CYP11A1 inhibitor and application thereof

Abstract

The invention belongs to the technical field of medicine. Particularly, the invention relates to a compound capable of being used as a CYP11A1 inhibitor, pharmaceutically acceptable salt, ester or stereoisomer of the compound, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer of the compound, and a preparation. 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, their pharmaceutically acceptable salts, their deuterated products, their esters and stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, their pharmaceutically acceptable salts, their deuterated products, their esters and stereoisomers thereof, and uses of the compounds, their pharmaceutically acceptable salts, their deuterated products, their 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 compound with novel structure and 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), a pharmaceutically acceptable salt, a deuterated substance, an ester or a stereoisomer thereof:

[0008]

[0009] in,

[0010] X1 and X2 are independently selected from CR a or N;

[0011] Y is selected from -S(O)2- or -C(O)-;

[0012] 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-;

[0013] 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” -;

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

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

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

[0017] R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 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 , -S(O)NR 4a R 4b , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocyclic group, -(CH2) p -5-10 membered heteroaryl, -(CH2) p -6-10 membered aryl; each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0018] or R1, R2 together with the N atom to which they are attached form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group optionally substituted by 1-4 Q2; each Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0019] R3 and R4 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 group optionally substituted by 1-4 Q3: -(CH2) t -3-10 membered cycloalkyl, -(CH2) t -3-10 membered heterocyclic group, -(CH2) t -5-10 membered heteroaryl, -(CH2) t -6-10 membered aryl; each Q3 is independently 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;

[0020] R a , R 1a , R 1a’ , R1b , R 1b’ , R 1c , R 2a , R 2b , R 2a’ , R 2b’ , R 2a” , R 2b” , 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, 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, -(CH2) s -3-10 membered cycloalkyl, -(CH2) s -3-10 membered heterocycloalkyl, -(CH2) s -5-10 membered heteroaryl or -(CH2) s -phenyl;

[0021] R 5a , R 5b is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy or the following group optionally substituted by 1-4 Q4: -(CH2) s -3-10 membered cycloalkyl, -(CH2) s -3-10 membered heterocycloalkyl, -(CH2) s -5-10 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0022] m, n, p, t, s are independently selected from 0, 1, 2, 3 or 4.

[0023] In certain embodiments, in the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, X is selected from O, S or NH.

[0024] In certain embodiments, in the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein X is selected from O or S.

[0025] In certain embodiments, in the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein X is O.

[0026] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein Y is selected from -S(O)2-.

[0027] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein ring A is selected from 5-12-membered cycloalkyl, 5-12-membered heterocyclic group, 6-12-membered aryl or 5-12-membered heteroaryl; preferably, ring A is selected from 5-6-membered monocyclic alkyl, 7-12-membered fused ring group, 7-12-membered spirocyclic group, 7-12-membered bridged ring group, 5-6-membered monoheterocyclic group, 7-12 membered fused heterocyclic group, 7-12 membered spiroheterocyclic group, 7-12 membered bridged heterocyclic group, 5-6 membered monoheteroaryl, 7-12 membered fused heteroaryl, 7-12 membered spiroheteroaryl, 7-12 membered bridged heteroaryl or phenyl; preferably, ring A is selected from 8-10 membered fused heterocyclic group or 8-10 membered fused heteroaryl; more preferably, ring A is selected from 8-10 membered nitrogen-containing fused heterocyclic group or 8-10 membered nitrogen-containing fused heteroaryl.

[0028] In certain embodiments, Ring A is selected from

[0029] 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.

[0030] In certain embodiments, Ring B is selected from cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, or piperazinyl.

[0031] In certain embodiments, Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, or piperazinyl.

[0032] In certain embodiments, Ring B is selected from cyclohexyl, piperidinyl, or piperazinyl.

[0033] In certain embodiments, Ring B is selected from cyclohexyl or piperidinyl.

[0034] In certain embodiments, R1 and R2 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 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 , -S(O)NR 4a R 4b , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocyclic group, -(CH2) p -5-10 membered heteroaryl, -(CH2) p-6-10 membered aryl; each Q1 is independently 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.

[0035] In certain embodiments, R1 and R2 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 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 , -S(O)NR 4a R 4b , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, -(CH2) p -5-6 membered heteroaryl, -(CH2) p -phenyl; each Q1 is independently 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.

[0036] In certain embodiments, R1 and R2 are independently selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -OR 4a , -SR 4a , -C(O)R 4a , -C(O)NR 4aR 4b , -C(O)OR 4a , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following groups optionally substituted by 1 to 3 substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic 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.

[0037] In certain embodiments, R1 and R2 are independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -OR 4a or the following group optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently 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.

[0038] In certain embodiments, R1 is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -OR 4a or the following group optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently 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; R2 is selected from hydrogen, C 1-6 Alkyl or -OR 4a .

[0039] In certain embodiments, R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;

[0040] R2 is selected from hydrogen or C 1-6 alkyl.

[0041] In certain embodiments, R1 is selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-4 membered cycloalkyl or 3-4 membered heterocyclic group;

[0042] R2 is selected from hydrogen or C 1-6 alkyl.

[0043] In certain embodiments, R1 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, or cyclobutyl;

[0044] R2 is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0045] In certain embodiments, R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted by 1-4 Q2, each Q2 being independently 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.

[0046] In certain embodiments, R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-2 Q2, each Q2 being independently 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.

[0047] In certain embodiments, R1, R2 together with the N atom to which they are attached form an aziridine, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with 1-2 Q2, each Q2 being independently 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.

[0048] In certain embodiments, R1, R2 together with the N atom to which they are attached form aziridine, azetidinyl, pyrrolidinyl or piperidinyl.

[0049] In certain embodiments, R3 and R4 are each 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 , -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 , -S(O)2R 5a or the following group optionally substituted by 1-4 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently 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.

[0050] In certain embodiments, R3 at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl 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)2NR5a R 5b or -S(O)2R 5a .

[0051] In certain embodiments, R3 at each occurrence is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0052] In certain embodiments, R3 at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, or carboxyl.

[0053] In certain embodiments, R3 is cyano.

[0054] In certain embodiments, R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 group optionally substituted by 1-4 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently 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.

[0055] In certain embodiments, R4 at each occurrence is independently selected from hydrogen, halogen, amino, cyano, -C(O)R 5a , -C(O)NR 5a R5b , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -phenyl, -(CH2) t -pyridyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0056] In certain embodiments, R4 at each occurrence is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, -C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O)2NR 5a R 5b 、-S(O)2R 5a or the following groups optionally substituted by 1-2 Q3: phenyl or pyridyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0057] In certain embodiments, R4 at each occurrence is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, -C(O)R 5a 、-C(O)NR 5a R 5b 、-C(O)OR 5a 、-S(O)2NR 5a R 5b 、-S(O)2R 5a , phenyl or pyridyl.

[0058] In certain embodiments, R a , 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 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.

[0059] In certain embodiments, R a , 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.

[0060] In certain embodiments, R a , 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.

[0061] In certain embodiments, R 5ais independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy or the following group optionally substituted by 1-3 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently 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 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.

[0062] In certain embodiments, R 5a is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl or the following group optionally substituted by 1-3 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R 5b are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0063] In certain embodiments, 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, -(CH2) s -3-10 membered cycloalkyl, -(CH2) s -3-10 membered heterocycloalkyl, -(CH2) s -5-10 membered heteroaryl or -(CH2) s -phenyl.

[0064] 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, -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; 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.

[0065] 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 1-6Alkyl, cyano C 1-6 Alkyl, -(CH2) s -3-6 membered cycloalkyl or -(CH2) s -3-6 membered heterocycloalkyl; R 5b are independently selected at each occurrence from hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0066] In certain embodiments, R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl or the following group optionally substituted by 1-2 Q4: -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R 5b are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0067] In certain embodiments, R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 alkyl or the following groups optionally substituted by 1-2 Q4: 3-6 membered heterocycloalkyl, pyridyl or phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R 5b are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0068] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein:

[0069] X1 and X2 are independently selected from CR a or N;

[0070] Y is selected from -S(O)2- or -C(O)-;

[0071] L1 is absent or selected from -CHR 1a -、-CHR 1a -CHR 1a’ -;

[0072] L2 is absent or selected from -CHR 2a -、-CHR 2a -CHR 2a’ -、-CHR 2a -CHR 2a’ -CHR 2a” -;

[0073] Ring A is selected from an 8-10 membered nitrogen-containing fused heterocyclic group or an 8-10 membered nitrogen-containing fused heteroaryl group;

[0074] Ring B is selected from a 5-6 membered monocycloalkyl group or a 5-6 membered monoheterocyclic group;

[0075] R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -OR 4a , -SR 4a , -C(O)R 4a , -C(O)NR 4a R 4b , -C(O)OR 4a , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, -(CH2) p -5-6 membered heteroaryl, -(CH2) p -phenyl; each Q1 is independently 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;

[0076] or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-4 Q2; each Q2 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0077] R3 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 ;

[0078] R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 , -S(O)2R 5a or the following group optionally substituted by 1-4 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently 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;

[0079] R a, 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;

[0080] R 5a , R 5b is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy or the following group optionally substituted by 1-4 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently 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;

[0081] m, n, s, p, t are each independently selected from 0, 1, 2 or 3.

[0082] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein:

[0083] X1 and X2 are independently selected from CR a or N;

[0084] Y is selected from -S(O)2- or -CO-;

[0085] L1 is selected from -CHR1a -or-CHR 1a -CHR 1a’ -;

[0086] L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0087] Ring A is selected from Preferably, ring A is

[0088] Ring B is selected from cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; preferably, ring B is cyclohexyl, piperidinyl or piperazinyl;

[0089] R1 and R2 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, -OR 4a or the following group optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0090] or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently 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;

[0091] R3 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 R5b or -S(O)2R 5a ;

[0092] R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 1-4 Alkyl, haloC 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 , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0093] 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 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;

[0094] R 5a is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, deuterated C 1-4Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl or the following group optionally substituted by 1-3 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0095] R 5b are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy;

[0096] m, n, s, p, t are each independently selected from 0, 1, 2 or 3.

[0097] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer has a structure shown in the general formula (II),

[0098]

[0099] Wherein, the definitions of L1, L2, X1, X2, R1, R2, R3, R4, m, and n are as described in any of the above schemes.

[0100] In certain embodiments, the compound of the aforementioned general formula (I), general formula (II), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, an ester thereof, or a stereoisomer thereof has a structure shown in general formula (III),

[0101]

[0102] Wherein, the definitions of L1, L2, X1, X2, R1, R2, R3, R4, and m are as described in any of the above schemes.

[0103] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer has a structure shown in the general formula (IV),

[0104]

[0105] Wherein, the definitions of L1, L2, X1, X2, R1, R2, R3, R4, m, and n are as described in any of the above schemes.

[0106] In certain embodiments, the compound of the aforementioned general formula (I) or general formula (IV), its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer has a structure shown in general formula (V),

[0107]

[0108] Wherein, the definitions of L1, L2, X1, X2, R1, R2, R3, R4, and m are as described in any of the above schemes.

[0109] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), pharmaceutically acceptable salts thereof, deuterated substances thereof, esters thereof, or stereoisomers thereof, wherein:

[0110] X1 from CR a or N;

[0111] X2 for CR a ;

[0112] L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -;

[0113] L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -;

[0114] R1 is selected from hydrogen, halogen, 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, -OR 4a or the following group optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, each Q1 is independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0115] R2 is selected from hydrogen, C 1-6 Alkyl or -OR 4a ;

[0116] or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently selected from halogen, hydroxyl, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0117] R3 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, R3 is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ;

[0118] R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, C 1-4 Alkyl, haloC 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 or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4Alkoxy;

[0119] Preferably, R4 at each occurrence is independently selected from hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)R 5a , -C(O)NR 5a R 5b , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0120] R a , R 1a , R 1a’ , R 2a , R 2a’ , R 4a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R a , R 1a , R 1a’ , R 2a , R 2a’ , R 4a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0121] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, cyano C 1-4 Alkyl, or the following group optionally substituted by 1-2 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl, -(CH2)s -phenyl; preferably, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, or the following groups optionally substituted with 1-2 Q4: -(CH2) s -cyclopropyl, -(CH2) s -cyclobutyl, -(CH2) s -cyclopentyl, -(CH2) s -cyclohexyl, -(CH2) s -aziridine, -(CH2) s -azetidinyl, -(CH2) s -pyrrolidinyl, -(CH2) s -imidazolidinyl, -(CH2) s -piperidinyl, -(CH2) s -piperazinyl, -(CH2) s -morpholinyl, -(CH2) s -Oxypropyl, -(CH2) s -Oxetane, -(CH2) s -tetrahydrofuranyl, -(CH2) s -tetrahydropyranyl, -(CH2) s -pyridyl, -(CH2) s -pyrimidinyl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0122] 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;

[0123] m, p, t, s are independently selected from 0, 1 or 2.

[0124] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), pharmaceutically acceptable salts thereof, deuterated substances thereof, esters thereof, or stereoisomers thereof, wherein:

[0125] X1 is selected from CH or N;

[0126] X2 is CH;

[0127] L1 is -CH2-;

[0128] L2 is selected from -CH2- or -CH2-CH2-;

[0129] R1 is selected from hydrogen, halogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or the following group optionally substituted by 1-2 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0130] R2 is selected from hydrogen or C 1-4 alkyl;

[0131] or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently selected from halogen, hydroxyl, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0132] R3 is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0133] R4 is independently selected at each occurrence from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0134] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl or the following group optionally substituted by 1-2 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl, -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0135] R 5b Each occurrence is independently selected from hydrogen or C 1-4 alkyl;

[0136] m, p, t, s are independently selected from 0, 1 or 2.

[0137] In certain embodiments, the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), pharmaceutically acceptable salts thereof, deuterated substances thereof, esters thereof, or stereoisomers thereof, wherein:

[0138] R1 is selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethyl, difluoromethoxy, trifluoromethoxy or the following groups optionally substituted by 1-2 Q1: -(CH2) p -cyclopropyl, -(CH2) p -cyclobutyl, -(CH2) p -cyclopentyl, -(CH2) p -cyclohexyl, -(CH2) p -aziridine, -(CH2) p -azetidinyl, -(CH2) p -pyrrolidinyl, -(CH2) p -pyrazolidinyl, -(CH2) p -imidazolidinyl, -(CH2) p -piperidinyl or -(CH2) p-piperazinyl; each Q1 is independently selected from halogen, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethyl, difluoromethoxy, trifluoromethoxy;

[0139] R2 is selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0140] Or R1, R2 together with the N atom to which they are attached form an aziridine, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl optionally substituted with 1-3 Q2; each Q2 is independently selected from halogen, hydroxyl, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethyl, difluoromethoxy, trifluoromethoxy;

[0141] R3 is independently selected at each occurrence from hydrogen, halogen, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0142] R4 is independently selected at each occurrence from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a 、-S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -cyclopropyl, -(CH2) t -cyclobutyl, -(CH2) t -cyclopentyl, -(CH2) t -cyclohexyl, -(CH2) t -aziridine, -(CH2) t -azetidinyl, -(CH2) t -pyrrolidinyl, -(CH2) t -pyrazolidinyl, -(CH2) t -imidazolidinyl, -(CH2) t -piperidinyl, -(CH2) t -piperazinyl, -(CH2) t -phenyl, -(CH2) t -pyridyl, -(CH2) t -pyrimidinyl, -(CH2) t -pyrazinyl, -(CH2) t -pyridazinyl;

[0143] Each Q3 is independently selected from halogen, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethyl, difluoromethoxy, trifluoromethoxy;

[0144] R 5a Each occurrence is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, or the following groups optionally substituted with 1-2 Q4: -(CH2) s -cyclopropyl, -(CH2) s -cyclobutyl, -(CH2) s -cyclopentyl, -(CH2) s -cyclohexyl, -(CH2) s -azetidinyl, -(CH2) s -aziridine, -(CH2) s -pyrrolidinyl, -(CH2) s -imidazolidinyl, -(CH2) s -piperidinyl, -(CH2) s -piperazinyl, -(CH2) s -Oxypropyl, -(CH2) s -Oxetane, -(CH2) s -tetrahydrofuranyl, -(CH2) s -pyridyl, -(CH2) s -pyrimidinyl, -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxy, amino, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, monofluoromethyl, difluoromethoxy, trifluoromethoxy;

[0145] R 5b is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl or isopropyl;

[0146] m, p, t, s are independently selected from 0, 1 or 2.

[0147] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein R1 is selected from hydrogen, C 1-6 alkyl or a 3-6 membered cycloalkyl optionally substituted by 1-2 Q1; each Q1 is independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R2 is selected from hydrogen or C 1-4 alkyl.

[0148] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein R1 is selected from hydrogen, methyl or cyclopropyl or cyclobutyl optionally substituted by 1-2 Q1; each Q1 is independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R2 is selected from hydrogen or methyl.

[0149] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein R1, R2 together with the N atom to which they are attached form an azetidinyl or pyrrolidinyl group optionally substituted with 1-3 Q2; each Q2 is independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0150] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated form, its ester or its stereoisomer, wherein R3 is independently selected from hydrogen, halogen, cyano, methyl or trifluoromethyl at each occurrence.

[0151] In certain embodiments, R 4 R4 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 , -S(O)2R 5a or the following group optionally substituted by 1-4 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl or -(CH2) t -phenyl.

[0152] In certain embodiments, R4 at each occurrence is independently selected from hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)R5a , -C(O)NR 5a R 5b , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl.

[0153] In certain embodiments, R4 at each occurrence is independently selected from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -pyrazolyl, -(CH2) t -Imidazolyl, -(CH2) t -pyridyl, -(CH2) t -pyrimidinyl, -(CH2) t -pyrazinyl, -(CH2) t -pyridazinyl or -(CH2) t -phenyl.

[0154] In certain embodiments, R4 at each occurrence is independently selected from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-2 Q3: -(CH2) t -pyridyl or -(CH2) t -phenyl.

[0155] In certain embodiments, R 5ais independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl or the following group optionally substituted by 1-3 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl.

[0156] In certain embodiments, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, cyanomethyl, cyanoethyl, cyanopropyl, or the following groups optionally substituted with 1-2 Q4: -(CH2) s -cyclopropyl, -(CH2) s -cyclobutyl, -(CH2) s -cyclopentyl, -(CH2) s -cyclohexyl, -(CH2) s -aziridine, -(CH2) s -azetidinyl, -(CH2) s -pyrrolidinyl, -(CH2) s -imidazolidinyl, -(CH2) s -piperidinyl, -(CH2) s -piperazinyl, -(CH2) s -morpholinyl, -(CH2) s -Oxypropyl, -(CH2) s -Oxetane, -(CH2) s -tetrahydrofuranyl, -(CH2) s -tetrahydropyranyl, -(CH2) s -pyridyl, -(CH2) s -pyrimidinyl or -(CH2) s -phenyl.

[0157] In certain embodiments, R 5aEach occurrence is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, or the following groups optionally substituted with 1-2 Q4: -(CH2) s -azetidinyl, -(CH2) s -pyrrolidinyl, -(CH2) s -imidazolidinyl, -(CH2) s -piperidinyl, -(CH2) s -piperazinyl, -(CH2) s -morpholinyl, -(CH2) s -Oxetane, -(CH2) s -tetrahydrofuranyl, -(CH2) s -tetrahydropyranyl, -(CH2) s -pyridyl, -(CH2) s -pyrimidinyl or -(CH2) s -phenyl.

[0158] In certain embodiments, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, or the following groups optionally substituted with 1-2 Q4: azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or phenyl; each Q4 is independently selected from halogen, hydroxyl or amino; R 5b is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl.

[0159] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated substance, its ester or its stereoisomer, wherein R4 is independently selected from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0160] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted by 1-2 Q4;

[0161] Each Q4 is independently selected from halogen, hydroxyl or C 1-4 alkyl;

[0162] R 5b Each occurrence is independently selected from hydrogen or C 1-4 alkyl.

[0163] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated substance, its ester or its stereoisomer, wherein R4 is independently selected from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a 、-S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0164] R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl optionally substituted by 1-2 Q4;

[0165] Each Q4 is independently selected from halogen, hydroxyl or C 1-4 alkyl;

[0166] R 5b Each occurrence is independently selected from hydrogen or C 1-4 alkyl.

[0167] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein R4 is independently selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)NR 5a R 5b , -C(O)R 5a , -S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0168] R 5a Each occurrence is independently selected from hydrogen, methyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or cyclobutyl, azetidinyl or oxetanyl optionally substituted with 1-2 Q4;

[0169] Each Q4 is independently selected from halogen, hydroxyl or methyl;

[0170] R 5b In certain embodiments, the aforementioned compounds, pharmaceutically acceptable salts thereof, deuterated substances thereof, esters thereof or stereoisomers thereof, wherein R4 is independently selected from methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a 、-S(O)2NR 5a R 5b or -S(O)2R 5a ;

[0171] R 5a is independently selected at each occurrence from hydrogen, methyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or cyclobutyl, azetidinyl, oxetanyl, cyclopentyl, pyrrolidinyl, phenyl, pyridinyl or pyrimidinyl optionally substituted with 1-2 Q4;

[0172] Each Q4 is independently selected from halogen, hydroxyl or methyl;

[0173] R 5b Each occurrence is independently selected from hydrogen or methyl.

[0174] In certain embodiments, R3 is selected from hydrogen or cyano.

[0175] In certain embodiments, m is selected from 0 or 1.

[0176] In certain embodiments, n is selected from 0 or 1.

[0177] In certain embodiments, p is selected from 0 or 1.

[0178] In certain embodiments, t is selected from 0 or 1.

[0179] In certain embodiments, s is selected from 0 or 1.

[0180] In certain embodiments, the aforementioned compound, its pharmaceutically acceptable salt, its deuterated substance, its ester or its stereoisomer is selected from the following compounds:

[0181]

[0182]

[0183] The present invention also provides a pharmaceutical composition comprising a compound of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), a pharmaceutically acceptable salt thereof, a deuterated product thereof, an ester thereof or a stereoisomer thereof, 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.

[0184] 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.

[0185] 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.

[0186] On the other hand, the present invention also relates to the use of the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), their pharmaceutically acceptable salts, deuterated substances, esters or stereoisomers thereof in the preparation of drugs for preventing and / or treating diseases mediated by CYP11A1 and related diseases, wherein the drugs 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 requiring inhibition of CYP11A1; in particular, the diseases and related conditions mediated by CYP11A1 are androgen receptor-dependent conditions and diseases requiring inhibition of CYP11A1. The diseases and related conditions are cancers, including carcinoma in situ and metastatic cancers.

[0187] In certain embodiments, the cancer is selected from prostate cancer or breast cancer. The prostate cancer includes but is not limited to hormone-sensitive prostate cancer (HSPC), metastatic hormone-sensitive prostate cancer (mHSPC), non-metastatic hormone-sensitive prostate cancer (nmHSPC), castration-resistant prostate cancer (CRPC), metastatic castration-resistant prostate cancer (mCRPC).

[0188] In certain embodiments, the cancer is selected from castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, or breast cancer.

[0189] Furthermore, the present invention also relates to the use of the compounds of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), their pharmaceutically acceptable salts, deuterated substances, 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 mediated by CYP11A1 and related conditions.

[0190] On the other hand, the present invention relates to the compounds described in the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), their pharmaceutically acceptable salts, deuterated substances, esters or stereoisomers thereof, which can be administered alone or used in combination with one or more second therapeutically active agents, which are combined with the CYP11A1 inhibitor compounds 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 therapeutically active agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

[0191] 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.

[0192] In certain embodiments, the components to be combined (e.g., a compound of the present invention, a pharmaceutically acceptable salt thereof, a deuterated substance 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, a deuterated substance 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.

[0193] In another aspect, the present invention also provides a method for treating diseases and related conditions mediated by CYP11A1, the method comprising administering to a patient in need thereof an effective amount of a compound of the aforementioned general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, an ester thereof or a stereoisomer thereof, the aforementioned preparation or pharmaceutical composition; the diseases and related conditions mediated by CYP11A1 are as defined above.

[0194] 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.

[0195]

Definitions and general terms

[0196] 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.

[0197] 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.

[0198] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0199] The "halogen" described in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0200] 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 point of attachment. The substituent is preferably selected from one or more of a deuterium (D) atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. 1-4 The term "alkyl" refers to a specific example of an alkyl group containing 1 to 4 carbon atoms.

[0201] 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.

[0202] The "deuterated C" of the present invention 1-6 Alkyl, hydroxyl 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 1-6One or more hydrogens in the alkyl group are replaced by one or more deuterium, hydroxyl, amino, cyano, halogen or carboxyl groups. 1-6 "Alkyl" is as defined above.

[0203] The "deuterated C" of the present invention 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, halogenated C 1-4 Alkyl, carboxyl C 1-4 "Alkyl" refers to C 1-4 One or more hydrogens in the alkyl group are replaced by one or more deuterium, hydroxyl, amino, cyano, halogen or carboxyl groups. 1-4 "Alkyl" is as defined above.

[0204] The "deuterated C 1-6 Alkoxy, hydroxyl 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" are replaced by one or more deuterium atoms, hydroxyl atoms, amino atoms, cyano atoms or halogen atoms. 1-6 "Alkyl" is as defined above.

[0205] The "deuterated C" of the present invention 1-4 Alkoxy, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy, cyano C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, carboxyl C 1-4 "Alkoxy" refers to C 1-4 One or more hydrogens in the alkoxy group are replaced by one or more deuterium, hydroxyl, amino, cyano, halogen or carboxyl groups. 1-4 "Alkoxy" is as defined above.

[0206] 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 1-6Alkyl-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-,

[0207] 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)2NR 5a R 5b 、-S(O)2R 5a ” refers to

[0208] 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.

[0209] "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:

[0210] 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.

[0211] 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:

[0212] 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.

[0213] 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.

[0214] 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:

[0215] 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

[0216] 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:

[0217] The heterocyclic group also includes the heterocyclic groups as described above (including monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups) fused to aryl, heteroaryl or cycloalkyl rings, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0218] 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.

[0219] 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:

[0220] 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.

[0221] The ring atoms described in the present invention may optionally form a C=O, N=O, S=O or SO2 structure.

[0222] 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.

[0223] The "L1 does not exist" mentioned in the present invention means that ring A is directly connected to the aromatic ring structure.

[0224] The "L2 does not exist" in the present invention means that ring B is directly connected to O.

[0225] The "pharmaceutically acceptable salts" described in the present invention refer to salts formed between acidic functional groups (such as -COOH, -OH, -SO3H, etc.) present in the compound and suitable inorganic or organic cations (bases), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed between basic functional groups (such as -NH2, etc.) present in the compound and suitable inorganic or organic anions (acids), including salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.).

[0226] The "deuterated" or "deuterated substance" mentioned in the present invention refers to the situation where the hydrogen atoms on the alkyl, cycloalkyl, alkylene, aryl, heteroaryl, heterocycloalkyl and other groups are replaced by at least one deuterium atom, and the upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.

[0227] In the general structures (II)-(V), This means that R3 may be substituted at any substitutable position of the heterocyclic group.

[0228] 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 1-20Straight 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).

[0229] 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.

[0230] 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.

[0231] Advantageous Effects of the Invention

[0232] (1) The compounds of the present invention, their pharmaceutically acceptable salts, deuterated substances, esters or stereoisomers thereof have excellent inhibitory activity against CYP11A1 and can treat diseases mediated by CYP11A1 and related diseases;

[0233] (2) The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have good pharmacokinetic properties, longer-lasting effects and high bioavailability;

[0234] (3) The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has good safety;

[0235] (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

[0236] 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.

[0237] 1. Preparation Examples of Compounds of the Present Invention

[0238] DCM: dichloromethane NaH: sodium hydride THF: tetrahydrofuran

[0239] Dioxane: 1,4-dioxaneHCl: Hydrogen chlorideDMF: N,N-dimethylformamide

[0240] EA: Ethyl acetate TEA: Triethylamine PE: Petroleum ether

[0241] MsCl: methanesulfonyl chloride MeOH: methanol SOCl2: thionyl chloride

[0242] DIEA: N,N-diisopropylethylamine TFA: trifluoroacetic acid NaBH4: sodium borohydride

[0243] NCS: N-chlorosuccinimide Pd2dba3: tris(dibenzylideneacetone)dipalladium

[0244] XphosPdG2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0245] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0246] Pd(dppf)Cl2:1,1-bis(diphenylphosphino)ferrocenepalladium dichloride

[0247] XPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0248] Preparation Example 1: Preparation of 4-(4-cyano-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 1)

[0249]

[0250] 1. Preparation of 5-bromo-2-fluoro-N-methylbenzenesulfonamide (Int-2)

[0251] Methylamine hydrochloride (1.6 g, 23.7 mmol) was dissolved in DCM (50 mL), and TEA (6.6 g, 65.2 mmol) and 5-bromo-2-fluoro-N-methylbenzenesulfonyl chloride (Int-1) (6.0 g, 21.9 mmol) were added. The mixture was reacted at 30 °C for 2 h, and then quenched with water. EA was added for extraction, and the concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 5.0 g of the target compound, with a yield of 85.0%.

[0252] 2. Preparation of tert-butyl 4-((4-bromo-2-(N-methylaminosulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-4)

[0253] Dissolve tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Int-3) (4.4 g, 20.4 mmol) in THF (50 mL), add 60% NaH (2.9 g, 72.5 mmol), react at 30°C for 30 min, then add Int-2 (5.0 g, 18.6 mmol), heat to 60°C and react for 2 h, then quench with water, add EA for extraction, concentrate the residue and purify it by column chromatography (EA:PE = 0-50%) to obtain 4.0 g of the target compound, yield: 46.3%.

[0254] 3. Preparation of tert-butyl 4-((4-(methoxycarbonyl)-2-(N-methylaminosulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-5)

[0255] Int-4 (4.0 g, 8.6 mmol) and TEA (10 mL) were dissolved in methanol (10 mL) and DMF (30 mL), and Pd(dppf)Cl2 (1.2 g, 1.6 mmol) was added, and the mixture was reacted at 100°C in CO for 5 h. After the reaction, EA was added for extraction, and the concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 2.0 g of the target compound, with a yield of 52.4%.

[0256] 4. Preparation of methyl 3-(N-methylsulfamoyl)-4-(piperidin-4-ylmethoxy)benzoate hydrochloride (Int-6)

[0257] Int-5 (1.0 g, 2.3 mmol) was dissolved in HCl / Dioxane (20 mL) and reacted at 30°C for 2 h. After concentration, the crude product was directly used in the next reaction.

[0258] 5. Preparation of methyl 3-(N-methylaminosulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (Int-7)

[0259] Int-6 (the crude product of the previous step) was dissolved in DCM (30 mL), and TEA (700 mg, 6.9 mmol) and MsCl (300 mg, 2.6 mmol) were added, and the mixture was reacted at 30° C. for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (EA:PE=0-60%) to obtain 500 mg of the target compound, with a two-step yield of 52.6%.

[0260] 6. Preparation of 5-(hydroxymethyl)-N-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Int-8)

[0261] Int-7 (400 mg, 0.95 mmol) was dissolved in THF (10 mL), and lithium borohydride (110 mg, 5.0 mmol) was added, and the mixture was reacted at 30° C. for 5 h. Water was added to quench the mixture, and EA was added for extraction. The residue was concentrated and subjected to column chromatography (EA:PE=0-100%) to obtain 300 mg of the target compound, with a yield of 80.4%.

[0262] 7. Preparation of 4-(4-cyano-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Int-9)

[0263] Int-8 (150 mg, 0.38 mmol) was dissolved in DCM (10 mL), and SOCl2 (140 mg, 1.2 mmol) was added. The mixture was reacted at 30 °C for 1 h and then the concentrated crude product was used directly in the next step.

[0264] 8. Preparation of 4-(4-cyano-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 1)

[0265] Int-9 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline (68 mg, 0.57 mmol) and potassium carbonate (260 mg, 1.9 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The concentrated residue was subjected to column chromatography (EA:PE = 0-100%) to obtain 40 mg of the target compound, with a two-step yield of 21.2%.

[0266] Molecular formula: C 23 H 31 N3O5S2 molecular weight: 493.6 LC-MS (M / e): 494.1 (M+H + )

[0267] 1H-NMR(400MHz, CDCl3)δ:7.91(s,1H),7.63(s,1H),7.18-7.15(m,4H),6.99(s,1H),4.61-4.58(m,1H),4.03-4.01(m,2H), 3.92-3.89(m,5H),3.88(m,3H),2.80(s,3H),2.80-2.77(m,2H),2.62-2.61(m,3H),2.09-1.95(m,3H),1.60-1.55(m,2H).

[0268] Preparation Example 2: Preparation of 4-(4-cyano-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 2)

[0269]

[0270] 1. Preparation of 5-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (Int-10)

[0271] Dissolve dimethylamine (1.3 g, 28.8 mmol) in DCM (50 mL), add TEA (6.6 g, 65.2 mmol) and Int-1 (6.0 g, 21.9 mmol), react at 30 °C for 2 h, quench with water, extract with EA, concentrate the residue and perform column chromatography (EA:PE = 0-50%) to obtain 5.0 g of the target compound, yield: 80.8%.

[0272] 2. Preparation of tert-butyl 4-(4-bromo-2-(N,N-dimethylaminosulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-11)

[0273] Int-3 (4.4 g, 20.4 mmol) was dissolved in THF (50 mL), and 60% NaH (2.9 g, 72.5 mmol) was added. The mixture was reacted at 30°C for 30 min. Then, Int-10 (5.0 g, 17.7 mmol) was added and the temperature was raised to 60°C for 2 h. The mixture was quenched with water and EA was added for extraction. The concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 3.0 g of the target compound. The yield was 35.5%.

[0274] 3. Preparation of tert-butyl 4-((4-(methoxycarbonyl)-2-(N,N-dimethylaminosulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-12)

[0275] Int-11 (3.0 g, 6.3 mmol) and TEA (10 mL) were dissolved in methanol (10 mL) and DMF (30 mL), and Pd(dppf)Cl2 (1.2 g, 1.6 mmol) was added, and the mixture was reacted at 100°C in CO for 5 h. After the reaction, EA was added for extraction, and the concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 2.0 g of the target compound, with a yield of 69.7%.

[0276] 4. Preparation of methyl 3-(N,N-dimethylaminosulfonyl)-4-(piperidin-4-ylmethoxy)benzoate hydrochloride (Int-13)

[0277] Int-12 (1.5 g, 3.3 mmol) was dissolved in HCl / Dioxane (20 mL) and reacted at 30°C for 2 h. After concentration, the crude product was directly used in the next reaction.

[0278] 5. Preparation of methyl 3-(N,N-dimethylaminosulfonyl)-4-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzoate (Int-14)

[0279] Int-13 (the crude product of the previous step) was dissolved in DCM (30 mL), and TEA (700 mg, 6.9 mmol) and MsCl (300 mg, 2.6 mmol) were added, and the mixture was reacted at 30°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The concentrated residue was purified by column chromatography (EA:PE = 0-60%) to obtain 900 mg of the target compound, with a two-step yield of 63.1%.

[0280] 6. Preparation of 5-(hydroxymethyl)-N,N-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Int-15)

[0281] Int-14 (800 mg, 1.8 mmol) was dissolved in THF (10 mL), and lithium borohydride (220 mg, 10.1 mmol) was added, and the mixture was reacted at 30° C. for 5 h. Water was added to quench the mixture, and EA was added for extraction. The concentrated residue was purified by column chromatography (EA:PE=0-100%) to obtain 600 mg of the target compound, with a yield of 80.2%.

[0282] 7. Preparation of 5-(chloromethyl)-N,N-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Int-16)

[0283] Int-15 (500 mg, 1.2 mmol) was dissolved in DCM (10 mL), and SOCl2 (720 mg, 6.1 mmol) was added. After reacting at 30°C for 1 h, the crude product was concentrated and used directly in the next step.

[0284] 8. Preparation of 4-(4-cyano-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 2)

[0285] Int-16 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline (150 mg, 1.3 mmol) and potassium carbonate (820 mg, 5.9 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (EA:PE = 0-100%) to obtain 400 mg of the target compound, with a two-step yield of 64.1%.

[0286] Molecular formula: C 24 H 33 N3O5S2 molecular weight: 507.7 LC-MS (M / e): 508.2 (M+H + )

[0287] 1 H-NMR(400MHz, CDCl3)δ:7.87(s,1H),7.59(s,1H),7.18-7.15(m,4H),6.99(s,1H),3.99-3.96(m,2H),3.92-3.89(m,8 H),2.85-2.80(m,6H),2.80-2.77(m,3H),2.72-2.61(m,2H),2.18-2.05(m,2H),1.60-1.55(m,2H),1.30-1.26(m,1H).

[0288] Preparation Example 3: Preparation of 5-((5-cyanoisoindolin-2-yl)methyl)-N-methyl-2-(1-(methylsulfonyl)piperidin-4-methoxy)benzenesulfonamide (Compound 3)

[0289]

[0290] 1. Preparation of 5-(chloromethyl)-N-methyl-2-((1-(methylsulfonyl)piperidin-4-methoxy)benzenesulfonamide (Int-17)

[0291] Int-8 (220 mg, 0.56 mmol) was dissolved in DCM (10 mL), and SOCl2 (140 mg, 1.2 mmol) was added. After reacting at 30°C for 1 h, the crude product was concentrated and used directly in the next step.

[0292] 2. Preparation of 5-((5-cyanoisoindol-2-yl)methyl)-N-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 3)

[0293] Int-17 (the crude product of the previous step) was dissolved in acetonitrile (20 mL), and isoindoline (125 mg, 0.69 mmol) and potassium carbonate (460 mg, 3.3 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (EA:PE = 0-100%) to obtain 45 mg of the target compound, with a two-step yield of 15.5%.

[0294] Molecular formula: C 24 H 30 N4O5S2 molecular weight: 518.6 LC-MS (M / e): 519.1 (M+H + )

[0295] 1 H-NMR(400MHz, CDCl3)δ:7.91(s,1H),7.59-7.56(m,1H),7.51-7.49(m,1H),7.45(s,1H),7.28(s,1H),6.99(s,1H),4.61-4.58(m,1H),4. 03-4.01(m,2H),3.92-3.89(m,5H),3.88(m,3H),2.80(s,3H),2.80-2 .77(m,2H),2.62-2.61(m,3H),2.09-1.95(m,3H),1.60-1.55(m,2H).

[0296] Preparation Example 4: Preparation of 5-((5-cyanoisoindolin-2-yl)methyl)-N,N-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 4)

[0297]

[0298] 1. Preparation of 5-(chloromethyl)-N,N-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Int-18)

[0299] Int-15 (150 mg, 0.37 mmol) was dissolved in DCM (10 mL), and SOCl2 (150 mg / l) was added. After reacting at 30 °C for 1 h, the crude product was concentrated and used directly in the next step.

[0300] 2. Preparation of 5-((5-cyanoisoindolin-2-yl)methyl)-N,N-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide

[0301] Int-18 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline (85 mg, 0.47 mmol) and potassium carbonate (280 mg, 2.0 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and EA was added for extraction. The concentrated residue was subjected to column chromatography (EA:PE = 0-100%) to obtain 55 mg of the target compound, with a two-step yield of 28.0%.

[0302] Molecular formula: C 25 H 32 N4O5S2 molecular weight: 532.7 LC-MS (M / e): 533.1 (M+H + )

[0303] 1 H-NMR(400MHz, CDCl3)δ:7.87(s,1H),7.56-7.51(m,2H),7.45(s,1H),7.28-7.25(m,1H),6.99(s,1H),3.99-3.96(m,2H),3.92- 3.89(m,8H),2.85-2.80(m,6H),2.80-2.77(m,3H),2.72-2.61(m,2H),2.18-2.05(m,2H),1.60-1.55(m,2H),1.30-1.26(m,1H).

[0304] Preparation Example 5: Preparation of 4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 5)

[0305]

[0306] 1. Preparation of 1-((5-bromo-2-fluorophenyl)sulfonyl)pyrrolidine (Int-20)

[0307] At 30°C, 5-bromo-2-fluorobenzenesulfonyl chloride (Int-19) (3.0 g, 11.0 mmol) was added in batches to DCM (60 mL) containing tetrahydropyrrole (1.5 g, 21.1 mmol) and TEA (4.5 g, 44.4 mmol) and reacted at 30°C for 3 hours. After the reaction was completed, the reaction solution was directly decompressed and dried, and purified by silica gel column chromatography (n-heptane: EA = 2:1) to obtain 3.0 g of the product with a yield of 88.7%. 2. Preparation of tert-butyl 4-(4-bromo-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-21)

[0308] At 0°C, NaH (1.2 g, 30.0 mmol) was added to THF (50 mL) containing Int-3 (2.5 g, 11.6 mmol), and after 5 minutes of reaction, Int-20 (2.97 g, 9.6 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 EA was extracted three times. The EA 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: MeOH = 20: 1) to obtain 3.9 g of the product with a yield of 80.4%.

[0309] 3. Preparation of tert-butyl 4-((4-(hydroxymethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-22)

[0310] Under N2 protection, 1,4-dioxane (20 mL) containing Int-21 (1.0 g, 2.0 mmol), tributyltin methanol (771 mg, 2.4 mmol) and XphosPdG2 (157 mg, 0.20 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 (n-heptane: EA = 1:1) to obtain 160 mg of the product with a yield of 17.7%.

[0311] 4. Preparation of tert-butyl 4-((4-(chloromethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-23)

[0312] SOCl2 (115 mg, 1.0 mmol) was added dropwise to DCM (10 mL) containing Int-22 (150 mg, 0.33 mmol) at 30°C 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.

[0313] 5. Preparation of tert-butyl 4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-24)

[0314] Under N2 protection, acetonitrile (15 mL) containing Int-23 (the crude product from the previous step), isoindoline hydrochloride (156 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) was reacted 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: MeOH = 30: 1) to obtain 130 mg of the product, with a two-step yield of 70.9%.

[0315] 6. Preparation of 2-(4-(piperidin-4-ylmethoxy)-3-(pyrrolidin-1-ylsulfonyl)benzyl)isoindoline (Int-25)

[0316] At 30°C, hydrochloric acid ethyl acetate solution (4 mL) was added dropwise to EA (1 mL) containing Int-24 (130 mg, 0.23 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.

[0317] 7. Preparation of 4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 4)

[0318] At 0°C, N-methyl-1H-imidazole-1-carboxamide (Int-26) (125 mg, 1.0 mmol) was added to DCM (5 mL) containing Int-25 (the crude product from the previous step) and TEA (303 mg, 3.0 mmol) and reacted at 0°C for 1 hour. After the reaction was completed, the product was directly dried under reduced pressure and purified by TLC (DCM: MeOH = 25: 1) to obtain 50 mg of the product with a yield of 41.7%.

[0319] Molecular formula: C 27 H 36 N4O4S molecular weight: 512.7 LC-MS (m / z): 513.2 (M+H + )

[0320] 1 H-NMR(400MHz,DMSO-d6):7.75(m,1H),7.54(m,1H),7.21-7.14(m,5H),6.34(m,1H),3.95(m,4H),3. 81(m,6H),3.21(m,4H),2.65(m,2H),2.48(m,3H),1.98-1.72(m,3H),1.70(m,4H),1.21-1.13(m,2H).

[0321] Preparation Example 6: Preparation of 4-((4-(isoindolin-2-ylmethyl)-2-(N-methylsulfamoyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 6)

[0322]

[0323] 1. Preparation of methyl 4-((1-(methylcarbamoyl)piperidin-4-yl)methoxy)-3-(N-methylsulfamoyl)benzoate (Int-27)

[0324] Int-6 (crude, 1.1 mmol) was dissolved in DCM (10 mL), and TEA (557 mg, 5.5 mmol) and Int-26 (213 mg, 1.7 mmol) were added, and the mixture was reacted at 30°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (MeOH:DCM=0-10%) to obtain 400 mg of the target compound, with a yield of 88.4%.

[0325] 2. Preparation of 4-((4-(hydroxymethyl)-2-(N-methylsulfamoyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Int-28)

[0326] Int-27 (100 mg, 0.25 mmol) was dissolved in THF (10 mL), and lithium borohydride (28 mg, 1.3 mmol) was added, and the mixture was reacted at 30°C for 5 h. Water was added to quench the mixture, and DCM was added to extract the mixture, and the crude product was concentrated and used directly in the next step.

[0327] 3. Preparation of 4-((4-(chloromethyl)-2-(N-methylsulfamoyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Int-29)

[0328] Int-28 (crude, 0.25 mmol) was dissolved in DCM (10 mL), and SOCl2 (89 mg, 0.75 mmol) was added. The mixture was reacted at 30 °C for 1 h, and the concentrated crude product was directly used in the next step.

[0329] 4. Preparation of 4-((4-(isoindolin-2-ylmethyl)-2-(N-methylsulfamoyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 6)

[0330] Int-29 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline (47 mg, 0.30 mmol) and DIEA (168 mg, 1.3 mmol) were added, and the mixture was reacted at 90°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to reverse phase chromatography (methanol: water = 0-70%) to obtain 7 mg of the target compound, with a three-step yield of 5.9%.

[0331] Molecular formula: C 24 H 32 N4O4S molecular weight: 472.6 LC-MS (M / e): 473.2 (M+H + )

[0332] 1H-NMR(400MHz, CDCl3)δ:7.91(s,1H),7.63(s,1H),7.15-7.20(m,4H),6.99(s,1H),4.61-4.58(m,1H),4.35-4.45( m,1H),4.00-4.10(m,4H),3.89-3.99(m,6H),2.80-2.90(m,5H),2.62(m,3H),2.09-1.95(m,2H),1.80-1.90(m,3H).

[0333] Preparation Example 7: Preparation of 4-(4-(isoindolin-2-ylmethyl)-2-aminosulfonylphenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 7)

[0334]

[0335] Dissolve 5-(isoindolin-2-ylmethyl)-2-(piperidin-4-ylmethoxy)benzenesulfonamide dihydrochloride (Int-30) (143 mg, 0.30 mmol) in acetonitrile (10 mL), add DIEA (129 mg, 1 mmol) and Int-26 (58 mg, 0.46 mmol), and react at 20°C for 16 h. Quench with water, concentrate the solvent, and the residue is subjected to reverse phase chromatography (MeOH:H2O=0-60%) to obtain 20 mg of the target compound, with a yield of 16%.

[0336] Molecular formula: C 23 H 30 N4O4S molecular weight: 458.6 LC-MS (M / e): 459.2 (M+H + )

[0337] 1 H-NMR (400MHz, DMSO) δ: 7.74 (s, 1H), 7.56 (d, J = 8.2Hz, 1H), 7.15-7.25 (m, 5H), 6.85 (m, 2H), 6.36 (m, 1H), 3.92 -3.72(m,10H),2.65-2.58(m,2H),2.52-2.42(m,3H),2.05-2.00(m,1H),1.85-1.72(m,2H),1.15-1.05(m,2H).

[0338] Preparation Example 8: Preparation of 4-((2-(N-cyclopropylaminosulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 8)

[0339]

[0340] 1. Preparation of 5-bromo-N-cyclopropyl-2-fluorobenzenesulfonamide (Int-31)

[0341] Dissolve cyclopropylamine hydrochloride (742 mg, 13 mmol) in DCM (30 mL), add TEA (3.3 g, 33 mmol) and Int-1 (3 g, 11 mmol), react at 30 °C for 4 h, quench with water, extract with EA, concentrate the residue and perform column chromatography (EA:PE = 0-50%) to obtain 3 g of the target compound, yield: 93.0%.

[0342] 2. Preparation of tert-butyl 4-((4-bromo-2-(N-cyclopropylaminosulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-32)

[0343] Int-3 (732 mg, 3.4 mmol) was dissolved in THF (20 mL), and 60% NaH (480 mg, 12 mmol) was added at 0°C. The reaction was continued for 30 min, and then Int-31 (1 g, 3.4 mmol) was added and the temperature was raised to 60°C. After reacting for 2 h, water was added to quench the reaction, and EA was added for extraction. The concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 1.3 g of the target compound, with a yield of 78.1%.

[0344] 3. Preparation of tert-butyl 4-((2-(N-cyclopropylaminosulfonyl)-4-(methoxycarbonyl)phenoxy)methyl)piperidine-1-carboxylate (Int-33)

[0345] Int-32 (1.3 g, 2.7 mmol) and TEA (818 mg, 8.1 mmol) were dissolved in methanol (10 mL) and DMF (20 mL), and Pd(dppf)Cl2 (395 mg, 0.54 mmol) was added, and the mixture was reacted at 90°C in CO for 5 h. After the reaction, EA was added for extraction, and the concentrated residue was subjected to column chromatography (EA:PE = 0-50%) to obtain 1.1 g of the target compound, with a yield of 88.4%.

[0346] 4. Preparation of methyl 3-(N-cyclopropylaminosulfonyl)-4-(piperidin-4-ylmethoxy)benzoate hydrochloride (Int-34)

[0347] Int-33 (500 mg, 1.07 mmol) was dissolved in HCl / Dioxane (20 mL) and reacted at 30°C for 2 h. After concentration, the crude product was directly used in the next reaction.

[0348] 5. Preparation of methyl 3-(N-cyclopropylaminosulfonyl)-4-((1-(methylcarbamoyl)piperidin-4-yl)methoxy)benzoate (Int-35)

[0349] Int-34 (the crude product of the previous step) was dissolved in DCM (30 mL), and TEA (506 mg, 5 mmol) and Int-26 (200 mg, 1.6 mmol) were added, and the mixture was reacted at 30°C for 2 h. Water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (MeOH:DCM=0-10%) to obtain 400 mg of the target compound, with a two-step yield of 88.0%.

[0350] 6. Preparation of 4-((2-(N-cyclopropylaminosulfonyl)-4-(hydroxymethyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Int-36)

[0351] Int-35 (100 mg, 0.23 mmol) was dissolved in THF (10 mL), and lithium borohydride (26 mg, 1.2 mmol) was added, and the mixture was reacted at 30°C for 16 h. Water was added to quench the mixture, and DCM was added to extract the mixture. The organic phase was spin-dried to obtain a crude product, which was directly used in the next step.

[0352] 7. Preparation of 4-((4-(chloromethyl)-2-(N-cyclopropylaminosulfonyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Int-37)

[0353] Int-36 (crude) was dissolved in DCM (5 mL), SOCl2 (82 mg, 0.69 mmol) was added, and the mixture was reacted at 30°C for 1 h. The crude product was concentrated and used directly in the next step.

[0354] 8. Preparation of 4-((2-(N-cyclopropylaminosulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 8)

[0355] Int-37 (the crude product of the previous step) was dissolved in acetonitrile (10 mL), and isoindoline hydrochloride (54 mg, 0.35 mmol) and DIEA (155 mg, 1.2 mmol) were added, and the mixture was reacted at 90°C for 3 h. Water was added to quench the mixture, and EA was added to extract the mixture. The concentrated residue was subjected to reverse phase column chromatography (MeOH:DCM=0-60%) to obtain 33 mg of the target compound, with a 3-step yield of 28.2%.

[0356] Molecular formula: C 26 H 34 N4O4S molecular weight: 498.6 LC-MS (M / e): 499.1 (M+H + )

[0357] 1H-NMR(400MHz, CDCl3)δ:7.97(s,1H),7.63(s,1H),7.18-7.15(m,4H),6.98(s,1H),5.12(s,1H),4.40-4.00(m,1H),4.00- 4.10(m,4H),3.92-3.89(m,6H),2.83(s,5H),2.00-2.10(m,2H),1.80-1.90(m,2H),1.40-1.50(m,2H),0.60-0.80(m,4H).

[0358] Preparation Example 9: Preparation of 2-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-5-(isoindolin-2-ylmethyl)benzenesulfonamide (Compound 9)

[0359]

[0360]

[0361] 1. Preparation of azetidine-1-carbonyl chloride (Int-39)

[0362] Dissolve azetidine (Int-38) (500 mg, 8.8 mmol) in DCM (10 mL), add sodium bicarbonate (2.2 g, 26.4 mmol), add triphosgene (520 mg, 17.6 mmol) at 0°C, react at 25°C for 2 hours, filter and concentrate to obtain 350 mg of crude product.

[0363] 2. Preparation of 5-bromo-2-fluorobenzenesulfonamide (Int-40)

[0364] 0.4M NH3 / THF solution (33 mL) was added to the reaction flask, and Int-19 (1.8 g, 6.6 mmol) was added at 0°C, and the mixture was reacted at 0°C for 2 hours. After the reaction was completed, water was added to quench the mixture, and EA was added to extract the mixture, and the mixture was washed with water and concentrated to obtain 1.5 g of crude product.

[0365] 3. Preparation of tert-butyl 4-(4-bromo-2-aminosulfonylphenoxy)methyl)piperidine-1-carboxylate (Int-41)

[0366] Int-3 (1.5 g, 0.59 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydrogen sulfide (60%) (94 mg, 2.36 mmol) was added, and the mixture was reacted at 25°C for 0.5 h, and Int-40 (84 mg, 0.39 mmol) was added, and the mixture was reacted at 60°C for 16 h. After the reaction was completed, water was added to quench the mixture, and EA was added for extraction. The residue was concentrated and subjected to column chromatography (EA / n-heptane = 30.0%) to obtain 2.5 g of the product, with a two-step yield of 83.9%.

[0367] 4. Preparation of tert-butyl 4-((4-(methoxycarbonyl)-2-aminosulfonylphenoxy)methyl)piperidine-1-carboxylate (Int-42)

[0368] Int-41 (1.3 g, 2.9 mmol) was dissolved in DMF (16 mL) and MeOH (4 mL), and TEA (1.2 g, 11.6 mmol) and Pd(dppf)Cl2 were added, and the mixture was reacted at 100°C for 16 h in a carbon monoxide environment. After the reaction was completed, water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and subjected to column chromatography (EA / n-heptane = 50%) to obtain 1.0 g of the target product, with a yield of 80.6%.

[0369] 5. Preparation of methyl 4-(piperidin-4-ylmethoxy)-3-aminosulfonylbenzoate hydrochloride (Int-43)

[0370] Int-42 (450 mg, 1.05 mmol) was dissolved in dioxane (5 mL), and 2N hydrochloric acid dioxane solution (10 mL) was added, and the mixture was reacted at 25°C for 1 h. After the reaction was completed, the mixture was directly concentrated to obtain 500 mg of crude product, which was used directly in the next step.

[0371] 6. Preparation of methyl 4-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-3-aminosulfonylbenzoate (Int-44)

[0372] Dissolve Int-43 (400 mg crude product, 0.84 mmol) in DCM (5 mL), add TEA (354 mg, 3.5 mmol), add Int-39 (125 mg, 1.05 mmol). React at 25°C for 1 h. Directly concentrate the residue and column chromatography (MeOH / DCM = 10%) to obtain 300 mg of the target product, yield (two steps): 86.8%.

[0373] 7. Preparation of 2-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-5-(hydroxymethyl)benzenesulfonamide (Int-45)

[0374] Int-44 (300 mg, 0.73 mmol) was dissolved in THF (5 mL), and lithium borohydride (79 mg, 3.65 mmol) was added, and the mixture was reacted at 25°C for 2 h. After the reaction was completed, water was added to quench the mixture, EA was added to extract, and the mixture was concentrated to obtain 220 mg, with a yield of 78.5%.

[0375] 8. Preparation of 4-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-3-aminosulfonylbenzyl methanesulfonate (Int-46)

[0376] Int-45 (100 mg, 0.26 mmol) was dissolved in THF (5 mL), TEA (158 mg, 1.56 mmol) was added, MsCl (120 mg, 1.04 mmol) was added at 0°C, and the mixture was reacted at 25°C for 1 h. After the reaction was completed, the reaction solution was directly used in the next step.

[0377] 9. Preparation of 2-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-5-(isoindolin-2-ylmethyl)benzenesulfonamide (Compound 9)

[0378] THF (5 mL) was added to Int-46 (the reaction solution in the previous step), TEA (79 mg, 0.78 mmol) and isoindoline hydrochloride (61 mg, 0.39 mmol), and the mixture was reacted at 25°C for 0.5 h. After the reaction was completed, water was added to quench the mixture, EA was added to extract the mixture, and the residue was concentrated and subjected to column chromatography (MeOH / DCM=60%) to obtain 25 mg of the crude product. The target product (14 mg) was obtained by TLC chromatography (MeOH / DCM=2.0%), with a yield (two steps): 11.1%.

[0379] Molecular formula: C 25 H 32 N4O4S molecular weight: 484.6 LC-MS (M / e): 485.2 (M+H + )

[0380] 1 H-NMR(400MHz,DMSO)δ:7.98-7.91(m,1H),7.71-7.70(m,1H),7.35-7.25(m,4H),7.00(m,1H),5.33-5.07(m,2H),4.17-3.9 9(m,6H),3.90-3.70(m,8H),2.78-2.69(m,2H),2.29-2.22(m,2H),2.08-1.86(m,1H),1.96-1.85(m,2H),1.43-1.25(m,2H).

[0381] Preparation Example 10: Preparation of 4-((6-(isoindolin-2-ylmethyl)-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 10)

[0382]

[0383] 1. Preparation of tert-butyl 4-(((6-chloro-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-48)

[0384] 4-(((6-chloro-4-(chlorosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (Int-47) (170 mg, 0.40 mmol) was added to DCM (10 mL) containing TEA (303 mg, 3.0 mmol) and methylamine hydrochloride (68 mg, 1.0 mmol), and the mixture was reacted at 30° C. for 1 h. After the reaction was completed, the sample was directly added to silica gel and purified by silica gel column chromatography (EA:PE=1:1) to obtain 120 mg of the target compound with a yield of 71.5%.

[0385] 2. Preparation of methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-4-(N-methylaminosulfonyl)picolinate (Int-49)

[0386] Int-48 (120 mg, 0.28 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and TEA (85 mg, 0.84 mmol) in methanol (20 mL) were reacted at 80°C for 1 hour under CO atmosphere. After the reaction, the sample was directly mixed with silica gel and purified by silica gel column chromatography (EA:PE=1:1) to obtain 120 mg of the target compound with a yield of 94.7%.

[0387] 3. Preparation of tert-butyl 4-(((6-(hydroxymethyl)-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-50)

[0388] Int-49 (120 mg, 0.27 mmol) was dissolved in THF (5 mL) and methanol (5 mL), and NaBH4 (38 mg, 1.0 mmol) was added, and the mixture was reacted at 30°C for 2 h. After the reaction was completed, the sample was directly mixed with silica gel and purified by silica gel column chromatography (DCM:MeOH=12:1) to obtain 110 mg of the target compound, with a yield of 97.8%.

[0389] 4. Preparation of tert-butyl 4-(((6-(chloromethyl)-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-51)

[0390] Int-50 (110 mg, 0.26 mmol) was dissolved in DCM (5 mL), SOCl2 (119 mg, 1.0 mmol) was added, and the mixture was reacted at 30°C for 1 h. The mixture was concentrated and the crude product was used directly in the next step.

[0391] 5. Preparation of tert-butyl 4-(((6-(isoindolin-2-ylmethyl)-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-52)

[0392] Under N2 protection, acetonitrile (10 mL) containing Int-51 (the crude product from the previous step), isoindoline hydrochloride (55 mg, 0.35 mmol), potassium carbonate (276 mg, 2.0 mmol) and potassium iodide (55 mg, 0.33 mmol) was reacted at 80°C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by TLC (EA) to obtain 100 mg of the product with a yield of 73.1% (combined yield of the two steps).

[0393] 6. Preparation of 2-(isoindolin-2-ylmethyl)-N-methyl-5-(piperidin-4-ylmethoxy)pyridine-4-sulfonamide (Int-53)

[0394] Hydrochloric acid ethyl acetate solution (4 mL) was added dropwise to ethyl acetate (1 mL) containing Int-52 (100 mg, 0.19 mmol) and reacted at 30°C for 1 h. After the reaction was completed, the solvent was removed under reduced pressure and the residue was directly used for the next reaction.

[0395] 7. Preparation of 4-((6-(isoindolin-2-ylmethyl)-4-(N-methylaminosulfonyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 10)

[0396] At 0°C, Int-26 (125 mg, 1.0 mmol) was added to DCM (5 mL) containing Int-53 (the crude product from the previous step) and TEA (303 mg, 3.0 mmol) and reacted at 30°C for 1 hour. After the reaction was completed, the product was directly dried under reduced pressure, and the residue was purified by TLC (DCM: MeOH = 11: 1) to obtain 20 mg of the product with a yield of 21.8% (combined yield of the two steps).

[0397] Molecular formula: C 23 H 31 N5O4S molecular weight: 473.6 LC-MS (m / z): 474.2 (M+H + )

[0398] 1 H-NMR(400MHz,DMSO-d6)8.56(s,1H),7.72(s,1H),7.74(s,1H),7.29-7.26(m,1H),7.25-7.19(m,4H ),6.34(m,1H),4.12(m,4H),4.00(m,6H),2.67(m,2H),2.48(m,6H),2.05-1.77(m,2H),1.21(m,2H).

[0399] Preparation Example 11: Preparation of 4-(((4-(N-cyclopropylaminosulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 12)

[0400]

[0401] 1. Preparation of 4-(Benzylthio)-2-chloro-5-fluoropyridine (Int-55)

[0402] 4-Bromo-2-chloro-5-fluoropyridine (Int-54) (5.0 g, 23.8 mmol), benzyl mercaptan (5.9 g, 47.5 mmol), DIEA (12.3 g, 95.3 mmol), Pd2dba3 (2.2 g, 2.4 mmol) and XantPhos (2.8 g, 4.8 mmol) were added to 1,4-dioxane (40 mL) and reacted at 100°C for 10 hours. After the reaction was completed, the sample was directly mixed with silica gel and 7.0 g of crude target compound was obtained by silica gel column chromatography (EA:PE=1:10).

[0403] 2. Preparation of tert-butyl 4-((4-(benzylthio)-6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-56)

[0404] Int-3 (3.2 g, 14.9 mmol), Int-55 (2.5 g crude product) and cesium carbonate (6.4 g, 19.7 mmol) were added to DMF (40 mL) and reacted at 110°C for 10 hours. After the reaction was completed, water was added to quench the reaction, and EA was extracted three times. The EA layers were combined, washed once with water and once with saturated brine, and the organic solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column (EA:PE=1:3) to obtain 520 mg of the target compound.

[0405] 3. Preparation of tert-butyl 4-(((6-chloro-4-(chlorosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-47)

[0406] NCS (494 mg, 3.7 mmol) was added in batches to acetic acid (3 mL) and water (1 mL) containing Int-56 (280 mg, 0.62 mmol) and reacted at 30°C for 2 hours. After the reaction was completed, water was added and EA was extracted three times. The EA layers were combined, washed once with water and once with saturated brine, and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE=1:2) to obtain 140 mg of the target compound with a yield of 52.8%.

[0407] 4. Preparation of tert-butyl 4-(((6-chloro-4-(N-cyclopropylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-57)

[0408] Int-47 (140 mg, 0.33 mmol) was added to DCM (5 mL) containing TEA (303 mg, 3.0 mmol) and cyclopropylamine (57 mg, 1.0 mmol) and reacted at 30°C for 1 h. After the reaction was completed, the sample was directly mixed with silica gel and purified by silica gel column chromatography (EA:PE=1:1) to obtain 100 mg of the target compound with a yield of 68.1%.

[0409] 5. Preparation of methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-4-(N-cyclopropylsulfamoyl)picolinate (Int-58)

[0410] Int-57 (100 mg, 0.22 mmol), Pd(dppf)Cl2 (50 mg, 0.062 mmol) and TEA (101 mg, 1.0 mmol) in methanol (40 mL) were reacted at 80°C for 3 hours under CO atmosphere. After the reaction, the sample was directly mixed with silica gel and purified by silica gel column chromatography (EA:PE=1:1) to obtain 30 mg of the target compound with a yield of 28.5%.

[0411] 6. Preparation of tert-butyl 4-(((4-(N-cyclopropylaminosulfonyl)-6-(hydroxymethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-59)

[0412] Int-58 (30 mg, 0.064 mmol) was dissolved in THF (1 mL) and methanol (1 mL), and NaBH4 (38 mg, 1.0 mmol) was added, and the mixture was reacted at 30°C for 2 h. After the reaction was completed, the sample was directly mixed with silica gel and purified by silica gel column chromatography (DCM:MeOH=12:1) to obtain 25 mg of the target compound, with a yield of 88.6%.

[0413] 7. Preparation of tert-butyl 4-(((6-(chloromethyl)-4-(N-cyclopropylaminosulfonyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-60)

[0414] Int-59 (25 mg, 0.057 mmol) was dissolved in DCM (5 mL), and SOCl2 (119 mg, 1.0 mmol) was added. After reacting at 30°C for 1 h, the concentrated crude product was directly used in the next reaction.

[0415] 8. Preparation of tert-butyl 4-(((4-(N-cyclopropylaminosulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-61)

[0416] Under N2 protection, acetonitrile (10 mL) containing Int-60 (the crude product from the previous step), isoindoline hydrochloride (30 mg, 0.19 mmol), potassium carbonate (138 mg, 1.0 mmol) and potassium iodide (166 mg, 1.0 mmol) was reacted at 80°C for 1 hour. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by TLC (pure EA) to obtain 28 mg of the product with a yield of 91.1% (combined yield of the two steps).

[0417] 9. Preparation of N-cyclopropyl-2-(isoindolin-2-ylmethyl)-5-(piperidin-4-ylmethoxy)pyridine-4-sulfonamide (Int-62)

[0418] EA (1 mL) containing Int-61 (28 mg, 0.052 mmol) was added dropwise to the hydrochloric acid ethyl acetate solution (4 mL) and reacted at 30° C. for 1 h. After the reaction was completed, the solvent was directly removed under reduced pressure and the residue was directly used for the next reaction.

[0419] 10. Preparation of 4-(((4-(N-cyclopropylaminosulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 12)

[0420] At 0°C, Int-26 (125 mg, 1.0 mmol) was added to DCM (5 mL) containing Int-62 (the crude product from the previous step) and TEA (303 mg, 3.0 mmol) and reacted at 0°C for 1 hour. After the reaction was completed, the product was directly dried under reduced pressure, and the residue was purified by TLC (DCM: MeOH = 25: 1) to obtain 10 mg of the product with a yield of 38.8% (combined yield of the two steps).

[0421] Molecular formula: C 25 H 33 N5O4S molecular weight: 499.6 LC-MS (m / z): 500.2 (M+H + )

[0422] 1H-NMR(400MHz,DMSO-d6)8.53(s,1H),7.83(m,1H),7.74(s,1H),7.23-7.16(m,4H) ,6.34(m,1H),4.08(m,2H),4.00(m,2H),3.95(m,1H),3.92(m,1H),3.85(m,4H),2. 65 (m, 2H), 2.48 (m, 3H), 2.24 (m, 1H), 1.98-1.72 (m, 3H), 1.21-1.13 (m, 2H), 0.47-0.41 (m, 4H). Preparation Example 12: Preparation of 5-(isoindolin-2-ylmethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 15)

[0423]

[0424] 1. Preparation of 5-(isoindolin-2-ylmethyl)-2-(piperidin-4-ylmethoxy)benzenesulfonamide dihydrochloride (Int-30)

[0425] Dissolve tert-butyl 4-((4-(isoindolin-2-ylmethyl)-2-sulfamophenoxy)methyl)piperidine-1-carboxylate (Int-63) (70 mg, 0.14 mmol) in DCM (4 mL), add 4N hydrochloric acid dioxane solution (4 mL), and react at 25°C for 1 h. After the reaction is complete, concentrate directly to obtain 81 mg of crude product, which is used in the next step.

[0426] 2. Preparation of 5-(isoindolin-2-ylmethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 15)

[0427] Int-30 (81 mg crude product, 0.14 mmol) was dissolved in DCM (5 mL), TEA (42 mg, 0.42 mmol) was added, MsCl (18 mg, 0.15 mmol) was added at 0°C, and the mixture was reacted at 0°C for 0.5 h. After the reaction was completed, water was added to quench the mixture, DCM was added to extract the mixture, and the residue was concentrated and subjected to column chromatography (MeOH:DCM=65%) to obtain 10 mg of the target product, with a yield (two steps): 15.0%.

[0428] Molecular formula: C 22 H 29 N3O5S2 molecular weight: 479.6 LC-MS (M / e): 480.2 (M+H + )

[0429] 1H-NMR(400MHz,DMSO)δ:7.91(s,1H),7.62-7.60(m,1H),7.25-7.15(m,4H),6.99(m,1H),5.30-5.08(m ,2H),4.05-4.00(m,2H),3.95-3.87(m,8H),2.84-2.70(m,5H),2.09-1.90(m,3H),1.54-1.47(m,2H).

[0430] Preparation Example 13: Preparation of 4-(((4-(N-cyclopropylaminosulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxamide (Compound 16)

[0431]

[0432] At 20°C, trimethylsilyl isocyanate (115 mg, 1.0 mmol) was added dropwise to DCM (10 mL) containing Int-62 (80 mg, 0.18 mmol) and TEA (101 mg, 1.0 mmol), and the reaction was continued for 10 hours. After the reaction was completed, the solvent was directly removed under reduced pressure, and the residue was purified by TLC (DCM: MeOH = 11: 1) to obtain 40 mg of the product with a yield of 45.6%.

[0433] Molecular formula: C 24 H 31 N5O4S molecular weight: 485.6 LC-MS (m / z): 486.1 (M+H + )

[0434] 1 H-NMR (400MHz, DMSO-d6) δ: 8.55(s,1H),7.84(brs,1H),7.76(s,1H),7.28-7.18(m,4H),5.86(brs,2H),4.12(m,2H),4.06(m,2 H),4.00(m,2H),3.92(m,4H),2.83(m,2H),2.26(m,1H),2.04(m,1H),1.98-1.90(m,2H),1.21-1.13(m,2H),0.49-0.43(m,4H).

[0435] Preparation Example 14: Preparation of N-cyclopropyl-5-((1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)pyridine-4-sulfonamide (Compound 18)

[0436]

[0437] 1. Preparation of ethyl 2-(4-(((4-(N-cyclopropylaminosulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)sulfonyl)acetate (Int-64)

[0438] At 0°C, ethyl (chlorosulfonyl)acetate (70 mg, 0.38 mmol) was added dropwise to DCM (10 mL) containing Int-62 (50 mg, 0.11 mmol) and TEA (101 mg, 1.0 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:MeOH=11:1) to obtain 20 mg of the product with a yield of 29.9%.

[0439] 2. Preparation of N-cyclopropyl-5-((1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)methoxy)-2-(isoindolin-2-ylmethyl)pyridine-4-sulfonamide (Compound 18)

[0440] NaBH4 (38 mg, 1.0 mmol) was added to THF (5 mL) and methanol (5 mL) containing Int-64 (20 mg, 0.034 mmol) and reacted at 25°C for 1 hour. After the reaction was completed, the product was directly dried under reduced pressure and purified by TLC (DCM: MeOH = 11: 1) to obtain 8 mg of the product with a yield of 43.0%.

[0441] Molecular formula: C 25 H 34 N4O6S2 molecular weight: 550.7 LC-MS (m / z): 551.1 (M+H + )

[0442] 1 H-NMR (400MHz, DMSO-d6) δ: 8.56 (s, 1H), 7.88 (m, 1H), 7.76 (s, 1H), 7.25-7.18 (m, 4H), 5.00 (m, 1H), 4.15 (m, 2H), 4.03 (m, 2H), 3.92 (m,4H),3.76(m,2H),3.60(m,2H),3.18(m,2H),2.83(m,2H),2.26(m,1H),1.98-1.90(m,3H),1.21-1.13(m,2H),0.49-0.43(m,4H).

[0443] Preparation Example 15: 7. Preparation of 4-(((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 19)

[0444]

[0445] 1. Preparation of tert-butyl 4-((4-(azetidin-1-ylsulfonyl)-6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-65)

[0446] Dissolve cyclobutylamine (57 mg, 1.0 mmol) in DCM (5 mL), add TEA (237 mg, 2.35 mmol), add Int-47 (393 mg, 0.92 mmol) at 0°C, and react at 25°C for 16 h. After the reaction is complete, directly concentrate the residue and column chromatography (ethyl acetate / n-heptane = 25%) to obtain 250 mg of the target product, with a yield of 60.7%.

[0447] 2. Preparation of methyl 4-(azetidin-1-ylsulfonyl)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)picolinate (Int-66)

[0448] Int-65 (250 mg, 0.56 mmol) was dissolved in DMF (4 mL) and MeOH (1 mL), and TEA (227 mg, 2.24 mmol) and Pd(dppf)Cl2 (82 mg, 0.11 mmol) were added, and the mixture was reacted at 100°C for 16 h under a carbon monoxide environment. After the reaction was completed, water was added to quench the mixture, and ethyl acetate was added to extract the mixture. The residue was concentrated and purified by column chromatography (ethyl acetate / n-heptane = 65%) to obtain 150 mg of the target product, with a yield of 57.0%.

[0449] 3. Preparation of tert-butyl 4-((4-(azetidin-1-ylsulfonyl)-6-(hydroxymethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-67)

[0450] Int-66 (150 mg, 0.32 mmol) was dissolved in THF (2 mL) and methanol (2 mL), and NaBH4 (72 mg, 1.9 mmol) was added, and the mixture was reacted at 25°C for 16 h. After the reaction was completed, water was added to quench the mixture, and ethyl acetate was added to extract the mixture, which was washed with water and concentrated to obtain 100 mg of the target product with a yield of 70.9%.

[0451] 4. Preparation of tert-butyl 4-((4-(azetidin-1-ylsulfonyl)-6-(chloromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-68)

[0452] Int-67 (100 mg, 0.23 mmol) was dissolved in DCM (5 mL), and SOCl2 (40 mg, 0.34 mmol) was added and reacted at 25°C for 2 h. After the reaction was completed, the product was directly concentrated to obtain 110 mg, which was used in the next step.

[0453] 5. Preparation of tert-butyl 4-((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (Int-69)

[0454] Int-68 (110 mg crude product, 0.23 mmol) was dissolved in acetonitrile (5 mL), DIEA (89 mg, 0.69 mmol) and isoindoline hydrochloride (44 mg, 0.28 mmol) were added, and the mixture was reacted at 25°C for 16 h. After the reaction was completed, the residue was directly concentrated and subjected to column chromatography (ethyl acetate / n-heptane = 95%) to obtain 80 mg of the target product, with a yield (two steps): 65.0%.

[0455] 6. Preparation of 2-((4-(azetidin-1-ylsulfonyl)-5-(piperidin-4-ylmethoxy)pyridin-2-yl)methyl)isoindoline (Int-70)

[0456] Int-69 (80 mg, 0.15 mmol) was dissolved in DCM (5 mL), TFA (2 mL) was added, and the mixture was reacted at 25°C for 1 h. After the reaction was completed, the mixture was concentrated, ethyl acetate was added, saturated sodium bicarbonate solution was added to adjust the pH to 8, the mixture was washed with water, and concentrated to obtain 64 mg (yield: 98.2%).

[0457] 7. Preparation of 4-(((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-carboxamide (Compound 19)

[0458] Int-70 (30 mg, 0.068 mmol) was dissolved in DCM (5 mL), TEA (34 mg, 0.34 mmol) was added, Int-26 (13 mg, 0.10 mmol) was added, and the mixture was reacted at 25°C for 2 h. After the reaction was completed, water was added to quench the mixture, and DCM was added to extract the mixture. The residue was concentrated and chromatographed by TLC (MeOH / DCM=1 / 20) to obtain 25 mg of the target product, with a yield of 73.5%.

[0459] Molecular formula: C 25 H 33 N5O4S molecular weight: 499.6 LC-MS (M / e): 500.2 (M+H + )

[0460] 1H-NMR(400MHz, CDCl3)δ:8.44(s,1H),7.85(s,1H),7.28-7.19(m,4H),4.53-4.52(m,1H),4.07-3.99(m ,14H),2.89-2.81(m,5H),2.24-2.20(m,2H),2.18-2.16(m,1H),1.95-1.92(m,2H),1.42-1.32(m,2H).

[0461] Preparation Example 16: Preparation of 4-((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxamide (Compound 20)

[0462]

[0463] Int-70 (30 mg, 0.068 mmol) was dissolved in DCM (5 mL), TEA (34 mg, 0.34 mmol) and isocyanotrimethylsilane (16 mg, 0.14 mmol) were added, and the mixture was reacted at 25°C for 2 h. After the reaction was completed, water was added to quench the mixture, and DCM was added to extract the mixture. The residue was concentrated and chromatographed by TLC (MeOH / DCM=1 / 20) to obtain 20 mg of the target product, with a yield of 60.6%.

[0464] Molecular formula: C 24 H 31 N5O4S molecular weight: 485.6 LC-MS (M / e): 486.2 (M+H + )

[0465] 1 H-NMR(400MHz, CDCl3)δ:8.44(s,1H),7.85(s,1H),7.27-7.19(m,4H),4.62(m,2H),4.08-3.99(m,1 4H),2.90-2.84(m,2H),2.23-2.08(m,2H),2.07-1.96(m,1H),1.94-1.93(m,2H),1.45-1.38(m,2H).

[0466] Preparation Example 17: Preparation of 2-(4-(((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)sulfonyl)ethan-1-ol (Compound 21)

[0467]

[0468] 1. Preparation of ethyl 2-(4-(((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)sulfonyl)acetate (Int-71)

[0469] Int-70 (50 mg, 0.11 mmol) was dissolved in DCM (5 mL), TEA (34 mg, 0.33 mmol) was added, ethyl 2-(chlorosulfonyl)acetate (21 mg, 0.22 mmol) was added at 0°C, and the mixture was reacted at 0°C for 2 h. After the reaction was completed, water was added to quench the mixture, and DCM was added to extract the mixture. The residue was concentrated and chromatographed by TLC (MeOH / DCM = 15%) to obtain 30 mg of the target product, with a yield of 44.8%.

[0470] 2. Preparation of 2-(4-(((4-(azetidin-1-ylsulfonyl)-6-(isoindolin-2-ylmethyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)sulfonyl)ethane-1-ol (Compound 21)

[0471] Int-71 (30 mg, 0.05 mmol) was dissolved in THF (2 mL) and methanol (2 mL), and NaBH4 (8 mg, 0.2 mmol) was added, and the mixture was reacted at 25°C for 1 h. After the reaction was completed, water was added to quench the mixture, and EA was added to extract the mixture. The residue was concentrated and chromatographed by TLC (MeOH / DCM=1 / 30) to obtain 19 mg of the target product, with a yield of 68.1%.

[0472] Molecular formula: C 25 H 34 N4O6S2 molecular weight: 550.7 LC-MS (M / e): 551.2 (M+H + )

[0473] 1 H-NMR (400MHz, CDCl3) δ: 8.45 (s, 1H), 7.86 (s, 1H), 7.27-7.20 (m, 4H), 4.12-3.99 (m, 16H), 3. 19-3.17(m,2H),2.90-2.84(m,2H),2.25-2.17(m,2H),2.17-1.98(m,3H),1.66-1.52(m,3H).

[0474] Preparation Example 18: Preparation of 2-((4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidin-1-yl)sulfonyl)ethan-1-ol (Compound 24)

[0475]

[0476] 1. Preparation of 1-((5-bromo-2-fluorophenyl)sulfonyl)azetidine (Int-72)

[0477] Int-19 (3.0 g, 11.0 mmol) and pyridine (1.7 g, 21.5 mmol) were dissolved in THF (70 mL), and azetidine (1.3 g, 22.8 mmol) was added, and the mixture was reacted at 25°C for 1 hour. The mixture was concentrated and purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1) to obtain 3.0 g of the product with a yield of 93.0%.

[0478] 2. Preparation of tert-butyl 4-((2-(azetidin-1-ylsulfonyl)-4-bromophenoxy)methyl)piperidine-1-carboxylate (Int-73)

[0479] Int-72 (2.9 g, 9.9 mmol) was dissolved in DMF (70 mL), NaH (1.2 g, 30.0 mmol) was added, and the mixture was stirred at 25°C for 20 minutes, and Int-3 (3.0 g, 13.9 mmol) was added, and the mixture was reacted at 25°C for 1 hour. The mixture was extracted with water and EA, and the organic phase was washed with water and purified by silica gel column chromatography (n-heptane: ethyl acetate = 0-100%) to obtain 5.0 g of a crude product.

[0480] 3. Preparation of tert-butyl 4-((2-(azetidin-1-ylsulfonyl)-4-(hydroxymethyl)phenoxy)methyl)piperidine-1-carboxylate (Int-74)

[0481] Int-73 (2.5 g, 5.1 mmol) was dissolved in 1,4-dioxane (100 mL), tributyltin methanol (3.3 g, 10.3 mmol) and XPhos Pd G3 (400 mg, 0.51 mmol) were added, the mixture was ventilated with nitrogen for 3 times, and the mixture was reacted at 85°C for 3 hours under nitrogen protection. The mixture was concentrated and purified by silica gel column chromatography (DCM: MeOH = 25: 1) to obtain 2.1 g of the product with a yield of 93.3%.

[0482] 4. Preparation of tert-butyl 4-((2-(azetidin-1-ylsulfonyl)-4-(chloromethyl)phenoxy)methyl)piperidine-1-carboxylate (Int-75)

[0483] Int-74 (2.1 g, 4.8 mmol) and DMF (104 mg, 1.4 mmol) were dissolved in DCM (150 mL), and SOCl2 (1.1 g, 9.2 mmol) was added and reacted at 25°C for 1 hour. After the reaction was completed, the mixture was concentrated and the crude product was used directly in the next step.

[0484] 5. Preparation of tert-butyl 4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidine-1-carboxylate (Int-76)

[0485] Int-75 (crude) and isoindoline hydrochloride (1.1 g, 7.1 mmol) were dissolved in acetonitrile (100 mL), DIEA (3.1 g, 24.0 mmol) was added, and the mixture was reacted at 80°C for 3 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 1.6 g of the product, with a two-step yield of 62.0%.

[0486] 6. Preparation of 2-(3-(azetidin-1-ylsulfonyl)-4-(piperidin-4-ylmethoxy)benzyl)isoindoline (Int-77)

[0487] Int-76 (1.2 g, 0.68 mmol) was dissolved in DCM (25 mL), TFA (5 mL) was added, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed, the mixture was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with EA, dried, and concentrated to obtain 900 mg of a crude product.

[0488] 7. Preparation of methyl 2-((4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidin-1-yl)sulfonyl)acetate (Int-78)

[0489] Int-77 (300 mg, 0.68 mmol) and TEA (206 mg, 2.0 mmol) were dissolved in DCM (15 mL), cooled to 0°C, methyl 2-(chlorosulfonyl)acetate (152 mg, 0.81 mmol) was added, and reacted at 0°C for 1 hour until the reaction was complete. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=30:1) to obtain 200 mg of the product with a yield of 49.8%.

[0490] 8. Preparation of 2-((4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidin-1-yl)sulfonyl)ethan-1-ol (Compound 24)

[0491] Int-78 (200 mg, 0.34 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), and NaBH4 (128 mg, 3.4 mmol) was added. The mixture was reacted at 20°C for 2 h, quenched with water, concentrated, extracted with water and EA, and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 90 mg of the product. The yield was 48.4%.

[0492] Molecular formula: C 26H 35 N3O6S2 molecular weight: 549.7 LC-MS (m / z): 550.2 (M+H + )

[0493] 1 H-NMR (400MHz, CDCl3) δ: 7.89 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.24-7.14 (m, 4H), 7.01 (d, J = 8.4Hz, 1H), 4.12-4.05 (m, 2 H),4.05-3.85(m,14H),3.20-3.15(m,2H),2.95-2.83(m,2H),2.23-2.12(m,2H),2.12-1.97(m,3H),1.65-1.50(m,2H).

[0494] Preparation Example 19: Preparation of 4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidine-1-sulfonamide (Compound 25)

[0495]

[0496] Int-77 (200 mg, 0.45 mmol) and TEA (137 mg, 1.4 mmol) were dissolved in DCM (10 mL), cooled to 0°C, and aminosulfonyl chloride (63 mg, 0.0.55 mmol) was added, and reacted at 0°C for 1 hour. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain 50 mg of the product with a yield of 21.2%.

[0497] Molecular formula: C 24 H 32 N4O5S2 molecular weight: 520.7 LC-MS (m / z): 521.2 (M+H + )

[0498] 1 H-NMR (400MHz, CDCl3) δ: 7.91 (s, 1H), 7.77-7.62 (m, 1H), 7.24-7.14 (m, 4H), 7.01 (d, J = 8.4Hz, 1H), 4.05-3. 79(m,14H),3.20-3.17(m,2H),2.85-2.70(m,2H),2.25-2.12(m,2H),2.12-1.97(m,3H),1.65-1.50(m,2H).

[0499] Preparation Example 20: Preparation of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-((1-(oxetane-3-carbonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 26)

[0500]

[0501] To a solution of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-(piperidin-4-ylmethoxy)benzenesulfonamide (Int-79) (50 mg, 0.11 mmol) in DMF (10 mL), DIEA (71 mg, 0.55 mmol), oxetane-3-carboxylic acid (22 mg, 0.22 mmol) and HATU (125 mg, 0.33 mmol) were added and reacted at 25°C for 3 h. Water was added to quench the mixture, ethyl acetate was added to extract the mixture, and the residue was concentrated and separated on a preparative plate (SiO2, methanol: dichloromethane = 10%) to obtain 3 mg of the target compound in a yield of 5.2%.

[0502] Molecular formula: C 28 H 35 N3O5S molecular weight: 525.2 LC-MS (M / e): 526.3 (M+H + )

[0503] 1 H-NMR (400MHz, CDCl3) δ: 7.97 (s, 1H), 7.80 (s, 1H), 7.25-7.15 (m, 4H), 7.03 (d, J = 8.5Hz, 1H),5.12(s,1H),5.01-4.91(m,2H),4.82-4.71(m,2H),4.70-4.52(m,1H),4.11-3.89(m ,9H),3.51-3.42(m,1H),3.13-3.02(m,1H),2.80-2.77(m,1H),2.25-2.12(m,2H),2.10- 2.00(m,1H),1.98-1.95(m,1H),1.39-1.27(m,2H),0.98-0.70(m,2H),0.70-0.60(m,2H).

[0504] Preparation Example 21: Preparation of (1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)-N-methylcyclohexane-1-carboxamide (Compound 27)

[0505]

[0506] 1. Preparation of methyl (1r,4r)-4-((4-bromo-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)cyclohexane-1-carboxylate (Int-82)

[0507] 4-Bromo-2-(pyrrolidin-1-ylsulfonyl)phenol (Int-80) (800 mg, 2.6 mmol), (1r,4r)-4-(hydroxymethyl)cyclohexane-1-carboxylic acid methyl ester (Int-81) (588 mg, 3.4 mmol) and triphenylphosphine (898 mg, 3.4 mmol) were dissolved in tetrahydrofuran (30 mL), diethyl azodicarboxylate (596 mg, 3.4 mmol) was added, and the mixture was reacted at 10° C. for 1 hour. The mixture was concentrated and purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1) ​​to obtain 650 mg of the product with a yield of 54.0%.

[0508] 2. Preparation of methyl (1r,4r)-4-((4-(hydroxymethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)cyclohexane-1-carboxylate (Int-83)

[0509] Int-82 (650 mg, 1.4 mmol) was dissolved in 1,4-dioxane (30 mL), tributyltin methanol (680 mg, 2.1 mmol) and XPhos Pd G3 (110 mg, 0.14 mmol) were added, the mixture was ventilated with nitrogen for 3 times, and the mixture was reacted at 85°C for 3 hours under nitrogen protection. The mixture was concentrated and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:2) to obtain 400 mg of the product with a yield of 68.8%.

[0510] 3. Preparation of methyl (1r,4r)-4-((4-(chloromethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)cyclohexane-1-carboxylate (Int-84)

[0511] Int-83 (400 mg, 0.97 mmol) was dissolved in DCM (20 mL), and thionyl chloride (232 mg, 1.9 mmol) was added, and the mixture was reacted at 10° C. for 1 hour. After the reaction was completed, the mixture was concentrated, and the crude product was used directly in the next step.

[0512] 4. Preparation of methyl (1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)cyclohexane-1-carboxylate (Int-85)

[0513] Int-84 (crude product) and isoindoline hydrochloride (290 mg, 1.9 mmol) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (600 mg, 4.6 mmol) was added, and the mixture was reacted at 80°C for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 300 mg of the product, with a two-step yield of 60.2%.

[0514] 5. Preparation of (1r,4r)-4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)-N-methylcyclohexane-1-carboxamide (Compound 27)

[0515] Int-85 (150 mg, 0.29 mmol), aqueous methylamine solution (40%) (15 mL) and methanol (15 mL) were added to the sealed tube, reacted at 90°C for 3 hours, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol = 30:1) to obtain 90 mg of the product, with a yield of 60.1%.

[0516] Molecular formula: C 28 H 37 N3O4S molecular weight: 511.7 LC-MS (m / z): 512.2 (M+H + )

[0517] 1 H-NMR (400MHz, CDCl3) δ: 7.92 (s, 1H), 7.62-7.60 (m, 1H), 7.22-7.16 (m, 4H), 6.97 (d, J = 8.4Hz, 1H), 5.55-5.48 (m, 1H), 4.00-3.85 (m, 8H), 3.43-3.35(m,4H),2.82(d,J=4.8Hz,3H),2.15-2.07(m,3H),2.07-1.98(m,2H),1.95-1.80(m,5H),1.70-1.50(m,2H),1.25-1.10(m,2H).

[0518] Preparation Example 22: Preparation of 4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)-N-methylcyclohexane-1-carboxamide (Compound 28)

[0519]

[0520] Using Int-80 and methyl 4-(hydroxymethyl)cyclohexane-1-carboxylate as raw materials, Compound 28 was prepared according to the method of Preparation Example 21.

[0521] Molecular formula: C 28 H37 N3O4S molecular weight: 511.7 LC-MS (m / z): 512.2 (M+H + )

[0522] 1 H-NMR(400MHz, CDCl3)δ:7.92(s,1H),7.60(d,J=8.0Hz,1H),7.24-7.16(m,4H),7.00(d,J=8.4Hz,1H),5.61-5.58(m,1H),4.07-4.01(m,2H ),4.01-3.85(m,6H),3.40-3.32(m,4H),2.82(d,J=4.8Hz,3H),2.33-2.25(m,1H),2.15-2.07(m,1H),1.95-1.84(m,6H),1.84-1.60(m,6H).

[0523] Preparation Example 23: Preparation of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 31)

[0524]

[0525] 1. Preparation of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-(piperidin-4-ylmethoxy)benzenesulfonamide hydrochloride (Int-87)

[0526] 4-((2-(N-cyclopropylaminosulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (Int-86) (100 mg, 0.18 mmol) was dissolved in 10 mL of DCM, 5 mL of HCl / Dioxane was added, and the system was reacted at 25°C for 2 hours. After concentration, the crude product was directly used in the next reaction.

[0527] 2. Preparation of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-((1-(methylsulfonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 31)

[0528] Int-87 was dissolved in DCM (30 mL), and DIEA (86 mg, 0.66 mmol) and methanesulfonyl chloride (32 mg, 0.28 mmol) were added. The system was reacted at 30 °C for 1 hour and then concentrated. 20 mg of the target product was obtained by column chromatography. The yield of the two steps was 20.8%.

[0529] Molecular formula: C 25 H 33N3O5S2 molecular weight: 519.7 LC-MS (M / e): 520.1 (M+H + )

[0530] 1 H-NMR (400MHz, CDCl3) δ: 7.98 (s, 1H), 7.69 (s, 1H), 7.21-7.16 (m, 4H), 7.03-7.01 (m, 1H), 5.11 (s, 1H), 4.06-3.89 (m ,10H),2.84(s,3H),2.76-2.75(m,2H),2.17-1.89(m,4H),1.61-1.52(m,2H),0.89-0.81(m,2H),0.65-0.61(m,2H).

[0531] Preparation Example 24: Preparation of 2-((1-acetylpiperidin-4-yl)methoxy)-N-cyclopropyl-5-(isoindolin-2-ylmethyl)benzenesulfonamide (Compound 32)

[0532]

[0533] Int-87 (0.18 mmol) was dissolved in DCM (30 mL), DIEA (86 mg, 0.66 mmol) and acetyl chloride (17 mg, 0.22 mmol) were added, and the system was reacted at 30°C for 1 hour, concentrated, and column chromatography was performed to obtain 20 mg of the target product with a yield of 22.4%.

[0534] Molecular formula: C 26 H 33 N3O4 molecular weight: 483.6 LC-MS (M / e): 484.1 (M+H + )

[0535] 1 H-NMR (400MHz, CDCl3) δ: 7.98 (s, 1H), 7.69 (s, 1H), 7.21-7.16 (m, 4H), 7.03-7.01 (m, 1H), 5 .15(s,1H),4.85-4.72(m,1H),4.06-3.89(m,9H),3.21-3.01(m,1H),2.76-2.75(m,1H),2.1 7-1.89 (m, 5H), 2.08-1.81 (m, 2H), 1.32-1.24 (m, 2H), 0.89-0.81 (m, 2H), 0.65-0.61 (m, 2H). Preparation Example 25: Preparation of 4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)-N-(methyl-d3)piperidine-1-carboxamide (Compound 33)

[0536]

[0537] 1. Preparation of phenyl (methyl-d3) carbamate (Int-89)

[0538] Dissolve deuterated methylamine (200 mg, 5.9 mmol) and triethylamine (1.8 g, 17.8 mmol) in acetonitrile (10 mL), add phenylphosgene (1.4 g, 8.9 mmol), and react at 10°C for 16 hours. After the reaction is complete, concentrate and purify by silica gel column chromatography (n-heptane: ethyl acetate = 1:1) to obtain 200 mg of the product with a yield of 22.1%.

[0539] 2. Preparation of 4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)-N-(methyl-d3)piperidine-1-carboxamide (Compound 33)

[0540] Int-77 (120 mg, 0.27 mmol) and Int-89 (83 mg, 0.54 mmol) were dissolved in DMF (5 mL), and DIPEA (175 mg, 1.4 mmol) was added, and the mixture was reacted at 120° C. for 2 hours. After the reaction was completed, the mixture was concentrated, extracted with water and EA, and purified by silica gel column chromatography (DCM:MeOH=25:1) to obtain 40 mg of the product, with a yield of 29.3%.

[0541] Molecular formula: C 26 H 31 D3N4O4S molecular weight: 501.7 LC-MS (m / z): 502.2 (M+H + )

[0542] 1 H-NMR (400MHz, CDCl3) δ: 7.88 (s, 1H), 7.65-7.62 (m, 1H), 7.19-7.13 (m, 4H), 7.00 (d, J = 8.4Hz, 1H), 4.42 (s, 1H), 4 .08-3.82(m,14H),2.88-2.75(m,2H),2.19-2.12(m,2H),2.12-2.00(m,1H),2.00-1.89(m,2H),1.45-1.28(m,2H).

[0543] Preparation Example 26: Preparation of 1-(4-((2-(azetidin-1-ylsulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidin-1-yl)-3-hydroxypropan-1-one (Compound 34)

[0544]

[0545] 3-Hydroxypropionic acid (37 mg, 0.41 mmol), HATU (205 mg, 0.54 mmol) and TEA (109 mg, 1.1 mmol) were dissolved in dichloromethane (15 mL), and Int-77 (120 mg, 0.27 mmol) was added, and the mixture was reacted at 10°C for 16 hours. After the reaction was completed, the mixture was concentrated, extracted with water and dichloromethane, and purified by silica gel column chromatography (DCM:MeOH=25:1) to obtain 40 mg of the product with a yield of 28.7%.

[0546] Molecular formula: C 27 H 35 N3O5S molecular weight: 513.7 LC-MS (m / z): 514.2 (M+H + )

[0547] 1 H-NMR (400MHz, CDCl3) δ: 7.88 (s, 1H), 7.79-7.65 (m, 1H), 7.21-7.15 (m, 4H), 7.03 (d, J = 8.4Hz, 1H), 4.72-4.66 (m, 1H), 4.10-3. 85(m,14H),3.55-3.46(m,1H),3.15-3.06(m,1H),2.70-2.55(m,3H),2.25-2.10(m,4H),2.00-1.90(m,1H),1.45-1.28(m,2H).

[0548] Preparation Example 27: Preparation of N-cyclopropyl-5-(isoindolin-2-ylmethyl)-2-((1-(pyrrolidine-1-carbonyl)piperidin-4-yl)methoxy)benzenesulfonamide (Compound 35)

[0549]

[0550] Int-87 (0.28 mmol) was dissolved in DCM (5 mL), TEA (113 mg, 1.12 mmol) and pyrrolidine-1-carbonyl chloride (41 mg, 0.31 mmol) were added, and the system was reacted at 25°C for 2 hours until the reaction was complete. The residue was directly concentrated and the target product (38 mg) was obtained by plate chromatography (MeOH / DCM = 5%) with a yield of 25.3%.

[0551] Molecular formula: C 29 H 38 N4O4S molecular weight: 538.7 LC-MS (M / e): 539.3 (M+H + )

[0552] 1H-NMR (400MHz, DMSO) δ: 7.70 (s, 1H), 7.53 (m, 1H), 7.26 (s, 1H), 7.19-7.16 (m, 5H), 3.96 (m, 2H), 3.83-3.80 (m, 6H), 3.68-3.64 ( m,2H),3.32-3.28(m,4H),3.23(s,1H),2.69-2.60(m,2H),2.161.95(m,3H),1.85-1.79(m,2H),1.72(m,4H),0.38-0.31(m,4H).

[0553] Preparation Example 28: Preparation of 2-((1-(azetidine-1-carbonyl)piperidin-4-yl)methoxy)-N-cyclopropyl-5-(isoindolin-2-ylmethyl)benzenesulfonamide (Compound 36)

[0554]

[0555] Int-87 (0.18 mmol) was dissolved in DCM (30 mL), and DIEA (86 mg, 0.66 mmol) and azetidine-1-carbonyl chloride (26 mg, 0.22 mmol) were added. The system was reacted at 30 °C for 1 hour, concentrated, and column chromatography was performed to obtain 20 mg of the target product with a yield of 20.6%.

[0556] Molecular formula: C 28 H 36 N4O4S molecular weight: 524.7 LC-MS (M / e): 525.1 (M+H + )

[0557] 1 H-NMR (400MHz, CDCl3) δ: 7.95 (s, 1H), 7.69 (s, 1H), 7.21-7.16 (m, 4H), 7.03-7.01 (m, 1H), 5.14 (s, 1H), 4.05-3.85 (m, 1 4H),2.89-2.71(m,2H),2.22-2.05(m,4H),1.89-1.75(m,2H),1.49-1.38(m,2H),0.89-0.81(m,2H),0.65-0.61(m,2H).

[0558] Preparation Example 29: Preparation of 4-fluorophenyl-4-((2-(N-cyclopropylaminosulfonyl)-4-(isoindolin-2-ylmethyl)phenoxy)methyl)piperidine-1-carboxylate (Compound 38)

[0559]

[0560] Int-87 (0.18 mmol) was dissolved in DCM (30 mL), and DIEA (86 mg, 0.66 mmol) and 4-fluorophenyl chloroformate (38 mg, 0.22 mmol) were added. The system was reacted at 30 °C for 1 hour and then concentrated. 20 mg of the target product was obtained by column chromatography with a yield of 18.7%.

[0561] Molecular formula: C 31 H 34 N3O5SF molecular weight: 579.7 LC-MS (M / e): 580.1 (M+H + )

[0562] 1 H-NMR (400MHz, CDCl3): 7.98(s,1H),7.69(s,1H),7.21-7.16(m,4H),7.03-7.01(m,5H),5.11(s,1H),4.35-4.25(m,2 H),4.09-3.89(m,8H),3.01-2.89(m,2H),2.21-1.89(m,4H),1.49-1.38(m,2H),0.89-0.81(m,2H),0.65-0.61(m,2H).

[0563] Preparation Example 30: Preparation of methyl 4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Compound 41)

[0564]

[0565] Compound 42 (50 mg, 0.087 mmol) was dissolved in methanol (10 mL), and sodium methoxide / methanol solution (1.0 M, 1 mL) was added. The system was reacted at 25°C for 2 hours, and the reaction solution was concentrated and separated on a preparative plate (SiO2, DCM:MeOH=10:1) to obtain 30 mg of the target product with a yield of 67.2%.

[0566] Molecular formula: C 27 H 35 N3O5S molecular weight: 513.6 LC-MS (M / e): 514.2 (M+H + )

[0567] 1H-NMR (400MHz, CDCl3) δ: 7.90 (s, 1H), 7.64 (s, 1H), 7.35-7.20 (m, 4H), 6.99-6.85 (m, 1H), 4.50-4.21 (m, 2H), 4.01-3.79(m,8H),3.69(s,3H),3.46-3.25(m,4H),2.90-2.65(m,2H),2.29-1.90(m,4H),1.90-1.75(m,5H).

[0568] Preparation Example 31: Preparation of pyridin-2-yl-4-((4-(isoindolin-2-ylmethyl)-2-(pyrrolidin-1-ylsulfonyl)phenoxy)methyl)piperidine-1-carboxylate (Compound 42)

[0569]

[0570] Pyridine-2-ol (500 mg, 5.3 mmol) was dissolved in DCM (10 mL), triphosgene (3.0 g, 10.6 mmol) and pyridine (1.6 g, 20.0 mmol) were added, and the system was reacted at 25°C for 2 hours, then filtered, the filtrate was collected, and after concentration, the residue was diluted with acetonitrile (20 mL), and Int-25 (200 mg, 0.44 mmol) and DIEA (2.6 g, 20.0 mmol) were added. The reaction was completed at 80°C for 16 hours, and the reaction solution was concentrated and separated on a preparative plate (SiO2, DCM: MeOH = 10: 1) to obtain 61 mg of the target product with a yield of 24.1%.

[0571] Molecular formula: C 31 H 36 N4O5S molecular weight: 576.7 LC-MS (M / e): 577.2 (M+H + )

[0572] 1 H-NMR (400MHz, CDCl3) δ: 8.37 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.58 (s, 1H), 7.25-6.84 (m, 7H), 4.50-4. 21(m,2H),4.01-3.79(m,8H),3.46-3.25(m,4H),3.15-2.90(m,2H),2.29-1.90(m,7H),1.65-1.38(m,2H).

[0573] The compounds shown in the following table were prepared using the same or similar methods as the above preparation examples:

[0574]

[0575] 2. Pharmacological Activity Test of the Compounds of the Invention

[0576] 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.

[0577] Experimental Example 1: In vitro enzymatic activity of the compounds of the present invention

[0578] This experiment evaluates the inhibitory effect of the inventive compounds on CYP11A1 by detecting the biosynthesis of pregnenolone.

[0579] Test sample: the compound of the present invention, its structural formula and preparation method are shown in the preparation examples.

[0580] Experimental reagents:

[0581]

[0582] Experimental method (ELISA assay):

[0583] 1. Cell Preparation

[0584] Cells were grown in NCI-H295R special 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 overnight at 37°C, 5% CO2.

[0585] 2. Compound dilution

[0586] 1) The compounds of the present invention and the positive control drug were prepared with DMSO to 10 mM as test stock solutions.

[0587] 2) Dilute the test stock solution 100 times to 100 μM as the test working solution.

[0588] 3) The test working solution was diluted 3-fold to 8 concentrations, with the highest concentration being 100 μM.

[0589] 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, 0.046 nM, and 0 nM.

[0590] 3. Pregnenolone biosynthesis detection

[0591] 1) Add 10 μL of compound to the above 96-well plate containing the cell suspension and incubate at 37° C., 5% CO 2 for 24 hours.

[0592] 2) Centrifuge the supernatant, transfer 10 μL of the supernatant into a new 96-well plate, and dilute 8 times with culture medium.

[0593] 3) Prepare pregnenolone-HRP conjugate working solution and wash buffer.

[0594] 4) Take out the required number of enzyme label strips.

[0595] 5) Add 50 μL of the standard, positive control and sample to the corresponding labeled wells in duplicate.

[0596] 6) Add 100 μL of pregnenolone-HRP conjugate working solution to each well.

[0597] 7) Incubate at room temperature on an orbital shaker at approximately 200 rpm for 1 hour.

[0598] 8) Wash each well three times with 300 μL of diluted washing buffer and pat dry on clean absorbent paper.

[0599] 9) Add 150 μL TMB substrate to each well.

[0600] 10) Incubate on an orbital shaker at room temperature for 10-15 minutes.

[0601] 11) At the same time intervals as in step 10, add 50 μL of stop solution to each well.

[0602] 4. Result detection

[0603] 1) Within 20 minutes after adding the stop solution, read the OD value at a wavelength of 450 nm using a multifunctional microplate reader.

[0604] 2) Collect data.

[0605] 5. Data processing

[0606] 1) Inhibition rate (%) = 1-(test substance well concentration - blank control well concentration) / (DMSO solvent control well concentration - blank control well concentration) × 100%;

[0607] 2) Input GraphPad Prism to draw a graph and obtain the curve and IC 50 .

[0608] Experimental results:

[0609] Table 1 Inhibitory activity of the compounds of the present invention on CYP11A1

[0610]

[0611] 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.

[0612] Experimental Example 2: In vitro enzymatic activity of the compounds of the present invention

[0613] The final concentrations of the test compounds in Experimental Example 1 were adjusted to 100 nM, 25 nM, 6.25 nM, 1.56 nM, 0.39 nM, 0.098 nM, and 0 nM. The inhibitory effect of the inventive compounds on CYP11A1 was evaluated by detecting the biosynthesis of pregnenolone according to the method described in Experimental Example 1.

[0614] Experimental results:

[0615] Table 2 Inhibitory activity of the compounds of the present invention on CYP11A1

[0616]

[0617] In addition, the inhibitory activity of compound 19, compound 20, compound 22, compound 33 and compound 34 on CYP11A1 is less than 100 nM. From the above experimental results, it can be seen 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 thereof, a deuterated product thereof, an ester thereof or a stereoisomer thereof, in, X1 and X2 are independently selected from CR a or N; Y is selected from -S(O)2- or -C(O)-; 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; R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 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 , -S(O)NR 4a R 4b , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocyclic group, -(CH2) p -5-10 membered heteroaryl, -(CH2) p -6-10 membered aryl; each Q1 is independently 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; or R1, R2 together with the N atom to which they are attached form a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group optionally substituted by 1-4 Q2; each Q2 is independently 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; R3 and R4 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 group optionally substituted by 1-4 Q3: -(CH2) t -3-10 membered cycloalkyl, -(CH2) t -3-10 membered heterocyclic group, -(CH2) t -5-10 membered heteroaryl, -(CH2) t -6-10 membered aryl; each Q3 is independently 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 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 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, -(CH2) s -3-10 membered cycloalkyl, -(CH2) s -3-10 membered heterocycloalkyl, -(CH2) s -5-10 membered heteroaryl or -(CH2) s -phenyl; R 5a , R 5b is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy or the following group optionally substituted by 1-4 Q4: -(CH2) s -3-10 membered cycloalkyl, -(CH2) s -3-10 membered heterocycloalkyl, -(CH2) s -5-10 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently 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; m, n, p, t, s are independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein: X1 and X2 are independently selected from CR a or N; Y is selected from -S(O)2- or -C(O)-; 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” -; 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; R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, -OR 4a , -SR 4a , -C(O)R 4a , -C(O)NR 4a R 4b , -C(O)OR 4a , -S(O)2NR 4a R 4b , -S(O)2R 4a or the following group optionally substituted by 1-4 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, -(CH2) p -5-6 membered heteroaryl, -(CH2) p -phenyl; each Q1 is independently 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; or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-4 Q2; each Q2 is independently 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; R3 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 ; R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, carboxyl, oxo, C 1-6 Alkyl, haloC 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 , -S(O)2R 5a or the following group optionally substituted by 1-4 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently 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 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 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, cyano C 1-6 Alkoxy or the following group optionally substituted by 1-4 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently 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; m, n, s, p, t are each independently selected from 0, 1, 2 or 3.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein: X1 and X2 are independently selected from CR a or N; Y is selected from -S(O)2- or -CO-; L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -; L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -; Ring A is selected from Preferably, ring A is Ring B is selected from cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, piperidinyl or piperazinyl; preferably, ring B is cyclohexyl, piperidinyl or piperazinyl; R1 and R2 are independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl, -OR 4a or the following groups optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently 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; R3 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 ; R4 at each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, oxo, C 1-4 Alkyl, haloC 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 , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; 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 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 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, cyano, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, cyano C 1-4 Alkyl or the following group optionally substituted by 1-3 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 5b are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy; m, n, s, p, t are each independently selected from 0, 1, 2 or 3.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, which has a structure represented by the general formula (II) or the general formula (IV), in, The definitions of L1, L2, X1, X2, R1, R2, R3, R4, m and n are as described in any one of claims 1-3.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein: X1 from CR a or N; X2 for CR a ; L1 is selected from -CHR 1a -or-CHR 1a -CHR 1a’ -; L2 is selected from -CHR 2a -or-CHR 2a -CHR 2a’ -; R1 is selected from hydrogen, halogen, 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, -OR 4a or the following groups optionally substituted by 1-3 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, each Q1 is independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R2 is selected from hydrogen, C 1-6 Alkyl or -OR 4a ; or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently selected from halogen, hydroxyl, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R3 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, R3 is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl or -C(O)NR 5a R 5b ; R4 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, C 1-4 Alkyl, haloC 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 or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; Preferably, R4 at each occurrence is independently selected from hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)R 5a , -C(O)NR 5a R 5b , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R a , R 1a , R 1a’ , R 2a , R 2a’ , R 4a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R a , R 1a , R 1a’ , R 2a , R 2a’ , R 4a 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, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl, cyano C 1-4 Alkyl, or the following group optionally substituted by 1-2 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl, -(CH2) s -phenyl; preferably, R 5a is independently selected at each occurrence from hydrogen, methyl, ethyl, propyl, isopropyl, -CD3, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, or the following groups optionally substituted with 1-2 Q4: -(CH2) s -cyclopropyl, -(CH2) s -cyclobutyl, -(CH2) s -cyclopentyl, -(CH2) s -cyclohexyl, -(CH2) s -aziridine, -(CH2) s -azetidinyl, -(CH2) s -pyrrolidinyl, -(CH2) s -imidazolidinyl, -(CH2) s -piperidinyl, -(CH2) s -piperazinyl, -(CH2) s -morpholinyl, -(CH2) s -Oxypropyl, -(CH2) s -Oxetane, -(CH2) s -tetrahydrofuranyl, -(CH2) s -tetrahydropyranyl, -(CH2) s -pyridyl, -(CH2) s -pyrimidinyl or -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl; 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; m, p, t, s are independently selected from 0, 1 or 2.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its deuterated product, its ester or its stereoisomer, wherein: X1 is selected from CH or N; X2 is CH; L1 is -CH2-; L2 is selected from -CH2- or -CH2-CH2-; R1 is selected from hydrogen, halogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or the following group optionally substituted by 1-2 Q1: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; each Q1 is independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R2 is selected from hydrogen or C 1-4 alkyl; or R1, R2 together with the N atom to which they are attached form a 3-6 membered heterocyclic group optionally substituted by 1-3 Q2; each Q2 is independently selected from halogen, hydroxyl, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R3 is independently selected at each occurrence from hydrogen, halogen, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl; R4 is independently selected at each occurrence from C 1-4 Alkyl, haloC 1-4 Alkyl, -C(O)NR 5a R 5b , -C(O)R 5a , -C(O)OR 5a , -S(O)2NR 5a R 5b , -S(O)2R 5a or the following group optionally substituted by 1-3 Q3: -(CH2) t -3-6 membered cycloalkyl, -(CH2) t -3-6 membered heterocyclic group, -(CH2) t -5-6 membered heteroaryl, -(CH2) t -phenyl; each Q3 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; R 5a are independently selected at each occurrence from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, haloC 1-4 Alkyl, hydroxyl C 1-4 Alkyl or the following group optionally substituted by 1-2 Q4: -(CH2) s -3-6 membered cycloalkyl, -(CH2) s -3-6 membered heterocycloalkyl, -(CH2) s -5-6 membered heteroaryl, -(CH2) s -phenyl; each Q4 is independently selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 5b Each occurrence is independently selected from hydrogen or C 1-4 alkyl; m, p, t, s are independently selected from 0, 1 or 2.

7. The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated substance, its ester or its stereoisomer, wherein 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 deuterated product, 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 deuterated product, its ester or its stereoisomer, characterized in that: The pharmaceutical composition comprises one or more second therapeutically active agents; the second therapeutically active agents are selected from glucocorticoids, mineralocorticoids or anticancer drugs; 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, its deuterated product, its ester or its stereoisomer, 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; preferably, the diseases and related conditions mediated by CYP11A1 are prostate cancer; preferably, the diseases and related conditions mediated by CYP11A1 are castration-resistant prostate cancer.

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