CYP11A1 inhibitor compound as well as preparation method and application thereof

Abstract

The invention discloses a compound shown in a general formula (I), and a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof. Compared with the prior art, the compound disclosed by the invention is a brand new skeleton, and the compound disclosed by the invention unexpectedly shows that the compound has a good inhibition effect on CYP11A1 and blocks biosynthesis of downstream steroids. Clinically, the pharmaceutical composition can be used for treating diseases dependent on steroid receptors.

Description

A class of CYP11A1 inhibitor compounds and their preparation methods and uses

[0001] This application claims the priority benefit of Chinese Patent Application No. 202310060807.3, filed with the China Intellectual Property Office on January 17, 2023, entitled “A Class of CYP11A1 Inhibitor Compounds and Their Preparation Methods and Uses”, the priority benefit of Chinese Patent Application No. 202310019758.9, filed with the China Intellectual Property Office on January 6, 2023, entitled “A Class of CYP11A1 Inhibitor Compounds and Their Preparation Methods and Uses”, and the priority benefit of Chinese Patent Application No. 202310670257.7, filed with the China Intellectual Property Office on June 7, 2023, entitled “A Class of CYP11A1 Inhibitor Compounds and Their Preparation Methods and Uses”, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to the field of drug synthesis, and in particular to a class of CYP11A1 (cytochrome P450 monooxygenase 11A1) inhibitor compounds, as well as preparation methods and uses of the compounds, and pharmaceutical compositions containing the compounds. The compounds can be used to treat steroid hormone-dependent diseases. Background Art

[0003] Prostate cancer is a common malignant tumor of the genitourinary system in elderly men. Its incidence and mortality rate rank second and fifth among male malignant tumors worldwide, respectively. It ranks first and third, respectively, among European and American men, and sixth and seventh, respectively, among Chinese men. In recent years, with the aging of China's population and other factors, the incidence and mortality of prostate cancer have shown a significant upward trend, increasing the burden of the disease. According to GLOBOCAN 2020 data, there were approximately 115,000 new cases of prostate cancer in my country in 2020, accounting for 4.7% of all malignant tumors in men. In 2019, new cases of prostate cancer in the United States accounted for 20% of all new cancer cases in men that year.

[0004] For patients with stage I-III prostate cancer, current standard treatments include surgery or radiotherapy. Treatment outcomes for early-stage prostate cancer (stage I / II) are relatively good, with a 90% five-year progression-free survival rate. However, the cure rate for advanced prostate cancer is much lower. Currently, the five-year survival rate for advanced prostate cancer is only 30%.

[0005] The binding of steroid hormones to their cognate receptors regulates the growth of most prostate and breast cancers. For patients with stage IV or high-risk prostate cancer, androgen ablation (surgical ablation) or chemical castration can effectively control disease progression. First-generation anti-androgen therapies, such as flutamide and bicalutamide, are used to treat prostate cancer at this stage.

[0006] Most prostate cancer patients eventually develop castration-resistant prostate cancer (CRPC). Castration therapy reduces plasma testosterone levels, but the disease still progresses. This disease is characterized by high expression of the androgen receptor (AR). Even trace amounts of androgens in the body can activate AR signaling, leading to persistent activation of the AR pathway.

[0007] Currently, there are limited treatment options for CRPC. Abiraterone and enzalutamide are new therapies developed to address the persistent activation of androgen receptors in CRPC. They treat advanced CRPC by further inhibiting androgen synthesis or blocking the binding of trace amounts of androgens in the body to receptors.

[0008] However, a significant proportion of prostate cancer patients are insensitive to abiraterone or enzalutamide. Furthermore, most patients who initially respond develop new resistance after 1-2 years of abiraterone or enzalutamide use. Furthermore, the majority of abiraterone- or enzalutamide-resistant tumors continue to have high AR expression and persistent activation.

[0009] Adrenal and prostate cancers can synthesize and convert pregnenolone, progesterone, dehydroepiandrosterone, and their derivatives into more active androgens that bind to and activate the AR. Elevated levels of pregnenolone in patients treated with abiraterone are considered a major mechanism driving drug resistance, particularly in tumors harboring point mutations in the androgen receptor. All steroid hormones in the body are converted from a single precursor, cholesterol, to pregnenolone. This reaction, catalyzed by cytochrome P450scc (also known as cholesterol side-chain cleavage enzyme or cytochrome P450 monooxygenase 11A1, CYP11A1), is the first sequential monooxygenation reaction and the rate-limiting step in steroidogenesis. It completes the C-C cleavage of 20R,22R-dihydroxycholesterol (20R,22R-DiOHCH), converting cholesterol to pregnenolone. Studies have demonstrated that inhibiting CYP11A1 can rapidly reduce blood levels of steroid hormones to undetectable levels. Simultaneous supplementation with glucocorticoids and mineralocorticoids can effectively mitigate the effects of steroid deficiency on normal physiological function.

[0010] CYP11A1 belongs to the steroid CYP gene family. CYP11A1 is overexpressed in several types of cancer and is associated with drug resistance. Inhibiting the CYP11A1 enzyme would inhibit the synthesis of all steroid hormones, including estrogen and progesterone, which promote breast cancer progression, and androgen, which promotes prostate cancer progression. This could fully inhibit the progression of steroid hormone-dependent tumors, making it a promising therapeutic target.

[0011] Summary of the Invention

[0012] According to one aspect of the present invention, an object of the present invention is to provide a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts:

[0013] R1 is selected from hydrogen atom, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 aryl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 Aryl, four to eight-membered heterocyclyl and five to eight-membered heteroaryl are optionally substituted by one or more R a Substituted by a substituent,

[0014] Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 1 to 3 substituents of the alkoxy group;

[0015] R2 is selected from hydrogen atom, halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14aryl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 Aryl, four to eight-membered heterocyclyl and five to eight-membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent,

[0016] Each R b The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 1 to 3 substituents of the alkoxy group;

[0017] R3 is selected from C 1-7 Alkylcarbonyl, C 2-7 Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, sulfonic acid, aminosulfonyl, a three- to eight-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-7 Alkyl S(O)2-, C 2-7 Alkenyl S(O)2-, C 2-7 Alkynyl S(O)2-, C 1-7 Alkoxy S(O)2-, C 3-7 Cycloalkyl S(O)2-, three to eight-membered heterocycloalkyl S(O)2- containing 1 to 3 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-7 Alkylcarbonyl, C 2-7Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, three to eight-membered heterocycloalkylcarbonyl, C 1-7 Alkyl S(O)2-, C 2-7 Alkenyl S(O)2-, C 2-7 Alkynyl S(O)2-, C 1-7 Alkoxy S(O)2-, C 3-7 Cycloalkyl S (O) 2-, three to eight membered heterocycloalkyl S (O) 2- optionally substituted by one or more R e substituted by a substituent;

[0018] R c and R d are each independently selected from hydrogen, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d Form a three- to six-membered heterocyclic ring with the attached nitrogen atom;

[0019] Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 The alkoxy group is substituted with 1 to 3 substituents.

[0020] n1 is an integer of 0, 1, 2, 3 or 4.

[0021] n2 is an integer of 1, 2, 3 or 4.

[0022] Preferably, R1 is selected from hydrogen atom, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by 1 to 3 R a Substituted by a substituent,

[0023] Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

[0024] Preferably, R2 is selected from hydrogen atom, halogen atom, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent,

[0025] Each R b The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

[0026] Preferably, R3 is selected from C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6Cycloalkylcarbonyl, sulfonic acid, aminosulfonyl, a three- to six-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-4 Alkyl S(O)2-, C 2-4 Alkenyl S(O)2-, C 2-4 Alkynyl S(O)2-, C 1-4 Alkoxy S(O)2-, C 3-6 Cycloalkyl S(O)2-, three to six membered heterocycloalkyl S(O)2- containing 1 to 3 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, three to six membered heterocycloalkylcarbonyl, C 1-4 Alkyl S(O)2-, C 2-4 Alkenyl S(O)2-, C 2-4 Alkynyl S(O)2-, C 1-4 Alkoxy S(O)2-, C 3-6 Cycloalkyl S (O) 2-, three to six membered heterocycloalkyl S (O) 2- optionally substituted by 1 to 3 R e substituted by a substituent;

[0027] R c and R d are each independently selected from hydrogen, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d Form a three- to six-membered heterocyclic ring with the attached nitrogen atom;

[0028] Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

[0029] Preferably, R1 is selected from hydrogen atom, C 1-3 Alkyl, C 3-6Cycloalkyl, four to six membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, five to six membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by 1 or 2 R a Substituted by a substituent,

[0030] Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0031] R2 is selected from hydrogen atom, halogen atom, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent,

[0032] Each R b The same as or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl;

[0033] R3 is selected from C 1-3 Alkylcarbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, sulfonic acid, aminosulfonyl, a three- to six-membered heterocycloalkylcarbonyl containing 1 or 2 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-3 Alkyl S(O)2-, C2-3 Alkenyl S(O)2-, C 2-3 Alkynyl S(O)2-, C 1-3 Alkoxy S(O)2-, C 3-6 Cycloalkyl S(O)2-, three to six membered heterocycloalkyl S(O)2- containing 1 or 2 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-3 Alkylcarbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, three to six membered heterocycloalkylcarbonyl, C 1-3 Alkyl S(O)2-, C 2-3 Alkenyl S(O)2-, C 2-3 Alkynyl S(O)2-, C 1-3 Alkoxy S(O)2-, C 3-6 Cycloalkyl S (O) 2-, three to six membered heterocycloalkyl S (O) 2- optionally substituted by 1 or 2 R e substituted by a substituent;

[0034] R c and R d are each independently selected from hydrogen, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d Form a three- to six-membered heterocyclic ring with the attached nitrogen atom;

[0035] Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl.

[0036] Preferably, R1 is selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl.

[0037] Preferably, R2 is selected from a hydrogen atom, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, pentachloroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monochloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, hexachloropropyl, perchloropropyl.

[0038] Preferably, R3 is selected from hydrogen atom, methyl-S(O)2-, ethyl-S(O)2-, n-propyl-S(O)2-, isopropyl-S(O)2-, cyclopropyl-S(O)2-, oxetanyl-S(O)2-, cyclobutyl-S(O)2-, oxetanyl-S(O)2-, methoxy-S(O)2-, ethoxy-S(O)2-, n-propoxy-S(O)2-, isopropoxy-S(O)2-, cyclopropyloxy-S(O)2-, oxetanyl-S(O)2-, cyclobutyloxy-S(O)2-, oxetanyl-S(O)2-, N,N-dimethyl ... Methylamino-S(O)2-, trifluoromethyl-S(O)2-, amino-S(O)2-, SO3H-, pyrroline-1-S(O)2-, piperidine-1-S(O)2-, morpholine-1-S(O)2-, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, oxetanylcarbonyl, cyclobutylcarbonyl, oxetanylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropyloxycarbonyl, oxetanyloxycarbonyl, cyclobutyloxycarbonyl, oxetanyloxycarbonyl, N,N-dimethylaminocarbonyl, trifluoromethylcarbonyl,

[0039] Preferably, n1 is 1.

[0040] Preferably, n2 is 1.

[0041] Preferably, the compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts is one of the following compounds:

[0042] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, the method comprising the steps of:

[0043] Step 1) A commercial compound (Ia) is reacted with a halogenated compound R1X through a substitution addition reaction to obtain a compound represented by the general formula (Ib);

[0044] Step 2) Compound represented by general formula (Ib) and piperidine compound having hydroxyalkyl substituent After the substitution reaction, a compound represented by general formula (Ic) is obtained;

[0045] Step 3) reducing the cyano group in the compound represented by general formula (Ic) to obtain a compound represented by general formula (Id) having a corresponding amino group;

[0046] Step 4) The compound represented by the general formula (Id) and the dibenzyl chloride compound containing the substituent R2 undergo a cyclization reaction to obtain the compound represented by the general formula (Ie);

[0047] Step 5) removing the amino protecting group (PG) from the compound represented by the general formula (Ie) to obtain the compound represented by the general formula (If);

[0048] Step 6) reacting the compound represented by the general formula (If) with R3Cl or R3OR3, or NH2SO2NH2 to obtain the compound represented by the general formula (I);

[0049] in:

[0050] PG is an amino protecting group selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc).

[0051] The substituents R1, R2, R3, n1 and n2 are as defined in the general formula (I).

[0052] According to another aspect of the present invention, the present invention provides use of a compound represented by general formula (I), a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof as a CYP11A1 inhibitor.

[0053] According to another aspect of the present invention, the present invention provides the use of a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts in the preparation of a drug for treating steroid hormone-dependent diseases.

[0054] Preferably, the steroid hormone-dependent disease is cancer.

[0055] According to another aspect of the present invention, the present invention provides the use of a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts in the preparation of a drug for treating steroid receptor-dependent diseases such as prostate cancer or breast cancer.

[0056] According to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts as an active ingredient, and pharmaceutically acceptable excipients.

[0057] According to another aspect of the present invention, the present invention provides a kit for treating prostate cancer or breast cancer, comprising:

[0058] According to the compound represented by general formula (I) of the present invention, its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt, or according to the pharmaceutical composition of the present invention comprising the compound represented by general formula (I), its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt as an active ingredient; and instructions for using the compound or the pharmaceutical composition.

[0059] The kits described herein can include a single dose or multiple doses of a compound or pharmaceutical composition. The kits can be used in the methods of the present disclosure. In certain embodiments, the kits further include instructions for using the compound or pharmaceutical composition.

[0060] According to another aspect of the present invention, the present invention provides a method for treating prostate cancer, which comprises administering a therapeutically effective amount of a compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention to a prostate cancer patient in need.

[0061] According to another aspect of the present invention, the present invention provides a method for treating breast cancer, comprising administering to a breast cancer patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) according to the present invention, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition according to the present invention.

[0062] According to another aspect of the present invention, the present invention provides a method for administering the compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, wherein the compound can be administered together with at least one selected from glucocorticoids and mineralocorticoids.

[0063] According to another aspect of the present invention, the present invention provides a method for administering the compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, wherein the compound can be administered together with one or more other anticancer drugs, wherein the anticancer drugs are selected from at least one of non-steroidal androgen receptor antagonists, steroid synthesis inhibitors, chemotherapeutic agents, and estrogen receptor antagonists. Beneficial effects

[0064] Compared to the prior art, the compounds of this invention have a novel skeleton and unexpectedly exhibit inhibitory effects on the biosynthesis of pregnenolone and testosterone. Because pregnenolone is synthesized by CYP11A1, the compounds exhibit a strong inhibitory effect on CYP11A. Clinically, they can be used to treat steroid receptor-dependent diseases, particularly steroid receptor-dependent cancers such as prostate cancer and breast cancer. DETAILED DESCRIPTION

[0065] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0066] As used herein, the terms "comprise," "include," "have," "contain," or any similar terms are open-ended transitional phrases that are intended to encompass non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements not expressly listed but generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprise," "include," "have," and "contain" should be interpreted as specifically disclosing and encompassing closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of."

[0067] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, a description of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0068] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0069] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0070] In this document, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this fully describes the claim that X is X1 and the claim that X is X1 and / or X2. Furthermore, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this fully describes the claim that X is X1, X2, or X3, and Y is Y1, Y2, or Y3.

[0071] definition

[0072] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as specific functional moieties and reactivities are described in the following books: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, New York, 2001. th Edition, John Wiley & Sons, Inc., New York, 2001); Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987. rd Edition, Cambridge University Press, Cambridge, 1987). It is not intended that the present invention be limited in any manner by the exemplary lists of substituents described herein.

[0073] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0074] When a range of values ​​is listed, it is intended to encompass every value and sub-range within that range. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 .

[0075] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 7 carbon atoms ("C 1-7In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7) and the like. Unless otherwise specified, each example of alkyl is independently unsubstituted or substituted with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is unsubstituted C 1-6 In certain embodiments, the alkyl group is a substituted C 1-6 Alkyl groups, such as -CF3.

[0076] "Alkoxy" refers to a monovalent C1-6 alkyl group, wherein the alkyl portion has the specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 16 carbon atoms ("C1-6 alkoxy"), and include, for example, methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents. In certain embodiments, alkoxy is unsubstituted C1-6 alkoxy. 1-6 In certain embodiments, alkoxy is substituted C 1-6 Alkoxy.

[0077] "Alkenyl" refers to a straight or branched chain hydrocarbon radical having 2 to 7 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C 2-7 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 In some embodiments, the C=C double bond in an alkenyl group may be an (E)- or (Z)-double bond.

[0078] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C 2-7 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl, etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, ie, unsubstituted or substituted with one or more substituents.

[0079] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl”) and a non-aromatic cyclic hydrocarbon group having zero heteroatoms. Exemplary C 3-6 Cycloalkyl includes but is not limited to cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) etc. As shown in the aforementioned examples, in certain embodiments, cycloalkyl is a monocycle ("monocyclic cycloalkyl") or contains a fused ring, a bridged ring or a spirocyclic ring system, such as a bicyclic ring system ("bicyclic cycloalkyl") and can be saturated or can be partially unsaturated. "Cycloalkyl" also includes a ring system in which the point of attachment of the cycloalkyl as defined above to one or more aryl or heteroaryl groups is fused to the carbocyclic ring, and in this case, the carbon number continues to refer to the carbon number in the carbocyclic ring system. Unless otherwise indicated, each example of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0080] "Heterocycloalkyl" refers to a group of a four to eight-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("four to eight-membered heterocyclyl"). In a heterocyclyl containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. Heterocycloalkyl may be a monocyclic ring ("monocyclic heterocycloalkyl") or a fused ring, bridged ring or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocycloalkyl"), and may be saturated or partially unsaturated. The heterocycloalkyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes a ring system in which the point of attachment of a heterocycle as defined above to one or more carbocyclyl groups is fused to a carbocyclyl or heterocycle, or a ring system in which the point of attachment of a heterocycle as defined above to one or more aryl or heteroaryl groups is fused to a heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocycle system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, ie, unsubstituted or substituted with one or more substituents.

[0081] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 5-membered heterocycloalkyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocycloalkyl groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0082] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, either monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aromatic ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C 6-14 In certain embodiments, aryl is substituted C 6-14 Aryl.

[0083] "Heteroaryl" refers to a group of a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0084] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0085] Unless otherwise specifically provided, atoms, moieties or groups described herein may be unsubstituted or substituted as far as valence permits.

[0086] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0087] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amino protecting group). Nitrogen protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999. rd

[0014] The amino protecting group may be selected from the group consisting of benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), tert-methoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc).

[0088] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Alkyl)4 - Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0089] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, and vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerization reactions.

[0090] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0091] Stereoisomers that are not mirror images of each other are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by Cahn and Prelog's rules of R- and S-sequencing or by the way the molecule rotates the plane of polarized light, and are denoted as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture."

[0092] The term "inhibit" or "inhibitor" refers to the ability of a compound to reduce, slow, arrest, or prevent the activity of a particular biological process (eg, the activity of the CYP11A1 enzyme in a cell relative to a carrier).

[0093] A "subject" intended for administration is a human (i.e., male or female of any age group, such as a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged, or elderly)). A "patient" is a human subject in need of treatment for a disease.

[0094] The term "biological sample" refers to any sample including tissue samples (e.g., tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (e.g., Pap smears or blood smears) or cell samples obtained by microdissection); samples of whole organisms (e.g., yeast or bacterial samples); or cell parts, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., buccal swabs), or any material containing biomolecules derived from a first biological sample.

[0095] The term "administering" refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0096] The term "treat" refers to reversing, alleviating, delaying the onset of a disease described herein, or inhibiting the development of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, for example, to delay or prevent recurrence.

[0097] An "effective amount" of a compound described herein is an amount sufficient to elicit the desired biological response (i.e., to treat a condition). As will be appreciated by one of ordinary skill in the art, the effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound described herein in a single dose. In certain embodiments, the effective amount is the combined amount of the compounds described herein in multiple doses.

[0098] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of the therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating the condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0099] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally speaking, such preparation methods include combining the compound described herein (i.e., the "active ingredient") with a carrier or excipient, and / or contacting one or more other auxiliary agents, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single- or multi-dose units.

[0100] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the subject, size, and / or condition of the subject to be treated, as well as the route by which the composition is to be administered. The composition may contain 0.1% to 100% (w / w) active ingredient.

[0101] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavorings, and fragrances may also be present in the compositions.

[0102] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, fatty acid esters of propylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and spices. In certain embodiments of parenteral administration, the conjugates described herein are mixed with solubilizers (e.g., alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof).

[0103] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example, solutions of 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP and physiological saline solutions. In addition, sterile, fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil that can be used includes synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used for the preparation of injectable preparations.

[0104] In order to prolong the effect of the drug, it is generally desirable to reduce absorption from subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the drug depends on the dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oily vehicle.

[0105] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retardants, such as petrolatum, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate, (h) absorbents, such as kaolin and bentonite, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets or pills, the dosage form may comprise buffering agents.

[0106] The active ingredient can be in the form of microcapsules with one or more of the excipients described above. Tablets, dragees, capsules, pills, and granules in the form of solid dosage forms can be prepared using coatings and shells (such as enteric coatings, release control agent coatings, and other coatings known in the pharmaceutical formulation field). In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Conventionally, such dosage forms can contain other substances in addition to inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, or pills, the dosage form can contain a buffer. They can optionally contain opacifiers and can be compositions with the following properties: they release the active ingredient only, or preferably, in certain parts of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymers and waxes.

[0107] Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to a variety of animals are readily understood, and those skilled in the art can design and / or perform such modifications using routine experimentation.

[0108] The compounds provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it is understood that all daily uses of the compositions described herein will be determined by a physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular subject or organism depends on a number of factors including: the severity of the disease and condition to be treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, health status, sex and diet of the subject; the time of administration, route of administration and excretion rate of the specific active ingredient; the duration of treatment; the combination or consistent drug with the specific active ingredient used; and other factors known in the medical field.

[0109] In addition, the present disclosure also encompasses kits (e.g., pharmaceutical packaging). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a medicine bottle, an ampoule, a bottle, a syringe and / or a subpackage or other suitable container). In some embodiments, the kit provided may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein, disposed in the first container and the second container, is combined to form a unit dosage form.

[0110] The compounds and compositions provided herein can be administered by conventional routes, including intestinal (e.g., oral) administration, parenteral administration, intravenous administration, intramuscular administration, intra-arterial administration, intramedullary administration, intracapsular administration, subcutaneous administration, intraventricular administration, transdermal administration, subcutaneous administration, rectal administration, intravaginal administration, intraperitoneal administration, topical administration (e.g., by powder, ointment, cream and / or droplets). Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration by blood and / or lymphatic supply and / or direct administration to a predetermined site. In general, the most appropriate route of administration will depend on a series of factors, including: the nature of the medicament (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether oral administration is permitted).

[0111] The exact amount of compound required to achieve an effective dose will vary according to the subject, depending on, for example, the race, age and general condition of the subject, the severity of the side effect or disease, the confirmation of the specific compound, the mode of administration, etc. An effective amount can be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue or cell, any two doses of the multiple doses comprise different or substantially identical compounds as described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue or cell, the frequency of multiple doses administered to the subject or multiple doses applied to tissue or cells is three doses per day, two doses per day, one dose per day, one dose every two days, one dose every three days, or one dose per week. In certain embodiments, the frequency of multiple doses administered to a subject or multiple doses applied to tissue or cells is one dose per day. In certain embodiments, the frequency of multiple doses administered to a subject or multiple doses applied to tissue or cells is two doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and the last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the life of the subject, biological sample, tissue, or cell. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and the last dose of the multiple doses is the life of the subject, biological sample, tissue, or cell. In certain embodiments, the doses described herein (e.g., any dose in a single dose or multiple doses) independently comprise 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g of a compound described herein. In certain embodiments, the doses described herein independently comprise 3 mg to 10 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 10 mg to 30 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 30 mg to 100 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 100 mg to 300 mg of a compound described herein. In certain embodiments, the doses described herein independently comprise 300 mg to 1000 mg of a compound described herein.

[0112] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.

[0113] The following examples are merely examples of embodiments of the present invention and do not constitute any limitation thereto. Those skilled in the art will appreciate that modifications without departing from the spirit and scope of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0114] 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0115] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0116] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0117] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0118] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0119] CD3OD: deuterated methanol.

[0120] CDCl3: deuterated chloroform.

[0121] DMSO-d6: deuterated dimethyl sulfoxide.

[0122] D2O: heavy water.

[0123] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0124] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0125] The compound is purified using a C18 reverse phase column for preparative or semi-preparative purification, a silica gel column chromatography eluent system, and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and water system; C: petroleum ether and ethyl acetate system; wherein the volume ratio of the solvent varies according to the polarity of the compound and can also be adjusted by adding a small amount of acidic or alkaline reagent, such as trifluoroacetic acid, acetic acid, or triethylamine.

[0126] Synthesis of intermediates

[0127] Synthesis of 4-fluoro-1,2-dichlorobenzyl (Intermediate 1):

[0128] Step 1: Add BH3·THF (6.52 mL, 6.52 mmol, 1 M) to a solution of 4-fluorophthalic acid (400 mg, 2.17 mmol) in THF (14.5 mL) at 0°C and stir at 25°C for 2 hr. The reaction mixture was quenched by adding MeOH (30 mL), dried by spin drying, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to afford 4-fluoro-1,2-benzenedimethanol (404.00 mg, crude) as a colorless oil.

[0129] LC-MS[M-17] + =139.2

[0130] Step 2: Dissolve 4-fluoro-1,2-benzenedimethanol (236 mg, 1.51 mmol), SOCl2 (899.01 mg, 7.56 mmol), and DMF (220.94 mg, 3.02 mmol) in toluene (15 mL) and stir at 60°C for 2 hours. The reaction mixture was spin-dried and added with saturated sodium chloride solution (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, and purified by silica gel column chromatography (PE:THF = 20:1) to afford Intermediate 1 (167.00 mg, 57.14% yield) as a colorless liquid.

[0131] 1H-NMR (400MHz, CDCl3) δ7.39-7.35 (m, 1H), 7.14 (dd, J = 8.8, 2.4H Z ,1H),7.06-7.01(m,1H),4.71(s,4H).

[0132] Synthesis of 4-trifluoromethyl 1,2-dichlorobenzyl (Intermediate 2):

[0133] Step 1: Dissolve 4-trifluoromethylphthalic acid (770 mg, 3.29 mol) in THF (33 mL), add BH3·THF (1 M, 9.87 mL) at 0°C, stir at 20°C for 3 hours, then add MeOH (23 mL) dropwise at 0°C to quench the mixture. After concentration, purify by silica gel column chromatography (DCM:MeOH=20:1) to give 4-trifluoromethyl 1,2-benzenedimethanol (820.00 mg, crude) as a colorless oil.

[0134] LC-MS[M-17] + =189.1

[0135] Step 2: Dissolve 4-trifluoromethyl-1,2-benzenedimethanol (820 mg, 3.93 mol) and DMF (574.36 mg, 7.86 mmol, 608.44 uL) in toluene (36 mL). Stir at 60°C under nitrogen for 2 hours. After concentration, the product was purified by silica gel column chromatography (PE:THF = 20:1) to afford Intermediate 2 (410.00 mg, 39.8% yield) as a colorless liquid.

[0136] 1 H NMR (400MHz, CDCl3) δ7.61 (s, 1H), 7.60 (dd, J = 8.0, 1.2Hz, 1H), 7.53 (d, J = 8.0Hz, 1H), 4.76-4.74 (m, 4H).

[0137] Example 1: Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one:

[0138] Step 1: Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (1b):

[0139] Compound 5-fluoro-6-hydroxypyridine 1a (500 mg, 3.62 mmol) was dissolved in DMF (10 mL), followed by the addition of MeI (591.24 mg, 4.16 mmol) and KCO (999.28 mg, 7.24 mmol). The mixture was stirred at 25°C for 1 hour. Saturated NaCl (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and purified by silica gel column chromatography (PE:THF = 3:1) to afford compound 1b (312.00 mg, 56.65% yield) as a white solid.

[0140] LC-MS[M+1] + =153.1

[0141] 1 H-NMR(400MHz,DMSO)δ7.53(dd,J=9.6,8.0H Z ,1H),7.18(dd,J=7.6,4.8H Z ,1H),3.60(s,3H).

[0142] Step 2: Synthesis of tert-butyl 4-(((6-cyano-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate 1d:

[0143] At 0°C, compound tert-butyl-4-(hydroxymethyl)piperidin-1-carbonate 1c (2.21 g, 10.25 mmol) was dissolved in THF (20 mL). NaH (656.24 mg, 16.41 mmol, 60% purity) was slowly added, and the mixture was stirred under nitrogen for 30 minutes. Compound 1b (312 mg, 2.05 mmol) was added to the reaction mixture, which was then heated to 25°C and stirred under nitrogen for 1 hour. The reaction mixture was quenched by pouring into ice water and extracted with ethyl acetate (50 mL × 3) and saturated NaCl (30 mL × 3). The organic phases were combined, dried, and purified by silica gel column chromatography [PE (0.1% NH4OH):THF = 0:1] to afford compound 1d (602.00 mg, 80.01% yield) as a white solid.

[0144] LC-MS[M+1] + =348.1

[0145] Step 3: Synthesis of tert-butyl 4-(((6-(aminomethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate 1e:

[0146] Compound 1d (257 mg, 0.74 mmol) and Raney nickel (43.42 mg, 0.74 mmol) were dissolved in a mixture of methanol (10 mL), tetrahydrofuran (10 mL), and aqueous ammonia (2 mL). The mixture was stirred at 25°C under hydrogen for 2 hours. The reaction solution was filtered with methanol (50 mL x 3), and the organic phases were combined, dried, and spin-dried to afford compound 1e (258.00 mg, crude) as a yellow oil.

[0147] LC-MS[M+1] + =352.2

[0148] Step 4: Synthesis of tert-butyl 4-(((6-(isoindolin-2-ylmethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate 1f:

[0149] Compound 1e (100 mg, 284.54 μmol) was dissolved in toluene (3 mL), followed by the addition of o-benzyl chloride (74.72 mg, 0.43 mmol) and DIEA (110.12 mg, 0.85 mmol). The mixture was stirred at 100°C for 2 hours. The reaction mixture was dried by rotary evaporation and extracted with ethyl acetate (30 mL x 3) and H₂O (10 mL x 3). The organic phases were combined, dried, and then purified by silica gel column chromatography (PE:THF = 0:1) to afford compound 1f (49.00 mg, 32.48% yield) as a yellow oil.

[0150] LC-MS[M+1] + =454.4

[0151] Step 5: Synthesis of 1 g of 6-(isoindolin-2-ylmethyl)-1-methyl-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one:

[0152] Compound 1e (46 mg, 101.42 μmol) was dissolved in HCl / dioxane (4 M, 20 mL) and stirred at 25°C for 30 minutes. The reaction mixture was directly spin-dried to afford compound 1g (75.00 mg, crude) as a gray solid. The product was used directly in the next reaction without purification.

[0153] Step 6: Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 1):

[0154] Compound 1g (75 mg, 192.35 μmol) and DIEA (74.44 mg, 577.04 μmol) were dissolved in dichloromethane (2 mL). MsCl (26.44 mg, 230.82 μmol) was slowly added at 0°C. The mixture was stirred for 30 minutes while maintaining the temperature at 0°C. The reaction solution was directly concentrated and purified using Prep.HPLC [ACN:H2O (0.1% NH4HCO3)] to afford compound 1 (5.84 mg, 7.04% yield) as a white solid. (Free base)

[0155] LC-MS[M+1] + =432.1

[0156] 1 H-NMR(400MHz,MeOD)δ7.20-7.16(m,4H),6.89(d,J=8.0Hz,1H),6.38(d,J=7.6H Z ,1H),3.91(s,4H),3.87(s,2H),3.84(d,J=6.0Hz,2H),3.78-3.74(m,5H),2 .83-2.75(m,5H),2.06-2.04(m,1H),2.02-1.97(m,2H),1.48-1.38(m,2H).

[0157] Example 2: Synthesis of 6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one

[0158] Step 1: Synthesis of tert-butyl 4-(((6-cyano-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2b):

[0159] Compound 1a (300 mg, 2.17 mmol) was dissolved in THF (22 mL). NaH (695.15 mg, 17.38 mmol) was added at 0°C and stirred for 30 minutes. 1c was then added to the reaction mixture, the reaction was allowed to warm to room temperature, and stirring was continued for 1 hour. The reaction mixture was quenched with saturated NaHCO₃ (20 mL). The mixture was extracted with EA (20 mL x 3), and the organic phases were combined. Purification by silica gel column chromatography (PE:THF = 3.3:1) afforded the desired compound 2b (153 mg, yield: 15.00%) as a light yellow oil.

[0160] LC-MS[M-56] + =278.1

[0161] Step 2: Synthesis of tert-butyl 4-(((6-(aminomethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2c):

[0162] Compound 2b (153 mg, 2.18 mmol) was dissolved in MeOH (15 mL), and Raney nickel (26.93 mg, 458.93 μmol) was added. After stirring for 1 hour at 25°C under a hydrogen atmosphere, the mixture was filtered and the filtrate was directly spin-dried to obtain crude compound 2c (153.00 mg, crude product) as a brown oil. This product was used directly in the next reaction without purification.

[0163] LC-MS[M+1] + =338.3

[0164] Step 3: Synthesis of tert-butyl 4-(((6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2d):

[0165] Compound 2c (153 mg, 136.04 μmol), o-dibenzyl chloride (19.05 mg, 108.83 μmol), and DIEA (52.74 mg, 408.11 μmol) were dissolved in toluene (2 mL) and stirred at 100°C for 16 hours. The reaction solution was directly spin-dried and purified by Prep-TLC [PE (0.1% NH4OH):THF = 1:4] to afford compound 2d (50.00 mg, 26.45% yield) as a brown solid.

[0166] LC-MS[M+1] + =440.3

[0167] Step 4: Synthesis of 6-(isoindolin-2-ylmethyl)-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one (2e):

[0168] Compound 2d (50 mg, 113.75 μmol) was dissolved in HCl / dioxane (4 mL) and stirred at 25°C for 30 minutes. The reaction mixture was removed under reduced pressure to yield compound 2e (50.00 mg, crude) as a brown solid. This product was used directly in the next reaction without purification.

[0169] LC-MS[M+1] + =340.2

[0170] Step 5: Synthesis of 6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (2)

[0171] Compound 2e (50 mg, 146.44 μmol) and DIEA (56.78 mg, 439.31 μmol) were dissolved in DCM (4 mL). MsCl (20.13 mg, 175.72 μmol) was slowly added at 0°C. The mixture was stirred for 30 minutes at 0°C. The reaction mixture was removed under reduced pressure to yield a brown oil. The mixture was dissolved in THF (2.2 mL) and H₂O (1.4 mL), followed by the addition of LiOH (4.28 mg, 178.77 μmol). The mixture was stirred at 25°C for 1 hour. The reaction mixture was purified by Prep.HPLC [ACN:H₂O (0.1% NH₄HCO₃)] to yield compound 2 (10.93 mg, purity: 98.07%, yield: 43.58%) as a white solid.

[0172] LC-MS[M-1] - =416.1

[0173] 1 HNMR(400MHz,DMSO-d6)δ11.43(s,1H),7.20-7.13(m,4H),6.75(d,J=8.0H Z ,1H),6.04(d,J=8.0H Z ,1H),3.81(s,4H),3.72(d,J=6.0H Z ,2H),3.58-3.54(m,4H),2.82(s,3H),2.72-2.67(m,2H),1.84-1.81(m,3H),1.32-1.24(m,2H).

[0174] Example 3, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 3):

[0175] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing methanesulfonyl chloride in step 6 with cyclopropylsulfonyl chloride.

[0176] LC-MS[M+1] + =458.1

[0177] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),6.79(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z,1H),3.86(s,4H),3.80-3.77(m,4H),3.66-3.62(m,2H),3.56(s,3H),2.89-2.82(m,2 H),2.53-2.50(m,1H),1.96-1.84(m,3H),1.37-1.27(m,2H),1.01(m,2H),0.90(m,2H).

[0178] Example 4, Synthesis of 4-(((6-(isoindolin-2-ylmethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-nitrogen, nitrogen-dimethylpiperidine-1-sulfonamide (Compound 4):

[0179] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing the methanesulfonyl chloride in step 6 with dimethylaminosulfonyl chloride.

[0180] LC-MS[M+1] + =460.9

[0181] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),6.78(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z ,1H),3.86(s,4H),3.80(s,2H),3.76(d,J=6.4Hz,2H),3.60(d,J=12.4Hz,2H),3.55 (s,3H),2.89-2.82(m,2H),2.75(s,6H),1.80(m,3H),1.32-1.22(m,2H).

[0182] Example 5, Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 5):

[0183] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1).

[0184] LC-MS[M+1] + =450.1

[0185] 1HNMR(400MHz,DMSO-d6)δ7.26-7.2(m,1H),7.10-7.07(m,1H),7.02-6.99(m,1H),6.79(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z ,1H),3.85-3.76(m,8H),3.60-3.57(m,2H),3.55(s,3H),2.86(s,3H),2.77-2.70(m,2H),1.86(d,J=10Hz,3H),1.37-1.28(m,2H).

[0186] Example 6, Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(oxetane-3-ylmethylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 6):

[0187] Step 1: 6-1 (1 g, 4.38 mmol) and potassium thioacetate 6-2 (1.00 g, 8.76 mmol) were dissolved in DMF (20 mL), stirred at 100 ° C for 4 hours, concentrated to remove DMF, added water (20 mL) and ethyl acetate (30 mL), separated, the aqueous phase was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, dried and concentrated, and purified by silica gel column chromatography (PE:THF=92:8) to obtain 6-3 (167.00 mg, yield: 25.96%) as a colorless oil.

[0188] LC-MS[M-56] + =132.9

[0189] Step 2: 6-3 (160 mg, 1.21 mmol) and aqueous hydrochloric acid solution (2 M, 151.31 μL) were dissolved in acetonitrile (4.85 mL). NCS (646.55 mg, 4.84 mmol) was added in batches at 0°C. After stirring at 0°C for 1 hr, the mixture was concentrated and purified by silica gel column chromatography (PE:THF=85:15) to obtain 6-4 (130.00 mg, yield: 61.73%) as a colorless oil.

[0190] 1 HNMR(400MHz, CDCl3)δ5.29-4.93(m,5H).

[0191] Step 3: Dissolve 1g (30mg, 42.44μmol) and DIEA (16.45mg, 127.31μmol) in DCM (2mL). Add 6-4 (6.65mg, 42.44μmol) at 0°C. Stir at 0°C for 30min, concentrate, and purify by Prep.HPLC [ACN:H2O (0.1% NH4HCO3)] to obtain 6 (8.28mg, yield: 40.84%, purity: 99.12%) as a white solid.

[0192] LC-MS[M+1] + =474.3

[0193] 1 HNMR(400MHz,DMSO-d6)δ7.20-7.14(m,4H),6.75(d,J=7.6H Z ,1H),6.17(d,J=7.6H Z ,1H),4.81-4.66(m,5H),3.82(s,4H),3.76(s,2H),3.73-3.72(m,2H),3.61-3.5 7(m,2H),3.52(s,3H),2.79-2.73(m,2H),1.88-1.76(m,3H),1.24-1.16(m,2H).

[0194] Example 7, Synthesis of 3-((1-acetylpiperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 7):

[0195] The above compound can be obtained by a synthetic route similar to that of Example 1, except that methanesulfonyl chloride in step 6 is replaced by acetyl chloride.

[0196] LC-MS[M+1] + =396.1

[0197] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),6.78(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z ,1H),4.39(d,J=13.2Hz,1H),3.86-3.74(m,9H),3.55(s,3H),3.08-3.01(m,1H ),2.52-2.49(m,2H),1.99(s,3H),1.83-1.72(m,2H),1.27(m,1H),1.03(m,1H).

[0198] Example 8, Synthesis of 3-((1-acetylpiperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 8):

[0199] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) and methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0200] LC-MS[M+1] + =476.1

[0201] 1 HNMR(400MHz,DMSO-d6)δ7.22-7.20(m,1H),7.10-7.07(m,1H),7.02-6.98(m,1H),6.78(d,J=8.0H Z ,1H),6.20(d,J=7.6H Z ,1H),3.83(d,J=11.6Hz,4H),3.79-3.76(m,4H),3.64(d,J=12Hz,2H),3.55(s,3H),2.89-2.82(m,2 H),2.59-2.54(m,1H),1.90-1.84(m,3H),1.34-1.28(m,2H),1.00-0.96(m,2H),0.93-0.90(m,2H).

[0202] Example 9, Synthesis of Methyl 4-(((6-(isoindolin-2-ylmethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (Compound 9):

[0203] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing methanesulfonyl chloride in step 6 with methyl chloroformate.

[0204] LC-MS[M+1] + =411.6

[0205] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),6.78(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z,1H),4.05(m,2H),3.85(s,4H),3.79(m,2H),3.74(d,J=6.0Hz,2H),3.59(s,3H), 3.55(s,3H),2.82(m,2H),2.00(m,1H),1.75(d,J=15.2Hz,2H),1.21-1.11(m,2H).

[0206] Example 10, Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 10):

[0207] The above compound can be obtained by a synthetic route similar to that of Example 1, except that the methanesulfonyl chloride in step 6 is replaced by trifluoromethanesulfonic anhydride.

[0208] LC-MS[M+1] + =486.1

[0209] 1 HNMR(400MHz,DMSO-d6)δ7.23-7.17(m,4H),6.79(d,J=7.6H Z ,1H),6.21(d,J=7.6H Z ,1H),3.85-3.78(m,10H),3.55(s,3H),3.27-3.21(m,2H),2.07(m,1H),1.91(d,J=12.8Hz,2H),1.37-1.27(m,2H).

[0210] Example 11, Synthesis of 4-(((6-((5-fluoroisoindolin-2-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-nitrogen, nitrogen-dimethylpiperidine-1-sulfonamide (Compound 11):

[0211] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) and methanesulfonyl chloride in step 6 is replaced by dimethylaminosulfonyl chloride.

[0212] LC-MS[M+1] + =479.3

[0213] 1HNMR(400MHz,DMSO-d6)δ7.26-7.22(m,1H),7.09-7.07(m,1H),7.02-6.98(m,1H),6.78(d,J=8.0H Z ,1H),6.20(d,J=7.6H Z ,1H),3.85-3.75(m,8H),3.59(d,J=12.4Hz,2H),3.55(s,3H),2.89-2.82 (m,2H),2.75(s,6H),1.95(m,1H),1.84-1.80(m,2H),1.32-1.22(m,2H).

[0214] Example 12, Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-methyl-3-((1-(oxetane-3-ylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 12):

[0215] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1), and methanesulfonyl chloride in step 6 is replaced by oxetane-3-sulfonyl chloride (6-4).

[0216] LC-MS[M+1] + =492.1

[0217] 1 HNMR(400MHz,DMSO-d6)δ7.26-7.22(m,1H),7.10-7.07(m,1H),7.03-6.98(m,1H),6.77(d,J=8.0H Z ,1H),6.19(d,J=7.6H Z ,1H),4.85-4.82(m,2H),4.78(m,1H),4.72-4.70(m,2H),3.85-3.75(m,8H),3.63(d,J=12Hz, 2H), 3.55 (s, 3H), 2.83-2.76 (m, 2H), 1.91 (m, 1H), 1.82 (d, J = 14.8Hz, 2H), 1.29-1.19 (m, 2H).

[0218] Example 13, Synthesis of 1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 13):

[0219] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2).

[0220] LC-MS[M+1] + =500.1

[0221] 1 HNMR(400MHz,DMSO-d6)δ7.58(s,1H),7.53(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),6.76(d,J=7.6H Z ,1H),6.18(d,J=7.6H Z ,1H),3.90(s,4H),3.79(s,2H),3.74,(d,J=5.6Hz,2H),3.52(m,5H),2.82(s,3H),2.73-2.70(m,2H),1.83(d,J=10Hz,3H),1.33-1.23(m,2H).

[0222] Example 14, Synthesis of 1-(methyl-d3)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 14):

[0223] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, and o-dichlorobenzyl in step 4 is replaced by 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2).

[0224] LC-MS[M+1] + =503.1

[0225] 1 HNMR (400MHz, DMSO-d6) δ7.62(s,1H),7.56(d,J=8.8Hz,1H),7.46(d,J=7.6Hz,1H),6.80(d,J=7.6H Z ,1H),6.21(d,J=7.6H Z ,1H),3.93(s,4H),3.82(s,2H),3.77,(d,J=6.0Hz,2H),3.59(d,J=11.6Hz,2H ), 2.86 (s, 3H), 2.76-2.70 (m, 2H), 1.86 (d, J = 14.8Hz, 3H), 1.37-1.27 (m, 2H).

[0226] Example 15, Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-(methyl-d3)-3-((1-(oxetane-3-ylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 15):

[0227] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1), and methanesulfonyl chloride in step 6 is replaced by oxetane-3-sulfonyl chloride (6-4).

[0228] LC-MS[M+1] + =495.1

[0229] 1 HNMR(400MHz,DMSO-d6)δ7.22-7.19(m,1H),7.06-7.03(m,1H),6.99-6.94(m,1H),6.74(d,J=7.6H Z ,1H),6.16(d,J=7.6H Z ,1H),4.81-4.66(m,5H),3.81-3.71(m,8H),3.59(d,J=12.0Hz,2H),2.79-2.73(m,2H),1.88-1.76(m,3H),1.26-1.17(m,2H).

[0230] Example 16, Synthesis of 6-(isoindolin-2-ylmethyl)-1-(methyl-d3)-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 16):

[0231] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, and methanesulfonyl chloride in step 6 is replaced by trifluoromethanesulfonic anhydride.

[0232] LC-MS[M+1] + =489.1

[0233] 1 HNMR(400MHz,DMSO-d6)δ7.23-7.17(m,4H),6.79(d,J=8.0H Z ,1H),6.21(d,J=7.6H Z,1H),3.85-3.78(m,10H),3.23-3.20(m,2H),2.10(m,1H),1.91(d,J=13.2Hz,2H),1.37-1.27(m,2H).

[0234] Example 17, Synthesis of 6-(isoindolin-2-ylmethyl)-1-(methyl-d3)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 17):

[0235] Similar to the synthetic route of Example 1, the above compound can be obtained by replacing iodomethane in step 1 with deuterated iodomethane.

[0236] LC-MS[M+1] + =435.3

[0237] 1 HNMR(400MHz,DMSO-d6)δ7.20-7.14(m,4H),6.76(d,J=8.0H Z ,1H),6.17(d,J=7.6H Z ,1H),3.82(s,4H),3.76-3.73(m,4H),3.55(d,J=11.6Hz,2H),2.82(s,3H),2.73-2.67(m,2H),1.83(d,J=9.6Hz,3H),1.32-1.24(m,2H).

[0238] Example 18, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-(methyl-d3)pyridin-2(1H)-one (Compound 18):

[0239] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, and methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0240] LC-MS[M+1] + =460.9

[0241] 1 HNMR(400MHz,DMSO-d6)δ7.20-7.14(m,4H),6.76(d,J=7.6H Z ,1H),6.17(d,J=7.6H Z,1H),3.82(s,4H),3.76-3.73(m,4H),3.61(d,J=12.0Hz,2H),2.85-2.79(m,2H),2.57-2 .50(m,1H),1.89-1.80(m,3H),1.33-1.23(m,2H),0.98-0.96(m,2H),0.90-0.86(m,2H).

[0242] Example 19, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-1-(methyl-d3)-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 19):

[0243] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, o-dichlorobenzyl in step 4 is replaced by 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2), and methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0244] LC-MS[M+1] + =529.2

[0245] 1 HNMR (400MHz, DMSO-d6) δ7.58(s,1H),7.52(d,J=7.6Hz,1H),7.42(d,J=8.0Hz,1H),6.76(d,J=7.6H Z ,1H),6.17(d,J=7.6H Z ,1H),3.89(s,4H),3.78(s,2H),3.74(d,J=6.4Hz,2H),3.63-3.59(m,2H),2.85-2.79 (m,2H),2.57-2.50(m,1H),1.85-1.80(m,3H),1.30-1.20(m,2H),0.98-0.86(m,4H).

[0246] Example 20, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-6-((5-fluoroisoindolin-2-yl)methyl)-1-(methyl-d3)pyridin-2(1H)-one (Compound 20):

[0247] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1), and methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0248] LC-MS[M+1] + =479.3

[0249] 1 HNMR(400MHz,DMSO-d6)δ7.22-7.19(m,1H),7.06-7.04(m,1H),6.99-6.94(m,1H),6.75(d,J=7.6H Z ,1H),6.16(d,J=7.6H Z ,1H),3.81-3.73(m,8H),3.61(d,J=12.0Hz,2H),2.85-2.79(m,2H),2.5 6-2.50(m,1H),1.85-1.79(m,3H),1.30-1.20(m,2H),0.96-0.86(m,4H).

[0250] Example 21, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-methyl)methoxy)-1-methyl-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 21):

[0251] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2), and methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0252] LC-MS[M+1] + =526.2

[0253] 1 HNMR (400MHz, DMSO-d6) δ7.59(s,1H),7.53(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),6.76(d,J=7.6H Z ,1H),6.18(d,J=7.6H Z ,1H),3.90(s,4H),3.79(s,2H),3.74(d,J=6.4Hz,2H),3.61(d,J=12.4Hz,2H),3.51(s,3H),2.85-2.79 (m,2H),2.56-2.50(m,1H),1.87-1.81(m,3H),1.30-1.20(m,2H),0.96-0.93(m,2H),0.90-0.86(m,2H).

[0254] Example 22, Synthesis of N,N-dimethyl-4-(((1-methyl-2-oxo-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-sulfonamide (Compound 22)

[0255] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2), and methanesulfonyl chloride in step 6 is replaced by dimethylaminosulfonyl chloride.

[0256] LC-MS[M+1] + =529.2

[0257] 1 HNMR (400MHz, DMSO-d6) δ7.62(s,1H),7.56(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),6.79(d,J=7.6H Z ,1H),6.21(d,J=7.6H Z ,1H),3.93(s,4H),3.82(s,2H),3.76(d,J=6.4Hz,2H),3.60(d,J=12.4Hz,2H),3.55(s,3H ),2.89-2.83(m,2H),2.75(s,6H),1.95(m,1H),1.82(d,J=13.2Hz,2H),1.33-1.23(m,2H).

[0258] Example 23, Synthesis of 1-methyl-3-((1-(oxetane-3-ylsulfonyl)piperidin-4-yl)methoxy)-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 23):

[0259] The above compound can be obtained by a synthetic route similar to that of Example 1, except that o-dichlorobenzyl in step 4 is replaced by 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2), and methanesulfonyl chloride in step 6 is replaced by oxetane-3-sulfonyl chloride (6-4).

[0260] LC-MS[M+1] + =542.1

[0261] 1 HNMR (400MHz, DMSO-d6) δ7.58(s,1H),7.53(d,J=8.8Hz,1H),7.42(d,J=8.0Hz,1H),6.75(d,J=7.6HZ ,1H),6.18(d,J=7.6H Z ,1H),4.82-4.66(m,5H),3.89(s,4H),3.78(s,2H),3.72(d,J=6.4Hz,2H),3.59(d,J=12.0Hz,2H ), 3.51 (s, 3H), 2.80-2.73 (m, 2H), 1.87-1.85 (m, 1H), 1.77 (d, J = 15.6Hz, 2H), 1.25-1.16 (m, 2H).

[0262] Example 24, Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-(methyl-d3)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 24):

[0263] The above compound can be obtained by a synthetic route similar to that of Example 1, except that iodomethane in step 1 is replaced by deuterated iodomethane, and o-dichlorobenzyl in step 4 is replaced by 4-fluoro-1,2-dichlorobenzyl (Intermediate 1).

[0264] LC-MS[M+1] + =453.1

[0265] 1 HNMR(400MHz,DMSO-d6)δ7.26-7.22(m,1H),7.10-7.07(m,1H),7.02-6.98(m,1H), 6.79(d,J=8.0H Z ,1H),6.20(d,J=7.6H Z ,1H),3.84(d,J=11.6Hz,4H),3.79-3.77(m,4H),3.59(d,J=11.6Hz,2H),2 .86(s,3H),2.77-2.70(m,2H),1.86(d,J=13.2Hz,3H),1.37-1.27(m,2H).

[0266] Example 25, Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 25):

[0267] Step 1: Synthesis of 5-fluoro-1-ethyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (25b):

[0268] Compound 5-fluoro-6-hydroxycyanopyridine 1a (150 mg, 1.09 mmol) and K2CO3 (299.78 mg, 2.17 mmol) were dissolved in DMF (3 mL). After adding iodoethane (203.29 mg, 1.30 mmol), the mixture was stirred at 25°C for 18 hours. After adding saturated NaCl (10 mL), the reaction solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried and evaporated to dryness, and purified by silica gel column chromatography (PE:THF = 3:1) to obtain compound 25b (50.00 mg, 27.71% yield) as a white solid.

[0269] 1 H-NMR (400MHz, DMSO) δ7.08 (t, J=8.0Hz, 1H), 6.74 (dd, J=7.6, 4.4Hz, 1H), 4.33-4.27 (m, 2H), 1.43 (s, 3H).

[0270] Step 2: Synthesis of tert-butyl 4-(((6-cyano-1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (25d):

[0271] At 0 ° C, compound VN2202-022-3 (194.36 mg, 902.79 μmol) was dissolved in anhydrous THF (3 mL), and NaH (60.19 mg, 1.50 mmol, 60% purity) was added. The mixture was stirred at 0 ° C for 30 min. Then, a solution of compound VN2202-022-2 (50 mg, 300.93 μmol) in anhydrous THF (1 mL) was added at 0 ° C. The temperature was raised to 20 ° C and stirred for 1 hr. After quenching with saturated NH4Cl (30 mL), the mixture was extracted three times with EA (30 mL), and the organic phases were combined, dried, concentrated, and purified by SGC (PE:THF = 75:25) to obtain compound VN2202-022-4 (100.00 mg, 82.75% yield) as a colorless oil.

[0272] LC-MS[M-99] + =262.20

[0273] At 0°C, compound tert-butyl-4-(hydroxymethyl)piperidin-1-carbonate 1c (194.36 mg, 902.79 μmol) was dissolved in THF (3 mL). NaH (60.19 mg, 1.50 mmol, 60% purity) was slowly added, and the mixture was stirred under nitrogen for 30 minutes. A solution of compound 25b (50 mg, 300.93 μmol) in anhydrous tetrahydrofuran (1 mL) was added to the reaction system, maintained at 0°C, and the temperature was raised to 25°C. The mixture was stirred under nitrogen for 1 hour. After quenching with saturated NH4Cl (30 mL), the mixture was extracted three times with EA (30 mL). The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography [PE:THF = 75:25] to afford compound 25d (100.00 mg, 82.75% yield) as a colorless oil.

[0274] LC-MS[M-99] + =262.20

[0275] Step 3: Synthesis of tert-butyl 4-(((6-(aminomethyl)-1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (25e):

[0276] Compound 25d (100 mg, 276.68 μmol) was dissolved in methanol (5 mL) and aqueous ammonia (1 mL), and Raney Ni (80 mg, 276.68 μmol) was added. The mixture was stirred at 20°C for 2 hours. After filtration and concentration of the filtrate, compound 25e (113.00 mg, crude) was obtained as a colorless oil.

[0277] LC-MS[M-99] + =366.3

[0278] Step 4: Synthesis of tert-butyl 4-(((1-ethyl-6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (25f):

[0279] Compound 1e (113 mg, 309.19 μmol) was dissolved in toluene (3 mL), followed by the addition of o-benzyl chloride (70.36 mg, 401.95 μmol) and DIEA (153 μL, 927 μmol). The mixture was stirred at 100°C for 2 hours. The reaction solution was concentrated and extracted with ethyl acetate (30 mL × 3) and H2O (10 mL × 3). The organic phases were combined, dried, and concentrated. Purification by silica gel column chromatography (PE:THF = 0:1) afforded compound 25f (90.00 mg, 56.02% yield) as a white solid.

[0280] LC-MS[M+1]+ =468.3

[0281] Step 5: Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one (25 g):

[0282] Compound 25e (90 mg, 192.47 μmol) was dissolved in hydrochloric acid / dioxane (4 M, 3 mL), stirred at 20° C. for 2 hours, and then concentrated to obtain compound 25g (130.00 mg, crude product) as a black solid.

[0283] Step 6: Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 25):

[0284] Compound 25g (20.62 mg, crude product) and diisopropylethylamine (21.75 mg, 168.31 μmol) were dissolved in dichloromethane (1 mL). Methanesulfonyl chloride (6.43 mg, 56.10 μmol) was added dropwise to the system under ice bath conditions. After stirring for 30 minutes, the mixture was concentrated and purified by semi-preparative HPLC [acetonitrile: water (0.1% ammonium bicarbonate)] to give compound 25 (2.64 mg, 9.83% yield) as a light brown solid.

[0285] LC-MS[M+1] + =446.1

[0286] 1 HNMR(400MHz,DMSO-d6)δ7.20-7.14(m,4H),6.74(d,J=7.6H Z ,1H),6.18(d,J=7.6H Z ,1H),4.11(q,J=6.8Hz,2H),3.82(s,4H),3.75-3.72(m,4H),3.56(d,J=11.6Hz,2H),2.82( s,3H),2.73-2.67(m,2H),1.84(d,J=11.2Hz,3H),1.34-1.22(m,2H),1.15(t,J=6.8Hz,3H).

[0287] Example 26, Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-1-ethyl-6-(isoindolin-2-ylmethyl)pyridin-2(1H)-one (Compound 26):

[0288] The above compound can be obtained by a synthetic route similar to that of Example 25, except that methanesulfonyl chloride in step 6 is replaced by cyclopropylsulfonyl chloride.

[0289] LC-MS[M+1] + =472.2

[0290] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),6.77(d,J=7.6H Z ,1H),6.21(d,J=7.6H Z ,1H),4.17(q,J=6.8Hz,2H),3.86(s,4H),3.79-3.75(m,4H),3.64(d,J=12.0Hz,2H),2.89-2.83(m,2H),2.6 0-2.55(m,1H),1.86(d,J=12.8Hz,3H),1.37-1.27(m,2H),1.18(t,J=6.8Hz,3H),1.01(m,2H),0.90(m,2H).

[0291] Example 27, Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 27):

[0292] A synthetic route similar to Example 25 is used, except that the methanesulfonyl chloride in step 6 is replaced with trifluoromethanesulfonic anhydride to obtain the above-mentioned compound 27.

[0293] LC-MS[M+H] + =500.1

[0294] 1 HNMR(400MHz,DMSO-d6)δ7.21-7.19(m,4H),6.77(d,J=7.6H Z ,1H),6.21(d,J=7.6H Z ,1H),4.14(q,J=6.8Hz,2H),3.85(s,6H),3.77(m,4H),3.26-3.20(m,2H),2. 07-2.05(m,1H),1.93-1.89(m,2H),1.37-1.27(m,2H),1.18(t,J=6.8Hz,3H).

[0295] Example 28, Synthesis of 4-(((1-ethyl-6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-sulfonamide (Compound 28) and 4-(((1-ethyl-6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-sulfonic acid (Compound 31):

[0296] Compound 25g (3.8g, 4.31mmol), sulfamide (1.66g, 17.26mmol), and DIEA (3.35g, 25.89mmol) were added sequentially to a mixture of dioxane (70mL) and acetonitrile (30mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling, the solvent was concentrated and purified by SGC (DCM:MeOH = 97:3 to 85:15) to obtain crude products 28 (800mg) and 31 (200mg).

[0297] 28 (800 mg crude product) was added to 3M aqueous hydrochloric acid (80 mL). Dichloromethane (80 mL) was slowly added with stirring. A solid precipitated and was filtered and dried to obtain the 28 hydrochloride salt (210.00 mg, 99.37% purity) as a light green solid. The mother liquor was separated and the aqueous phase was adjusted to pH 8 with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane (80 mL). The combined organic phases were dried and concentrated to obtain a solid. This solid was then purified by Prep.HPLC to obtain the free base of 28 (270.00 mg, 13.81% yield, 98.55% purity) as a white solid.

[0298] The crude product 31 (200 mg) was purified by Prep. HPLC to afford 31 (30.00 mg, 99.23% purity) as a white solid (trifluoroacetic acid salt).

[0299] The free base data of compound 28 are as follows:

[0300] LC-MS[M+H] + =447.1

[0301] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.19(m,4H),6.77(d,J=7.6H Z ,1H),6.73(s,2H),6.21(d,J=7.6H Z,1H),4.14(q,J=6.8Hz,2H),3.85(s,4H),3.79(s,2H),3.74(d,J=6.0Hz,2H),3.52-3.49 (m,2H),2.56-2.50(m,2H),1.87-1.78(m,3H),1.37-1.30(m,2H),1.18(t,J=6.8Hz,3H).

[0302] The data of compound 28 hydrochloride are as follows:

[0303] 1H-NMR (400MHz, DMSO-d6) δ7.37-7.36(m,4H),6.84(d,J=7.6Hz,1H),6.54(d,J=7.6Hz,1H),4.62-4.58(m,6H),4.07-4.05(m,2 H),3.82-3.76(m,2H),3.46(d,J=10.8Hz,2H),2.54-2.51(m,2H),1.85-1.82(m,3H),1.36-1.26(m,2H),1.12(t,J=6.8Hz,3H).

[0304] The data of compound 31 trifluoroacetate are as follows:

[0305] LC-MS[M+H] + =448.2

[0306] 1 H-NMR (400MHz, DMSO-d6) δ7.23-7.19 (m, 4H), 6.78 (d, J = 7.6Hz, 1H), 6.26 (s, 1H), 4. 13-3.56(m,12H),3.50-3.35(m,2H),2.82(s,1H),1.96-1.90(m,3H),1.43-1.33(m, 2H),1.15(t,J=7.2Hz,3H).

[0307] Example 29, Synthesis of 4-(((1-ethyl-6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-N-methylpiperidine-1-sulfonamide (Compound 29):

[0308] Under ice-cooling conditions, 25 g (50 mg, 113.53 μmol, crude product), methylsulfonyl chloride (16.18 mg, 124.88 μmol), and diisopropylethylamine (44.02 mg, 340.60 μmol) were added to dichloromethane (2 mL) in sequence. After complete addition, the mixture was stirred for 30 minutes. The reaction solution was directly concentrated and purified by Prep-HPLC to obtain the desired product 29 (2.18 mg, 4.39 μmol, 3.87% yield) as a white solid.

[0309] LC-MS[M+H] + =461.3

[0310] 1 HNMR(400MHz,DMSO-d6)δ7.24-7.17(m,4H),7.04(q,J=4.2Hz,1H),6.77(d,J=7.6H Z ,1H),6.20(d,J=7.6H Z ,1H),4.14(q,J=6.8Hz,2H),3.86(s,4H),3.79(s,2H),3.74(d,J=6.0Hz,2H),3.54(d,J=11.6Hz,2H) ,2.73-2.67(m,2H),2.52-2.50(m,3H),1.90-1.82(m,3H),1.33-1.24(m,2H),1.17(t,J=6.8Hz,3H).

[0311] Example 30, Synthesis of 4-(((1-ethyl-6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-N-sulfamoylpiperidine-1-sulfonamide (Compound 30):

[0312] Under ice bath, compound 25g (800 mg, 2.18 mmol) and DIEA (844.07 mg, 6.53 mmol) were dissolved in DCM (30 mL) in sequence. Compound aminosulfonyl chloride (301.83 mg, 2.61 mmol) was added to the system, and the mixture was stirred for 2 hr. 1 M aqueous hydrochloric acid solution (30 mL) was added, and the mixture was extracted three times with dichloromethane (50 mL). The organic phases were combined, dried, and concentrated. After purification by SGC (DCM:MeOH=5:1), 30 (30.00 mg, 2.58% yield) was obtained by Prep.HPLC.

[0313] LC-MS[M+1] + =526.2

[0314] 1H-NMR (400MHz, DMSO-d6) δ7.26-7.24(m,4H),6.78(d,J=7.6Hz,1H),6.29(s,1H),4.71-3.90(m,8H),3.73(d,J=6.0H z,2H),3.52(d,J=12.0Hz,2H),2.67(d,J=11.6Hz,2H),1.80-1.78(m,3H),1.32-1.23(m,2H),1.15(t,J=7.2Hz,3H).

[0315] Test Example 1

[0316] The conversion of cholesterol to pregnenolone is the first rate-limiting step in the synthesis of all steroid hormones in vertebrates. This conversion reaction involves two consecutive monooxidation reactions catalyzed by the only cytochrome P450scc (CYP11A) to produce C 22 -Hydroxycholesterol and C 20 ,C 22 -dihydroxycholesterol, followed by C 20 ,C 22 -C in dihydroxycholesterol 20 -C 22 The cleavage of the carbon-carbon single bond generates one molecule of pregnenolone and one molecule of 4-methylvaleraldehyde. Therefore, the inhibitory effect of compounds on CYP11A1 is identified by testing their ability to inhibit pregnenolone synthesis.

[0317] The ability of various compounds to inhibit pregnenolone biosynthesis, and thus their ability to inhibit CYP11A1, was determined by enzyme-linked immunosorbent assay (ELISA) using the Abnova Pregnenolone ELISA Kit, KA1912. The human adrenocortical carcinoma cell line NCI-H295R (Procell, CL-0399), which has been shown to express all key steroidogenic enzymes, was used as an enzyme source. To determine the half-inhibitory concentration (IC50) of various compounds for CYP11A1 inhibition, compounds were added to NCI-H295R cell cultures, and the pregnenolone concentration in the culture supernatant was measured after incubation.

[0318] 95 μl of NCI-H295R cells were cultured in a 96-well plate using proprietary cell culture medium (Procell, CM-0399) overnight in a cell culture incubator at 37°C, 5% CO2. 5 μl of the test compound (Sigma, D8418) in DMSO (at varying concentrations) was then added to each well and incubated for 24 hours. The final concentrations of the test compound were 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0 nM. After incubation, the cells were centrifuged, and 80 μl of the cell culture supernatant was collected from each well and diluted 1:8 with cell culture medium. The pregnenolone concentration was then determined by ELISA. A pregnenolone standard was used to generate a standard curve, and the assay was performed in duplicate. The ELISA plate was pre-coated with an anti-pregnenolone rabbit polyclonal antibody. In the ELISA strips, 50 μl of diluted culture supernatant or standard solution or control was added to each well, followed by 100 μl of pregnenolone-HRP complex solution and incubation at 200 rpm on a plate shaker (QILINBEIER, QB-9002) at room temperature for 1 hour. Then, the cells were washed three times with 300 μl of washing solution each time and patted dry on absorbent paper. 150 μl of TMB substrate was added, and after incubation at room temperature on a plate shaker for 10-15 minutes, 50 μl of stop solution was added. The absorbance was measured at 450 nm using a microplate reader (PerkinElmer, 2105). IC was calculated using GraphPad Prism software. 50 value.

[0319] Inhibition rate (%) = 100% - (reading value 化合物 -Average reading 阳性对照 ) / (average reading 空白对照 -Average reading 阳性对照 )x100%.

[0320] Test Example 2

[0321] The ability of different compounds to inhibit testosterone biosynthesis, and thus CYP11A1, was determined by measuring testosterone concentration using an enzyme-linked immunosorbent assay (ELISA) (Abnova Testosterone ELISA Kit, KA6502). The human adrenocortical carcinoma cell line NCI-H295R (Procell, CL-0399) was used as the enzyme source. Compounds were added to the NCI-H295R cells during incubation, and testosterone concentrations in the culture supernatant were measured after incubation.

[0322] 95 μl of NCI-H295R cells were cultured in a 96-well plate using proprietary cell culture medium (Procell, CM-0399) overnight in a cell culture incubator at 37°C, 5% CO2. 5 μl of the test compound (Sigma, D8418) in DMSO (Sigma, D8418) at varying concentrations was then added to each well and incubated for 24 hours. The final concentrations of the test compound were 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0 nM. After incubation, the cells were centrifuged and 80 μl of the cell culture supernatant was collected from each well for assaying testosterone concentrations using an ELISA. A testosterone standard was used to generate a standard curve, and the assay was performed in duplicate. The ELISA plate was pre-coated with an anti-testosterone monoclonal antibody. In the ELISA strips, 25 μl of culture supernatant or standard solution or control was added to each well, followed by 200 μl of testosterone-HRP complex solution and incubation at room temperature for 1 hour on a plate shaker (QILINBEIER, QB-9002) at 200 rpm. The plates were then washed three times with 300 μl of cleaning solution each time and patted dry on absorbent paper. 200 μl of TMB substrate was added, and after incubation at room temperature on a plate shaker for 15 minutes, 100 μl of stop solution was added. The absorbance was measured at 450 nm using a microplate reader (PerkinElmer, 2105). IC was calculated using GraphPad Prism software. 50 Inhibition rate (%) = 100% - (reading value 化合物 -Average reading 阳性对照 ) / (average reading 空白对照 -Average reading 阳性对照 )x100%.

[0323] Test Example 3, Pharmacokinetic Evaluation

[0324] Comparative Example 1, referring to patent WO2018115591A1, Example 185 was synthesized, and the structural formula is as follows:

[0325] ICR mouse experiments

[0326] 1. Abstract

[0327] ICR mice were used as test animals, and the drug concentration in the plasma of the disclosed compounds at different time points after gavage (ig) was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in ICR mice was studied and their pharmacokinetic characteristics were evaluated.

[0328] 2. Experimental Plan

[0329] 2.1 Investigational Drugs

[0330] Example 1 Compound

[0331] Example 28 Compound

[0332] Comparative Example 1 Compound

[0333] 2.2 Experimental animals

[0334] Twenty-seven male ICR mice were divided equally into three groups and provided by Zhaoyan (Suzhou) New Drug Research Center Co., Ltd. The mice were fasted overnight for at least 12 hours before dosing. Normal saline was used as drinking water during the fasting period and the experimental period.

[0335] 2.3 Drug preparation

[0336] Take a certain amount of the compound to be tested and prepare the test sample to a final concentration of 2 mg / mL for oral administration. The preparation solvent is 0.5% Tween 80 in 0.5% methylcellulose aqueous solution. After the preparation is completed, add 1N hydrochloric acid aqueous solution to adjust to a clear solution (pH 4-5).

[0337] 2.4 Administration

[0338] The dosage is 20.0 mg / kg and the administration volume is 10.0 ml / kg.

[0339] 3. Operation

[0340] At 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after dosing, collect at least 0.2 mL of venous blood (from three animals at each time point) and place it in an EDTA-K2 anticoagulant tube. After collection, place the blood sample in a labeled centrifuge tube in an ice-water bath and rapidly centrifuge to separate the plasma at 4000 rpm for 10 minutes at 4°C. Store the plasma at -40°C until testing. Resume feeding 4 hours after dosing.

[0341] Determine the concentration of the test compound in ICR mouse plasma: Thaw plasma samples at room temperature, aspirate 50 μL, add 300 μL of 200 ng / mL terfenadine (acetonitrile) as the internal standard, vortex mix for 1 minute, and centrifuge at 15,400 g for 10 minutes at 4°C. Inject the supernatant for LC / MS / MS analysis.

[0342] 4. Data Collection and Statistical Analysis

[0343] Analyst 1.6.3 software outputs original spectra, concentration, accuracy and other data.

[0344] Microsoft Excel 2007 software was used to calculate the mean, standard deviation, and coefficient of variation.

[0345] WinNonlin software non-compartmental model method (NCA) was used to perform AUC and C max , t 1 / 2 Calculation of main pharmacokinetic parameters.

[0346] 5. Pharmacokinetic parameter results

[0347] The above are only specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in this invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts: R1 is selected from hydrogen atom, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 aryl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 Aryl, four to eight-membered heterocyclyl and five to eight-membered heteroaryl are optionally substituted by one or more R a Substituted by a substituent, Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 1 to 3 substituents of the alkoxy group; R2 is selected from hydrogen atom, halogen atom, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 aryl, a four- to eight-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to eight-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 Aryl, four to eight-membered heterocyclyl and five to eight-membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent, Each R b The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 1 to 3 substituents of the alkoxy group; R3 is selected from C 1-7 Alkylcarbonyl, C 2-7 Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, a three- to eight-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O and S, NR c R d Carbonyl, sulfonic acid, aminosulfonyl C 1-7 Alkyl S(O)2-, C 2-7 Alkenyl S(O)2-, C 2-7 Alkynyl S(O)2-, C 1-7 Alkoxy S(O)2-, C 3-7 Cycloalkyl S(O)2-, three to eight-membered heterocycloalkyl S(O)2- containing 1 to 3 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-7 Alkylcarbonyl, C 2-7 Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, three to eight-membered heterocycloalkylcarbonyl, C 1-7 Alkyl S(O)2-, C 2-7 Alkenyl S(O)2-, C 2-7 Alkynyl S(O)2-, C 1-7 Alkoxy S(O)2-, C 3-7 Cycloalkyl S (O) 2-, three to eight membered heterocycloalkyl S (O) 2- optionally substituted by one or more R e substituted by a substituent; R c and R d are each independently selected from hydrogen, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d It forms a three- to six-membered heterocyclic ring with the attached nitrogen atom; Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, four to eight membered heterocycloalkyl are optionally selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, amino, hydroxy, cyano or C 1-6 1 to 3 substituents of the alkoxy group; n1 is an integer of 0, 1, 2, 3 or 4; n2 is an integer of 1, 2, 3 or 4.

2. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: R1 is selected from hydrogen atom, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by 1 to 3 R a Substituted by a substituent, Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; Preferably, R2 is selected from hydrogen atom, halogen atom, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent, Each R b The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; Preferably, R3 is selected from C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, sulfonic acid, aminosulfonyl, a three- to six-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-4 Alkyl S(O)2-, C 2-4 Alkenyl S(O)2-, C 2-4 Alkynyl S(O)2-, C 1-4 Alkoxy S(O)2-, C 3-6 Cycloalkyl S(O)2-, three to six membered heterocycloalkyl S(O)2- containing 1 to 3 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-4 Alkylcarbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, three to six membered heterocycloalkylcarbonyl, C 1-4 Alkyl S(O)2-, C 2-4 Alkenyl S(O)2-, C 2-4 Alkynyl S(O)2-, C 1-4 Alkoxy S(O)2-, C 3-6 Cycloalkyl S (O) 2-, three to six membered heterocycloalkyl S (O) 2- optionally substituted by 1 to 3 R e substituted by a substituent; R c and R d are each independently selected from hydrogen, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d It forms a three- to six-membered heterocyclic ring with the attached nitrogen atom; Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, four to six membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

3. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: R1 is selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl, four to six membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, five to six membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by 1 or 2 R a Substituted by a substituent, Each R a The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl; Preferably, R2 is selected from hydrogen atom, halogen atom, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, a four- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, a five- to six-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S, wherein the C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, four to six membered heterocyclyl and five to six membered heteroaryl are optionally substituted by one or more R b Substituted by a substituent, Each R b The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl; Preferably, R3 is selected from C 1-3 Alkylcarbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, sulfonic acid, aminosulfonyl, a three- to six-membered heterocycloalkylcarbonyl containing 1 or 2 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-3 Alkyl S(O)2-, C 2-3 Alkenyl S(O)2-, C 2-3 Alkynyl S(O)2-, C 1-3 Alkoxy S(O)2-, C 3-6 Cycloalkyl S(O)2-, three to six membered heterocycloalkyl S(O)2- containing 1 or 2 heteroatoms selected from N, O and S, NR c R d S(O)2-, wherein the C 1-3 Alkylcarbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 alkyl Oxycarbonyl, C 3-6 Cycloalkylcarbonyl, three to six membered heterocycloalkylcarbonyl, C 1-3 Alkyl S(O)2-, C 2-3 Alkenyl S(O)2-, C 2-3 Alkynyl S(O)2-, C 1-3 Alkoxy S(O)2-, C 3-6 Cycloalkyl S (O) 2-, three to six membered heterocycloalkyl S (O) 2- optionally substituted by 1 or 2 R e substituted by a substituent; R c and R d are each independently selected from hydrogen, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 Cycloalkyl, aminosulfonyl, or R c and R d It forms a three- to six-membered heterocyclic ring with the attached nitrogen atom; Each R e The same or different from each other, each independently selected from hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 Cycloalkyl.

4. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl; Preferably, R2 is selected from hydrogen atom, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trichloromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, pentachloroethyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, perfluoropropyl, monochloropropyl, dichloropropyl, trichloropropyl, tetrachloropropyl, pentachloropropyl, hexachloropropyl, perchloropropyl; Preferably, R3 is selected from hydrogen atom, methyl-S(O)2-, ethyl-S(O)2-, n-propyl-S(O)2-, isopropyl-S(O)2-, cyclopropyl-S(O)2-, oxetanyl-S(O)2-, cyclobutyl-S(O)2-, oxetanyl-S(O)2-, methoxy-S(O)2-, ethoxy-S(O)2-, n-propoxy-S(O)2-, isopropoxy-S(O)2-, cyclopropyloxy-S(O)2-, oxetanyl-S(O)2-, cyclobutyloxy-S(O)2-, oxetanyl-S(O)2-, N,N-dimethyl ... Methylamino-S(O)2-, trifluoromethyl-S(O)2-, amino-S(O)2-, SO3H-, pyrroline-1-S(O)2-, piperidine-1-S(O)2-, morpholine-1-S(O)2-, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, oxetanylcarbonyl, cyclobutylcarbonyl, oxetanylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropyloxycarbonyl, oxetanyloxycarbonyl, cyclobutyloxycarbonyl, oxetanyloxycarbonyl, N,N-dimethylaminocarbonyl, trifluoromethylcarbonyl, Preferably, n1 is 1; Preferably, n2 is 1.

5. The compound represented by general formula (I) according to claim 1, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: The compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts is one of the following compounds:

6. Use of the compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts as a CYP11A1 inhibitor.

7. Use of the compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts in the preparation of a medicament for treating steroid hormone-dependent diseases.

8. Use of the compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts in the preparation of a medicament for treating steroid receptor-dependent diseases such as prostate cancer or breast cancer.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts as an active ingredient, and a pharmaceutically acceptable excipient.

10. A method for treating prostate cancer, comprising administering to a prostate cancer patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, or a pharmaceutical composition according to claim 9.

11. A method for treating breast cancer, comprising administering to a breast cancer patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 5, a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9.

12. The compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: The compound may be administered together with at least one selected from glucocorticoids and mineralocorticoids.

13. The compound represented by general formula (I) according to any one of claims 1 to 5, its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, characterized in that: The compound can be administered together with one or more other anticancer drugs, wherein the anticancer drugs are selected from at least one of nonsteroidal androgen receptor antagonists, steroid synthesis inhibitors, chemotherapeutic agents, and estrogen receptor antagonists.

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