Polycyclic compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a polycyclic compound, and a preparation method therefor and a use thereof. Specifically, disclosed in the present invention are a compound represented by formula (I), a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, a preparation method therefor, and a use thereof. The compound of the present invention is a CYP11A1 inhibitor, and can be used for treating and / or preventing CYP11A1-related diseases, especially cancer, such as prostate cancer and breast cancer.

Description

A polycyclic compound and its preparation method and application Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a polycyclic compound and a preparation method and application thereof. Background Art

[0002] Interfering with the binding of endogenous steroid hormones to their receptors to achieve anti-tumor effects using hormonal drugs is an important approach in the treatment of endocrine cancers such as prostate and breast cancer. Many patients respond very well to treatment initially, achieving good disease control. However, over time, acquired drug resistance inevitably develops, ultimately leading to disease recurrence and progression. The mechanisms of acquired drug resistance are generally complex, and disease progression is often the result of multiple factors.

[0003] Prostate cancer is a common malignancy of the male genitourinary system. According to data released by the World Health Organization, there were over 1.4 million new cases of prostate cancer worldwide in 2020, posing a significant threat to men's health. Signaling through the androgen receptor (AR) pathway, driven by androgens (testosterone and dihydrotestosterone), can influence the growth and proliferation of prostate cancer cells and play a crucial role in disease progression. Therefore, inhibiting testicular androgen synthesis, thereby reducing androgen levels in the body, through medication or surgery, can effectively inhibit prostate cancer cell growth and achieve disease regression. This treatment, known as androgen deprivation therapy (ADT), is the standard of care for prostate cancer. However, because adrenal glands and prostate cancer cells also produce androgens, prostate cancer can continue to progress even after a period of ADT treatment, despite low circulating androgen levels. This is also known as castration resistance. Among the currently approved treatments for castration-resistant prostate cancer (CRPC), besides AR inhibitors such as enzalutamide, abiraterone is the most important. Abiraterone is a CYP17 inhibitor that inhibits the adrenal glands from synthesizing androgens such as pregnenolone, further depleting tumor cells of androgens needed for growth. Although abiraterone is highly effective initially, resistance inevitably develops, leaving patients with progressive CRPC with limited treatment options. Therefore, novel mechanistic therapies and drugs are urgently needed. Studies on CRPC progression have shown that activation of the AR signaling pathway continues to play a crucial role in tumor growth. AR gene amplification and AR mutations, which increase AR's affinity for endogenous hormones other than testosterone and dihydrotestosterone, are key drivers of AR signaling. Therefore, profoundly disrupting AR signaling in CRPC by inhibiting the synthesis of most, or even all, steroid hormones is a promising approach for prostate cancer treatment.

[0004] The synthesis of all steroid hormones in the human body, including glucocorticoids, mineralocorticoids and sex hormones, is derived from the same precursor cholesterol. The entire process is a series of complex transformations catalyzed by P450 cytochromes and hydroxysteroid dehydrogenases, ultimately resulting in the various hormones needed by the human body. In the first step of these transformations, the CYP11A1 enzyme catalyzes the side-fragmentation oxidation reaction of cholesterol. Therefore, inhibiting the catalytic activity of CYP11A1 can effectively cut off the body's use of cholesterol to synthesize various hormones, thereby blocking various hormone-mediated physiological functions. CYP11A1 has therefore become a potential target for the treatment of endocrine cancers such as prostate cancer and breast cancer. Currently, no drugs have been approved for this target, and there is a strong demand for the development of highly active CYP11A1 inhibitors. Summary of the Invention

[0005] The purpose of this application is to provide a polycyclic compound with a completely new structure.

[0006] The present application also aims to provide a use of the polycyclic compound as a CYP11A1 inhibitor.

[0007] The present application also aims to provide a pharmaceutical composition comprising the polycyclic compound as described above and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0008] The present application also aims to provide a use of the polycyclic compound as described above in a drug for treating CYP11A1-related diseases.

[0009] The present application also aims to provide a method for preventing or treating CYP11A1-related diseases, such as cancer, particularly prostate cancer and breast cancer.

[0010] In a first aspect of the present invention, there is provided a compound as represented by formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs,

[0011] wherein n and p are each independently 1, 2, 3, 4 or 5;

[0012] Each R 20 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, SF5, C 1-6 Alkyl, C 1-6 Alkenyl, C 1- 6 alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8Cycloalkoxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, -P(O)(C 1-6 Alkyl)2, NR 14 R 15 The above groups may be further optionally replaced by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution;

[0013] R d and R d ' are each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution;

[0014] or R d 、R d ' and the C atoms to which it is connected together form C 3-6 Carbocyclic or 4-6 membered heterocyclic ring, said carbocyclic and heterocyclic ring may be further optionally substituted by one or more selected from D, halogen, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)C 1-6 Alkyl, -S(O)2-C 1-6 substituted by an alkyl substituent;

[0015] R 1 Independently selected from the group consisting of H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, oxo (=O), C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 1-6Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution;

[0016] R b and R b ' are each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3- 8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution;

[0017] Ring B is selected from the group consisting of 4-14 membered heterocyclic rings, 4-10 membered carbocyclic rings, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, 7-14 membered fused bicyclic ring;

[0018] Each R 3 Independently selected from the group consisting of H, D, halogen, cyano, -C 0-4 Alkylene-OR 12 、-C 0-4 Alkylene-CONR 10 R 11 、-C(O)C 1-6 Alkyl, -P(O)(OR 12 )2、-S(O)2C 1-6 Alkyl, -S(O)2-C 6-10 Aryl, -S(O)2-5-12 membered heteroaryl, -S(O)(NR 31 )C 1-6 Alkyl, -C 0-4 Alkylene-S(O)2NR 10 R 11 、-C 0-4 Alkylene-S(O)(NR 31 )NR 10 R 11 、-C 0- 4-Alkylene-S(O)NR 10 R 11 、-C 0-4 Alkylene-COOR 12 , oxo (=O), =C (R 13 )2、C 1-6 Alkyl, C 3-6Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution;

[0019] Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, 5-12 membered heteroaryl, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), which may be further optionally substituted by one or more R j replace;

[0020] Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a 4-10 membered nitrogen-containing heterocyclic ring, which may be further optionally replaced by one or more R j replace;

[0021] Each R j Independently selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, -C 0-4 Alkylene-NR 16 R 17 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic oxy, C 3-10 Halogenated cycloalkoxy, 4-10 membered halogenated heterocyclic oxy, -C(O)C 1-6 Alkyl, -CONR 32 R 33 、-S(O)2C 1-6 Alkyl, -S(O)2NR 32 R 33 ;

[0022] Alternatively, two R jAll atoms connected to it together form C 3-6 Carbocyclic or 4-7 membered heterocyclic ring;

[0023] Each R 12 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Heterocyclic group, said group may be optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1- 4-halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group;

[0024] Each R 13 Each independently selected from the group consisting of H, D, halogen, C 1-3 Alkyl, C 1-3 alkyl halide;

[0025] Or two R 13 Together with the carbon atoms where they are located, they form a 3-6 membered cycloalkylene or 4-6 membered heterocyclylene, wherein the cycloalkylene and heterocyclylene may be further optionally substituted by one or more selected from D, halogen, C 1-4 Alkoxy, C 1- 4-substituted by a haloalkoxy substituent;

[0026] Each R 14 , each R 15 , each R 16 , each R 17 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, -SO2(C 1- 6 alkyl), -CO(C 1-6 alkyl), -SO2(C 3-6 Cycloalkyl), -CO(C 3-6 Cycloalkyl), -SO2 (4-6 membered heterocyclic group), -CO (4-6 membered heterocyclic group), -CO (-OC 1-6 Alkyl), -SO2NH(C 0-6 Alkyl), -SO2N(C 1-6 alkyl)2, -CONH(C 0-6 alkyl), -CON(C 1-6 Alkyl) 2, said group may be further optionally substituted by one or more selected from deuterium, halogen, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group;

[0027] Alternatively, R attached to the same nitrogen atom 14 and R 15 Together with the nitrogen atom, a 4-8 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from D, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) substituent;

[0028] Each R 31 Independently selected from the group consisting of H, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic group, said group may be further optionally substituted by one or more selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group;

[0029] Each R 32 , each R 33 Independently selected from the group consisting of H, C 1-6 Alkyl, said group may be further optionally substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 substituted by an alkoxy substituent;

[0030] Alternatively, R attached to the same nitrogen atom 32 and R 33 Together with the nitrogen atom, a 4-8 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) is substituted; provided that when R 1 is H, and any R 3 None of them are -S(O)2-C6-10 Aryl, -S(O)2-5-12 membered heteroaryl or S(O)2NR 10 R 11 When R 20 It is H or D.

[0031] In a preferred embodiment, each R 20 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, SF5, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-4 Alkoxy, -SCF3, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-7 membered heterocyclyl, 4-7 membered heterocyclyl, -P(O)Me2, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NHC(O)(C 1-4 Alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 Alkyl), -NHS(O)2(C 1-4 Alkyl), -N(C 1-4 Alkyl)S(O)2(C 1-4 Alkyl), each of the above groups may be further optionally substituted by one or more selected from D, halogen, hydroxyl, C 1-3 Alkoxy, C 1-3 The haloalkoxy group is substituted.

[0032] In another preferred embodiment, each R 20 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -N(C 1-4 Alkyl)2;

[0033] More preferably, each R 20 Independently selected from the group consisting of H, D, F, Cl, cyano, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Fluorinated alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -N(C 1-4 Alkyl)2.

[0034] In a preferred embodiment, each R 3 Independently selected from the group consisting of H, D, halogen, cyano, C 1-4 Alkoxy, CONR 10R 11 、-C(O)C 1-4 Alkyl, -S(O)2C 1-4 Alkyl, -S(O)2C 1-4 Hydroxyalkyl, -S(O)(NR 31 )C 1-4 Alkyl, -S(O)2NR 10 R 11 、-S(O)(NR 31 )NR 10 R 11 、-S(O)NR 10 R 11 、-COOR 12 , oxo (=O), =C(R 13 )2、C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, -S(O)2-phenyl, -S(O)2-5-7 membered heteroaryl, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, C 3-6 halocycloalkoxy group substitution;

[0035] Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl, -SO2(C 1-4 alkyl), -CO(C 1-4 alkyl), which may be further optionally substituted by 1, 2, 3, 4, 5 or 6 R j replace;

[0036] Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a 4-7 membered nitrogen-containing heterocyclic ring, which may be optionally further replaced by 1, 2, 3, 4, 5 or 6 R j replace;

[0037] Each R j Independently selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, -C 0-2 Alkylene-NR 16 R 17 、C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 3-6 Halogenated cycloalkyl, 4-7 membered halogenated heterocyclic group, C 3-6 Cycloalkoxy, 4-7 membered heterocyclic oxy, C 3-6 Halogenated cycloalkoxy, 4-7 membered halogenated heterocyclic oxy, -C(O)C 1-4 Alkyl, -CONR 32 R 33 、-S(O)2C 1-4 Alkyl, -S(O)2NR 32 R 33 ;

[0038] Alternatively, two R j All atoms connected to it together form C 3-6 Carbocyclic or 4-7 membered heterocyclic ring;

[0039] Among them, R 12 、R 13 、R 16 、R 17 、R 31 、R 32 、R 33 The definition of is as above.

[0040] In a preferred embodiment, at least one R 3 Selected from the group consisting of: -S(O)2C 1-4 Alkyl, -S(O)2NR 10 R 11 , -S(O)2-5-7 membered nitrogen-containing heteroaryl, said group may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, C 3-6 halocycloalkoxy group substitution;

[0041] Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -SO2(C 1-4 alkyl), -CO(C 1-4 alkyl), which may be further optionally substituted by 1, 2, 3, 4, 5 or 6 R j replace;

[0042] Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom, it forms a 4-6 membered nitrogen-containing heterocyclic ring, which may be further optionally replaced by 1, 2, 3, 4, 5 or 6 R j replace;

[0043] Each R j Independently selected from the group consisting of D, halogen, amino, =O, CN, hydroxy, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-4 alkyl), -CO(C 1-4 Alkyl), -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NHC(O)(C 1-4 Alkyl), -N(C 1-4 alkyl)CO-C 1-4 Alkyl, -NHS(O)2(C 1-4 Alkyl), -N(C 1-4 alkyl)S(O)2-C 1-4 alkyl;

[0044] Alternatively, two R j All atoms connected to it together form C 3-6 Carbocyclic ring or 4-7 membered heterocyclic ring.

[0045] In another preferred embodiment, two R substituted on the same or different atoms j All atoms to which it is attached together form a ring system structure selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane, azetidine, piperidine, and morpholine.

[0046] In another preferred embodiment, each R 3 Independently selected from the group consisting of H, D, halogen, cyano, C 1-4 Alkoxy, CONR 10 R 11 、-C(O)C 1-4 Alkyl, -S(O)2C 1-4 Alkyl, -S(O)2C1-4 Hydroxyalkyl, -S(O)(NR 31 )C 1-4 Alkyl, -S(O)2NR 10 R 11 、-S(O)(NR 31 )NR 10 R 11 、-S(O)NR 10 R 11 、-COOR 12 , oxo (=O), =C (R 13 )2、C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, -S(O)2-phenyl, -S(O)2-5-7 membered heteroaryl, -S(O)2-C 1-4 Alkylene-C 3-6 Cycloalkyl, -S(O)2-C 1-4 Alkylene-4-7 membered heterocyclic group;

[0047] Among them, R 10 、R 11 、R 12 、R 13 and R 31 The definition of is as above.

[0048] In another preferred embodiment, each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl, -SO2(C 1-4 alkyl), -CO(C 1-4 alkyl), which may be further optionally substituted by 1, 2, 3, 4, 5 or 6 R j replace;

[0049] or R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a 4-7 membered nitrogen-containing heterocyclic ring, which may be further optionally replaced by one or more R j replace;

[0050] Among them, R j The definition of is as above.

[0051] In another preferred embodiment, each R j Independently selected from the group consisting of D, halogen, amino, =O, CN, hydroxy, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-4 alkyl), -CO(C 1- 4 alkyl), -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NHC(O)(C 1-4 Alkyl), -N(C 1-4 alkyl)CO-C 1-4 Alkyl, -NHS(O)2(C 1-4 Alkyl), -N(C 1-4 alkyl)S(O)2-C 1-4 alkyl.

[0052] In a preferred embodiment, the R 3 -S(O)2NR 10 R 11 , and R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a ring structure selected from the group consisting of azetidine, 1,3-thiazetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, and thiomorpholine, wherein the ring structure may be further optionally replaced by 1, 2, 3, or 4 R j replace;

[0053] Among them, R j The definition of is as above.

[0054] In a preferred embodiment, ring B is selected from the following group: a 4-7 membered heterocyclic ring, a benzene ring, a naphthalene ring, and a 5-7 membered heteroaromatic ring.

[0055] In another preferred embodiment, the ring B is selected from the following group: a 4-7 membered nitrogen-containing heterocyclic ring, a benzene ring, a naphthalene ring, and a 5-7 membered heteroaromatic ring.

[0056] In another preferred embodiment, the ring B is selected from the following group: azetidine, tetrahydropyrrole, piperidine, benzene ring, furan, thiophene, pyrrole, thiazole, imidazole, pyrazole, pyran, pyridine, and pyrimidine.

[0057] In a preferred embodiment, R 1 Selected from the group consisting of H, D, halogen, cyano, C 1-4 Alkyl, -C containing 0, 1, 2, 3, 4, 5 or 6 fluorine substituted 1-3 Alkylene-C 1-3 Alkoxy, C 1-4 Alkenyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl.

[0058] In another preferred embodiment, the R 1 Selected from the group consisting of H, D, halogen, cyano, C 1-4 Alkyl, -C containing 0, 1, 2, 3, 4, 5 or 6 fluorine substituted 1-2 Alkylene-C 1-2 Alkoxy, C 1-4 Alkenyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 1-4 Fluorinated alkyl, C 1-4 Hydroxyalkyl.

[0059] In a preferred embodiment, the R b and R b ' are each independently selected from the following group: H, D, F, Cl, Br, C 1-4 Alkyl, -C containing 0, 1, 2, 3, 4, 5 or 6 fluorine substituted 1-3 Alkylene-C 1-3 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Tritiated alkyl.

[0060] In another preferred embodiment, R b and R b ' are each independently selected from the following group: H, D, F, Cl, Br, C 1-4 Alkyl, -CH2-C 1-3 Alkoxy, C 1-4 Fluorinated alkyl, C 1-4 tritiated alkyl;

[0061] Preferably, R b and R b ' are each independently selected from the following group: H, D, F, Cl, methyl, ethyl, trideuterated methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, methoxymethyl containing 0, 1, 2 or 3 fluorine-substituted groups, and ethoxymethyl containing 0, 1, 2, 3, 4 or 5 fluorine-substituted groups.

[0062] In a preferred embodiment, the R d and R d 'Each independently selected from the following group: H, D, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 tritiated alkyl;

[0063] or R d 、R d ' and the carbon atoms to which it is connected together form C 3-6Cycloalkyl or 4-6 membered heterocyclic group.

[0064] In a preferred embodiment, the compound has a structure represented by formula (II),

[0065] Where m is 0, 1, 2, 3 or 4;

[0066] R i Select from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, NR 10 R 11 , 5-7 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, C 1-4 Alkylene-4-7 membered heterocyclic group;

[0067] Ring B, R 10 、R 11 、R b 、R b '、R 1 、R 3 、R d 、R d ', p and R 20 The definition of is as above.

[0068] In another preferred embodiment, the R i Select from the following group: C 1-4 Alkyl, C 1-4 Hydroxyalkyl, NR 10 R 11 , 5-7 membered nitrogen-containing heteroaryl, -CH2-C 3-6 Cycloalkyl, -CH2-4-7 membered heterocyclic group.

[0069] In another preferred embodiment, the compound has a structure represented by formula (III),

[0070] Among them, m, ring B, R 10 、R 11 、R b 、R b '、R 1 、R 3 、R d 、R d ', p and R 20 The definition of is as above.

[0071] In another preferred embodiment, the compound has a structure represented by formula (IV),

[0072] Among them, m, R 10 、R11 、R b 、R b '、R 1 、R 3 、R d 、R d ', p and R 20 The definition of is as above.

[0073] In a preferred embodiment, the compound is selected from the following group:

[0074] The second aspect of the present invention provides a pharmaceutical composition, characterized in that the composition comprises:

[0075] (i) the compound according to the first aspect of the present invention, its stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug; and

[0076] (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

[0077] The third aspect of the present invention provides a use of the compound according to the first aspect of the present invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used for preparing a medicament for treating and / or preventing diseases associated with CYP11A1;

[0078] Preferably, the disease associated with CYP11A1 is cancer;

[0079] More preferably, the disease associated with CYP11A1 is prostate cancer and breast cancer.

[0080] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0081] After long and in-depth research and extensive screening, the inventors discovered for the first time a polycyclic compound with strong inhibitory activity against CYP11A1, effectively inhibiting its oxidation of cholesterol side chains in vitro. Based on this discovery, the inventors completed the present invention.

[0082] the term

[0083] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0084] As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1-6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, etc. In the present application, alkyl groups are also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, CH2CD3, CD2CD2CD3.

[0085] As used herein, the term "alkylene" refers to a group obtained by removing a hydrogen atom from an alkyl group as described above, for example, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0086] As used herein, the terms "carbocyclyl" and "carbocycle" refer to a saturated or partially unsaturated all-carbon ring structure composed of carbon and hydrogen atoms, such as a monocyclic, bicyclic, or tricyclic ring structure, wherein the ring structure as a whole is not aromatic but may contain one or more unsaturated structures. The ring may be further substituted with one or more substituents. When the carbocyclyl contains two or more rings, the rings may further form a fused ring, a bridged ring, a spirocyclic ring, or any combination thereof.

[0087] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group composed of carbon and hydrogen atoms, such as "C 3- "8-cycloalkyl" refers to a cycloalkyl group containing 3-8 (e.g., 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C 3-6 Cycloalkyl. A cycloalkyl group may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, or a bicyclic ring, such as a fused ring, a bridged ring or a spiro ring.

[0088] As used herein, the term "alkoxy" refers to a group of the formula -OR z group, where R z Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0089] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and the definition of alkyl is as described above. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH2OH, and the like.

[0090] As used herein, the term "halogen" refers to halogen and its isotopes, including but not limited to F, 18 F. 32 Cl, Br, I.

[0091] As used herein, the term "amino" refers to -NH2.

[0092] As used herein, the term "carboxyl" refers to -COOH.

[0093] As used herein, the term "oxo" refers to a =0 moiety.

[0094] As used herein, the term "ester group" refers to -COOR y , where R y Can be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic. Examples of ester groups include, but are not limited to, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH2CH(CH3)2, and the like.

[0095] As used herein, the term "amido" refers to -CONR x R x ', where R x and R x R may be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. x and R x Examples of amide groups include, but are not limited to, -CONH2, -CONHCH3, -CON(CH3)2, and the like.

[0096] As used herein, the term "sulfonamide" refers to -SO2NR w R w ', where R w and R w R' can be independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl. R and R' can be the same or different. Examples of sulfonamide groups include, but are not limited to, -SO2NH2, -SO2NHCH3, and -SO2N(CH3)2.

[0097] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms in the alkyl group described above are replaced by the same or different halogen atoms. 1-6 "Alkyl" is preferably a halogenated C 1-4 Examples of alkyl and halogenated alkyl groups include, but are not limited to, -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (eg, -CF3-, -CF2CF3), and the like.

[0098] As used herein, the term "alkylamino" refers to a group of the formula -NR u R u 'group, wherein R u and R u ' are each independently H or alkyl as defined herein, and R u and R u ' is not H at the same time. The alkylamino group may be a monoalkylamino group or a dialkylamino group. Examples of the alkylamino group include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0099] As used herein, the term "haloalkylamino" refers to an alkylamino group as described above in which one or more hydrogen atoms are replaced by the same or different halogen atoms.

[0100] As used herein, the term "alkylthio" refers to a group of the formula -SR t group, where R t is H or alkyl as defined herein.

[0101] As used herein, the term "acyl" refers to a group of formula -C(O)-.

[0102] As used herein, the term "sulfone" refers to a group of formula -S(O)2-.

[0103] As used herein, the terms "heterocyclyl" and "heterocycle" refer to fully saturated or partially saturated monocyclic, bicyclic, or polycyclic groups containing one or more heteroatoms selected from N, S, or O in the ring backbone. For example, a "3- to 8-membered heterocyclyl" refers to a group having 3-8 ring members. The nitrogen or sulfur atoms may be oxidized, and the nitrogen atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue in the ring or ring system. Monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-1,1-dioxythiophene. Polycyclic heterocyclic groups include, but are not limited to, spirocyclic, fused, and bridged heterocyclic groups; the spirocyclic, fused, and bridged heterocyclic groups are optionally linked to other groups via single bonds, or further linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups via any two or more atoms on the ring.

[0104] As used herein, the term "1,3-thiazepine" refers to structure.

[0105] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic or polycyclic groups), for example, "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11 or 12) ring carbon atoms. Examples of aryl (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, naphthyl, anthracene.

[0106] As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic or polycyclic groups) whose ring backbone contains at least one heteroatom selected from N, S or O, for example, "5-12 membered heteroaryl" refers to a monocyclic, bicyclic or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11 or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Acridinium, etc.

[0107] As used herein, the term "polysubstituted" means comprising two or more substitutions.

[0108] As used herein, the term "deuterium" refers to a compound in which one or more hydrogen atoms (H) in the compound are replaced by deuterium atoms (D).

[0109] As used herein, the term "fused bicyclic ring" refers to a bicyclic ring structure formed by the fusion of two rings, wherein one ring is a benzene ring or a 5-6 membered heteroaromatic ring, and the other ring is a partially saturated 5-8 membered carbocyclic ring or a partially saturated 5-8 membered heterocyclic ring, but the fused bicyclic ring system as a whole is not aromatic. The fused bicyclic ring can be attached to other groups at any possible position. Examples of fused bicyclic rings include, but are not limited to: wait.

[0110] As used herein, "fused tricyclic ring" refers to three rings fused together to form a tricyclic structure, wherein one or two rings are independently a benzene ring or a 5-6 membered heteroaromatic ring, and the other rings are independently a saturated or partially saturated 3-8 membered carbocyclic ring or a saturated or partially saturated 4-8 membered heterocyclic ring, but the fused tricyclic ring system as a whole does not have aromaticity. When there are two saturated or partially saturated ring systems in this tricyclic structure, the two rings can form a fused ring, a spirocyclic ring, or a bridged ring. The fused tricyclic ring can be connected to other groups at any possible position. Examples of fused tricyclic rings include, but are not limited to: wait.

[0111] When each group loses one H atom, it is a subunit of the corresponding group, and it is a divalent group. For example, when an alkyl group loses one H atom, it becomes an alkylene group (for example, methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as ), heptylene (such as ) etc.); cycloalkyl corresponds to cycloalkylene (such as: etc.); heterocyclic groups correspond to heterocyclic groups (such as: ), alkoxy corresponds to alkyleneoxy (such as: -CH2O-, -CH2CH2O-, -OCH2CH2CH2-), heteroalkyl corresponds to heteroalkylene (such as: -CH2-O-CH2CH2-, -CH2-O-(CH2)2CH2-, -CH2CH2-O-CH2CH2-, -CH2-O-CH2CH2CH2-, -CH2-S-CH2CH2-, -CH2-S-(CH2)2CH2-, -CH2CH2-S-CH2CH2-, -CH2-S-CH2CH2CH2-, -CH2-NH-CH2CH2-, -CH2-NH-(CH2)2CH2-, -CH2CH2-NH-CH2CH2-, -CH2-NH-CH2CH2CH2-), etc.

[0112] In the present invention, the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and other groups include substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and the like unless otherwise specified, and the substituents include but are not limited to halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, ester and the like.

[0113] As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or as appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specified group at any substitutable position on the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0114] Unless otherwise specified, the groups of the present invention may be substituted by a substituent selected from the group consisting of: D, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C 12 Cycloalkyl, 5-10 membered heteroaryl and C6-C 10 Aryl.

[0115] As used herein, "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0116] The term "plurality" herein refers to a positive integer of 2, 3, 4, 5 or more.

[0117] Active ingredient

[0118] As used herein, "compound of the present invention" refers to the compound represented by formula (I), and also includes its stereoisomers, optical isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates or hydrates thereof.

[0119] Unless otherwise indicated, the structural formulas described herein are intended to include all stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or conformational isomers are all within the scope of the present invention.

[0120] The compounds of the present invention may contain cis- and trans-isomers, one or more chiral carbon atoms, and thus may produce stereoisomeric forms such as cis- and trans-isomers, chiral isomers, enantiomers, diastereomers, and other combinations thereof. Cis- and trans-isomerism refers to the diastereoisomerism that occurs due to restrictions on the free rotation of the compound molecule, resulting in different spatial arrangements of the various groups. These restrictions are generally caused by the presence of functional groups in the organic compound structure that cannot rotate freely, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis- and trans-isomers. The cis form refers to the presence of ligands of the same type in adjacent positions, typically designated "cis" or "cis-"; the trans form refers to the presence of ligands of the same type in diagonal positions, typically designated "trans" or "trans-". Each chiral carbon atom can be defined as either (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, cis-trans isomers, chiral isomers, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0121] If a synthesis of a specific stereoisomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting stereomixture and removal of the chiral auxiliary to obtain a pure cis-trans monomer, chiral monomer, or mixed stereoisomer. If the molecule contains a cis-trans isomeric center, pure cis- or trans-forms can be obtained by purification via column chromatography (normal-phase silica gel or reverse-phase high-performance liquid chromatography). Furthermore, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomers.

[0122] The present invention also includes isotopically labeled compounds (i.e., isotopic derivatives) that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes in the isotopic derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. The isotopic derivatives of the compounds of the present invention are all within the scope of protection of the present invention. 3 H-labeled compounds and 14 C-labeled compounds are useful in drug and substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 The preparation and detection of C) labeled compounds are relatively easy and are the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain situations. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0123] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0124] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0125] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0126] Metabolites of the compound represented by formula (I) and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted into the compound represented by formula (I) and pharmaceutically acceptable salts thereof in vivo, are also included in the scope of protection of the present invention.

[0127] As used herein, the term "solvate" refers to a complex in which the compound represented by formula (I) is coordinated with solvent molecules to form a specific ratio.

[0128] As used herein, the term "hydrate" refers to a complex formed by the compound represented by formula (I) coordinated with water molecules to form a specific ratio.

[0129] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" refers to the replacement of a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted with multiple substituents of a specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible organic group substitutions. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. Herein, for example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic groups described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible organic groups in any way. The present invention recognizes that combinations of substituents and variable groups are advantageous for the treatment of diseases by forming stable compounds. The term "stable" herein refers to compounds that are stable and maintain the structural integrity of the compound over a sufficient period of time for testing, preferably for a sufficient period of time for efficacy, and is used herein for such purposes.

[0130] Pharmaceutical compositions and methods of administration

[0131] Because the compounds of the present invention can inhibit cytochrome P450 monooxygenase 11A1 (CYP11A1) and are useful for treating diseases such as prostate cancer, the compounds of the present invention, their stereoisomers, optical isomers, pharmaceutically acceptable salts, crystalline forms, isotopic derivatives, prodrugs, metabolites, solvates, or hydrates thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate, or cure) CYP11A1-related diseases (such as prostate cancer and breast cancer).

[0132] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0133] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0134] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0135] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0136] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0137] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0138] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0139] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0140] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0141] Dosage forms of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0142] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0143] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat diseases associated with CYP11A1.

[0144] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0145] Compared with the prior art, the beneficial effect of the present invention is that the polycyclic compounds described in the present invention have strong inhibitory activity on CYP11A1, and can effectively inhibit its oxidation of cholesterol side chains in vitro, thereby blocking the production of necessary precursors required for testosterone synthesis in the body, and achieving a strong anti-tumor inhibitory effect.

[0146] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

[0147] In the following examples, the characterization methods used are as follows.

[0148] H NMR spectroscopy ( 1 H NMR):

[0149] The NMR spectra of the reaction products and intermediates ( 1 H NMR spectra were obtained on a Bruker AVANCE III HD 400 / 500 in Germany. Sample preparation is as follows: In a clean, dry glass NMR tube, completely dissolve the appropriate amount of sample in approximately 0.5 mL of a deuterated solvent. Most compounds have good solubility in DMSO-d6, making it the preferred deuterated solvent. DMSO-d6 readily solidifies at relatively low room temperatures and requires a hair dryer to dissolve it before loading. Other suitable deuterated reagents, such as CDCl3 and CD3OD, can also be used depending on testing needs. Tetramethylsilane (TMS) was used as the internal standard for room temperature testing, with a chemical shift of 0 ppm.

[0150] Preparation of intermediates

[0151] Intermediate 1a: Preparation of (E)-tert-butyl 4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)piperidine-1-carboxylate

[0152] Under nitrogen protection, dissolve biboronic acid pinacol ester (315.47 mg, 1.242 mmol) in anhydrous tetrahydrofuran (5 mL), cool to 0 ° C, add chloro (1,3-di-mesityl imidazol-2-ylidene) copper (I) (11.57 mg, 0.029 mmol) and potassium tert-butoxide (160.84 mg, 1.433 mmol) in sequence, and stir for 10 minutes. Add tert-butyl-4-vinylpiperidine-1-carboxylate (200 mg, 0.956 mmol) and iodomethane (0.233 mL, 2.867 mmol) was added dropwise to the reaction system, and the temperature was raised to room temperature for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography to obtain tert-butyl (E)-4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)piperidine-1-carboxylate (125 mg, 37.24% yield) as a colorless oil.

[0153] Intermediates 1b-1h can be prepared by selecting appropriate raw materials according to the synthesis method of intermediate 1a, and their structures are shown in Table 1.

[0154] Table 1. Structural formulas and chemical names of intermediates 1b-1h

[0155] Intermediate 2: Preparation of tert-butyl (Z)-4-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate

[0156] Step 1: Dissolve tert-butyl 4-ethynylpiperidine-1-carboxylate (2.5 g, 11.95 mmol), N-bromosuccinimide (2.34 g, 13.14 mmol), and silver fluoride (3.79 g, 29.86 mmol) in acetonitrile (29 mL) and water (1.5 mL). The system was evacuated and replaced with nitrogen three times, then heated to 80°C and stirred for 16 hours. After completion of the reaction, the system was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated. The crude product was separated and purified by normal phase column chromatography to obtain tert-butyl (Z)-4-(2-bromo-1-fluorovinyl)piperidine-1-carboxylate (2.56 g, yield: 70.063%).

[0157] Step 2: Dissolve tert-butyl (Z)-4-(2-bromo-1-fluorovinyl)piperidine-1-carboxylate (700 mg, 2.27 mmol), bis(1,2-naphthoyl)boronic acid ester (750 mg, 2.95 mmol), potassium acetate (669 mg, 6.81 mmol), and bis(diphenylphosphino)ferrocene]palladium dichloride (332 mg, 0.45 mmol) in dioxane (20 mL). The system was evacuated and replaced with nitrogen three times, then heated to 80°C and stirred for 16 hours. After completion of the reaction, the system was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated. The crude product was separated and purified by normal phase column chromatography to obtain tert-butyl (Z)-4-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (300 mg, yield: 37.18%).

[0158] Intermediate 3: Preparation of 2-methyl-2-propyl 4-[(1Z)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl]piperidine-1-carboxylate

[0159] Step 1: To a solution of 2-methyl-2-propyl-4-ethynylpiperidine-1-carboxylate (500 mg, 2.389 mmol) in tetrahydrofuran (5 mL) at -78°C was added n-butyllithium (306.08 mg, 4.778 mmol) dropwise. The reaction mixture was stirred at -78°C for 1 hour, and iodomethane (926.27 mg, 7.167 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography to afford 2-methyl-2-propan-2-yl 4-(prop-1-ynyl)piperidine-1-carboxylate (453 mg, 2.028 mmol, 84.91%) as a yellow oil.

[0160] Step 2: Under nitrogen, to a solution of 2-methyl-2-propan-2-yl 4-(prop-1-ynyl)piperidine-1-carboxylate (300 mg, 1.343 mmol) in toluene (5 mL) was added cuprous chloride (39.90 mg, 0.403 mmol), sodium tert-butoxide (103.28 mg, 1.075 mmol), tricyclohexylphosphine fluoroborate (197.88 mg, 0.537 mmol), biboronic acid pinacol ester (682.27 mg, 2.687 mmol), and methanol (0.218 mL, 5.373 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by normal phase column chromatography to give 2-methyl-2-propyl 4-[(1Z)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enyl]hexahydropyridine-1-carboxylate (400 mg, 1.139 mmol, 84.76%) as a white solid.

[0161] Intermediate 4: Preparation of (Z)-tert-butyl 4-(3,3,3-trifluoro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)piperidine-1-carboxylate

[0162] Step 1: To a mixture of tert-butyl 4-formylpiperidine-1-carboxylate (2.14 g, 10.03 mmol) and trimethyl(trifluoromethyl)silane (2.00 g, 14.05 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1 M tetrabutylammonium fluoride solution (1 mL, 1.00 mmol in THF) at room temperature. The mixture was stirred for 18 hours. The reaction was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, and the crude product was purified by silica gel column chromatography to obtain tert-butyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (2.0 g, yield: 70.36%) as a white solid.

[0163] Step 2: At 0°C, Dess-Martin periodinane (3.59 g, 8.47 mmol) was added to a solution of tert-butyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate (2 g, 7.06 mmol) in dichloromethane (30 mL). The mixture was slowly warmed to room temperature and the reaction was continued for 3 hours. Saturated sodium carbonate solution was added to quench the reaction and the mixture was extracted twice with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, the crude product was separated and purified by silica gel column chromatography to obtain tert-butyl 4-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (1.8 g, yield: 90.65%) as a colorless oil.

[0164] Step 3: To a solution of iodomethyl-triphenylphosphonium iodide (2.71 g, 5.12 mmol) in anhydrous tetrahydrofuran (20 mL) was added potassium tert-butoxide solution (5.12 mL, 1.0 M in THF) at 0°C. The mixture was stirred at room temperature for 0.5 hours, then cooled to 0°C and added with a solution of tert-butyl 4-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (1.2 g, 4.27 mmol) in anhydrous tetrahydrofuran (5 mL). After addition, the mixture was allowed to react at room temperature for 18 hours. The mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain tert-butyl (Z)-4-(3,3,3-trifluoro-1-iodopropyl-1-en-2-yl)piperidine-1-carboxylate (450 mg, yield: 26.03%) as a yellow oil.

[0165] Step 4: Dissolve tert-butyl (Z)-4-(3,3,3-trifluoro-1-iodopropyl-1-en-2-yl)piperidine-1-carboxylate (450 mg, 1.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (423.02 mg, 1.67 mmol), potassium acetate (272.48 mg, 2.2.78 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (81.26 mg, 0.11 mmol) in dry dioxane (10 mL). Heat the mixture to 100°C for 5 hours. Cool to room temperature, pour into water, and extract twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl (Z)-4-(3,3,3-trifluoro-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)piperidine-1-carboxylate (450 mg crude product), which was used directly in the next step.

[0166] Intermediate 5: Preparation of tert-butyl (Z)-4-(2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate

[0167] In a dry microwave tube, cuprous chloride (2.00 mg, 0.02 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (11.70 mg, 0.02 mmol), and bis(pinacolato)diboron (256.79 mg, 1.01 mmol) were dissolved in ultra-dry N,N-dimethylformamide (1 mL). The system was evacuated and replaced with nitrogen three times. Potassium tert-butoxide in tetrahydrofuran (1 M, 1 mL), tert-butyl 4-(2,2-difluorovinyl)piperidine-1-carboxylate (100 mg, 0.40 mmol), and methanol (32.80 μL, 0.81 mmol) were added dropwise to the reaction system. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was separated and purified by normal phase column chromatography to give tert-butyl (Z)-4-(2-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (100 mg, yield: 69.61%).

[0168] Intermediate 6: Preparation of isoindoline-1,1,3,3-d4

[0169] Step 1: Dissolve 2-benzylisoindoline-1,3-dione (7 g, 29.50 mmol) in ultra-dry tetrahydrofuran (50 mL). Evacuate the system and replace with nitrogen three times. Add lithium aluminum tetrahydride-d (4.96 g, 118.01 mmol) at 0°C. Stir and react at room temperature for 2 hours. After completion of the reaction, add the reaction mixture dropwise to saturated ammonium chloride solution at 0°C. The filtrate is diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The crude product is purified by normal phase column chromatography to afford 2-benzylisoindoline-1,1,3,3-d4 (3.2 g, yield: 50.85%).

[0170] Step 2: Dissolve 2-benzylisoindoline-1,1,3,3-d4 (3 g, 14.06 mmol) in ultra-dry dichloromethane (20 mL). Evacuate the system and replace with nitrogen three times. Add 1-chloroethyl chloroformate (10.06 g, 70.23 mmol) at 0°C. Stir and react at room temperature for 24 hours. Then, raise the temperature to reflux and react for 4 hours. Cool the reaction mixture to room temperature and concentrate to obtain the crude product. The crude product was slurried with dichloromethane to obtain isoindoline-1,1,3,3-d4 (3.2 g, yield: 100%).

[0171] Intermediate 7: Preparation of 5-hydroxy-2-(hydroxymethyl-d2)-4H-pyran-4-one

[0172] Step 1: Dissolve 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (10 g, 70.37 mmol) in methanol (80 mL), add 10 M sodium hydroxide solution (9.2 mL) and benzyl bromide (13.24 g, 77.40 mmol), and stir at 80°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Acetone (12 mL) and water (120 mL) were added to the residue to form a precipitate, which was filtered and dried at 40°C to obtain 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (14.43 g, yield: 88.30%).

[0173] Step 2: Dissolve 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (8 g, 34.45 mmol) in water (13.76 mL) and acetone (227.2 mL). Cool the clear solution to +5°C in an ice bath. While maintaining the temperature between +5°C and 10°C, add Jones reagent (22 mL) dropwise over 1 hour. After stirring at room temperature for 16 hours, the reaction mixture is filtered using a Buchner funnel, and the dark green filter cake is washed with 30 mL of acetone. The filtrate is collected and concentrated to remove the solvent to yield 5-(benzyloxy)-4-oxopyran-2-carboxylic acid (8.4 g, 99.04% yield).

[0174] Step 3: Dissolve 5-(Benzyloxy)-4-oxopyran-2-carboxylic acid (8.4 g, 34.12 mmol) in methanol (30 mL). Add thionyl chloride (3.8 mL, 51.17 mmol) at 0°C and allow to react overnight at room temperature. The reaction system was concentrated, diluted with water, and extracted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by normal phase column chromatography to afford methyl 5-(benzyloxy)-4-oxopyran-2-carboxylate (6.0 g, yield: 67.58%).

[0175] Step 4: 5-(Benzyloxy)-4-oxopyran-2-carboxylic acid methyl ester (6 g, 23.06 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium deuterated borohydride (0.97 g, 23.06 mmol) was added at 0°C. The reaction was allowed to react at room temperature for 16 hours, quenched with D2O, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by normal phase column chromatography to give 5-(benzyloxy)-2-[dideuterio(hydroxy)methyl]-4H-pyran-4-one (2.7 g, yield: 49.99%).

[0176] Step 5: Dissolve 5-(benzyloxy)-2-[dideuterio(hydroxy)methyl]-4H-pyran-4-one (2.7 g, 11.53 mmol) in dichloromethane (30 mL), add boron trichloride (28.82 mL, 28.82 mmol) at 0°C, slowly return to room temperature, react for 16 hours, add deuterated methanol to quench, concentrate the system, and after concentration, separate and purify the crude product by normal phase column chromatography to obtain 5-hydroxy-2-(hydroxymethyl-d2)-4H-pyran-4-one (900 mg, yield: 54.18%).

[0177] Intermediate 8: Preparation of (Z)-4-(1-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1-(methylsulfonyl)piperidine

[0178] Step 1: To tert-butyl 4-ethynylpiperidine-1-carboxylate (2 g, 9.56 mmol) and water (1.5 mL) was added hydrochloric acid (20 mL, 4 M in 1,4-dioxane). After stirring at room temperature for 1 hour, the reaction solution was concentrated to obtain the hydrochloride salt of 4-ethynylpiperidine (1.35 g, crude product).

[0179] Step 2: Dissolve 4-ethynylpiperidine hydrochloride (1.35 g, 9.27 mmol) in dichloromethane (30 mL) and add N,N-diisopropylethylamine (6.46 mL, 37.08 mmol) and methanesulfonyl chloride (1.44 mL, 18.54 mmol) at 0°C. Stir the reaction at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative purification to yield 4-ethynyl-1-(methylsulfonyl)piperidine (1.5 g, yield: 86.41%).

[0180] Step 3: Boron trichloride was slowly added dropwise to a solution of 4-ethynyl-1-(methylsulfonyl)piperidine (1 g, 5.34 mmol) in dichloromethane (20 mL). The reaction was allowed to react at room temperature for 0.5 hours. The reaction solution was then added dropwise to a solution of pinacol (0.65 mL, 5.34 mmol) and triethylamine (3.0 mL, 21.36 mmol) in dichloromethane (10 mL) at 0°C. After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was then purified by normal phase column chromatography to yield (Z)-4-(1-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1-(methylsulfonyl)piperidine (410 mg, yield: 21.96%).

[0181] Intermediate 9: Preparation of 3-hydroxy-6-(hydroxymethyl)-2-methyl-4H-pyran-4-one

[0182] Step 1: Dissolve sodium hydroxide (9.48 g, 232.21 mmol) in water (220 mL). Add 5-hydroxy-2-(hydroxymethyl)pyran-4-one (30 g, 211.10 mmol) at room temperature to dissolve the mixture. Cool to 0°C and add formaldehyde (17.91 mL, 242.77 mmol, 37%) dropwise. After addition, warm to room temperature and stir for 48 hours. Adjust the pH to approximately 1 with concentrated hydrochloric acid (22 mL) at -5°C. Continue stirring at -5°C for 1.5 hours. Filter, wash the filter cake with petroleum ether, collect the filter cake, and dry it in vacuo to yield 2,6-dihydroxymethyl-3-hydroxy-4-pyrone (34.8 g, yield: 95.76%). ESI-MS: found 173.0 [M+H] + .

[0183] Step 2: Dissolve 2,6-dihydroxymethyl-3-hydroxy-4-pyrone (7 g, 40.66 mmol) in water (23.5 mL). Add zinc powder (5.32 g, 81.33 mmol) at room temperature. Add concentrated hydrochloric acid (33.83 mL) dropwise at 40°C, maintaining the internal temperature between 40 and 60°C. After the addition is complete, stir the reaction mixture at 40°C for 0.5 hours. Cool the reaction mixture and filter. The filtrate is stirred at -5°C for 2 hours, filtered, and the filter cake is collected and dried under vacuum to yield 3-hydroxy-6-(hydroxymethyl)-2-methyl-4H-pyran-4-one (5.9 g, yield: 92.92%). ESI-MS: found 156.9 [M+H] + .

[0184] Intermediate 10: Preparation of 5-(trifluoromethyl)isoindoline

[0185] Step 1: Dissolve 2-chloro-5-(trifluoromethyl)benzoic acid (1.04 g, 4.45 mmol) in N,N-dimethylacetamide (20 mL), add cuprous cyanide (700 mg, 7.74 mmol), and heat to 130°C with stirring for 20 hours. After cooling to room temperature, ferric chloride (1.50 g, 9.16 mmol) and concentrated hydrochloric acid (5 mL, 59.24 mmol) dissolved in water (10 mL) were added dropwise. Heat to 65°C with stirring for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography to yield 5-(trifluoromethyl)isoindoline-1,3-dione (3670 mg, yield: 69.94%). ESI-MS: 216.0 [M+1] + .

[0186] Step 2: To a solution of 5-(trifluoromethyl)isoindoline-1,3-dione (670 mg, 3.11 mmol) in N,N-dimethylacetamide (14 mL) were added potassium carbonate (869.58 mg, 6.23 mmol) and benzyl bromide (645.68 mg, 3.74 mmol) in sequence. The mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by normal phase column chromatography to yield 2-benzyl-5-(trifluoromethyl)isoindoline-1,3-dione (820 mg, yield: 86.25%). ESI-MS 306.1 [M+1] + .

[0187] Step 3: Dissolve 2-benzyl-5-(trifluoromethyl)isoindoline-1,3-dione (800 mg, 2.62 mmol) in 1,4-dioxane (12 mL). Add phenylsilane (877.08 mg, 7.86 mmol) and tris(pentafluorophenyl)borane (138.33 mg, 0.26 mmol) sequentially. Heat to 100°C and stir for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by normal phase column chromatography to yield 2-benzyl-5-(trifluoromethyl)isoindoline (510 mg, yield: 70.18%). ESI-MS: 278.2 [M+1] + .

[0188] Step 4: Dissolve 2-benzyl-5-(trifluoromethyl)isoindoline (100 mg, 0.36 mmol) in dichloromethane (2 mL), add 1-chloroethyl chloroformate (103.11 mg, 0.72 mmol), and stir at room temperature for 12 hours. After the reaction solution is concentrated, methanol (2 mL) is added and stirring is continued at room temperature for 2 hours. The reaction solution is concentrated to obtain crude 5-(trifluoromethyl)isoindoline (80 mg). ESI-MS 188.1 [M+1] + .

[0189] Intermediate 11a: Preparation of 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0190] Step 1: Dissolve 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (2.04 g, 14.07 mmol) in thionyl chloride (15.3 mL) and stir at 50°C for 2 hours. Filter the reaction mixture, wash the filter cake with petroleum ether, and vacuum dry to obtain 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (1.65 g, yield: 73.02%) as a yellow solid.

[0191] Step 2: Dissolve 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (500 mg, 3.11 mmol) in acetonitrile (8 mL) and add N,N-diisopropylethylamine (813.11 mg, 6.23 mmol) and isoindoline hydrochloride (1.02 g, 6.23 mmol) sequentially. The reaction mixture was stirred at 50°C for 16 hours. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ethyl acetate and dried under vacuum to yield 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (920 mg, crude).

[0192] Intermediates 11b-11f can be prepared by selecting appropriate raw materials according to the synthesis method of intermediate 11a, and their structures are shown in Table 2.

[0193] Table 2. Structural formulas and chemical names of intermediates 11b-11f

[0194] Intermediate 12: Preparation of tert-butyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate

[0195] tert-Butyl 4-ethynylpiperidine-1-carboxylate (1.03 g, 4.78 mmol) was dissolved in toluene (15 mL). 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl (630.44 mg, 4.78 mmol) and zirconocene hydrochloride (129.70 mg, 0.48 mmol) were added sequentially. The system was evacuated and replaced with nitrogen three times. The reaction was stirred at 65°C for 12 hours. After completion, the reaction was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain tert-butyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (1.25 g, yield: 77.56%).

[0196] Intermediate 13a: Preparation of (E)-2-(isoindolin-2-ylmethyl)-5-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one

[0197] Step 1: Dissolve 5-hydroxy-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (2.35 g, 9.66 mmol) in dichloromethane (40 mL). Add triethylamine (4.07 mL, 28.98 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (5.28 g, 14.49 mmol), and 4-dimethylaminopyridine (119.21 mg, 0.97 mmol) sequentially. React at room temperature for half an hour. The reaction solution is concentrated, and the crude product is purified by normal phase purification to yield 6-(isoindolin-2-ylmethyl)-4-carbonyl-4H-pyran-3-yltrifluoromethanesulfonic acid (1.30 g, yield: 35.85%). ESI-MS found 361.1 [M+H] + :.

[0198] Step 2: 6-(Isodihydroindole-2-ylmethyl)-4-carbonyl-4H-pyran-3-yltrifluoromethanesulfonic acid (650 mg, 1.73 mmol) was dissolved in 1,4-dioxane (8 mL) and water (1.6 mL), and tert-butyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (759.40 mg, 2.25 mmol), potassium carbonate (604.44 mg, 4.33 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (129.31 mg, 0.17 mmol) were added in sequence. The system was evacuated and replaced with nitrogen three times, heated to 80°C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain tert-butyl (E)-4-(2-(6-(isoindolin-2-ylmethyl)-4-carbonyl-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (630 mg, yield: 83.33%). ESI-MS: found 437.3 [M+H] + .

[0199] Step 3: Dissolve tert-butyl (E)-4-(2-(6-(isoindolin-2-ylmethyl)-4-carbonyl-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (100 mg, 229.07 μmol) in dichloromethane (10 mL). Add hydrochloric acid / ethyl acetate solution (3.3 mL, 4 M) dropwise and react at room temperature for one hour. The reaction mixture is concentrated to yield crude (E)-2-(isoindolin-2-ylmethyl)-5-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one (77 mg, yield: 99.91%).

[0200] Intermediates 13b-13v can be prepared by selecting appropriate raw materials according to the synthesis method of intermediate 13a, and their structures are shown in Table 3.

[0201] Table 3. Structural formulas and chemical names of intermediates 13b-13v

[0202] Intermediate 14: Preparation of (E)-2-(difluoromethyl)-6-(isoindolin-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one

[0203] Step 1: To a 1.85 M sodium hydroxide solution (42.6 mL) at room temperature was added 5-hydroxy-2-(isoindol-2-ylmethyl)-4H-pyran-4-one (17.5 g, 72.02 mmol). After 5 minutes of reaction, a 37% aqueous formaldehyde solution (1.38 mL, 79.13 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2 hours, and then 12 M hydrochloric acid was added to adjust the pH to approximately 2-3. After lyophilization, 3-hydroxy-2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (11.5 g, 85.8% yield) was obtained as an off-white solid.

[0204] Step 2: To a solution of 3-hydroxy-2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (11.5 g, 42.12 mmol) and imidazole (11.45 g, 168.48 mmol) in dichloromethane (200 mL) was added tert-butyldimethylsilyl chloride (15.80 g, 105.31 mmol) at room temperature. The reaction was allowed to proceed for 12 hours. The reaction was quenched with water and extracted twice with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by reverse-phase column chromatography to afford 3-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldimethylsilyl)oxy)methyl)-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (11.2 g, 57.97% yield) as a brown solid.

[0205] Step 3: 3-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldimethylsilyl)oxy)methyl)-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (3.9 g, 7.78 mmol) was dissolved in chloroform (40 mL). Formic acid (6 mL) was added at 0°C and allowed to react at room temperature for 1 hour. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate, the crude product was purified by silica gel column chromatography to obtain 2-((tert-butyldimethylsilyl)oxy)methyl)-3-hydroxy-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (2.4 g, yield: 79.51%).

[0206] Step 4: To a solution of 2-((tert-butyldimethylsilyl)oxy)methyl)-3-hydroxy-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (10 g, 25.84 mmol), N,N-diisopropylethylamine (10 g, 77.52 mmol) and 4-dimethylaminopyridine (0.31 g, 2.58 mmol) in dichloromethane (150 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl)methanesulfonamide (3.30 g, 9.30 mmol) at room temperature. The reaction was allowed to react at room temperature for 2 hours. The reaction was then quenched with water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by reverse phase column chromatography to give 2-((tert-butyldimethylsilyl)oxy)methyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (11 g, yield: 82.02%) as a brown solid.

[0207] Step 5: 2-((tert-Butyldimethylsilyl)oxy)methyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (5 g, 9.63 mmol), (E)-1-(methylsulfonyl)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine (3.57 g, 10.53 mmol), potassium carbonate (2.66 g, 19.26 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (785.81 mg, 0.963 mmol) in dioxane (80 mL) were heated to 90°C and stirred for 2 hours. The mixture was then cooled to room temperature, poured into water, and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give tert-butyl (E)-4-(2-(2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (2.5 g, yield: 44.68%).

[0208] Step 6: tert-Butyl (E)-4-(2-(2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (2.15 g, 3.62 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (4 mL, 1 M solution in tetrahydrofuran) was added. The system was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain tert-butyl (E)-4-(2-(2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (1.40 g, yield: 82.91%).

[0209] Step 7: To a solution of tert-butyl (E)-4-(2-(2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (1.4 g, 3.01 mmol) in dichloromethane (15 mL) was added Dess-Martin reagent (1.53 g, 3.60 mmol) at 0°C. The resulting solution was allowed to warm to room temperature and react for 2 hours. After dilution with dichloromethane, the resulting mixture was washed sequentially with saturated sodium carbonate solution, saturated Na2S2O3 solution, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give tert-butyl (E)-4-(2-(2-formyl-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (600 mg, yield: 43.01%).

[0210] Step 8: To a solution of tert-butyl (E)-4-(2-(2-formyl-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (600 mg, 1.29 mmol) in dichloromethane (10 ml) was added diethylaminosulfur trifluoride (250.08 mg, 1.55 mmol) at 0°C. The resulting solution was stirred for 0.5 hours. Saturated sodium bicarbonate solution was then added and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography to obtain tert-butyl (E)-4-(2-(difluoromethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (320 mg, yield: 64.2%).

[0211] Step 9: To a solution of tert-butyl (E)-4-(2-(difluoromethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (320 mg, 0.83 mmol) in dioxane (3 mL) was added 4 M hydrochloric acid solution in dioxane (5 mL) at 0°C. The resulting solution was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated to yield (E)-2-(difluoromethyl)-6-(isoindolin-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one (400 mg, crude).

[0212] Intermediate 15: Preparation of (E)-2-(difluoromethyl)-6-(isoindolin-2-ylmethyl)-3-(2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-4H-pyran-4-one

[0213] To a solution of 3-hydroxy-2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4H-pyran-4-one (1 g, 3.66 mmol) in dichloromethane (10 mL) were added N,N-diisopropylethylamine (1.42 g, 10.98 mmol), p-dimethylaminopyridine (45 mg, 0.37 mmol), and N-phenylbis(trifluoromethanesulfonic acid imide) (1.57 g, 4.39 mmol) in sequence. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was isolated and purified by normal phase column chromatography to yield 2-(hydroxymethyl)-6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (720 mg, yield: 72.00%).

[0214] Intermediate 16: Preparation of (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzenesulfonamide

[0215] 4-Bromobenzenesulfonamide (1 g, 4.26 mmol) was dissolved in 1,4-dioxane (20 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (655 mg, 4.26 mmol), bis(tri-tert-butylphosphine)palladium (218.5 mg, 0.426 mmol), and triethylamine (430 mg, 4.26 mmol) were added. The system was evacuated and replaced with nitrogen three times, and then stirred at 100°C overnight. After completion of the reaction, the system was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by normal phase column chromatography to yield (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzenesulfonamide (330 mg, yield: 24.8%).

[0216] Intermediate 17: Preparation of (E)-2-ethyl-6-(isoindolin-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one

[0217] Step 1: To a solution of kojic acid (30 g, 211 mmol) in phosphoric acid (150 mL) at 0°C, liquid bromine (13 mL, 249 mmol) and a solution of sodium dihydrogen phosphate (153 g, 1.25 mol) in water (430 mL) were added dropwise. The mixture was stirred at 4°C for 72 hours. After completion of the reaction, the reaction mixture was filtered and the filter cake was dried under vacuum to yield 2-bromo-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (18 g, 38.63% yield).

[0218] Step 2: To a solution of 2-bromo-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (10 g, 45.25 mmol) in N,N-dimethylformamide (100 mL) was added imidazole (6.46 g, 95 mmol) and tert-butyldimethylsilyl chloride (14.32 g, 95 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 2-bromo-3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4H-pyran-4-one (12.5 g, 61.52% yield).

[0219] Step 3: To a solution of 2-bromo-3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4H-pyran-4-one (9 g, 20.1 mmol) in dioxane (135 mL) and water (9 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.64 g, 30.1 mmol), potassium carbonate (5.54 g, 40.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol). After the addition, the mixture was heated to 90°C and stirred for 4 hours. After the reaction, the system was cooled to room temperature, the reaction solution was directly concentrated, and the crude product was purified by normal phase column chromatography to obtain 3-((tert-butyldimethylsilyl)oxy)-6-((tert-butyldimethylsilyl)oxy)methyl)-2-vinyl-4H-pyran-4-one (2.1 g, yield: 26.25%).

[0220] Step 4: To a solution of 3-((tert-butyldimethylsilyl)oxy)-6-((tert-butyldimethylsilyl)oxy)methyl)-2-vinyl-4H-pyran-4-one (3.2 g, 8.06 mmol) in chloroform (48 mL) was slowly added formic acid (16 mL) at room temperature and stirred for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography to give 6-(((tert-butyldimethylsilyl)oxy)methyl)-3-hydroxy-2-vinyl-4H-pyran-4-one (2 g, yield: 88.11%).

[0221] Step 5: 6-(((tert-Butyldimethylsilyl)oxy)methyl)-3-hydroxy-2-vinyl-4H-pyran-4-one (2.46 g, 8.72 mmol) was dissolved in ethyl acetate (50 mL), and palladium hydroxide (500 mg, 20 w / w) was added. The system was replaced with hydrogen three times and then maintained in a hydrogen atmosphere (balloon) for 1.5 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated and purified by normal phase column chromatography to give 6-(((tert-Butyldimethylsilyl)oxy)methyl)-2-ethyl-3-hydroxy-4H-pyran-4-one (700 mg, yield: 32.31%).

[0222] Step 6: To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethyl-3-hydroxy-4H-pyran-4-one (800 mg, 2.82 mmol) in dichloromethane (10 mL) was added N-phenylbis(trifluoromethanesulfonyl)imide (1.21 g, 3.38 mmol), N,N-diisopropylethylamine (1.21 g, 3.38 mmol) and 4-dimethylaminopyridine (34 mg, 0.28 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction, water (30 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by normal phase column chromatography to give 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethyl-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (1.2 g, yield: 102.56%) as a yellow oil.

[0223] Step 7: To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-ethyl-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (1.1 g, 2.63 mmol) in dioxane (22 mL) were added (E)-tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)tert-butyl-1-carboxylate (1.06 g, 3.15 mmol), potassium carbonate (726 mg, 5.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (192 mg, 0.26 mmol) at room temperature, and the reaction was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to give tert-butyl (E)-4-(2-(6-((tert-butyldimethylsilyl)oxy)methyl)-2-ethyl-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (860 mg, yield: 68.47%) as a yellow oil.

[0224] Step 8: To a solution of tert-butyl (E)-4-(2-(6-((tert-butyldimethylsilyl)oxy)methyl)-2-ethyl-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (860 mg, 1.80 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (3.6 mL, 3.6 mmol, 1.0 M solution in tetrahydrofuran) and the mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with water (40 mL) and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated. The crude product was purified by normal phase column chromatography to afford tert-butyl (E)-4-(2-(2-ethyl-6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (590 mg, 90.35% yield) as a yellow oil.

[0225] Step 9: tert-Butyl (E)-4-(2-(2-ethyl-6-(hydroxymethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (300 mg, 0.83 mmol) was dissolved in dichloromethane (6 mL). Triethylamine (167 mg, 1.65 mmol) and methylsulfonyl chloride (115 mg, 0.99 mmol) were added sequentially at 0°C. The reaction was maintained at 0°C for 20 minutes. After completion of the reaction, the reaction solution was directly concentrated to obtain crude tert-butyl (E)-4-(2-(2-ethyl-6-(((methylsulfonyl)oxy)methyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (366 mg, yield: 100%).

[0226] Step 10: To a solution of tert-butyl (E)-4-(2-(2-ethyl-6-(((methylsulfonyl)oxy)methyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (366 mg, 0.83 mmol) in acetonitrile (6 mL) were added isoindoline hydrochloride (130 mg, 0.83 mmol) and N,N-diisopropylethylamine (535 mg, 4.20 mmol) in sequence at room temperature. The temperature was raised to 50°C and the reaction mixture was allowed to react for 16 hours. After the reaction, the system was cooled to room temperature, the reaction solution was directly concentrated, and the crude product was purified by normal phase column chromatography to obtain tert-butyl (E)-4-(2-(2-ethyl-6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (230 mg, yield: 59.74%).

[0227] Step 11: To a solution of tert-butyl (E)-4-(2-(2-ethyl-6-(isoindol-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidine-1-carboxylate (230 mg, 0.49 mmol) in dioxane (4 mL) was added a 4 M solution of dioxane hydrochloride (2 mL, 8 mmol) at room temperature. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to afford crude (E)-2-ethyl-6-(isoindol-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one (178 mg, 100% yield).

[0228] Intermediate 18: Preparation of (E)-2-cyclopropyl-6-(isoindolin-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one

[0229] Step 1: Dissolve 2-bromo-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (10 g, 45.2 mmol) and imidazole (9.2 g, 135.7 mmol) in dichloromethane (100 mL). Add tert-butyldimethylsilyl chloride (14.9 g, 99.44 mmol) and react at room temperature for 2 hours. After completion of the reaction, quench the reaction with water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the crude product is separated and purified by normal phase column chromatography to obtain 2-bromo-3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4H-pyran-4-one (12.5 g, yield: 61.57%).

[0230] Step 2: Dissolve 2-bromo-3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4H-pyran-4-one (12.5 g, 27.8 mmol), cyclopropylboronic acid (3.58 g, 41.7 mmol), potassium carbonate (7.67 g, 55.6 mmol) and [bis(diphenylphosphino)ferrocene]palladium dichloride (2.2 g, 2.7 mmol) in dioxane (150 mL) and water (15 mL). The system was evacuated and replaced with nitrogen three times, then heated to 100 ° C and stirred for 16 hours. After the reaction, the system was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the crude product was separated and purified by normal phase column chromatography to obtain 3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyclopropyl-4H-pyran-4-one (6 g, yield: 52.64%).

[0231] Step 3: Dissolve 3-((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyclopropyl-4H-pyran-4-one (6 g, 14.6 mmol) in dichloromethane (100 mL). Add formic acid (30 mL) at room temperature and stir at room temperature for 1 hour. After the reaction, add saturated sodium carbonate solution to adjust the pH to 6-7. Extract with ethyl acetate, and the organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated, and the crude product is separated and purified by normal phase column chromatography to obtain 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyclopropyl-3-hydroxy-4H-pyran-4-one (800 mg, yield: 18.51%).

[0232] Using 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyclopropyl-3-hydroxy-4H-pyran-4-one as the starting material, and referring to the operations of steps 6 to 11 in the preparation of intermediate 17, (E)-2-cyclopropyl-6-(isoindolin-2-ylmethyl)-3-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one can be prepared through six steps.

[0233] Preparation of Examples

[0234] Example 1: Preparation of (E)-2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-4H-pyran-4-one

[0235] Methanesulfonyl chloride (39.32 mg, 343.30 μmol) was added dropwise to a solution of (E)-2-(isoindolin-2-ylmethyl)-5-(2-(piperidin-4-yl)vinyl)-4H-pyran-4-one (77 mg, 228.87 μmol) and triethylamine (69.48 mg, 686.60 μmol) in dichloromethane (2 mL) at 0°C. The mixture was stirred at room temperature for one hour. The reaction solution was concentrated and purified by high pressure reverse phase chromatography to afford (E)-2-(isoindolin-2-ylmethyl)-5-(2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-4H-pyran-4-one (28.30 mg, yield: 19.03%, purity: 96.55%). ESI-MS: found 415.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.30-7.14(m,4H),6.69(dd,J=16.0,6.8Hz,1H),6.36(s,1H),6.15(d,J=16.0Hz,1H),3.95(s,4H),3. 79(s,2H),3.56(d,J=11.6Hz,2H),2.85(s,3H),2.80-2.70(m,2H),2.20-2.19(m,1H),1.80(d,J=12.4Hz,2H),1.37(qd,J=12.4,4.0Hz,2H).

[0236] Examples 2-19 can be prepared by selecting appropriate raw materials by referring to the synthesis method of Example 1, and their structures are shown in Table 4.

[0237] Table 4. Structural formula, chemical name and mass spectrometry data of Examples 2-19

[0238] The NMR data of some of the compounds in the examples are as follows:

[0239] Example 19: Preparation of (E)-2-((isoindolin-2-yl-1,1,3,3-d4)methyl-d2)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)prop-1-en-2-yl)-4H-pyran-4-one

[0240] (E)-2-((isoindolin-2-yl-1,1,3,3-d4)methyl-d2)-5-(1-(piperidin-4-yl)prop-1-en-2-yl)-4H-pyran-4-one (50 mg, 0.1 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (0.5 mL) and methanesulfonic anhydride (20 mg, 0.11 mmol) were added. The mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative purification to give (E)-2-((isoindolin-2-yl-1,1,3,3-d4)methyl-d2)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)prop-1-en-2-yl)-4H-pyran-4-one (15.86 mg, yield: 36.5%, purity: 99.791%). ESI-MS: found 435.5[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.46(s,0.18H,FA),8.07(s,1H),7.27-7.17(m,4H),6.32(s,1H),5.61-5.54(m,1H),3.57- 3.47(m,2H),2.85(s,3H),2.83-2.75(m,2H),2.47-2.38(m,1H),1.88(s,3H),1.75-1.65(m,2H),1.42-1.30(m,2H).

[0241] Example 20 can be prepared by selecting appropriate raw materials by referring to the synthesis method of Example 19, and its structure is shown in Table 5.

[0242] Table 5. Structural formula, chemical name and mass spectrometry data of Example 20

[0243] The NMR data of some of the compounds in the examples are as follows:

[0244] Example 21: Preparation of (Z)-5-(2-chloro-2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0245] (Z)-4-(1-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-1-(methylsulfonyl)piperidine (300 mg, 0.86 mmol), 6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl trifluoromethanesulfonate (322.00 mg, 0.86 mmol), potassium carbonate (356 mg, 2.57 mmol), and bis(diphenylphosphino)ferrocene]palladium dichloride (94 mg, 0.13 mmol) were dissolved in dioxane (10 mL). The system was evacuated and replaced with nitrogen three times, then heated to 80°C and stirred for 16 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, and the crude product was purified by reverse phase preparative purification to give (Z)-5-(2-chloro-2-(1-(methylsulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (10.8 mg, yield: 2.8%, purity: 97.905%). ESI-MS: found 449.1 [M+H] + . 1H NMR(400MHz,MeOH-d4)δ8.73(s,1H),7.41(s,3H),7.36-7.27(m,1H),6.68(s,1H),6.56(s,1H),4.77(s,4H),4.60(s, 2H),3.82(d,J=11.6Hz,2H),2.85(s,3H),2.84-2.72(m,2H),2.70-2.57(m,1H),2.08-1.96(m,2H),1.88-1.69(m,2H).

[0246] Examples 22-25 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 21, and their structures are shown in Table 6.

[0247] Table 6. Structural formula, chemical name and mass spectrometry data of Examples 22-25

[0248] The NMR data of some of the compounds in the examples are as follows:

[0249] Example 26: Preparation of (E)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide

[0250] Step 1: Dissolve potassium tert-butoxide (157.5 mg, 2.13 mmol) in dichloromethane (500 mL) and add chlorosulfonyl isocyanate (300 mg, 2.13 mmol) under ice-cooling. Maintain the reaction at this temperature for 1.5 hours. Dissolve (E)-2-(isoindolin-2-ylmethyl)-5-(2-(piperidin-4-yl)prop-1-en-1-yl)-4H-pyran-4-one (448.6 mg, 1.28 mmol) and triethylamine (856.8 mg, 8.48 mmol) in dichloromethane and slowly add to the reaction system at 0°C. Stir and react at room temperature for 1 hour. The reaction solution was concentrated, and the residue was separated and purified by normal phase column chromatography to give tert-butyl (E)-((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (220 mg, yield: 29.4%).

[0251] Step 2: Dissolve tert-butyl (E)-((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (220 mg, 0.38 mmol) in dioxane (2 mL), add 4M hydrochloric acid solution in dioxane (5 mL), and stir at room temperature for 2 hours. After the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative purification to give (E)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide (70.18 mg, 31.5%, purity: 99.473%). ESI-MS: found 433.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.26(d,J=8.0Hz,4H),6.47(s,1H),5.71(d,J=43.6Hz,1H),4.29-3.89(m,4H),3.63(d,J=12 .0Hz,2H),2.88(s,3H),2.77(t,J=11.2Hz,2H),2.61-2.53(m,2H),1.94(d,J=11.6Hz,2H),1.60-1.46(m,3H),1.33-1.25(m,1H).

[0252] Examples 27-39 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 26, and their structures are shown in Table 7.

[0253] Table 7. Structural formula, chemical name and mass spectrometry data of Examples 27-39

[0254] The NMR data of some of the compounds in the examples are as follows:

[0255] Example 40: Preparation of (E)-N-(tert-butyl)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide

[0256] (E)-2-(Isoindolin-2-ylmethyl)-5-(2-(piperidin-4-yl)prop-1-en-1-yl)-4H-pyran-4-one (100 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL). tert-Butylsulfamoyl chloride (97.7 mg, 0.57 mmol, crude product, prepared by heating tert-butylamine and sulfonyl chloride in acetonitrile under reflux overnight) was added at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative method to yield (E)-N-(tert-butyl)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide (5.13 mg, 3.64%, purity: 99.442%). ESI-MS: found 486.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.27-7.18(m,4H),6.85(s,1H),6.35(s,1H),5.93(s,1H),3.97(s,4H),3.80( s,2H),3.66-3.58(m,2H),2.68-2.56(m,2H),2.19-2.08(m,1H),1.84-1.69(m,5H),1.50-1.39(m,2H),1.23(s,9H).

[0257] Examples 41-54 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 40, and their structures are shown in Table 8.

[0258] Table 8. Structural formula, chemical name and mass spectrometry data of Examples 41-54

[0259] The NMR data of some of the compounds in the examples are as follows:

[0260] Example 55: Preparation of (E)-N-(2-hydroxyethyl)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide

[0261] Step 1: tert-Butyl (E)-((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (3.0 g, 5.67 mmol) was dissolved in anhydrous toluene (40 mL), and 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (1.49 g, 8.51 mmol) and cyanomethylenetri-n-butylphosphine (2.05 g, 8.51 mmol) were added. The mixture was heated to 110 degrees under nitrogen and stirred for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and the reaction solution was concentrated. The crude product was purified by reverse phase preparation to give tert-butyl (E)-(2-((tert-butyldimethylsilyl)oxy)ethyl)((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (2.0 g, yield: 51.27%).

[0262] Step 2: Tert-butyl (E)-(2-((tert-butyldimethylsilyl)oxy)ethyl)((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (2.0 g, 2.90 mmol) was dissolved in tetrahydrofuran (20 mL), and 1 M tetrabutylammonium fluoride (3.5 mL) was added. The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated to obtain tert-butyl (E)-(2-hydroxyethyl)((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (1.6 mg, crude product).

[0263] Step 3: Tert-butyl (E)-(2-hydroxyethyl)((4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidin-1-yl)sulfonyl)carbamate (1.6 g, 2.79 mmol) was dissolved in dioxane (8 mL), and 4 M hydrochloric acid in dioxane (50 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was purified by reverse phase preparative purification to give (E)-N-(2-hydroxyethyl)-4-(1-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)prop-1-en-2-yl)piperidine-1-sulfonamide (647.87 mg, 49.09%, purity: 99.008%). ESI-MS: found 474.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.27-7.13(m,5H),6.35(s,1H),5.93(s,1H),4.69(s,1H),3.97(s,4H),3.80(s,2H),3.65-3.55( m,2H),3.44(t,J=6.4Hz,2H),2.94(q,J=6.2Hz,2H),2.67(t,J=11.5Hz,2H),2.20-2.07(m,1H),1.80-1.68(m,5H),1.54-1.39(m,2H).

[0264] Examples 56-60 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 55, and their structures are shown in Table 9.

[0265] Table 9. Structural formula, chemical name and mass spectrometry data of Examples 56-60

[0266] The NMR data of some of the compounds in the examples are as follows:

[0267] Example 61: Preparation of (Z)-5-(2-fluoro-2-(1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0268] Step 1: Dissolve (2-bromoethoxy)(tert-butyl)diphenylsilane (2 g, 5.5 mmol) and potassium thioacetate (1.25 g, 11.0 mmol) in N,N-dimethylformamide (20 mL). Heat to 80°C and stir for 16 hours. After the reaction, cool the system to room temperature, dilute with water, and extract with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to obtain S-(2-((tert-butyldiphenylsilyl)oxy)ethyl)ethylsulfate (1.7 g, yield: 86.33%).

[0269] Step 2: Dissolve S-(2-((tert-butyldiphenylsilyl)oxy)ethyl)ethanesulfate (400 mg, 1.12 mmol) in acetonitrile (4 mL) and 6 M hydrochloric acid (4 mL). Add N-chlorosuccinimide (178.32 mg, 1.34 mmol) at room temperature and stir at room temperature for 4 hours. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain 2-((tert-butyldiphenylsilyl)oxy)ethane-1-sulfonyl chloride (300 mg, crude).

[0270] Step 3: (Z)-5-(2-fluoro-2-(piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (100 mg, 0.28 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (114.1 mg, 1.13 mmol) and 2-((tert-butyldiphenylsilyl)oxy)ethane-1-sulfonyl chloride (300 mg, crude) were added sequentially at 0°C. The mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated and purified by normal phase column chromatography to obtain (Z)-5-(2-(1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (70 mg, yield: 35.7%).

[0271] Step 4: (Z)-5-(2-(1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (70 mg, 0.1 mmol)) was dissolved in tetrahydrofuran (2 mL), and 1 M tetrabutylammonium fluoride (0.1 mL) was added. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative purification to give (Z)-5-(2-fluoro-2-(1-((2-hydroxyethyl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (3.76 mg, yield: 8.1%, purity: 99.566%). ESI-MS: found 463.2 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δ8.51(s,1H),8.40(s,2H,FA),7.26-7.18(m,4H),6.52(s,1H),5.76(d,J=42.3Hz,1H),4.06(s,4H),3.92(t,J=6.1H z,2H),3.88(s,2H),3.85-3.76(m,2H),3.21(t,J=6.1Hz,2H),2.99-2.88(m,2H),2.59-2.44(m,1H),2.06-1.96(m,2H),1.72-1.59(m,2H).

[0272] Examples 62-63 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 61, and their structures are shown in Table 10.

[0273] Table 10. Structural formula, chemical name and mass spectrometry data of Examples 62-63

[0274] The NMR data of some of the compounds in the examples are as follows:

[0275] Example 64: Preparation of (Z)-5-(2-fluoro-2-(1-((3-hydroxypyrrolidin-1-yl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0276] Step 1: Dissolve tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.476 mmol), tert-butyldiphenylsilyl chloride (14.6 g, 53.476 mmol), and imidazole (4.4 g, 64.171 mmol) in N,N-dimethylformamide (100 mL) and react at room temperature for 4 hours. After completion of the reaction, dilute with water and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The crude product is purified by normal phase column chromatography to yield tert-butyl 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (13 g, yield: 56.52%).

[0277] Step 2: Dissolve tert-butyl 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate (3 g, 7.059 mmol) in hydrochloric acid-dioxane solution (30 mL, 4 M) and stir at room temperature for 1 hour. After the reaction, the reaction solution was directly concentrated to obtain 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine (2.9 g, crude product).

[0278] Step 3: Dissolve 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine (1 g, 3.077 mmol) and N,N-diisopropylethylamine (1.6 g, 12.308 mmol) in dichloromethane (10 mL). Slowly add sulfonyl chloride (825 mg, 6.154 mmol) dropwise at 0°C and stir overnight at room temperature. After completion of the reaction, the reaction system was washed with 1N HCl solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield 3-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-sulfonyl chloride (crude product).

[0279] Step 4: Dissolve 3-((tert-Butyldiphenylsilyl)oxy)pyrrolidine-1-sulfonyl chloride (crude), (Z)-5-(2-fluoro-2-(piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (100 mg, 0.28 mmol) (200 mg, 0.565 mmol), and triethylamine (228 mg, 2.260 mmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 30 minutes. After the reaction, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to give (Z)-5-(2-(1-((3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (210 mg, yield: 36.08%).

[0280] Step 5: (Z)-5-(2-(1-((3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (210 mg, 0.283 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (0.3 mL, 0.283 mmol, 1.0 M in THF) was added dropwise, and the reaction was stirred at room temperature for 10 minutes. After the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative method to give (Z)-5-(2-fluoro-2-(1-((3-hydroxypyrrolidin-1-yl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (41.00 mg, yield: 28.87%, purity: 99.595%). ESI-MS: found 504.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.28-7.18(m,4H),6.41(s,1H),5.68 (d,J=43.6Hz,1H),5.05(s,1H),4.29(s,1H),3.97(s,4H),3.81(s,2H),3.6 7-3.58(m,2H),3.36-3.25(m,3H),3.14-3.07(m,1H),2.88-2.77(m,2H),2 .58-2.50(m,1H),1.97-1.84(m,3H),1.82-1.74(m,1H),1.57-1.42(m,2H).

[0281] Examples 65-67 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 64, and their structures are shown in Table 11.

[0282] Table 11. Structural formula, chemical name and mass spectrometry data of Examples 65-67

[0283] The NMR data of some of the compounds in the examples are as follows:

[0284] Example 68: Preparation of (Z)-5-(2-(1-((3-aminoazetidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0285] Step 1: Dissolve tert-butyl azetidin-3-ylcarbamate (1 g, 5.8 mmol) in dichloromethane (15 mL). Add triethylamine (585.8 mg, 5.8 mmol) and sulfonyl chloride (685.8 mg, 5.8 mmol) at 0°C and stir for 2 hours. After completion, quench the reaction with water (20 mL) and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to yield tert-butyl (1-(chlorosulfonyl)azetidin-3-yl)carbamate (1.2 g, crude).

[0286] Step 2: To a solution of (Z)-5-(2-fluoro-2-(piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (300 mg, 0.85 mmol) in dichloromethane (6 mL) was added tert-butyl(1-(chlorosulfonyl)azetidin-3-yl)carbamate (1.2 g, crude) and triethylamine (341.38 mg, 3.38 mmol) sequentially at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by normal phase column chromatography to give tert-butyl (Z)-(1-((4-(1-fluoro-2-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate (220 mg, yield: 44.32%).

[0287] Step 3: Tert-butyl (Z)-(1-((4-(1-fluoro-2-(6-(isoindolin-2-ylmethyl)-4-oxo-4H-pyran-3-yl)vinyl)piperidin-1-yl)sulfonyl)azetidin-3-yl)carbamate (100 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated, and the crude product was purified by reverse phase preparative chromatography to give (Z)-5-(2-(1-((3-aminoazetidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (54.68 mg, yield: 65.91%, purity: 96.470%). ESI-MS: found 489.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.27-7.17(m,4H),6.41(s,1H),5.68(d,J=43.6Hz,1H),3.97(s,4H),3.88-3.77(m ,4H),3.66-3.54(m,3H),3.52-3.44(m,2H),2.87-2.77(m,2H),2.60-2.50(m,1H),1.94-1.84(m,2H),1.54-1.41(m,2H).

[0288] Example 69: Preparation of (Z)-5-(2-(1-((3-(dimethylamino)azetidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0289] (Z)-5-(2-(1-((3-aminoazetidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (100 mg, 0.205 mmol) was dissolved in methanol (3 mL). Sodium acetate borohydride (173.03 mg, 0.82 mmol), acetic acid (0.05 mL) and 37% formaldehyde aqueous solution (0.5 mL) were added at room temperature. The mixture was heated to 50°C and stirred for 2 hours. After the reaction, the reaction solution was directly concentrated to remove the low-boiling solvent, and the residue was purified by reverse phase preparative purification to give (Z)-5-(2-(1-((3-(dimethylamino)azetidin-1-yl)sulfonyl)piperidin-4-yl)-2-fluorovinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (33.41 mg, yield: 31.58%, purity: 99.184%). ESI-MS: found 517.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.50(s,1H),7.27-7.18(m,4H),6.41(s,1H),5.68(d,J=43.7Hz,1H),3.97(s,4H),3.81(s,2H),3.78-3.70(m ,2H),3.68-3.59(m,4H),3.07-2.97(m,1H),2.89-2.78(m,2H),2.61-2.53(m,1H),2.05(s,6H),1.93-1.84(m,2H),1.54-1.41(m,2H).

[0290] Example 70: Preparation of (Z)-5-(2-fluoro-2-(1-((3-hydroxy-3-methylazetidin-1-yl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one

[0291] Step 1: Dissolve tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (5g, 26.7mmol) in dichloromethane (50mL). Add triethylamine (4.05g, 40.06mmol) and benzoyl chloride (4.5g, 32.04mmol) at 0°C and stir at this temperature for 2 hours. After the reaction is completed, water is added to quench the reaction and the product is extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The crude product is purified by normal phase column chromatography to obtain tert-butyl 3-(benzoyloxy)-3-methylazetidine-1-carboxylate (6.2g, yield: 79.70%).

[0292] Step 2: Dissolve tert-butyl 3-(benzoyloxy)-3-methylazetidine-1-carboxylate (1 g, 3.43 mmol) in dichloromethane (10 mL). Add trifluoroacetic acid (1 mL) at room temperature and stir for 2 hours. After the reaction, concentrate the reaction solution to obtain 3-methylazetidine-3-ylbenzoate (620 mg, yield: 94.5%).

[0293] Step 3: Dissolve 3-methylazetidin-3-ylbenzoate (0.3 g, 1.57 mmol) in dichloromethane (10 mL). Add triethylamine (811 mg, 6.28 mmol) and sulfonyl chloride (423 mg, 3.14 mmol) at 0°C. Maintain the mixture at this temperature and stir for 12 hours. After completion of the reaction, quench the reaction with water and extract with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to yield 1-(chlorosulfonyl)-3-methylazetidin-3-ylbenzoate (0.5 g, crude). The crude product is used directly in the next reaction.

[0294] Step 4: (Z)-5-(2-Fluoro-2-(piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (0.5 g, crude) (100 mg, 0.28 mmol) was dissolved in dichloromethane (6 mL), and triethylamine (114.28 mg, 1.13 mmol) and 1-(chlorosulfonyl)-3-methylazetidin-3-ylbenzoate (0.5 g, crude) were added at 0°C, and the system was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated to obtain a crude product, which was purified by normal phase purification to obtain (Z)-1-((4-(1-fluoro-2-(6-(isoindolin-2-ylmethyl)-4-carbonyl-4H-pyran-3-yl)vinyl)piperidin-1-yl)sulfonyl)-3-methylazetidin-3-ylbenzoate (40 mg, yield: 23.4%).

[0295] Step 5: (Z)-1-((4-(1-fluoro-2-(6-(isoindolin-2-ylmethyl)-4-carbonyl-4H-pyran-3-yl)vinyl)piperidin-1-yl)sulfonyl)-3-methylazetidin-3-ylbenzoate (40 mg, 0.065 mmol) was dissolved in methanol (3 mL). 1N sodium hydroxide solution (0.1 mL) was added at room temperature and stirred for 1 hour. After the reaction, the reaction solution was concentrated and the crude product was purified by reverse phase preparative purification to give (Z)-5-(2-fluoro-2-(1-((3-hydroxy-3-methylazetidin-1-yl)sulfonyl)piperidin-4-yl)vinyl)-2-(isoindolin-2-ylmethyl)-4H-pyran-4-one (3.1 mg, yield: 9.3%). ESI-MS: found 504.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.48(brs,5H,FA),7.26-7.14(m,4H),6.41(s,1H),5.78-5.56(m,2H),3.97(s,4H),3.81(s,2H),3.74- 3.67(m,2H),3.66-3.59(m,2H),3.58-3.52(m,3H),2.88-2.78(m,2H), 2.02-1.96(m,1H),1.95-2.84(m,2H),1.52-1.44(m,2H),1.39(s,3H).

[0296] Examples 71-72 can be prepared by selecting appropriate raw materials according to the synthesis method of Example 70, and their structures are shown in Table 12.

[0297] Table 12. Structural formula, chemical name and mass spectrometry data of Examples 71-72

[0298] Biological test evaluation

[0299] The present invention is further described and explained below in conjunction with biological test experiments, but these experiments are not intended to limit the scope of the present invention.

[0300] 1. Pregnenolone and Testosterone Biosynthesis Inhibition Experiment

[0301] Pregnenolone and testosterone biosynthesis inhibition experiments were conducted using the NCI-H295R cell line. NCI-H295R cells were revived and cultured in complete DMEM medium. Once cells were in good condition, they were added to a 96-well plate at a concentration of 95 μL per well (60,000 cells / well) and incubated overnight in a 37°C, 5% CO2 incubator. After the cells adhered, the diluted test compound was added to the 96-well plate in duplicate according to a concentration gradient, with 5 μL added to each well. Positive and blank controls were treated with equal volumes of complete DMEM medium containing the same DMSO content, mixed by vortexing, and incubated in a 37°C, 5% CO2 incubator for 48 hours. After incubation, 50 μL of the supernatant from the centrifuged culture medium sample was collected and quenched with 50 μL of ice-pure methanol. Subsequently, 150 μL of 100 mM hydroxylamine hydrochloride in 50% methanol (containing 2 ng / mL verapamil) was added. The sample was vortexed for 5 minutes and reacted in a 60°C water bath for 1 hour. After centrifugation, the secretion of pregnenolone and testosterone was analyzed by LC-MS / MS. Data were analyzed using GraphPad Prism 9 software and IC was calculated. 50IC values ​​of some compounds against CYP11A1 obtained by the pregnenolone biosynthesis inhibition experiment 50 See Table 13. Where: "Preg" is the abbreviation of Pregnenolone, "Test" is the abbreviation of Testosterone. "A" represents IC 50 ≤30nM, “B” means 30nM <IC 50 ≤100nM, “C” means 100nM <IC 50 .

[0302] Table 13. CYP11A1 inhibitory activity test results of some example compounds

[0303] 2. Pharmacokinetic testing in mice

[0304] This experiment tests the metabolic stability of the example compounds after oral administration in mice. Male ICR mice, 20-25g, 3 mice / compound, purchased from Weitonglihua Experimental Animal Co., Ltd. were used in the experiment. On the day of the test, the mice were randomly divided into groups according to body weight. The mice were fasted but not watered for 12 hours one day before administration, and were fed 4 hours after administration. Oral gavage solvent: 0.5% CMCNa. Dose: 5mg / kg. Before and after administration, 30uL of blood was collected from the mandibular vein under isoflurane anesthesia and placed in an EDTA-K2 test tube. After whole blood collection, it was temporarily stored in an ice water bath and centrifuged at 11000rpm for 5 minutes within 30 minutes to separate the plasma. The blood collection points for gavage administration were 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h. The samples were quantitatively analyzed by HPLC-MS / MS. The relevant pharmacokinetic parameters Tmax, Cmax, AUC were calculated using WinNonlin software. 0-t , t 1 / 2 The test results of some example compounds are shown in Table 14.

[0305] Table 14. Results of pharmacokinetic test (oral administration) of some compounds in mice

[0306] 3. Hormone level suppression test in non-castrated mice

[0307] This experiment tests the effect of the example compounds on the steroid hormone levels in non-castrated mice. The experiment used male ICR mice, 20-25g, 12 mice / compound, purchased from Weitong Lihua Experimental Animal Co., Ltd. The mice were randomly divided into groups according to body weight before administration. The dosage was 20 mg / kg, and the solvent for oral administration was 0.5% CMCNa. Twice a day, after oral administration for several consecutive days, the last dose was given on the morning of the last day, and plasma and adrenal tissue at different time points were collected according to 3 mice / time point. The samples were quantitatively analyzed by HPLC-MS / MS. Graphpad Prim8.0 software was used for drawing. The test results of some example compounds are shown in Table 15. Among them, the positive compound is Example 185 in patent WO2018115591, and its structure is as follows:

[0308] Table 15. Adrenal gland hormone concentrations after administration of some of the compounds in the examples

[0309] The above test results indicate that, compared to the positive compounds, the example compounds of the present invention have stronger and more profound inhibitory activity on the production of the direct biomarker pregnelonone and its downstream metabolite progesterone in the mouse adrenal gland, indicating that they have the potential for superior efficacy in clinical practice.

[0310] In summary, the polycyclic compounds of the present invention exhibit strong inhibitory activity against CYP11A1 and have good development prospects.

[0311] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, in, n and p are each independently 1, 2, 3, 4 or 5; Each R 20 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, SF5, C 1-6 Alkyl, C 1-6 Alkenyl, C 1- 6 alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclyl, 4-8 membered heterocyclyloxy, -P(O)(C 1-6 Alkyl)2, NR 14 R 15 The above groups may be further optionally replaced by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution; R d and R d ' are each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution; or R d 、R d ' and the C atoms to which it is connected together form C 3-6 Carbocyclic or 4-6 membered heterocyclic ring, said carbocyclic and heterocyclic ring may be further optionally substituted by one or more selected from D, halogen, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C(O)C 1-6 Alkyl, -S(O)2-C 1-6 substituted by an alkyl substituent; R 1 Independently selected from the group consisting of H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, oxo (=O), C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution; R b and R b ' are each independently selected from the group consisting of H, D, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3- 8 cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution; Ring B is selected from the group consisting of 4-14 membered heterocyclic rings, 4-10 membered carbocyclic rings, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, 7-14 membered fused bicyclic ring; Each R 3 Independently selected from the group consisting of H, D, halogen, cyano, -C 0-4 Alkylene-OR 12 、-C 0-4 Alkylene-CONR 10 R 11 、-C(O)C 1-6 Alkyl, -P(O)(OR 12 )2、-S(O)2C 1-6 Alkyl, -S(O)2-C 6-10 Aryl, -S(O)2-5-12 membered heteroaryl, -S(O)(NR 31 )C 1-6 Alkyl, -C 0-4 Alkylene-S(O)2NR 10 R 11 、-C 0-4 Alkylene-S(O)(NR 31 )NR 10 R 11 、-C 0- 4-Alkylene-S(O)NR 10 R 11 、-C 0-4 Alkylene-COOR 12 , oxo (=O), =C (R 13 )2、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-8 membered heterocyclic group, C 1-6 Halogenated alkoxy, C 3-8 Halogenated cycloalkyl, C 3-8 halocycloalkoxy group substitution; Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, 5-12 membered heteroaryl, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl), which may be further optionally substituted by one or more R j replace; Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a 4-10 membered nitrogen-containing heterocyclic ring, which may be further optionally replaced by one or more R j replace; Each R j Independently selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, -C 0-4 Alkylene-NR 16 R 17 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 Halogenated cycloalkyl, 4-10 membered halogenated heterocyclic group, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic oxy, C 3-10 Halogenated cycloalkoxy, 4-10 membered halogenated heterocyclic oxy, -C(O)C 1-6 Alkyl, -CONR 32 R 33 、-S(O)2C 1-6 Alkyl, -S(O)2NR 32 R 33 ; Alternatively, two R j All atoms connected to it together form C 3-6 Carbocyclic or 4-7 membered heterocyclic ring; Each R 12 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Heterocyclic group, said group may be optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1- 4-halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group; Each R 13 Each independently selected from the group consisting of H, D, halogen, C 1-3 Alkyl, C 1-3 alkyl halide; Or two R 13 Together with the carbon atoms where they are located, they form a 3-6 membered cycloalkylene or 4-6 membered heterocyclylene, wherein the cycloalkylene and heterocyclylene may be further optionally substituted by one or more selected from D, halogen, C 1-4 Alkoxy, C 1- 4-substituted by a haloalkoxy substituent; Each R 14 , each R 15 , each R 16 , each R 17 Independently selected from the group consisting of H, C 1-6 Alkyl, C 3-10 Cycloalkyl, -SO2(C 1- 6 alkyl), -CO(C 1-6 alkyl), -SO2(C 3-6 Cycloalkyl), -CO(C 3-6 Cycloalkyl), -SO2 (4-6 membered heterocyclic group), -CO (4-6 membered heterocyclic group), -CO (-OC 1-6 Alkyl), -SO2NH(C 0-6 Alkyl), -SO2N(C 1-6 alkyl)2, -CONH(C 0-6 alkyl), -CON(C 1-6 Alkyl) 2, said group may be further optionally substituted by one or more selected from deuterium, halogen, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group; Alternatively, R attached to the same nitrogen atom 14 and R 15 Together with the nitrogen atom, a 4-8 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from D, halogen, =O, CN, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) substituent; Each R 31 Independently selected from the group consisting of H, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkoxy, 4-10 membered heterocyclic group, said group may be further optionally substituted with one or more selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 3-10 substituted by a halogenated cycloalkyl group or a 4-10-membered halogenated heterocyclic group; Each R 32 , each R 33 Independently selected from the group consisting of H, C 1-6 Alkyl, said group may be further optionally substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 substituted by an alkoxy substituent; Alternatively, R attached to the same nitrogen atom 32 and R 33 Together with the nitrogen atom, a 4-8 membered heterocyclic ring is formed, wherein the heterocyclic ring may be optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-4 Alkoxy, -SO2(C 1-6 alkyl), -CO(C 1-6 alkyl) is substituted; provided that when R 1 is H, and any R 3 None of them are -S(O)2-C 6-10 Aryl, -S(O)2-5-12 membered heteroaryl or S(O)2NR 10 R 11 When R 20 It is H or D.

2. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: Each R 20 Independently selected from the group consisting of H, D, halogen, cyano, hydroxyl, SF5, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, C 1-4 Alkoxy, -SCF3, C 3-6 Cycloalkyl, C 3- 6-membered cycloalkoxy, 4-7-membered heterocyclyl, 4-7-membered heterocyclyl, -P(O)Me2, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NHC(O)(C 1-4 Alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 Alkyl), -NHS(O)2(C 1-4 Alkyl), -N(C 1- 4-alkyl)S(O)2(C 1-4 Alkyl), each of the above groups may be further optionally substituted by one or more selected from D, halogen, hydroxyl, C 1-3 Alkoxy, C 1-3 The haloalkoxy group is substituted.

3. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: Each R 3 Independently selected from the group consisting of H, D, halogen, cyano, C 1-4 Alkoxy, CONR 10 R 11 、-C(O)C 1-4 Alkyl, -S(O)2C 1-4 Alkyl, -S(O)2C 1-4 Hydroxyalkyl, -S(O)(NR 31 )C 1-4 Alkyl, -S(O)2NR 10 R 11 、-S(O)(NR 31 )NR 10 R 11 、-S(O)NR 10 R 11 、-COOR 12 , oxo (=O), =C (R 13 )2、C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclic group, -S(O)2-phenyl, -S(O)2-5-7 membered heteroaryl, each of which may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, C 3-6 halocycloalkoxy group substitution; Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl, -SO2(C 1-4 alkyl), -CO(C 1-4 alkyl), which may be further optionally substituted by 1, 2, 3, 4, 5 or 6 R j replace; Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a 4-7 membered nitrogen-containing heterocyclic ring, which may be optionally further replaced by 1, 2, 3, 4, 5 or 6 R j replace; Each R j Independently selected from the group consisting of deuterium, halogen, =O, CN, hydroxyl, -C 0-2 Alkylene-NR 16 R 17 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 3-6 Halogenated cycloalkyl, 4-7 membered halogenated heterocyclic group, C 3-6 Cycloalkoxy, 4-7 membered heterocyclic oxy, C 3-6 Halogenated cycloalkoxy, 4-7 membered halogenated heterocyclic oxy, -C(O)C 1-4 Alkyl, -CONR 32 R 33 、-S(O)2C 1-4 Alkyl, -S(O)2NR 32 R 33 ; Alternatively, two R j All atoms connected to it together form C 3-6 Carbocyclic or 4-7 membered heterocyclic ring; Among them, R 12 、R 13 、R 16 、R 17 、R 31 、R 32 、R 33 The definition as in claim 1.

4. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: At least one R 3 Selected from the group consisting of: -S(O)2C 1-4 Alkyl, -S(O)2NR 10 R 11 , -S(O)2-5-7 membered nitrogen-containing heteroaryl, said group may be further optionally substituted by one or more selected from D, halogen, cyano, hydroxyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, C 3-6 halocycloalkoxy group substitution; Each R 10 , each R 11 Independently selected from the group consisting of H, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -SO2(C 1-4 alkyl), -CO(C 1-4 alkyl), which may be further optionally substituted by 1, 2, 3, 4, 5 or 6 R j replace; Alternatively, R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom, it forms a 4-6 membered nitrogen-containing heterocyclic ring, which may be further optionally replaced by 1, 2, 3, 4, 5 or 6 R j replace; Each R j Independently selected from the group consisting of D, halogen, amino, =O, CN, hydroxy, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SO2(C 1-4 alkyl), -CO(C 1-4 Alkyl), -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NHC(O)(C 1-4 Alkyl), -N(C 1-4 alkyl)CO-C 1-4 Alkyl, -NHS(O)2(C 1-4 Alkyl), -N(C 1-4 alkyl)S(O)2-C 1-4 alkyl; Alternatively, two R j All atoms connected to it together form C 3-6 Carbocyclic ring or 4-7 membered heterocyclic ring.

5. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: The R 3 -S(O)2NR 10 R 11 , and R attached to the same nitrogen atom 10 and R 11 Together with the nitrogen atom to which it is connected, it forms a ring structure selected from the group consisting of azetidine, 1,3-thiazetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, and thiomorpholine, wherein the ring structure may be further optionally replaced by 1, 2, 3, or 4 R j replace; Among them, R j The definition as in claim 1.

6. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: Ring B is selected from the group consisting of a 4-7 membered heterocyclic ring, a benzene ring, a naphthalene ring, and a 5-7 membered heteroaromatic ring.

7. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: R 1 Selected from the group consisting of H, D, halogen, cyano, C 1- 4-alkyl, containing 0, 1, 2, 3, 4, 5 or 6 fluorine-substituted -C 1-3 Alkylene-C 1-3 Alkoxy, C 1-4 Alkenyl, C 3- 6-membered cycloalkyl, 4-7-membered heterocyclic group, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl.

8. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: The R b and R b ' are each independently selected from the following group: H, D, F, Cl, Br, C 1-4 Alkyl, -C containing 0, 1, 2, 3, 4, 5 or 6 fluorine substituted 1-3 Alkylene-C 1-3 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Tritiated alkyl.

9. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: The R d and R d 'Each independently selected from the following group: H, D, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 tritiated alkyl; or R d 、R d ' and the carbon atoms to which it is connected together form C 3-6 Cycloalkyl or 4-6 membered heterocyclic group.

10. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: The compound has a structure shown in formula (II), Where m is 0, 1, 2, 3 or 4; R i Select from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, NR 10 R 11 , 5-7 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, C 1-4 Alkylene-4-7 membered heterocyclic group; Ring B, R 10 、R 11 、R b 、R b '、R 1 、R 3 、R d 、R d ', p and R 20 The definition as in claim 1.

11. The compound according to claim 1, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, wherein: The compound is selected from the group consisting of:

12. A pharmaceutical composition, characterized in that The composition comprises: (i) a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

13. Use of the compound according to any one of claims 1 to 11, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition according to claim 12, wherein: For preparing a drug for treating and / or preventing diseases associated with CYP11A1; Preferably, the disease associated with CYP11A1 is cancer; More preferably, the disease associated with CYP11A1 is prostate cancer and breast cancer.

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