 4-(((4-(chloromethyl)-1,1-dioxo-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-35)

[0393] Int-34 (80 mg, 0.19 mmol) was dissolved in DCM (5 mL) and SOCl was added. 2 (68 mg, 0.57 mmol). The solvent was removed from the reaction solution under reduced pressure, and the crude product was used directly in the next step.

[0394] 10. Preparation of tert-butyl 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-36)

[0395] To a solution of Int-35 (N / A, 0.19 mmol) in acetonitrile (10 mL) was added K 2 CO 3 (105 mg, 0.76 mmol), potassium iodide (13 mg, 0.078 mmol) and Int-12 (59 mg, 0.38 mmol) were added and then reacted at 60°C for 1 hour. After the reaction was completed, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, concentrated, and purified by silica gel column (ethyl acetate: petroleum ether = 2:1) to obtain 80 mg of the target compound, with a two-step yield of 80.3%.

[0396] 11. Preparation of 4-(isoindolin-2-ylmethyl)-7-(piperidin-4-ylmethoxy)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide hydrochloride (Int-37 hydrochloride)

[0397] To a solution of Int-36 (65 mg, 0.13 mmol) in DCM (2 mL), add hydrochloric acid ethyl acetate solution (3 mL) and react at 25° C. for 10 minutes. After the reaction is complete, the reaction solution is concentrated and dried by rotation and used directly in the next reaction.

[0398] 12. Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 6)

[0399] TEA (66 mg, 0.65 mmol) and methanesulfonyl chloride (22 mg, 0.19 mmol) were added to a solution of Int-37 hydrochloride (N / A, 0.13 mmol) in DCM (5 mL) and the reaction was continued for 30 minutes. After the reaction was completed, water was added to the system to quench the reaction, the organic phase was extracted with DCM, and the concentrated residue was subjected to TLC plate (ethyl acetate: petroleum ether = 4:1) to obtain 15 mg of the target product, with a two-step yield of 24.1%.

[0400] Molecular formula: C 24 H 30 S 2 N 5 O 2 Molecular weight: 490.6 LC-MS (m / z): 491.2 (M+H + )

[0401] 1H-NMR (400MHz, CDCl 3)δ:7.49(d,J=8.4Hz,1H),7.25-7.16(m,4H),6.81(d,J=8.4Hz,1H),4.05-3.97(m,2H),3.95-3.82 (m,8H),3.55-3.45(m,4H),2.82(s,3H),2.81-2.79(m,2H),2.15-2.02(m,3H),0.95-.080(m,2H).

[0402] Preparation Example 5: Preparation of (4-(isoindolin-2-ylmethyl)-2-methyl-7-((1-methylsulfonyl)piperidin-4-yl-methoxy)-2,3-dihydrobenzo[d]isothiazole-1.1-dioxide (Compound 7)

[0403]

[0404] 1. Preparation of 3-bromo-6-fluoro-2-methylaniline (Int-39)

[0405] 1-Bromo-4-fluoro-2-methyl-3-nitrobenzene (Int-38) (15g, 64.1mmol) was dissolved in methanol (70mL) and concentrated hydrochloric acid (70mL), and anhydrous stannous chloride (24.3g, 128.2mmol) was added thereto. After the addition was completed, the mixture was reacted at 40°C for 3 hours under nitrogen protection. The reaction was completed by LCMS. The mixture was poured into water, and the pH was adjusted to alkaline with potassium hydroxide aqueous solution. The mixture was extracted with ethyl acetate 3 times, the ethyl acetate layers were combined, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 3:1) to obtain 20.0g of the product with a yield of 91.8%.

[0406] 2. Preparation of 3-bromo-6-fluoro-2-methylbenzenesulfonyl chloride (Int-40)

[0407] At 0°C, Int-39 (3.0 g, 14.7 mmol) was added to concentrated hydrochloric acid (15 mL), and an aqueous solution of sodium nitrite (1.0 g, 14.7 mmol) (10 mL) was slowly added dropwise. After the addition, the mixture was reacted at 0°C for 1 hour.

[0408] At 0℃, SOCl 2 (10 mL) was added dropwise to 2 O (50mL), and continue the reaction for 15 minutes. Add chlorinated ketone (149mg, 1.5mmol), and continue the reaction for 1 hour. Slowly add the reaction solution obtained above to this reaction solution, and react at 0℃ for 1 hour. After the reaction is completed, filter to obtain a crude compound, which is not purified and directly used in the next step.

[0409] 3. Preparation of 3-bromo-6-fluoro-N,2-dimethylbenzenesulfonamide (Int-41)

[0410] At 30°C, the DCM solution of Int-40 (the crude product of the previous step) was slowly added dropwise to DCM (60 mL) containing methylamine hydrochloride (1.5 g, 22.2 mmol) and TEA (4.5 g, 44.4 mmol), and the mixture was reacted at 30°C for 3 hours. After the reaction was completed, the reaction solution was directly dried under reduced pressure and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 2.0 g of the product with a yield of 48.2%.

[0411] 4. Preparation of 3-bromo-2-(bromomethyl)-6-fluoro-N-methylbenzenesulfonamide (Int-42)

[0412] CCl containing Int-41 (2.0 g, 7.1 mmol), NBS (1.9 g, 10.7 mmol) and AIBN (230 mg, 1.4 mmol) 4 (30 mL) solution was reacted at 80°C for 16 hours. After the reaction was completed, the sample was directly mixed with silica gel, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 1.4 g of the product with a yield of 54.7%.

[0413] 5. Preparation of 4-bromo-7-fluoro-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Int-43)

[0414] Int-42 (1.2 g, 3.3 mmol) was dissolved in acetonitrile (30 mL), anhydrous potassium carbonate (911 mg, 6.6 mmol) was added, and the mixture was reacted at 80°C for 3 hours. After the reaction was completed, the sample was directly mixed with silica gel, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 0.6 g of the product with a yield of 64.4%.

[0415] 6. Preparation of tert-butyl 4-(((4-bromo-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-44)

[0416] At 0°C, NaH (320 mg, 8 mmol) was added to THF (20 mL) containing tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (646 mg, 3.0 mmol), and after 5 minutes of reaction, Int-43 (600 mg, 2.1 mmol) was added, and the reaction was continued at 0°C for 3 hours. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was extracted three times. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 680 mg of the product with a yield of 66.8%.

[0417] 7. Preparation of tert-butyl 4-(((4-(hydroxymethyl)-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-45)

[0418] N 2 Under protection, 1,4-dioxane (20 mL) containing Int-44 (680 mg, 1.43 mmol), Int-9 (918 mg, 2.8 mmol) and XphosPdG2 (225 mg, 0.29 mmol) was reacted at 90°C for 7 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 190 mg of the product with a yield of 31.1%.

[0419] 8. Preparation of tert-butyl 4-(((4-(chloromethyl)-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-46)

[0420] At 30℃, SOCl 2 (57 mg, 0.48 mmol) was added dropwise to DCM (1 mL) containing Int-45 (50 mg, 0.12 mmol) and the reaction was continued for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure and the crude product was directly used for the next reaction.

[0421] 9. Preparation of tert-butyl 4-(((4-(isoindolin-2-ylmethyl)-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-47)

[0422] N 2 Under protection, containing Int-46 (the crude product of the previous step), Int-12 (156 mg, 1.0 mmol) and K 2 CO 3 (276 mg, 2.0 mmol) in acetonitrile (10 mL), react at 80° C. for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 50 mg of the product with a yield of 80.8%.

[0423] 10. Preparation of (4-(isoindolin-2-ylmethyl)-2-methyl-7-(piperidin-4-yl-methoxy)-2,3-dihydrobenzo[d]isothiazole-1.1-dioxide (Int-48)

[0424] At 30°C, hydrochloric acid ethyl acetate solution (4 mL) was added dropwise to ethyl acetate (1 mL) containing Int-47 (50 mg, 0.095 mmol), and the reaction was continued for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly used for the next reaction.

[0425] 11. Preparation of (4-(isoindolin-2-ylmethyl)-2-methyl-7-((1-methylsulfonyl)piperidin-4-yl-methoxy)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide (Compound 7)

[0426] MsCl (115 mg, 1.0 mmol) was added to DCM (5 mL) containing Int-48 (the crude product from the previous step) and TEA (303 mg, 3.0 mmol) at 0°C and reacted for 1 hour at 0°C. After the reaction was completed, the mixture was directly dried under reduced pressure, and the residue was purified by TLC (DCM: methanol = 15:1) to obtain 10 mg of the product with a yield of 20.9%.

[0427] Molecular formula: C 24 H 31 N 3 O 5 S 2 Molecular weight: 505.6 LC-MS (m / z): 506.1 (M+H + )

[0428] 1 H-NMR (400 MHz, DMSO-d 6 )δ: 7.61 (m, 1H), 7.19-7.14 (m, 5H), 4.40 (m, 2H), 4.05 (m, 3H), 3.86 (m, 5H), 3.60 (m, 2H), 2.84 (m, 3H), 2.75 (m, 5H), 1.98-1.83 (m, 3H), 1.38-1.32 (m, 2H). Preparation Example 6: Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Compound 8)

[0429]

[0430]

[0431] 1. Preparation of 3-bromo-N-(tert-butyl)-6-fluoro-2-methylbenzenesulfonamide (Int-50)

[0432] At 30°C, a DCM solution of 3-bromo-6-fluoro-2-methylbenzenesulfonyl chloride (Int-49) (7.0 g, 24.3 mmol) was slowly added dropwise to DCM (60 mL) containing tert-butylamine (3.6 g, 49.2 mmol) and TEA (5.0 g, 49.2 mmol), and the mixture was reacted at 30°C for 3 hours. After the reaction was completed, the reaction solution was directly dried under reduced pressure and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 3.0 g of the product with a yield of 38.0%.

[0433] 2. Preparation of 3-bromo-2-(bromomethyl)-N-(tert-butyl)-6-fluorobenzenesulfonamide (Int-51)

[0434] CCl containing Int-50 (3.0 g, 9.2 mmol), NBS (3.2 g, 18.0 mmol) and AIBN (296 mg, 0.2 mmol) 4 (40 mL) solution was reacted at 80°C for 10 hours. After the reaction was completed, the sample was directly mixed with silica gel, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 3.5 g of the product with a yield of 93.8%.

[0435] 3. Preparation of 4-bromo-2-(tert-butyl)-7-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Int-52)

[0436] Int-51 (3.3 g, 8.2 mmol) was dissolved in acetonitrile (50 mL), anhydrous potassium carbonate (2.3 g, 16.6 mmol) was added, and the mixture was reacted at 80°C for 3 hours. After the reaction was completed, the sample was directly mixed with silica gel, and the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 2.3 g of the product with a yield of 87.2%.

[0437] 4. Preparation of tert-butyl 4-(((4-bromo-2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-53)

[0438] At 0°C, NaH (544 mg, 13.6 mmol) was added to THF (20 mL) containing tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.1 g, 5.1 mmol), and reacted for 5 minutes before adding Int-52 (1.1 g, 3.4 mmol). After the addition was complete, the mixture was reacted at 0°C for 3 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated sodium chloride solution, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 1.3 g of the product with a yield of 73.6%.

[0439] 5. Preparation of tert-butyl 4-(((2-(tert-butyl)-4-(hydroxymethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-54)

[0440] N 2 Under protection, 1,4-dioxane (40 mL) containing Int-53 (1.2 g, 2.3 mmol), Int-9 (1.1 g, 3.4 mmol) and XphosPdG2 (363 mg, 0.46 mmol) was reacted at 90°C for 7 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol = 30: 1) to obtain 340 mg of the product with a yield of 31.3%.

[0441] 6. Preparation of tert-butyl 4-(((4-(chloromethyl)-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-55)

[0442] At 30°C, SOCl 2 (167 mg, 1.4 mmol) was added dropwise to DCM (10 mL) containing Int-54 (340 mg, 0.72 mmol) and the reaction was continued for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure and the crude product was directly used for the next reaction.

[0443] 7. Preparation of tert-butyl 4-(((2-(tert-butyl)-4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-56)

[0444] N 2 Under protection, containing Int-55 (the crude product of the previous step), Int-12 (120 mg, 0.77 mmol) and K 2 CO 3 (200 mg, 1.44 mmol) in acetonitrile (40 mL), react at 80° C. for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol = 20: 1) to obtain 300 mg of the product with a yield of 72.6%.

[0445] 8. Preparation of 2-(tert-butyl)-4-(isoindolin-2-ylmethyl)-7-(piperidin-4-ylmethoxy)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Int-57)

[0446] At 30°C, hydrochloric acid ethyl acetate solution (4 mL) was added dropwise to ethyl acetate (1 mL) containing Int-56 (300 mg, 0.53 mmol), and the reaction was continued for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the crude product was directly used for the next reaction.

[0447] 9. Preparation of 2-(tert-butyl)-4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Int-58)

[0448] MsCl (115 mg, 1.0 mmol) was added to DCM (5 mL) containing Int-57 (the crude product from the previous step) and TEA (303 mg, 3.0 mmol) at 0°C and reacted for 1 hour at 0°C. After the reaction was completed, the product was directly dried under reduced pressure and purified by TLC (DCM: methanol = 15: 1) to obtain 120 mg of the product with a yield of 41.6% (combined yield of the two steps).

[0449] 10. Preparation of 4-(isoindolin-2-ylmethyl)-7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Compound 8)

[0450] Trifluoroacetic acid (5 mL) and DCM (1 mL) containing Int-58 (120 mg, 0.22 mmol) were reacted at 50°C for 10 hours. After the reaction was completed, the solvent was removed under reduced pressure, dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, and the solvent was removed under reduced pressure. The residue was purified by TLC (DCM: methanol = 15: 1) to obtain 80 mg of the product with a yield of 74.3%.

[0451] Molecular formula: C 23 H 29 N 3 O 5 S 2 Molecular weight: 491.6 LC-MS (m / z): 492.1 (M+H + )

[0452] 1 H-NMR (400 MHz, DMSO-d 6 )δ: 7.59(m,2H),7.20-7.12(m,5H),4.40(m,2H),4.06(m,3H),3.86(m,5H),3 .60(m,2H),2.84(s,3H),2.75(m,2H),1.98-1.83(m,3H),1.38-1.32(m,2H).

[0453] Preparation Example 7: Preparation of 2-((7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)methyl)isoindoline-5-carbonitrile (Compound 9)

[0454]

[0455] 1. Preparation of tert-butyl 4-(((4-(chloromethyl)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-59)

[0456] Int-34 (100 mg, 0.24 mmol) was dissolved in DCM (5 mL) and SOCl was added. 2 (86 mg, 0.72 mmol). The solvent was removed from the reaction solution under reduced pressure, and the crude product was used directly in the next step.

[0457] 2. Preparation of tert-butyl 4-(((4-((5-cyanoisoindolin-2-yl)methyl)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-60)

[0458] To a solution of Int-59 (N / A, 0.24 mmol) in acetonitrile (5 mL) was added K 2 CO 3 (199 mg, 1.4 mmol), potassium iodide (8 mg, 0.048 mmol) and isoindoline-5-carbonitrile hydrochloride (87 mg, 0.48 mmol), and then reacted at 60°C for 1 hour. After the reaction was completed, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, concentrated, and purified by silica gel column (ethyl acetate: petroleum ether = 7:3) to obtain 100 mg of the target compound, with a two-step yield of 76.5%.

[0459] 3. Preparation of 2-((1,1-dioxido-7-(piperidin-4-ylmethoxy)-2,3-dihydrobenzothiophen-4-yl)methyl)isoindoline-5-carbonitrile hydrochloride (Int-61)

[0460] To a solution of Int-60 (100 mg, 0.19 mmol) in DCM (1 mL), add 1,4-dioxane hydrochloride solution (3 mL) and react at 25° C. for 1 hour. After the reaction is complete, the reaction solution is concentrated and dried by swirl, and used directly in the next reaction.

[0461] 4. Preparation of 2-((7-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-4-yl)methyl)isoindoline-5-carbonitrile (Compound 9)

[0462] TEA (115 mg, 1.1 mmol) and methanesulfonyl chloride (44 mg, 0.38 mmol) were added to a solution of Int-61 (N / A, 0.19 mmol) in DCM (5 mL), and the reaction was continued for 30 minutes. After the reaction was completed, water was added to the system to quench the reaction, the organic phase was extracted with DCM, and the concentrated residue was subjected to TLC plate (DCM: methanol = 30:1) to obtain 15 mg of the target product, with a two-step yield of 52.1%.

[0463] Molecular formula: C 25 H 29 S 2 N 3 O 2 Molecular weight: 515.6 LC-MS (m / z): 516.2 (M+H + )

[0464] 1 H-NMR (400MHz, CDCl 3 )δ:7.50-7.45(m,3H),7.28(s,1H),6.82(d,J=8.4Hz,1H),4.05-3.97(m,2H),3.95-3.82(m,8 H),3.47-3.40(m,4H),2.81(s,3H),2.80-2.77(m,2H),2.15-2.00(m,3H),1.55-1.25(m,2H).

[0465] Preparation Example 8: Preparation of 7-((1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)methoxy)-4-(isoindolin-2-ylmethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 10)

[0466]

[0467] 1. Preparation of ethyl 2-(4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-7-yl)oxy)methyl)piperidin-1-yl)sulfonyl)acetate (Int-62)

[0468] At 0°C, ethyl (chlorosulfonyl)acetate (187 mg, 1.0 mmol) was added dropwise to DCM (10 mL) containing Int-37 (50 mg, 0.12 mmol) and TEA (303 mg, 3.0 mmol) and the reaction was continued for 1 hour. After the reaction was completed, the solvent was directly removed under reduced pressure, and the residue was purified by TLC (DCM: methanol = 30: 1) to obtain 40 mg of the product with a yield of 58.6%.

[0469] 2. Preparation of 7-((1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)methoxy)-4-(isoindolin-2-ylmethyl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (Compound 10)

[0470] NaBH 4 (38 mg, 1.0 mmol) was added to THF (5 mL) and methanol (5 mL) containing Int-62 (40 mg, 0.071 mmol) and reacted at 25°C for 1 hour. After the reaction was completed, the product was directly dried under reduced pressure, and the residue was purified on a silica gel plate (DCM: methanol = 10: 1) to obtain 20 mg of the product with a yield of 54.0%.

[0471] Molecular formula: C 25 H 32 N 2 O 6 S 2 Molecular weight: 520.7 LC-MS (m / z): 521.2 (M+H + )

[0472] 1 H-NMR (400 MHz, DMSO-d 6 )δ: 7.56(m,1H),7.21-7.14(m,4H),7.05(m,1H),4.98(t,J=5.5Hz,1H),4.01(m,2H),3.87-3.81(m,6H),3.73( m,2H),3.62(m,2H),3.50(m,2H),3.35(m,2H),3.15(m,2H),2.82(m,2H),1.87-1.83(m,3H),1.38-1.31(m,2H).

[0473] Preparation Example 9: Preparation of 2-(4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)piperidin-1-yl)sulfonyl)acetonitrile (Compound 11)

[0474]

[0475] At 0°C, cyanomethanesulfonyl chloride (20 mg, 0.14 mmol) was added dropwise to DCM (5 mL) containing Int-37 (30 mg, 0.073 mmol) and TEA (29 mg, 0.29 mmol) and the reaction was continued for 1 hour. After the reaction was completed, the solvent was directly removed under reduced pressure, and the residue was purified by TLC (100% ethyl acetate) to obtain 20 mg of the product with a yield of 53.3%.

[0476] Molecular formula: C 25 H29 N 3 O 5 S 2 Molecular weight: 515.6 LC-MS (m / z): 516.2 (M+H + )

[0477] 1 H-NMR (400 MHz, DMSO-d 6 )7.56(m,1H),7.21-7.14(m,4H),7.06(m,1H),4.81(s,2H),4.02(d,J=6.2Hz,2H),3.84-3.81(m ,6H),3.73(m,2H),3.51(m,2H),3.35(m,2H),3.01(m,2H),1.99-1.87(m,3H),1.42-1.34(m,2H).

[0478] Preparation Example 10: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 12)

[0479]

[0480] Int-37 (40 mg, 0.097 mmol) was dissolved in DCM (5 mL), and TEA (50 mg, 0.49 mmol) was added. N-methyl-1H-imidazole-1-carboxamide (19 mg, 0.15 mmol) was added at 0°C. After reacting at 0°C for 2 hours, the mixture was directly concentrated and purified by plate chromatography (methanol:DCM=1:15) to obtain 23 mg of the product with a yield of 50.5%.

[0481] Molecular formula: C 25 H 31 N 3 O 4 S molecular weight: 469.6 LC-MS (M / e): 470.2 (M+H + )

[0482] 1H-NMR(400MHz,DMSO)δ:7.50-7.60(m,1H),7.10-7.30(m,4H),7.01-7.08(m,1H),6.33(s,1H),4.00-3.90(m,5H),3.79-3.8 9(m,6H),3.50-3.60(m,2H),2.65-2.75(m,2H),2.60-2.70(m,3H),1.90-2.00(m,2H),1.70-1.80(m,2H),1.10-1.20(m,2H).

[0483] Preparation Example 11: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N,N-dimethylpiperidine-1-carboxamide (Compound 13)

[0484]

[0485] Int-37 (40 mg, 0.1 mmol) was dissolved in DCM (5 mL), and TEA (30 mg, 0.3 mmol) was added. Dimethylcarbamoyl chloride (20 mg, 0.2 mmol) was added at 0°C. After reacting at 0°C for 2 hours, the mixture was directly concentrated and purified by plate chromatography (methanol:DCM=1:50) to obtain 30 mg of the product with a yield of 63.8%.

[0486] Molecular formula: C 26 H 33 N 3 O 4 S molecular weight: 483.6 LC-MS (M / e): 484.2 (M+H + )

[0487] 1 H-NMR(400MHz,DMSO)δ:7.57-7.55(m,1H),7.20-7.14(m,4H),7.07-7.04(m,1H),4.00-3.98(m,2H),3.83-3.80(m,6H),3.5 7-3.50(m,2H),3.49-3.47(m,2H),3.36(m,1H),2.70-2.65(m,8H),1.97-1.95(m,2H),1.78-1.75(m,2H),1.29-1.27(m,2H).

[0488] Preparation Example 12: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N-methylpiperidine-1-sulfonamide (Compound 14)

[0489]

[0490] Int-37 (42 mg, 0.10 mmol) was dissolved in DCM (5 mL), and TEA (40 mg, 0.4 mmol) was added. Methanesulfamoyl chloride (26 mg, 0.20 mmol) was added at 0°C, and the reaction was continued for 15 minutes. Water was added to the system, and the organic phase was extracted with DCM. The product was purified by concentrator chromatography (methanol: DCM = 1:30) to obtain 40 mg of the product with a yield of 77.8%.

[0491] Molecular formula: C 24 H 31 S 2 N 3 O 5 Molecular weight: 505.6 LC-MS (m / z): 506.2 (M+H + )

[0492] 1 H-NMR (400MHz, CDCl 3 )δ:7.49(d,J=8.4Hz,1H),7.21-7.16(m,4H),6.81(d,J=8.4Hz,1H),4.12-4.08(m,1H),4.05-3.98(m,2H),4.9 2-3.78(m,8H),3.52-3.40(m,4H),2.88-2.82(m,2H),2.80-2.74(m,3H),2.15-1.95(m,3H),1.55-1.50(m,2H).

[0493] Preparation Example 13: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 15)

[0494]

[0495] Int-37 (40 mg, 0.1 mmol) was dissolved in DCM (5 mL), and TEA (30 mg, 0.3 mmol) was added. Dimethylsulfamoyl chloride (29 mg, 0.2 mmol) was added at 0°C. After reacting at 25°C for 2 hours, the product was directly purified by concentrator chromatography (methanol: DCM = 1:50) to obtain 35 mg of the product with a yield of 70.0%.

[0496] Molecular formula: C 25 H 33 N 3 O 5 S 2Molecular weight: 519.7 LC-MS (M / e): 520.2 (M+H + )

[0497] 1 H-NMR(400MHz,DMSO)δ:7.57-7.55(m,1H),7.19-7.17(m,4H),7.07-7.05(m,1H),4.01-4.00(m,2H),3.83-3.80(m,6H),3.6 0-3.57(m,2H),3.51-3.48(m,2H),3.35-3.30(m,2H),2.87-2.82(m,2H),2.73(s,6H),1.97-1.81(m,3H),1.35-1.29(m,2H).

[0498] Preparation Example 14: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 16)

[0499]

[0500] 1. Preparation of S-(2-((tert-butyldimethylsilyl)oxy)ethyl)ethanethiol (Int-64)

[0501] Dissolve (2-bromoethoxy)(tert-butyl)dimethylsilane (Int-63) (5.0 g, 20.9 mmol) in DMF (50 mL), add potassium thioacetate (2.4 g, 21.0 mmol), heat the system to 80 ° C and react for 1 h. After concentration, 4.6 g of the target product is obtained with a yield of 93.9%.

[0502] 2. Preparation of 2-((tert-butyldimethylsilyl)oxy)ethane-1-sulfonyl chloride (Int-65)

[0503]

[0504] Int-64 (1.0 g, 4.3 mmol) was dissolved in acetonitrile (10 mL) and water (5 mL), acetic acid (0.5 mL) and dichlorohydantoin (850 mg, 4.3 mmol) were added, the system was reacted at 0°C for 1 h, and concentrated to obtain the crude target compound Int-65.

[0505] 3. Preparation of tert-butyl 4-((4-bromobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-67)

[0506] 4-Bromobenzo[b]thiophene-7-ol (Int-66) (750 mg, 3.3 mmol) was dissolved in acetonitrile (25 mL), and potassium carbonate (1.0 g, 7.2 mmol) and tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.3 g, 3.9 mmol) were added. The system was heated to 85°C and reacted for 3 h. After concentration, the target product (1.2 g) was obtained by column chromatography (EA:PE=1:1) with a yield of 86.0%.

[0507] 4. Preparation of tert-butyl 4-(((4-bromo-1,1-dioxybenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-68)

[0508] Int-67 (1.1 g, 2.6 mmol) was dissolved in DCM (30 mL), and m-CPBA (1.4 g, 8.1 mmol) was added. The system was reacted at 25°C for 1 h, and then ethyl acetate was added for extraction. The concentrated residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 1.1 g of the target compound in a yield of 93.0%.

[0509] 5. Preparation of tert-butyl 4-(((4-(hydroxymethyl)-1,1-dioxidobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-69)

[0510] Int-68 (1.0 g, 2.2 mmol) was dissolved in 1,4-dioxane (30 mL), and XphosPdG2 (350 mg, 0.44 mmol) and Int-9 (850 mg, 2.06 mmol) were added. The mixture was reacted at 90°C for 2 h. The concentrated residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 850 mg of the target compound. The yield was 95.2%.

[0511] 6. Preparation of tert-butyl 4-((((methylsulfonyl)oxy)methyl)-1,1-dioxidobenzo[b]thiophen-7-yl)oxymethyl)piperidine-1-carboxylate (Int-70)

[0512] Int-69 (800 mg, 2.0 mmol) was dissolved in DCM (10 mL), and methanesulfonyl chloride (230 mg, 2.0 mmol) and TEA (250 mg, 2.5 mmol) were added, and the mixture was reacted at 25°C for 1 h. Water was added to quench the mixture, and ethyl acetate was added to extract the mixture. The concentrated crude product was directly used in the next step.

[0513] 7. Preparation of tert-butyl 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxidobenzo[b]thiophen-7-yl)oxy)methyl)piperidine-1-carboxylate (Int-71)

[0514] Int-70 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline (320 mg, 2.1 mmol) and potassium carbonate (700 mg, 5.1 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and ethyl acetate was added to extract the mixture, and the mixture was concentrated. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 850 mg of the target compound, with a two-step yield of 85.2%.

[0515] 8. Preparation of 4-(isoindolin-2-ylmethyl)-7-(piperidin-4-ylmethoxy)benzo[b]thiophene 1,1-dioxide hydrochloride (Int-72)

[0516] Int-71 (350 mg, 0.69 mmol) was dissolved in DCM (5 mL), HCl / dioxane (5 mL) was added, and the mixture was reacted at 25°C for 1 h. The mixture was concentrated and the crude product was directly used in the next step.

[0517] 9. Preparation of 7-((1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)piperidin-4-yl)methoxy)-4-(isoindolin-2-ylmethyl)benzo[b]thiophene 1,1-dioxide (Int-73)

[0518] Int-72 (the crude product of the previous step) was dissolved in DCM (20 mL), and 2-((tert-butyldimethylsilyl)oxy)ethane-1-sulfonyl chloride (200 mg, 0.77 mmol) and TEA (210 mg, 2.1 mmol) were added, and the mixture was reacted at 25° C. for 1 h. Water was added to quench the mixture, and ethyl acetate was added to extract the mixture. The concentrated residue was subjected to column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain 100 mg of the target compound, with a two-step yield of 23.1%.

[0519] 10. Preparation of 7-((1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)methoxy)-4-(isoindolin-2-ylmethyl)benzo[b]thiophene 1,1-dioxide (Compound 16)

[0520] 7-((1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)piperidin-4-yl)methoxy)-4-(isoindolin-2-ylmethyl)benzo[b]thiophene 1,1-dioxide (60 mg, 0.095 mmol) was dissolved in THF (5 mL), tetrabutylammonium fluoride (0.3 mL, 0.3 mmol) was added, and the mixture was reacted at 25°C for 1 h. Water was added to quench the mixture, ethyl acetate was added to extract the mixture, and the residue was concentrated and subjected to column chromatography (MeOH:DCM=1:25) to obtain 17 mg of the target compound, with a yield of 31.1%.

[0521] Molecular formula: C 25 H 30 N2 O 6 S 2 Molecular weight: 518.6 LC-MS (M / e): 519.1 (M+H + )

[0522] 1 H-NMR (400MHz, CDCl 3 )δ: 7.63-7.61(m,1H),7.48-7.46(m,1H),7.19-7.18(m,4H),6.93(s,1H),6.61(s,1H),4.12-3.96(m,4H),3.92-3.82(m ,7H),3.22-3.20(m,2H),2.97-2.87(m,2H),2.22-2.01(m,1H),2.00-1.95(m,2H),1.60-1.55(m,2H),1.30-1.26(m,2H).

[0523] Preparation Example 15: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 17)

[0524]

[0525] Int-72 (crude, 0.59 mmol) was dissolved in DMF (10 mL), and N-methyl-1H-imidazole-1-carboxamide (85 mg, 0.68 mmol) and potassium carbonate (200 mg, 1.4 mmol) were added, and the mixture was reacted at 50°C for 1 h. Water was added to quench the mixture, and ethyl acetate was added to extract the mixture. The residue was concentrated and subjected to column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 15 mg of the target compound, with a two-step yield of 5.5%.

[0526] Molecular formula: C 25 H 29 N 3 O 4 S molecular weight: 467.6 LC-MS (M / e): 468.2 (M+H + )

[0527] 1 H-NMR (400MHz, CDCl 3)δ: 7.63-7.61(m,1H),7.48-7.46(m,1H),7.19-7.18(m,4H),6.93(s,1H),6.61(s,1H),4.42-4.38(m,1H),4.08-4.01(m ,1H),4.00-3.97(m,3H),3.91-3.81(m,6H),2.92-2.81(m,5H),2.20-2.12(m,1H),1.99-1.92(m,2H),1.30-1.26(m,2H).

[0528] Preparation Example 16: Preparation of 4-(((4-(isoindolin-2-ylmethyl)-1,1-dioxido-2,3-dihydrobenzothiophen-7-yl)oxy)methyl)piperidine-1-sulfonamide (Compound 20)

[0529]

[0530] The hydrochloride of Int-37 (0.14 mmol) and TEA (69 mg, 0.68 mmol) were dissolved in DCM (10 mL), cooled to 0°C, and aminosulfonyl chloride (24 mg, 0.21 mmol) was added, and the reaction was continued for 1 hour. After the reaction was completed, it was concentrated, diluted with (dichloromethane: methanol = 10: 1), filtered to remove the solid, and purified by PREP-TLC (dichloromethane: methanol = 27: 1) to obtain 15 mg of the target product with a yield of 22.3%.

[0531] Molecular formula: C 23 H 29 S 2 N 3 O 5 Molecular weight: 491.6 LC-MS (m / z): 492.2 (M+H + )

[0532] 1 H-NMR (400MHz, CDCl 3 )δ:7.50(d,J=8.4Hz,1H),7.24-7.14(m,4H),6.81(d,J=8.4Hz,1H),4.46(s,2H),4.02(d,J=5.6Hz,2H),3 .92-3.77(m,8H),3.49-3.35(m,4H),2.85(dt,J=2.6,12.0Hz,2H),2.15-1.95(m,3H),1.75-1.55(m,2H).

[0533] The compounds shown in the following table were prepared using the same or similar methods as the above preparation examples:

[0534]

[0535] 2. Pharmacological Activity Test of the Compounds of the Invention

[0536] The beneficial effects of the compounds of the present invention are further described below through pharmacological experimental examples, but this should not be understood as the compounds of the present invention having only the following beneficial effects.

[0537] Experimental Example 1: In vitro enzymatic activity of the compounds of the present invention

[0538] This experiment evaluates the inhibitory effect of the inventive compounds on CYP11A1 by detecting the biosynthesis of pregnenolone.

[0539] Test sample: The compound of the present invention, its structural formula and preparation method are shown in the preparation examples.

[0540] Positive control drug: Orion's CYP11A1 inhibitor ODM-208

[0541]

[0542] Experimental reagents:

[0543]

[0544] Experimental method (ELISA assay):

[0545] 1. Cell Preparation

[0546] Cells were grown in NCI-H295R special culture medium. Cells in the logarithmic growth phase were harvested and cell viability was detected by trypan blue exclusion method to ensure that the cell viability was above 90%. Cells were counted using an automatic cell counter and the cell suspension was adjusted to an appropriate concentration. 95 μL of cell suspension was added to each 96-well plate and incubated at 37°C, 5% CO 2 Incubate overnight.

[0547] 2. Compound dilution

[0548] 1) The compounds of the present invention and the positive control drug were prepared with DMSO to 10 mM as test stock solutions.

[0549] 2) Dilute the test stock solution 100 times to 100 μM as the test working solution.

[0550] 3) The test working solution was diluted 3-fold to 8 concentrations, with the highest concentration being 100 μM.

[0551] 4) The final concentrations of the test compounds were 100 nM, 33.33 nM, 11.11 nM, 3.704 nM, 1.235 nM, 0.412 nM, 0.137 nM, and 0.046 nM.

[0552] 3. Pregnenolone biosynthesis detection

[0553] 1) Add 5 μL of compound to the 96-well plate containing the cell suspension and incubate at 37°C, 5% CO 2 Incubate for 24 hours.

[0554] 2) Centrifuge the 96-well plate, transfer 80 μL of the supernatant into a new 96-well plate, and dilute 8 times with culture medium.

[0555] 3) Prepare pregnenolone-HRP conjugate working solution and wash buffer.

[0556] 4) Take out the required number of enzyme label strips.

[0557] 5) Add 50 μL of each standard, positive control drug and sample to the corresponding labeled wells in duplicate.

[0558] 6) Add 100 μL of pregnenolone-HRP conjugate working solution to each well.

[0559] 7) Incubate at room temperature on an orbital shaker at approximately 200 rpm for 1 hour.

[0560] 8) Wash each well three times with 300 μL of diluted washing buffer and pat dry on clean absorbent paper.

[0561] 9) Add 150 μL TMB substrate to each well.

[0562] 10) Incubate on an orbital shaker at room temperature for 10-15 minutes.

[0563] 11) At the same time intervals as in step 10, add 50 μL of stop solution to each well.

[0564] 3. Result detection

[0565] 1) Within 20 minutes after adding the stop solution, read the OD value at a wavelength of 450 nm using a multifunctional microplate reader.

[0566] 2) Collect data.

[0567] 4. Data Analysis

[0568] The inhibition rate (%inh) was calculated using the following formula:

[0569] Inhibition rate (%inh) = 100-(Signal cmpd-Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )*100

[0570] Among them, Signal cmpd It means: the concentration of pregnenolone after treatment with the test compound;

[0571] Signal Ave_PC Indicates: Pregnenolone concentration in the positive control wells after treatment with the highest concentration of the positive control drug (100 nM);

[0572] Signal Ave_VC Indicates: pregnenolone concentration in negative control wells without compound treatment;

[0573] Experimental results:

[0574] Table 1 Inhibitory activity of the compounds of the present invention on CYP11A1

[0575] Compound <![CDATA[IC 50 (nM)]]> Compound 1 13.35 Compound 6 2.41

[0576] It can be seen from the above experimental results that the compounds of the present invention can effectively inhibit the enzyme activity of CYP11A1 and are effective CYP11A1 inhibitors.

[0577] Experimental Example 2: In vitro enzymatic activity of the compounds of the present invention

[0578] Test sample: The compound of the present invention, its structural formula and preparation method are shown in the preparation examples.

[0579] Experimental method (ELISA assay):

[0580] 1. Cell Preparation

[0581] Cells were grown in NCI-H295R special culture medium. Cells in the logarithmic growth phase were harvested and cell viability was detected by trypan blue exclusion method to ensure that the cell viability was above 90%. Cells were counted using an automatic cell counter and the cell suspension was adjusted to an appropriate concentration. 90 μL of cell suspension was added to each 96-well plate and incubated at 37°C, 5% CO 2 Incubate overnight.

[0582] 2. Compound dilution

[0583] 1) The compounds of the present invention and the positive control drug were prepared with DMSO to 10 mM as test stock solutions.

[0584] 2) Dilute the test stock solution 100 times to 100 μM as the test working solution.

[0585] 3) The experimental working solution was diluted 4-fold to 6 concentrations, with the highest concentration being 100 μM.

[0586] 4) The final concentrations of the test compounds were 100 nM, 25 nM, 6.25 nM, 1.56 nM, 0.39 nM, 0.098 nM, and 0 nM.

[0587] 3. Pregnenolone biosynthesis detection

[0588] 1) Add 10 μL of compound to the 96-well plate containing the cell suspension and incubate at 37°C, 5% CO 2 Incubate for 24 hours.

[0589] 2) Centrifuge the supernatant, transfer 10 μL of the supernatant into a new 96-well plate, and dilute 8 times with culture medium.

[0590] 3) Prepare pregnenolone-HRP conjugate working solution and wash buffer.

[0591] 4) Take out the required number of enzyme label strips.

[0592] 5) Add 50 μL of each standard, positive control drug and sample to the corresponding labeled wells in duplicate.

[0593] 6) Add 100 μL of pregnenolone-HRP conjugate working solution to each well.

[0594] 7) Incubate at room temperature on an orbital shaker at approximately 200 rpm for 1 hour.

[0595] 8) Wash each well three times with 300 μL of diluted washing buffer and pat dry on clean absorbent paper.

[0596] 9) Add 150 μL TMB substrate to each well.

[0597] 10) Incubate on an orbital shaker at room temperature for 10-15 minutes.

[0598] 11) At the same time intervals as in step 10, add 50 μL of stop solution to each well.

[0599] 3. Result detection

[0600] 1) Within 20 minutes after adding the stop solution, read the OD value at a wavelength of 450 nm using a multifunctional microplate reader.

[0601] 2) Collect data.

[0602] 4. Data processing

[0603] 1) Inhibition rate (%) = 1-(test substance well concentration - blank control well concentration) / (DMSO solvent control well concentration - blank control well concentration) × 100%;

[0604] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0605] Experimental results:

[0606] Table 2 Inhibitory activity of the compounds of the present invention on CYP11A1

[0607] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM) <!-- 40 -->]]> Compound 2 B Compound 12 B Compound 5 A Compound 13 A Compound 7 A Compound 14 A Compound 8 B Compound 15 A Compound 9 B Compound 16 A Compound 10 A Compound 17 B Compound 11 A Compound 20 A

[0608] Among them, A:IC 50 <10nM; B: 10nM≤IC 50 <100nM C: 100nM≤IC 50 <200nM; D: 200nM≤IC 50 <1 μM.

[0609] It can be seen from the above experimental results that the compounds of the present invention can effectively inhibit the enzyme activity of CYP11A1 and are effective CYP11A1 inhibitors.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, in, X1 is selected from C(O), S(O) or S(O)2; when When it is a single bond, X2 is selected from CR a R b or NR c , X3 is selected from CR a’ R b’ ; when When it is a double bond, X2 is selected from CR a or N, X3 selected from CR a’ ; X4 and X5 are independently selected from CR or N; L1 is absent or 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 is absent or 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 at each occurrence is independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, 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, -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, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 or the following groups optionally substituted by 1 to 4 substituents: -(CH2) t -3-10 membered cycloalkyl, -(CH2) t -3-10 membered heterocyclic group, -(CH2) t -5-10 membered heteroaryl, -(CH2) t -6-10 membered aromatic 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 a , R b , R c , R a’ , R b’ , 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 occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy; or, R 5a , R 5b Together with the N to which it is attached, it forms a 3-7 membered heterocycloalkyl or 5-6 membered heteroaryl group optionally substituted by 1-2 Q; the substituent Q is independently selected from 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy or cyano C 1-6 Alkoxy; m, n, t are independently selected from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein: X1 is selected from C(O), S(O) or S(O)2; when When it is a single bond, X2 is selected from CR a R b or NR c , X3 is selected from CR a’ R b’ ; when When it is a double bond, X2 is selected from CR a or N, X3 selected from CR a’ ; X4 and X5 are independently selected from CR or N; L1 is absent or selected from -CHR 1a -、-CHR 1a -CHR 1a’ -; L2 is absent or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -; X is selected from O, S or NH; Ring A is selected from an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group; Ring B is selected from a 5-6 membered monocycloalkyl group or a 5-6 membered monoheterocyclic group; R is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -NR 4a R 4b 、-OR 4a ; R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, oxo, C 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 at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 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 a , R b , R c , R a’ , R b’ , R 1a , R 1a’ , R 2a , R 2a’ , R 2a” , R 4a , R 4b is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy; or, R 5a , R 5b Together with the N to which it is attached, it forms a 4-6 membered heterocycloalkyl optionally substituted by 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkoxy or amino C 1-6 Alkoxy; m and n are independently selected from 0, 1, 2 or 3; p is selected from 0, 1 or 2.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has the structure of general formula (II-1) or general formula (II-2), in, L1, L2, X, X2, X3, X4, X5, R1, R2, Ring A, Ring B, m, n, p, The definition as described in any one of claims 1 or 2.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein: when When it is a single bond, X2 is selected from CHR a or NR c , X3 is selected from CHR a’ ; when When it is a double bond, X2 is selected from CR a or N, X3 selected from CR a’ ; L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -; L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -; X4 and X5 are independently selected from CR or N; Ring A is selected from Preferably, ring A is Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; preferably, ring B is piperidinyl; R at each occurrence is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -OR 4a ; R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, oxo, C 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 at each occurrence from hydrogen, halogen, hydroxy, cyano, oxo, C 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 a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, halogen, 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 is independently selected at each occurrence from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; R 5a , R 5b Each occurrence is independently selected from hydrogen, halogen, hydroxy, 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, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy; or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or amino C 1-6 alkyl; m and n are independently selected from 0, 1, 2 or 3; p is selected from 0, 1 or 2.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its ester or its stereoisomer, which has the structure shown in the general formula (III-1) or the general formula (III-2), in, L1, L2, X2, X3, X4, X5, R1, R2, m, n, p, The definition as described in any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein: X4 is selected from CH or N; L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -; L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -; R1 is independently selected at each occurrence from hydrogen, halogen, cyano, C 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 at each occurrence from hydrogen, halogen, hydroxy, cyano, C 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 -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 a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R a , R c , R a’ , R 1a , R 1a’ , R 2a , R 2a’ is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl or cyano C 1-4 Alkyl; preferably, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl or cyanopropyl; R 5b Each occurrence is independently selected from hydrogen or C 1-4 Alkyl; preferably, R 5b is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl or isopropyl; Or, R 5a , R 5b Together with the N to which it is attached, it forms an azetidinyl group optionally substituted with 1-2 Q; the substituent Q is independently selected from hydroxyl, C 1-6 Alkyl or hydroxyl C 1-6 alkyl.

7. The following compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, the compound is selected from:

8. A pharmaceutical preparation containing the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its ester or its stereoisomer, characterized in that: Containing one or more pharmaceutically acceptable excipients, the pharmaceutical preparation is in any pharmaceutically acceptable dosage form.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its ester or its stereoisomer, characterized in that: Contains one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

10. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the pharmaceutical preparation according to claim 8, or the pharmaceutical composition according to 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 conditions and diseases; preferably, the diseases and related conditions mediated by CYP11A1 are androgen receptor-dependent conditions and diseases; preferably, the diseases and related conditions mediated by CYP11A1 are cancer.

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