CYP11A1 INHIBITOR COMPOUNDS AND METHODS FOR PREPARATION THEREOF AND USE THEREOF - Patent application

Abstract

The present invention discloses a compound represented by general formula (I), and its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts.Compared with the prior art, the compound of the present invention has a new skeleton.Unexpectedly, the compound of the present invention exhibits a good inhibitory effect on CYP11A1, blocking the biosynthesis of downstream steroids.Clinically, the compound can be used to treat steroid receptor-dependent diseases. JPEG2026503938000050.jpg22149

Description

Detailed Description of the Invention

[0001] This application claims the benefit of priority to a Chinese patent having application number 202310060807.3, filed with the State Intellectual Property Office of China on January 17, 2023, and having the disclosure title "CYP11A1 INHIBITOR COMPOUND, AND PREPARATION METHOD THEREFOR AND USETHEREOF," and application number 202310019758.9, filed with the State Intellectual Property Office of China on January 6, 2023, and having the disclosure title "CYP11A1 INHIBITOR COMPOUND, AND PREPARATION METHOD THEREFOR AND USETHEREOF," and application number 202310019758.9, filed with the State Intellectual Property Office of China on June 7, 2023, and having the disclosure title "CYP11A1 INHIBITOR COMPOUND, AND PREPARATION METHOD THEREFOR AND USETHEREOF," each of which is incorporated herein by reference in its entirety. The present application claims the benefit of priority from Chinese patent application number 202310670257.7 bearing the title "US ETHEREOF". [Technical field] The present disclosure relates to the field of pharmaceutical synthesis, in particular to CYP11A1 (cytochrome P450 monooxygenase 11A1) inhibitor compounds, and methods for preparing and using the same, as well as pharmaceutical compositions containing such compounds, which can be used to treat steroid hormone-dependent diseases.

[0002] [Background technology] Prostate cancer is a common malignant tumor of the genitourinary system in elderly men. Its incidence and mortality rates rank second and fifth, respectively, among the overall incidence and mortality rates of male malignancies worldwide, first and third, respectively, among men in Europe and the United States, and sixth and seventh, respectively, among men in China. In recent years, due to the aging of China's population and other factors, the incidence and mortality rates of prostate cancer have shown a significant upward trend, and the disease burden is becoming increasingly severe. GLOBOCAN2020 data show that approximately 115,000 new cases of prostate cancer were reported in China in 2020, accounting for 4.7% of all male malignancies. In the United States in 2019, new cases of prostate cancer accounted for 20% of new male cancer patients that year.

[0003] For patients with stage I to III prostate cancer, existing standard treatments include surgery and radiation therapy. Treatment outcomes for early stage prostate cancer (stage I / II) are relatively good, with a 5-year disease-free progression period of up to 90%. However, the cure rate for advanced prostate cancer is extremely low. Currently, the 5-year survival rate for advanced prostate cancer is only 30%.

[0004] Steroid hormone binding to cognate receptors regulates the growth of most prostate and breast cancers. In patients with stage IV or high-risk prostate cancer, androgen ablation by surgery or chemical castration can effectively control disease progression. First-generation antiandrogen therapies, such as flutamide and bicalutamide, are used to treat this stage of prostate cancer.

[0005] Most prostate cancer patients eventually develop castration-resistant prostate cancer (CRPC). Castration reduces plasma testosterone levels, but the disease still progresses. This is characterized by high expression of the androgen receptor (AR), and trace amounts of androgens in the body can still activate androgen receptor (AR) signaling, thus resulting in continuous activation of the AR pathway.

[0006] Currently, there are limited treatment options for CRPC. Abiraterone and enzalutamide are new therapies developed for the continuous activation of androgen receptors in CRPC, and can treat advanced CRPC by further inhibiting androgen synthesis or blocking the binding of trace amounts of androgen to the receptor in the body.

[0007] However, a significant proportion of prostate cancer patients are insensitive to abiraterone or enzalutamide. Furthermore, most patients who initially respond develop new resistance within 1–2 years of abiraterone or enzalutamide therapy. However, most abiraterone-resistant or enzalutamide-resistant tumors still express highly persistently activated AR.

[0008] Adrenal and prostate cancers themselves can synthesize pregnenolone, progesterone, dehydroepiandrosterone, and their derivatives, which can then be converted into more active androgens that bind and activate AR. Increased pregnenolone levels in patients treated with abiraterone are thought to be the primary mechanism driving resistance, particularly in tumors with point mutations in the androgen receptor. All steroid hormones in the body are derived from the conversion of a single precursor (cholesterol) to pregnenolone. This reaction step, catalyzed by cytochrome P450scc (cholesterol side-chain cleavage enzyme, also known as cytochrome P450 monooxygenase 11A1, CYP11A1), is the rate-limiting first step in a series of monooxygenation reactions to catalyze steroidogenesis, whereby the CC in 20R,22R-dihydroxycholesterol (20R,22R-DiOHCH) is cleaved, converting cholesterol to pregnenolone. Studies have shown that inhibiting CYP11A1 can rapidly reduce blood steroid hormone levels below the detection limit. By simultaneously supplementing the body with glucocorticoids and mineralocorticoids, the body's normal physiological functions can be effectively prevented from being affected by steroid hormone deficiency.

[0009] CYP11A1 belongs to the steroid CYP gene family. CYP11A1 is overexpressed in several types of cancer and is associated with cancer resistance. Inhibition of the CYP11A1 enzyme can inhibit the synthesis of all steroid hormones, including estrogen and progesterone, which promote breast cancer progression, and androgen, which promote prostate cancer progression, thus completely inhibiting the progression of steroid hormone-dependent tumors. This makes it a promising therapeutic target.

[0010] [overview] According to one aspect of the present disclosure, it is an object of the present disclosure to provide a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: [ka] (R1 is a hydrogen atom, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 aryl, a 4- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-14 Aryl, 4- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl may be one or more R a optionally substituted by substituents, Each R a are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-6 cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl are C 1-6 Alkyl, HaloC 1-6 Alkyl, halogen, amino, hydroxyl, cyano or C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; R2 is a hydrogen atom, a halogen atom, or C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14aryl, a 4- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 6-14 Aryl, 4- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl may be one or more R b optionally substituted by substituents, Each R b are the same or different and are 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, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl are C 1-6 Alkyl, HaloC 1-6 Alkyl, halogen, amino, hydroxyl, cyano or C 1-6 optionally substituted by 1 to 3 substituents selected from alkoxy; R3 is C 1-7 Alkyl carbonyl, C 2-7 Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, sulfonic acid group, aminosulfonyl, 3- to 8-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O, and S, NR c R d Carbonyl, C 1-7AlkylS(O)2-, C 2-7 AlkenylS(O)2-, C 2-7 AlkynylS(O)2-, C 1-7 AlkoxyS(O)2-, C 3-7 CycloalkylS(O)2-, 3- to 8-membered heterocycloalkylS(O)2- containing 1 to 3 heteroatoms selected from N, O, and S, NR c R d S(O)2-, C 1-7 Alkyl carbonyl, C 2-7 Alkenylcarbonyl, C 2-7 Alkynylcarbonyl, C 1-7 Alkoxycarbonyl, C 3-7 Cycloalkylcarbonyl, 3-8 membered heterocycloalkylcarbonyl, C 1-7 AlkylS(O)2-, C 2-7 AlkenylS(O)2-, C 2-7 AlkynylS(O)2-, C 1-7 AlkoxyS(O)2-, C 3-7 CycloalkylS(O)2- and 3- to 8-membered heterocycloalkylS(O)2- are each independently one or more R e optionally substituted by substituents, R c and R d is hydrogen, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl and aminosulfonyl, or R c and R d forms a 3- to 6-membered heterocyclic ring together with the attached N atom, Each R e are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; amino, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl are C 1-6 Alkyl, HaloC 1-6 Alkyl, halogen, amino, hydroxyl, cyano or C 1-6 Optionally substituted by 1 to 3 substituents selected from alkoxy).

[0011] n1 is an integer of 0, 1, 2, 3 or 4.

[0012] n2 is an integer of 1, 2, 3 or 4.

[0013] Preferably, R1 is a hydrogen atom, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each 1 to 3 R a optionally substituted by substituents, Each R a are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S.

[0014] Preferably, R2 is a hydrogen atom, a halogen atom, or C1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 aryl, a 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl may be one or more R b optionally substituted by substituents, Each R b are the same or different and are 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, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. Preferably, R3 is C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, sulfonic acid group, aminosulfonyl, 3- to 6-membered heterocycloalkylcarbonyl containing 1-3 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-4 AlkylS(O)2-, C 2-4 AlkenylS(O)2-, C 2-4 AlkynylS(O)2-, C 1-4 AlkoxyS(O)2-, C 3-6CycloalkylS(O)2-, 3- to 6-membered heterocycloalkylS(O)2- containing 1 to 3 heteroatoms selected from N, O, and S, NR c R d S(O)2-, C 1-4 Alkyl carbonyl, C 2-4 Alkenylcarbonyl, C 2-4 Alkynylcarbonyl, C 1-4 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocycloalkylcarbonyl, C 1-4 AlkylS(O)2-, C 2-4 AlkenylS(O)2-, C 2-4 AlkynylS(O)2-, C 1-4 AlkoxyS(O)2-, C 3-6 CycloalkylS(O)2- and 3- to 6-membered heterocycloalkylS(O)2- are 1 to 3 R e optionally substituted by substituents, R c and R d is 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 forms a 3- to 6-membered heterocyclic ring together with the attached N atom, Each R e are the same or different and are 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, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S.

[0015] Preferably, R1 is a hydrogen atom, C 1-3 Alkyl, C 3-6cycloalkyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 1-3 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently one or two R a optionally substituted by substituents, Each R a are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 cycloalkyl; R2 is a hydrogen atom, a halogen atom, or 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 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, C 6-10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl may be one or more R b optionally substituted by substituents, Each R b are the same or different and are 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; R3 is C 1-3Alkyl carbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, sulfonic acid group, aminosulfonyl, 3- to 6-membered heterocycloalkylcarbonyl containing 1 or 2 heteroatoms selected from N, O and S, NR c R d Carbonyl, C 1-3 AlkylS(O)2-, C 2-3 AlkenylS(O)2-, C 2-3 AlkynylS(O)2-, C 1-3 AlkoxyS(O)2-, C 3-6 CycloalkylS(O)2-, 3- to 6-membered heterocycloalkylS(O)2- containing 1 or 2 heteroatoms selected from N, O and S, NR c R d S(O)2-, C 1-3 Alkyl carbonyl, C 2-3 Alkenylcarbonyl, C 2-3 Alkynylcarbonyl, C 1-3 Alkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocycloalkylcarbonyl, C 1-3 AlkylS(O)2-, C 2-3 AlkenylS(O)2-, C 2-3 AlkynylS(O)2-, C 1-3 AlkoxyS(O)2-, C 3-6 CycloalkylS(O)2-, 3- to 6-membered heterocycloalkylS(O)2- are substituted with one or two R e optionally substituted by substituents, R c and R d is hydrogen, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-6 cycloalkyl, aminosulfonyl, or R c and R d forms a 3- to 6-membered heterocyclic ring together with the attached N atom, Each R eare the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C 1-3 Alkoxy, C 1-3 Alkyl, C 3-6 cycloalkyl.

[0016] Preferably, R1 is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated cyclopropyl.

[0017] 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.

[0018] Preferably, R3 is a hydrogen atom, methyl-S(O)2-, ethyl-S(O)2-, n-propyl-S(O)2-, isopropyl-S(O)2-, cyclopropyl-S(O)2-, oxiranyl-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-, cyclopropoxy-S(O)2-, oxiranyloxy-S(O)2-, cyclobutoxy-S(O)2-, oxetanyloxy-S(O)2-, N,N-dimethylamino-S(O)2-, trifluoromethyl-S(O)2-, amino-S(O)2-, O)2-, SO3H-, pyrroline-1-S(O)2-, piperidine-1-S(O)2-, morpholine-1-S(O)2-, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, oxiranylcarbonyl, cyclobutylcarbonyl, oxetanylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, oxiranyloxycarbonyl, cyclobutoxycarbonyl, oxetanyloxycarbonyl, N,N-dimethylaminocarbonyl, trifluoromethylcarbonyl, and [ka] is selected from.

[0019] Preferably, n1 is 1.

[0020] Preferably, n2 is 1.

[0021] Preferably, the compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, is one of the following compounds: [ka] JPEG2026503938000005.jpg214149 JPEG2026503938000006.jpg55149 According to another aspect of the present disclosure, another object of the present disclosure is to provide a method for preparing a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, comprising the steps of: [ka]

[0022] Step 1) subjecting the commercialized compound (Ia) to a substitution addition reaction with a halogenated compound R1X to obtain a compound represented by general formula (Ib); Step 2) Reaction of a compound represented by general formula (Ib) with a piperidine compound having a hydroxyalkyl substituent [ka] and a substitution reaction to obtain a compound represented by general formula (Ic), Step 3) reducing the cyano in the compound of formula (Ic) to give the corresponding amino-containing compound of formula (Id); Step 4) subjecting a compound represented by general formula (Id) to a cyclization reaction with a dibenzyl chloride compound containing an R2 substituent to obtain a compound represented by general formula (Ie); Step 5) removing the amino protecting group (PG) from the compound represented by general formula (Ie) to obtain a compound represented by general formula (If); Step 6) reacting the compound represented by general formula (If) with R3Cl or R3OR3, or NH2SO2NH2 to obtain the compound represented by general formula (I); where: PG is an amino-protecting group selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc).

[0023] The substituents R1, R2, R3, n1 and n2 are defined as in general formula (I).

[0024] According to another aspect of the present disclosure, the present disclosure provides the use of a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, as a CYP11A1 inhibitor.

[0025] According to another aspect of the present disclosure, the present disclosure provides the use of a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a steroid hormone-dependent disease.

[0026] Preferably, the steroid hormone dependent disease is cancer.

[0027] According to another aspect of the present disclosure, the present disclosure provides the use of a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a steroid receptor-dependent disease, such as prostate cancer or breast cancer.

[0028] According to another aspect of the present disclosure, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound represented by general formula (I) according to the present disclosure, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] According to another aspect of the present disclosure, the present disclosure provides a kit for treating prostate cancer or breast cancer, comprising: A kit is provided which includes, as an active ingredient, a compound represented by general formula (I) according to the present disclosure, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound represented by general formula (I) according to the present disclosure, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, and instructions for using the compound or pharmaceutical composition.

[0030] The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition. The kits may be used in the methods of the present disclosure. In certain embodiments, the kits further include instructions for using the compound or pharmaceutical composition.

[0031] According to another aspect of the present disclosure, the present disclosure provides a method of treating prostate cancer, comprising administering a therapeutically effective amount of a compound represented by general formula (I) according to the present disclosure, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure, to a prostate cancer patient in need thereof.

[0032] According to another aspect of the present disclosure, the present disclosure provides a method of treating breast cancer, comprising administering a therapeutically effective amount of a compound represented by general formula (I) according to the present disclosure, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure, to a breast cancer patient in need thereof.

[0033] According to another aspect of the present disclosure, the present disclosure provides a method of administering a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which may be administered together with at least one selected from a glucocorticoid and a mineralocorticoid.

[0034] According to another aspect of the present disclosure, the present disclosure provides a method of administering a compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which may be administered together with one or more other anti-cancer drugs, wherein the anti-cancer drugs are selected from at least one of a non-steroidal androgen receptor antagonist, a steroid synthesis inhibitor, a chemotherapeutic agent, and an estrogen receptor antagonist.

[0035] [Beneficial effects] Compared with the prior art, the compound of the present disclosure has a new skeleton.Unexpectedly, the compound of the present disclosure exhibits an inhibitory effect on the biosynthesis of pregnenolone and testosterone.Because pregnenolone is synthesized by CYP11A1, the compound exhibits a good inhibitory effect on CYP11A.Clinically, the compound can be used to treat steroid receptor-dependent related diseases, especially steroid receptor-dependent cancers such as prostate cancer and breast cancer.

[0036] Detailed Description of the Embodiments The present disclosure will be described in detail below.Before the description, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to their general meanings and dictionary meanings, but should be interpreted according to the meanings and concepts corresponding to the technical aspects of the present disclosure, based on the principle that allows the inventors to properly define terms for the best interpretation.Therefore, it should be understood that the descriptions presented in this specification are preferred examples for illustrative purposes only, and are not intended to limit the scope of the present disclosure, and other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present disclosure.

[0037] As used herein, the terms "comprise," "include," "have," "contain," or any other similar term are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to those elements listed herein and may include other elements not explicitly listed but normally inherent in the composition or article. Furthermore, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, the condition "A or B" is satisfied when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), or when both A and B are true (or present). In addition, the interpretation of the terms "comprise," "include," "have," and "contain" is specifically disclosed herein and should be considered to encompass closed or semi-closed conjunctions such as "consisting of..." and "substantially consisting of...."

[0038] All characteristics or conditions defined herein in the form of numerical ranges or percentage ranges are for brevity and convenience only. Thus, the description of a numerical range or percentage range should be considered to encompass and specifically disclose all possible subranges and individual values, particularly integer values, within the range. For example, a description of a range "1 to 8" should be considered to specifically disclose all subranges, such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, and 3 to 8, particularly subranges defined by all integer values, and should be considered to specifically disclose individual values ​​within the range, for example, 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise specified, the above interpretation method is applicable to the entire content of the entire disclosure, regardless of whether the range is broad or not.

[0039] When a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it is understood that all ranges formed by any pairing of an upper range limit or preferred value with a lower range limit or preferred value are specifically disclosed herein, whether or not these ranges are separately disclosed. Additionally, when a range of numerical values ​​is referred to herein, unless otherwise specified, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

[0040] In this specification, numerical values ​​should be understood to have the accuracy of that numerical value's significant digits, provided that the purpose of this disclosure can be achieved. For example, the number 40.0 should be understood to encompass the range 39.50 to 40.49.

[0041] When Markush groups or alternative language are used herein to describe features or examples of the present disclosure, those skilled in the art should understand that any subgroup of elements or any individual element within the Markush group or alternative language can also be used to describe the present disclosure. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this also means that a statement that X is X1 and / or a statement that X is X1 and / or X2 is fully described. Furthermore, when Markush groups or alternative language are used to describe features or examples of the present disclosure, those skilled in the art should understand that any combination of any subgroup of elements or individual elements within the Markush group or alternative language can also be used to describe the present disclosure. Thus, 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 means that a statement that X is X1, X2, or X3, and Y is Y1, Y2, or Y3 is fully described.

[0042] [Definition] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the Periodic Table of the Elements on the inside cover of the CAS edition, Handbook of Chemistry and Physics, 75th edition, 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 reactivity, are described in the following books: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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 Edition, Cambridge University Press, Cambridge, 1987. This disclosure is in no way intended to be limited by the exemplary list of substituents described herein.

[0043] The compounds described herein may contain one or more asymmetric centers and therefore may 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 stereoisomeric mixtures, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures 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 can be prepared by asymmetric synthesis. See, for example, 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, page 268 (edited by E. L. Eliel, The University of Notre Dame Press, Notre Dame de Paris, IN 1972). The present disclosure further encompasses that the compounds described herein are individual isomers substantially free of other isomers or mixtures of various isomers. When a series of values ​​is listed, it is intended to encompass every value and subrange within the range. For example, "C 1-6 ” is 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 , C4-6 , C 4-5 , and C 5-6 is intended to encompass:

[0044] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 7 carbon atoms ("C 1-7 In some embodiments, alkyl has 1 to 7 carbon atoms ("C 1-7 In some embodiments, alkyl has 1 to 6 carbon atoms ("C 1-6 In some embodiments, alkyl has 1 to 5 carbon atoms ("C 1-5 In some embodiments, alkyl has 1 to 4 carbon atoms ("C 1-4 In some embodiments, alkyl has 1 to 3 carbon atoms ("C 1-3 In some embodiments, alkyl has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl and 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). Further examples of alkyl include n-heptyl (C7), and the like. Unless otherwise specified, each instance of alkyl is independently unsubstituted or substituted with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl is an unsubstituted C, such as -CH3. 1-6 In certain embodiments, alkyl is a substituted C alkyl, such as -CF. 1-6 It is alkyl.

[0045] "Alkoxy" refers to a monovalent □O□alkyl, where the alkyl portion has the specified number of carbon atoms. Alkoxy in this disclosure typically contains 1□6 carbon atoms ("C1-6 alkoxy"), including, for example, methoxy, ethoxy, isopropoxy, tert-butoxy, etc. Unless otherwise specified, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted with one or more substituents ("substituted alkoxy"). In certain embodiments, alkoxy is an unsubstituted C 1-6 In certain embodiments, the alkoxy is a substituted C 1-6 It is an alkoxy.

[0046] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 7 carbon atoms with one or more carbon-carbon double bonds and no triple bonds ("C 2-7 In some embodiments, alkenyl refers to 2 to 7 carbon atoms ("C 2-7 In some embodiments, alkenyl has 2 to 6 carbon atoms ("C 2-6 In some embodiments, alkenyl has 2 to 5 carbon atoms ("C 2-5 In some embodiments, alkenyl has 2 to 4 carbon atoms ("C 2-4 In some embodiments, alkenyl has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl include the C 2-4Alkenyl includes pentenyl (C), pentadienyl (C), hexenyl (C), and the like. Further examples of alkenyl include heptenyl (C). Unless otherwise specified, each instance of alkenyl is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents. In certain embodiments, in alkenyl, a C=C double bond with unspecified stereochemistry can be an (E)- or (Z)-double bond.

[0047] "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 7 carbon atoms with one or more carbon-carbon triple bonds and, optionally, one or more double bonds ("C 2-7 In some embodiments, alkynyl has 2 to 7 carbon atoms ("C 2-7 In some embodiments, alkynyl has 2 to 6 carbon atoms ("C 2-6 In some embodiments, alkynyl has 2 to 5 carbon atoms ("C 2-5 In some embodiments, alkynyl has 2 to 4 carbon atoms ("C 2-4 In some embodiments, alkynyl has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). C 2-4 Examples of alkynyl 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 include the C 2-4Alkynyl includes pentynyl (C), hexynyl (C), etc. Further examples of alkynyl include heptylynyl, etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents.

[0048] "Cycloalkyl" means a non-aromatic ring system having 3 to 6 ring carbon atoms ("C 3-6 A non-aromatic cyclic hydrocarbon group having 1 or more carbon atoms (e.g., cycloalkyl) and 0 heteroatoms. 3-6 Cycloalkyl includes, but is not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. As indicated by the preceding examples, in certain embodiments, cycloalkyl is a single ring ("monocyclic cycloalkyl") or comprises a fused, bridged, or spiro ring system, e.g., a bicyclic ring system ("bicyclic cycloalkyl"), which can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on a carbocyclic ring, in which case the number of carbons still refers to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0049] "Heterocycloalkyl" refers to a group having a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("4- to 8-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as far as valence allows. Heterocycloalkyls can be monocyclic ("monocyclic heterocycloalkyl"), or fused, bridged, or spirocyclic ring systems, e.g., bicyclic ring systems ("bicyclic heterocycloalkyl"), and can be saturated or partially unsaturated. Heterocycloalkyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes ring systems in which a heterocycle, as defined above, is fused to one or more carbocyclic groups, and the point of attachment is on the carbocyclic group or heterocyclic ring, or in which a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclic ring, in which case the number of ring members still refers to the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted or substituted by one or more substituents.

[0050] Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, triazinyl. Exemplary groups in which a 5-membered heterocycloalkyl is fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuryl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary groups in which a 6-membered heterocycloalkyl is fused to an aromatic ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0051] "Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared within the cyclic array) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in the aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared within the cyclic array). 6-14 In some embodiments, an aryl has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl has 14 ring carbon atoms ("C 14 "Aryl" (e.g., anthryl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, where the group or point of attachment is on the aromatic ring, in which case the number of carbon atoms still refers 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 ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, aryl is an unsubstituted C 6-14 In certain embodiments, the aryl is a substituted C 6-14 It is aryl.

[0052] "Heteroaryl" refers to a group having a 5-8 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6 π electrons are shared within the ring array) in which ring carbon atoms and 1-4 ring heteroatoms are provided to the aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as long as the valence allows. 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 with one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, in which case the number of ring members still refers 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 aryls, where the point of attachment is on the aryl ring or the heteroaryl ring, in which case the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0053] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0054] Unless expressly stated otherwise, atoms, moieties, or groups described herein may be unsubstituted or substituted, where valence allows.

[0055] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0056] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen-protecting group (also referred to as an amino-protecting group). Nitrogen-protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. For example, the amino-protecting group can be selected from benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc).

[0057] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Examples include the pharmaceutically acceptable salts described in detail by Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or 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, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1-4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where applicable, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carboxylates, sulfates, phosphates, nitrates, lower alkyl and aryl sulfonates, and the like.

[0058] The term "tautomer" or "tautomerism" refers to two or more compounds that interconvert into one another, produced by at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportion of tautomers depends on several factors, including temperature, solvent, and pH. Tautomeric reactions (i.e., reactions that provide tautomeric pairs) can be catalyzed by acids or bases. Exemplary tautomeric reactions include ketone-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine) tautomerization reactions.

[0059] It should also be understood that compounds that have the same molecular formula but differ in the properties, or the sequence of bonding of their atoms, or the arrangement of their atoms in space are referred to as "isomers." Isomers that have different arrangements of their atoms in space are referred to as "stereoisomers."

[0060] Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when the compound is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0061] The terms "inhibition" or "inhibitor" refer to the ability of a compound to decrease, slow down, interfere with, or prevent the activity of a particular biological process (such as the activity of the CYP11A1 enzyme in a cell relative to a carrier).

[0062] A "subject" to which administration is intended refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (such as an infant, child, or adolescent) or an adult subject (young adult, middle-aged human, or elderly human). A "patient" refers to a human subject in need of treatment for a disease.

[0063] The term "biological sample" is meant to include tissue samples (such as tissue sections and needle biopsy specimens of tissue), cell samples (such as cytological smears (such as Pap smears or blood smears) or cell samples obtained by microdissection), whole organism samples (such as yeast or bacterial samples), or any sample of cell parts, debris, or organelles (e.g., obtained by lysing cells and separating components therefrom by centrifugation or other means). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., oral swabs), or any material containing biomolecules derived from a first biological sample.

[0064] The term "administering" refers to the introduction of a compound described herein or a composition thereof to or onto a subject by implantation, absorption, ingestion, injection, inhalation or other means.

[0065] The term "treating" refers to reversing, alleviating, or delaying the onset of a disease described herein, or inhibiting the onset of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of a disease. For example, treatment can be administered to a susceptible subject before the onset of symptoms (e.g., based on a history of symptoms and / or exposure to a pathogen) to delay or prevent the onset of a disease. Treatment can be continued after symptoms have subsided, for example, to delay or prevent recurrence.

[0066] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response (i.e., to treat a condition). As will be understood 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 for 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 total amount of a compound described herein in multiple doses.

[0067] 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 a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in treating a 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 effectiveness of another therapeutic agent.

[0068] The pharmaceutical composition described herein can be prepared by any method known in the field of pharmacology.Generally, this preparation method comprises: combining the compound described herein (i.e., " active ingredient ") with carrier or excipient, and / or contacting the compound with one or more other auxiliary agents, then, if necessary and / or if necessary, shaping the product, and / or packaging the product into desired single-dose or multi-dose units.

[0069] Pharmaceutical compositions may be prepared, packaged, and / or sold as single unit doses and / or multiple single unit doses, as whole batches. 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 identity, size, and / or condition of the subject being treated, and the route of administration of the composition. The compositions may contain 0.1% to 100% (w / w) active ingredient.

[0070] Pharmaceutically acceptable excipients used in preparing the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents and spices may also be present in the compositions.

[0071] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, propylene glycol and sorbitan fatty acid esters and mixtures thereof.In addition to the inert diluent, oral compositions may contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, seasonings and spices. In certain embodiments for parenteral administration, the conjugates described herein are mixed with a solubilizing agent, such as an alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0072] Injectable dosage forms, such as sterile injectable aqueous suspensions or sterile injectable oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents.Sterile injectable dosage forms can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions.Acceptable carriers and solvents that can be used include water, Ringer's solution, USP, and physiological saline solution.In addition, sterile fixed oils are commonly used as solvents or suspending media.For this purpose, any mild fixed oil that can be used includes synthetic monoglycerides or synthetic diglycerides.In addition, fatty acids (such as oleic acid) can be used to prepare injectable dosage forms.

[0073] To prolong the effect of a drug, it is usually desirable to reduce absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of a drug depends on the dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a drug form for parenteral administration can be achieved by dissolving or suspending the drug in an oil vehicle.

[0074] 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 of the following inert pharmaceutically acceptable substances: excipients or carriers, such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerol; and (d) disintegrants, such as agar, calcium carbonate, and the like. The formulation may be mixed with (a) an aqueous solution of calcium, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (b) an anticoagulant such as petrolatum, (c) an absorption promoter such as quaternary ammonium compounds, (d) a wetting agent such as cetyl alcohol and glycerol monostearate, (e) an absorbent such as kaolin and bentonite, and (f) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. In the case of capsules, tablets, or pills, the dosage form may contain a buffering agent.

[0075] The active ingredient may be in the form of microcapsules with one or more of the above-mentioned excipients. Tablets, sugar-coated tablets, capsules, pills, and granules in the form of solid dosage forms may be prepared by using coatings and shells (such as enteric coatings, release-controlling coatings, and other coatings known in the field of pharmaceutical preparations). In such solid preparations, the active ingredient may be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Conventionally, such dosage forms may contain other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, or pills, the dosage form may contain a buffering agent. They may optionally contain opacifying agents and may have the following characteristics: They release the active ingredient only, or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymers and waxes.

[0076] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to any type of animal. It is readily apparent that pharmaceutical compositions suitable for administration to humans can be modified to produce compositions suitable for administration to various animals, and those skilled in the art can design and / or use routine experiments for such modifications.

[0077] The compound provided herein is usually formulated in the form of dosage unit to facilitate administration and dosage uniformity.However, it is understood that the daily use of the compositions described herein is determined by a doctor in the scope of reasonable medical judgment in any case.The specific therapeutically effective dose level for any specific subject or organism depends on a number of factors, including the severity of the disease and symptoms to be treated, the activity of the specific active ingredient used, the specific composition used, the age, weight, health condition, sex and diet of the subject, the administration time, administration route and excretion rate of the specific active ingredient, the duration of treatment, the drug that is combined with or coordinated with the specific active ingredient used, and other factors known in the medical field.

[0078] In addition, the present disclosure also encompasses kits (such as pharmaceutical packages). The provided kits can include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a subpackage or other suitable container). In some embodiments, the provided kits can optionally further include a second container containing 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 are combined to form a unit dosage form.

[0079] The compounds and compositions provided herein can be administered by conventional routes, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intravesical, subcutaneous, intracerebroventricular, transdermal, subcutaneous, rectal, vaginal, intraperitoneal, and topical administration (e.g., by powder, ointment, cream, and / or drops).Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), topical administration via blood and / or lymphatic supply, and / or direct administration to a predetermined site.In general, the most suitable administration route depends on a number of factors, including the properties of the drug (e.g., stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether oral administration is acceptable).

[0080] The exact amount of compound required to achieve an effective dose varies from subject to subject, depending on, for example, the subject's race, age, and general condition, the severity of side effects or conditions, the identity of the specific compound, the mode of administration, etc. An effective amount can be contained 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 of the multiple doses contain different compounds described herein or substantially the same compounds 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 administration of the multiple doses to a subject or application of the multiple doses to a tissue or cell is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every 2 days, 1 dose every 3 days, or 1 dose per week. In certain embodiments, the frequency of administration of multiple doses to a subject or application of multiple doses to a tissue or cell is 1 dose per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cell is 2 doses per day.In certain embodiments, when multiple doses are administered to a subject or applied to biological sample, tissue or cell, the period between the first dose and the last dose of the multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of a subject, biological sample, tissue or cell.In certain embodiments, the period between the first dose and the last dose of the multiple doses is 3 months, 6 months or 1 year.In certain embodiments, the period between the first dose and the last dose of the multiple doses is the lifespan of a subject, biological sample, tissue or cell. In certain embodiments, the dosage amounts described herein (e.g., single doses or multiple doses of any dosage amount) independently comprise between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g of a compound described herein.In certain embodiments, the dosage amounts described herein independently include 3 mg to 10 mg of a compound described herein. In certain embodiments, the dosage amounts described herein independently include 10 mg to 30 mg of a compound described herein. In certain embodiments, the dosage amounts described herein independently include 30 mg to 100 mg of a compound described herein. In certain embodiments, the dosage amounts described herein independently include 100 mg to 300 mg of a compound described herein. In certain embodiments, the dosage amounts described herein independently include 300 mg to 1000 mg of a compound described herein.

[0081] The term "cancer" refers to a class of diseases characterized by the abnormal development of cells that grow uncontrollably and have the ability to invade and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed., Hensyl ed., Williams & Wilkins: Philadelphia, 1990.

[0082] The following examples are merely listed as examples of embodiments of the present disclosure and do not constitute any limitations on the present disclosure. Those skilled in the art can understand that any modifications that do not deviate from the essence and concept of the present disclosure will fall within the scope of protection of the present disclosure. Unless otherwise specified, all reagents and equipment used in the following examples are commercially available.

[0083] By Bruker equipment (400MHz) 1 H NMR spectra were measured and chemical shifts are expressed in ppm using an internal standard of tetramethylsilane (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, and dt = doublet of triplets. Coupling constants, when given, are in Hz.

[0084] Mass spectra are obtained by measurement using an LC / MS instrument, and the ionization mode can be ESI or APCI.

[0085] Yantai Huanghai HSGF254 silica gel plates or Qingdao GF254 silica gel plates were used as silica gel plates for thin-layer chromatography. The silica gel plates used for thin-layer chromatography (TLC) had a specification of 0.15-0.2 mm, and those used for separating and purifying the products by thin-layer chromatography had a specification of 0.4-0.5 mm.

[0086] For column chromatography, Yantai Huanghai silica gel 200-300 mesh silica gel is generally used as the carrier.

[0087] In the following examples, all temperatures are in degrees Celsius unless otherwise specified. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods, and commercially available materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Huagong Keji Youxian Gongsi, Jingyan Huagong Keji Youxian Gongsi, etc.

[0088] CD3OD, deuterated methanol. CDCl3, deuterated chloroform. DMSO-d6, deuterated dimethyl sulfoxide. D2O, heavy water.

[0089] By argon atmosphere, it is meant that the reaction flask is connected to an argon balloon with a volume of approximately 1 L.

[0090] Unless otherwise specified in the examples, solutions in the reactions refer to aqueous solutions.

[0091] Compound purification is performed using C18 reverse-phase column preparative purification or C18 reverse-phase column semi-preparative purification, silica gel column chromatography elution system, and thin-layer chromatography, where the elution system is selected from A: petroleum ether and tetrahydrofuran system, B: acetonitrile and water system, and C: petroleum ether and ethyl acetate system, and the volume ratio of the solvents varies depending on the polarity of the compound, and may be adjusted by adding a small amount of an acidic or alkaline reagent such as trifluoroacetic acid, acetic acid, or triethylamine.

[0092] Synthesis of intermediates Synthesis of 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) [ka]

[0093] Step 1: To a solution of 4-fluorophthalic acid (400 mg, 2.17 mmol) in 14.5 mL of THF was added BH3·THF (6.52 mL, 6.52 mmol, 1 M) at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was quenched by adding 30 mL of MeOH, spun dry, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give 4-fluoro-1,2-benzenedimethanol (404.00 mg, crude) as a colorless oil. LC-MS [M-17] + =139.2

[0094] Step 2: Compound 4-fluoro-1,2-benzenedimethanol (236 mg, 1.51 mmol), SOCl (899.01 mg, 7.56 mmol), and DMF (220.94 mg, 3.02 mmol) were dissolved in toluene (15 mL) and stirred at 60 °C for 2 hours. The reaction mixture was spin-dried. After adding saturated aqueous sodium chloride solution (30 mL), the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were spin-dried and purified by silica gel column chromatography (PE:THF = 20:1) to obtain intermediate 1 compound (167.00 mg, yield 57.14%) as a colorless liquid. 1 H-NMR(400MHz,CDCl3) δ 7.39-7.35(m,1H),7.14(dd,J=8.8,2.4H Z ,1H),7.06-7.01(m,1H),4.71(s,4H).

[0095] Synthesis of 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2) [ka] Step 1: 4-Trifluoromethylphthalic acid (770 mg, 3.29 mol) was dissolved in THF (33 mL). At 0 °C, BH3·THF (1 M, 9.87 mL) was added, and the mixture was stirred at 20 °C for 3 h. Then, MeOH (23 mL) was added dropwise at 0 °C to quench the reaction. The quenched product was concentrated and purified by silica gel column chromatography (DCM:MeOH = 20:1) to give 4-trifluoromethyl-1,2-benzenedimethanol (820.00 mg, crude) as a colorless oil. LC-MS [M-17] + =189.1

[0096] Step 2: 4-Trifluoromethyl-1,2-benzenedimethanol (820 mg, 3.93 mol) and DMF (574.36 mg, 7.86 mmol, 608.44 μL) were dissolved in toluene (36 mL) and stirred at 60° C. for 2 hours under nitrogen protection. After concentration, the concentrated product was purified by silica gel column chromatography (PE:THF=20:1) to give Intermediate 2 (410.00 mg, 39.8% yield) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ7.61(s,1H),7.60(dd,J=8.0,1.2Hz,1H),7.53(d,J=8.0 Hz,1H),4.76-4.74(m,4H).

[0097] Example 1: Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one [ka] Step 1: Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (1b) Compound 5-fluoro-6-hydroxycyanopyridine 1a (500 mg, 3.62 mmol) was dissolved in DMF (10 mL), and then MeI (591.24 mg, 4.16 mmol) and KCO (999.28 mg, 7.24 mmol) were added separately. The mixture was stirred at 25 °C for 1 hour. After saturated NaCl (30 mL) was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried, spin-dried, and purified by silica gel column chromatography (PE:THF = 3:1) to obtain compound 1b (312.00 mg, 56.65% yield) as a white solid. LC-MS [M+1] + =153.1 1 H-NMR(400MHz,DMSO) δ 7.53(dd,J=9.6,8.0H Z,1H),7.18(dd,J=7.6,4.8H Z ,1H),3.60(s,3H).

[0098] Step 2: Synthesis of tert-butyl 4-(((6-cyano-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate 1d At 0 °C, compound tert-butyl-4-(hydroxymethyl)piperidine-1-carbonate 1c (2.21 g, 10.25 mmol) was dissolved in THF (20 mL), and NaH (656.24 mg, 16.41 mmol, 60% purity) was slowly added. The mixture was stirred under nitrogen protection for 30 minutes. At 0 °C, compound 1b (312 mg, 2.05 mmol) was added to the reaction mixture, and the mixture was heated to 25 °C and stirred under nitrogen protection for 1 hour. The reaction mixture was quenched by pouring into ice water, extracted with ethyl acetate (50 mL × 3) and saturated NaCl (30 mL × 3), and the combined organic phases were dried, spin-dried, and purified by silica gel column chromatography [PE (0.1% NH4OH):THF = 0:1] to obtain compound 1d (602.00 mg, 80.01% yield) as a white solid. LC-MS [M+1] + =348.1

[0099] Step 3: Synthesis of tert-butyl 4-(((6-(aminomethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate 1e 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), and the mixture was stirred under hydrogen at 25° C. for 2 hours. The reaction mixture was filtered with methanol (50 mL×3), and the organic phases were combined, dried, and spin-dried to give compound 1e (258.00 mg, crude) as a yellow oil. LC-MS [M+1] + =352.2

[0100] 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 Compound 1e (100 mg, 284.54 μmol) was dissolved in toluene (3 mL), followed by the addition of compound o-dichlorobenzyl (74.72 mg, 0.43 mmol) and DIEA (110.12 mg, 0.85 mmol), and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was spun dry and extracted with ethyl acetate (30 mL × 3) and HO (10 mL × 3). The organic phases were combined, dried, and spun dry. After purification by silica gel column chromatography (PE:THF = 0:1), compound 1f (49.00 mg, 32.48% yield) was obtained as a yellow oil. LC-MS [M+1] + =454.4

[0101] Step 5: Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one 1g 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 spun to dryness to give compound 1g (75.00 mg, crude) as a gray solid. The product could be used directly in the next reaction without purification.

[0102] Step 6: Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 1) Compound 1g (75 mg, 192.35 μmol) and DIEA (74.44 mg, 577.04 μmol) were mixed and 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 at 0° C. The reaction mixture was directly concentrated and purified by preparative HPLC [ACN:H2O (0.1% NH4HCO3)] to give compound 1 (5.84 mg, 7.04% yield) as a white solid. (Free base) LC-MS [M+1] + =432.1 1 H-NMR(400MHz,MeOD) δ 7.20-7.16(m,4H),6.89(d,J=8.0 Hz,1H),6.38(d,J=7.6H Z ,1H),3.91(s,4H),3.87(s,2H),3.84(d,J=6.0 Hz,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).

[0103] Example 2: Synthesis of 6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one [ka] Step 1: Synthesis of tert-butyl 4-(((6-cyano-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2b) Compound 1a (300 mg, 2.17 mmol) was dissolved in THF (22 mL), and NaH (695.15 mg, 17.38 mmol) was added at 0 °C, and the mixture was stirred for 30 min. Subsequently, 1c was added to the reaction mixture, and the reaction was heated to room temperature and further stirred for 1 h. The reaction mixture was quenched with saturated NaHCO3 (20 mL). After extraction with EA (20 mL × 3), the organic phases were combined. After purification by silica gel column chromatography (PE:THF = 3.3:1), the desired compound 2b (153 mg, 15.00% yield) was obtained as a pale yellow oil. LC-MS [M-56] + =278.1

[0104] Step 2: Synthesis of tert-butyl 4-(((6-(aminomethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2c) Compound 2b (153 mg, 2.18 mmol) was dissolved in MeOH (15 mL) and Raney nickel (26.93 mg, 458.93 mmol) was added. The mixture was stirred under a hydrogen atmosphere at 25 °C for 1 h, filtered, and the filtrate was directly spun to dryness to give crude compound 2c (153.00 mg, crude) as a brown oil, which could be used directly in the next reaction without further purification. LC-MS [M+1] + =338.3

[0105] Step 3: Synthesis of tert-butyl 4-(((6-(isoindolin-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (2d) Compound 2c (153 mg, 136.04 μmol), compound o-dichlorobenzyl (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 mixture was directly spun dry and purified by preparative TLC [PE (0.1% NH4OH):THF = 1:4] to give compound 2d (50.00 mg, 26.45% yield) as a brown solid. LC-MS [M+1] + =440.3

[0106] Step 4: Synthesis of 6-(isoindolin-2-ylmethyl)-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one (2e) Compound 2d (50 mg, 113.75 μmol) was dissolved in HCl / dioxane (4 mL) and stirred at 25° C. for 30 minutes. The reaction solution was directly removed under reduced pressure to give compound 2e (50.00 mg, crude) as a brown solid. The product could be used directly in the next reaction without purification. LC-MS [M+1] + =340.2

[0107] Step 5: Synthesis of 6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (2) Compound 2e (50 mg, 146.44 μmol) and DIEA (56.78 mg, 439.31 μmol) were mixed and 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 solution was directly removed under reduced pressure to give a brown oil. The mixture was dissolved in THF (2.2 mL) and HO (1.4 mL), followed by the addition of LiOH (4.28 mg, 178.77 μmol). The mixture was stirred for 1 hour at 25° C. The reaction mixture was purified by preparative HPLC [ACN:HO (0.1% NHHCO)] to give compound 2 (10.93 mg, purity 98.07%, yield 43.58%) as a white solid. LC-MS [M-1]=416.1 1 HNMR(400MHz,DMSO-d6) δ 11.43(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).

[0108] Example 3. Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 3) [ka] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =458.1 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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).

[0109] Example 4. Synthesis of 4-(((6-(isoindolin-2-ylmethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 4) [ka]

[0110] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing methylsulfonyl chloride in step 6 with dimethylaminosulfonyl chloride. LC-MS [M+1] + =460.9 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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).

[0111] 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) [ka]

[0112] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1). LC-MS [M+1] + =450.1 1 HNMR(400MHz,DMSO-d6) δ 7.26-7.2(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=10 Hz,3H),1.37-1.28(m,2H).

[0113] Example 6. Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-(oxetan-3-ylmethylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 6) [ka] 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) and stirred at 100 °C for 4 h. After concentration to remove DMF, water (20 mL) and ethyl acetate (30 mL) were added and the liquid was separated. The aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried, concentrated, and then purified by silica gel column chromatography (PE:THF = 92:8) to give 6-3 (167.00 mg, 25.96% yield) as a colorless oil. LC-MS [M-56] + =132.9

[0114] Step 2: 6-3 (160 mg, 1.21 mmol) and aqueous hydrochloric acid (2 M, 151.31 μL) were dissolved in acetonitrile (4.85 mL), and NCS (646.55 mg, 4.84 mmol) was added portionwise at 0 °C. The mixture was stirred at 0 °C for 1 h, then concentrated and purified by silica gel column chromatography (PE:THF = 85:15) to give 6-4 (130.00 mg, 61.73% yield) as a colorless oil. 1 HNMR(400MHz,CDCl3) δ 5.29-4.93(m,5H).

[0115] Step 3: 1g (30 mg, 42.44 μmol) and DIEA (16.45 mg, 127.31 μmol) were dissolved in DCM (2 mL), and 6-4 (6.65 mg, 42.44 μmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min, then concentrated and purified by preparative HPLC [ACN:HO (0.1% NHHCO)] to give 6 (8.28 mg, 40.84% ​​yield, 99.12% purity) as a white solid. LC-MS [M+1] + =474.3 1 HNMR(400MHz,DMSO-d6) δ 7.20-7.14(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).

[0116] Example 7. Synthesis of 3-((1-acetylpiperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 7) [ka]

[0117] Similar to the synthetic route in Example 1, the above compound could be obtained by replacing methylsulfonyl chloride with acetyl chloride in step 6. LC-MS [M+1] + =396.1 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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).

[0118] Example 8. Synthesis of 3-((1-acetylpiperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-methylpyridin-2(1H)-one (Compound 8) [ka]

[0119] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) and replacing methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =476.1 1 HNMR(400MHz,DMSO-d6) δ 7.22-7.20(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).

[0120] 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) [ka]

[0121] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing methylsulfonyl chloride with methyl chloroformate in step 6. LC-MS [M+1] + =411.6 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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=6.0 Hz,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).

[0122] Example 10. Synthesis of 6-(isoindolin-2-ylmethyl)-1-methyl-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 10) [ka]

[0123] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing methylsulfonyl chloride in step 6 with trifluoromethanesulfonic anhydride. LC-MS [M+1] + =486.1 1 HNMR(400MHz,DMSO-d6) δ 7.23-7.17(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).

[0124] Example 11. Synthesis of 4-(((6-((5-fluoroisoindolin-2-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)-N,N-dimethylpiperidine-1-sulfonamide (Compound 11) [ka]

[0125] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) and replacing methylsulfonyl chloride in step 6 with dimethylaminosulfonyl chloride. LC-MS [M+1] + =479.3 1 HNMR(400MHz,DMSO-d6) δ 7.26-7.22(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).

[0126] Example 12. Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-methyl-3-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 12) [ka]

[0127] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1) and replacing methylsulfonyl chloride in step 6 with oxetane-3-sulfonyl chloride (6-4). LC-MS [M+1] + =492.1 1 HNMR(400MHz,DMSO-d6) δ 7.26-7.22(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).

[0128] 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) [ka]

[0129] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2). LC-MS [M+1] + =500.1 1HNMR(400MHz,DMSO-d6) δ 7.58(s,1H),7.53(d,J=8.0 Hz,1H),7.42(d,J=8.0 Hz,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=10 Hz,3H),1.33-1.23(m,2H).

[0130] 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) [ka]

[0131] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane and o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2). LC-MS [M+1] + =503.1 1 HNMR(400MHz,DMSO-d6) δ 7.62(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=6.0 Hz,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).

[0132] Example 15. Synthesis of 6-((5-fluoroisoindolin-2-yl)methyl)-1-(methyl-d3)-3-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 15) [ka]

[0133] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane, o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1), and methylsulfonyl chloride in step 6 with oxetane-3-sulfonyl chloride (6-4). LC-MS [M+1] + =495.1 1 HNMR(400MHz,DMSO-d6) δ 7.22-7.19(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=12.0 Hz,2H),2.79-2.73(m,2H),1.88-1.76(m,3H),1.26-1.17(m,2H).

[0134] 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) [ka]

[0135] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane and methylsulfonyl chloride in step 6 with trifluoromethanesulfonic anhydride. LC-MS [M+1] + =489.1 1 HNMR(400MHz,DMSO-d6) δ 7.23-7.17(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).

[0136] Example 17. Synthesis of 6-(isoindolin-2-ylmethyl)-1-(methyl-d3)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 17) [ka]

[0137] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane. LC-MS [M+1] + =435.3 1 HNMR(400MHz,DMSO-d6) δ 7.20-7.14(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).

[0138] Example 18. Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-6-(isoindolin-2-ylmethyl)-1-(methyl-d3)pyridin-2(1H)-one (Compound 18) [ka]

[0139] Similar to the synthetic route of Example 1, by replacing iodomethane in step 1 with deuterated iodomethane and methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride, the above compound could be obtained. LC-MS [M+1] + =460.9 1 HNMR(400MHz,DMSO-d6) δ 7.20-7.14(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=12.0 Hz,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).

[0140] 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) [ka]

[0141] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane, o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2), and methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =529.2 1 HNMR(400MHz,DMSO-d6) δ 7.58(s,1H),7.52(d,J=7.6Hz,1H),7.42(d,J=8.0 Hz,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).

[0142] 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) [ka]

[0143] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane, o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1), and methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =479.3 1HNMR(400MHz,DMSO-d6) δ 7.22-7.19(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=12.0 Hz,2H),2.85-2.79(m,2H),2.56-2.50(m,1H),1.85-1.79(m,3H),1.30-1.20(m,2H),0.96-0.86(m,4H).

[0144] Example 21. Synthesis of 3-((1-(cyclopropylsulfonyl)piperidine-4-methyl)methoxy)-1-methyl-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 21) [ka]

[0145] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (intermediate 2) and replacing methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =526.2 1 HNMR(400MHz,DMSO-d6) δ 7.59(s,1H),7.53(d,J=8.0 Hz,1H),7.43(d,J=8.0 Hz,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).

[0146] 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) [ka]

[0147] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (Intermediate 2) and replacing methylsulfonyl chloride in step 6 with dimethylaminosulfonyl chloride. LC-MS [M+1] + =529.2 1 HNMR(400MHz,DMSO-d6) δ 7.62(s,1H),7.56(d,J=8.0 Hz,1H),7.46(d,J=8.0 Hz,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).

[0148] Example 23. Synthesis of 1-methyl-3-((1-(oxetan-3-ylsulfonyl)piperidin-4-yl)methoxy)-6-((5-(trifluoromethyl)isoindolin-2-yl)methyl)pyridin-2(1H)-one (Compound 23) [ka]

[0149] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing o-dichlorobenzyl in step 4 with 4-trifluoromethyl-1,2-dichlorobenzyl (intermediate 2) and replacing methylsulfonyl chloride in step 6 with oxetane-3-sulfonyl chloride (6-4). LC-MS [M+1] + =542.1 1 HNMR(400MHz,DMSO-d6) δ 7.58(s,1H),7.53(d,J=8.8Hz,1H),7.42(d,J=8.0 Hz,1H),6.75(d,J=7.6H Z ,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=12.0 Hz,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).

[0150] 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) [ka]

[0151] Similar to the synthetic route of Example 1, the above compound could be obtained by replacing iodomethane in step 1 with deuterated iodomethane and o-dichlorobenzyl in step 4 with 4-fluoro-1,2-dichlorobenzyl (Intermediate 1). LC-MS [M+1] + =453.1 1 HNMR(400MHz,DMSO-d6) δ 7.26-7.22(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).

[0152] Example 25. Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 25) [ka]

[0153] Step 1: Synthesis of 5-fluoro-1-ethyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (25b) 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), and iodoethane (203.29 mg, 1.30 mmol) was added. The mixture was stirred at 25 °C for 18 hours. Saturated NaCl (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, spin-dried, and purified by silica gel column chromatography (PE:THF = 3:1) to give compound 25b (50.00 mg, 27.71% yield) as a white solid. 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).

[0154] Step 2: Synthesis of tert-butyl 4-(((6-cyano-1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (25d) 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, purity 60%) was added. The mixture was then stirred at 0 ° C. for 30 minutes. A solution of compound VN2202-022-2 (50 mg, 300.93 μmol) in anhydrous THF (1 mL) was added at 0 ° C., and the mixture was heated to 20 ° C. and stirred for 1 hour. After quenching by adding saturated NH Cl (30 mL), the system was extracted three times with EA (30 mL). The organic phases were then combined, dried, concentrated, and purified by SGC (PE:THF = 75:25) to obtain compound VN2202-022-4 (100.00 mg, yield 82.75%) as a colorless oil. LC-MS [M-99] + =262.20

[0155] At 0 °C, compound tert-butyl-4-(hydroxymethyl)piperidine-1-carbonate 1c (194.36 mg, 902.79 μmol) was dissolved in THF (3 mL), and NaH (60.19 mg, 1.50 mmol, purity 60%) was slowly added and stirred under nitrogen protection for 30 minutes. At 0 °C, a solution of compound 25b (50 mg, 300.93 μmol) in anhydrous tetrahydrofuran (1 mL) was added to the reaction system, which was heated to 25 °C and stirred under nitrogen protection for 1 hour. After quenching by adding saturated NH4Cl (30 mL), the system was extracted three times with EA (30 mL). The organic phases were combined, dried, concentrated, and then purified by silica gel column chromatography [PE:THF = 75:25] to obtain compound 25d (100.00 mg, yield 82.75%) as a colorless oil. LC-MS [M-99] + =262.20

[0156] Step 3: Synthesis of tert-butyl 4-(((6-(aminomethyl)-1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)methyl)piperidine-1-carbonate (25e) 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, followed by stirring for 2 hours at 20° C. After filtration, the filtrate was concentrated to give compound 25e (113.00 mg, crude) as a colorless oil. LC-MS [M-99] + =366.3

[0157] 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) Compound 1e (113 mg, 309.19 μmol) was dissolved in toluene (3 mL), and then compound o-dichlorobenzyl (70.36 mg, 401.95 μmol) and DIEA (153 μL, 927 μmol) were added and stirred at 100 °C for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate (30 mL × 3) and HO (10 mL × 3). The organic phases were combined, dried, and concentrated. After purification by silica gel column chromatography (PE:THF = 0:1), compound 25f (90.00 mg, 56.02% yield) was obtained as a white solid. LC-MS [M+1] + =468.3

[0158] Step 5: Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-(piperidin-4-ylmethoxy)pyridin-2(1H)-one (25 g) Compound 25e (90 mg, 192.47 μmol) was dissolved in hydrochloric acid / dioxane (4 M, 3 mL) and stirred at 20° C. for 2 hours, and then the system was concentrated to give compound 25g (130.00 mg, crude) as a black solid.

[0159] Step 6: Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 25) Compound 25g (20.62 mg, crude) and diisopropylethylamine (21.75 mg, 168.31 μmol) were dissolved in dichloromethane (1 mL), and methylsulfonyl chloride (6.43 mg, 56.10 μmol) was added dropwise to the system under ice bath conditions, which was stirred for 30 minutes, then concentrated and purified by semi-preparative HPLC [acetonitrile:water (0.1% ammonium bicarbonate)] to give compound 25 (2.64 mg, yield 9.83%) as a light brown solid. LC-MS [M+1] + =446.1 1 HNMR(400MHz,DMSO-d6) δ 7.20-7.14(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).

[0160] Example 26. Synthesis of 3-((1-(cyclopropylsulfonyl)piperidin-4-yl)methoxy)-1-ethyl-6-(isoindolin-2-ylmethyl)pyridin-2(1H)-one (Compound 26) [ka]

[0161] Similar to the synthetic route of Example 25, the above compound could be obtained by replacing methylsulfonyl chloride in step 6 with cyclopropylsulfonyl chloride. LC-MS [M+1] + =472.2 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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=12.0 Hz,2H),2.89-2.83(m,2H),2.60-2.55(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).

[0162] Example 27. Synthesis of 1-ethyl-6-(isoindolin-2-ylmethyl)-3-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)methoxy)pyridin-2(1H)-one (Compound 27) [ka]

[0163] Similar to the synthetic route of Example 25, by replacing methylsulfonyl chloride in step 6 with trifluoromethanesulfonic anhydride, the above compound 27 could be obtained. LC-MS [M+H] + =500.1 1 HNMR(400MHz,DMSO-d6) δ 7.21-7.19(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).

[0164] 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) [ka]

[0165] To a mixture of dioxane (70 mL) and acetonitrile (30 mL), compound 25g (3.8 g, 4.31 mmol), compound sulfamide (1.66 g, 17.26 mmol), and DIEA (3.35 g, 25.89 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 16 h. After cooling, the mixture was concentrated to remove the solvent and purified by SGC (DCM:MeOH = 97:3 to 85:15) to give crude product 28 (800 mg) and crude product 31 (200 mg). 28 (800 mg, crude) was added to 3 M aqueous hydrochloric acid (80 mL), and dichloromethane (80 mL) was added slowly with stirring, resulting in precipitation of a solid. After filtration, the filter cake was dried to give the hydrochloride salt of 28 (210.00 mg, 99.37% purity) as a pale green solid. After layering the mother liquor, the aqueous phase was adjusted to pH-8 with sodium bicarbonate and extracted twice with dichloromethane (80 mL). The organic phases were combined, dried, and concentrated to give a solid, which was then purified by preparative HPLC to give the free base of 28 (270.00 mg, 13.81% yield, 98.55% purity) as a white solid. The crude product 31 (200 mg) was purified by preparative HPLC to give 31 (30.00 mg, purity 99.23%) as a white solid (trifluoroacetate salt).

[0166] The data for the free base of compound 28 were as follows: LC-MS [M+H] + =447.1 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.19(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).

[0167] The data for the hydrochloride salt of compound 28 were as follows: 1H-NMR(400MHz,DMSO-d6) δ 7.37-7.36(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,2H),3.82-3.7 6(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).

[0168] The data for the trifluoroacetate salt of compound 31 were as follows: LC-MS [M+H] + =448.2 1 H-NMR(400MHz,DMSO-d6) δ 7.23-7.19(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).

[0169] 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) [ka] Under ice-bath conditions, 25g (50 mg, 113.53 μmol, crude), methylsulfamoyl chloride (16.18 mg, 124.88 μmol), and diisopropylethylamine (44.02 mg, 340.60 μmol) were added to dichloromethane (2 mL). After the addition was complete, the mixture was stirred for 30 min. The reaction mixture was directly concentrated and subjected to preparative HPLC to obtain the desired product 29 (2.18 mg, 4.39 μmol, 3.87% yield) as a white solid. LC-MS [M+H] + =461.3 1 HNMR(400MHz,DMSO-d6) δ 7.24-7.17(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).

[0170] 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) [ka] Compound 25g (800 mg, 2.18 mmol) and DIEA (844.07 mg, 6.53 mmol) were dissolved in DCM (30 mL) in an ice bath, and compound aminosulfonyl chloride (301.83 mg, 2.61 mmol) was added to the system, followed by stirring for 2 hours. 1 M aqueous hydrochloric acid (30 mL) was added, and the system was extracted three times with dichloromethane (50 mL). The organic phases were combined, dried, concentrated, and purified by SGC (DCM:MeOH = 5:1) followed by preparative HPLC to give 30 (30.00 mg, 2.58% yield) as a white solid. LC-MS [M+1] + =526.2 1H-NMR(400MHz,DMSO-d6) δ 7.26-7.24(m,4H),6.78(d,J=7.6Hz,1H),6.29(s,1H),4.71-3.90(m,8H),3.73(d,J=6.0Hz,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).

[0171] Test Example 1 In the synthesis of all vertebrate steroid hormones, the conversion of cholesterol to pregnenolone is the first and rate-limiting step. This conversion reaction is catalyzed by a unique cytochrome P450scc (CYP11A) and is carried out by the C 22 -Hydroxycholesterol and C 20 ,C 22 -dihydroxycholesterol and C 20 ,C 22 -C in dihydroxycholesterol 20 -C 22 CYP11A1-catalyzed cleavage of a carbon-carbon single bond involves a two-step sequential monooxygenation reaction to generate one molecule of pregnenolone and one molecule of 4-methylvaleraldehyde. Therefore, the inhibitory effect of compounds on CYP11A1 was identified by detecting their ability to inhibit pregnenolone synthesis.

[0172] To detect the ability of compounds to inhibit CYP11A1, we determined the ability of various compounds to inhibit pregnenolone biosynthesis by detecting the concentration of pregnenolone using an enzyme-linked immunosorbent assay (ELISA) (Abnova Pregnenolone ELISA Kit, KA1912). The human adrenocortical carcinoma cell line NCI-H295R (Procell, CL-0399) was used as an enzyme source because it has been demonstrated to express all essential steroid synthetases. To determine the 50% inhibitory concentration (IC50) of CYP11A1 inhibition by various compounds, compounds were added to NCI-H295R cell cultures, and after incubation, the concentration of pregnenolone in the culture supernatant was determined.

[0173] 95 μl of NCI-H295R cells were harvested and cultured overnight in a 96-well culture plate in a cell incubator at 37°C and 5% CO2 using specialized cell culture medium (Procell, CM-0399). Then, 5 μl / well of various concentrations of test compounds in DMSO (Sigma, D8418) was added, followed by 24-hour incubation. The final concentrations of the test compounds 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 to obtain 80 μl / well of cell culture supernatant, which was diluted 1:8 with cell culture medium. The concentration of pregnenolone therein was then determined by ELISA. A standard curve was constructed using pregnenolone standards during ELISA detection. Experiments were performed using replicate wells. ELISA well plates were coated with anti-pregnenolone rabbit polyclonal antibody. 50 μl / well of diluted culture supernatant or standard or reference substance was added to the ELISA plate strip, followed by 100 μl of pregnenolone-HRP conjugate solution. The plate was incubated at room temperature at 200 rpm on a plate shaker (QILINBEIER, QB-9002) for 1 hour. The plate was then washed three times with 300 μl of wash solution each time and tapped dry on absorbent paper. 150 μl of TMB substrate was added. The plate was incubated at room temperature on a plate shaker for 10-15 minutes, after which 50 μl of stop solution was added. Absorbance was measured at 450 nm using a microplate reader (PerkinElmer, 2105). IC was determined using GraphPad Prism software. 50 values ​​were calculated. Inhibition rate (%) = 100% - (readout 化合物 -Average reading 陽性対照 ) / (average read ブランク対照 -Average reading 陽性対照 )×100%. [Table 1]

[0174] Test Example 2 To detect the ability of compounds to inhibit CYP11A1, we determined the ability of various compounds to inhibit testosterone biosynthesis by detecting the concentration of testosterone (Abnova Testosterone ELISA Kit, KA6502) using an enzyme-linked immunosorbent assay (ELISA). Similarly, the human adrenocortical carcinoma cell line NCI-H295R (Procell, CL-0399) was used as the enzyme source. Compounds were added to NCI-H295R cell cultures. After incubation, the testosterone concentration in the culture supernatant was determined.

[0175] 95 μl of NCI-H295R cells were harvested and cultured overnight in a 96-well culture plate in a specialized cell culture medium (Procell, CM-0399) in a cell incubator at 37°C and 5% CO2. 5 μl / well of various concentrations of test compounds in DMSO (Sigma, D8418) was then added, followed by incubation for 24 hours. The final concentrations of the test compounds 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 to obtain 80 μl / well of cell culture supernatant, in which the testosterone concentration was determined by ELISA. A standard curve was generated using testosterone standards during ELISA detection. Experiments were performed with replicate wells. ELISA well plates were coated with anti-testosterone monoclonal antibodies. 25 μl / well of culture supernatant or standard solution or reference substance was added to the ELISA plate strip, followed by 200 μl of testosterone-HRP conjugate solution. The plate was incubated at room temperature at 200 rpm on a plate shaker (QILINBEIER, QB-9002) for 1 hour. The plate was then washed three times with 300 μl of washing solution each time and tapped dry on absorbent paper. 200 μl of TMB substrate was added. The plate was incubated at room temperature on a plate shaker for 15 minutes, and then 100 μl of stop solution was added. The absorbance was measured at 450 nm using a microplate reader (PerkinElmer, 2105). IC was determined using GraphPad Prism software. 50 values ​​were calculated. Inhibition rate (%) = 100% - (readout 化合物 -Average reading 陽性対照 ) / (average read ブランク対照 -Average reading 陽性対照 )×100%. [Table 2]

[0176] Test Example 3. Pharmacokinetic evaluation Comparative Example 1, Example 185 was synthesized by referring to WO 2018115591, and the structural formula was as follows: [ka]

[0177] ICR mouse experiments 1. Overview ICR mice are used as test animals, and the plasma drug concentrations of the compounds of the present disclosure are determined by LC / MS / MS at various times after intragastric administration (ig).The pharmacokinetic behavior of the compounds of the present disclosure in ICR mice is tested, and their pharmacokinetic characteristics are evaluated.

[0178] 2. Experimental Protocol 2.1 Experimental Drugs Compound of Example 1 Compound of Example 28 Compound of Comparative Example 1

[0179] 2.2 Experimental animals Twenty-seven male ICR mice were recruited and randomly divided into three groups. The mice were provided by JOINNLaboratories (Suzhou) Co., Ltd. The mice were fasted overnight for at least 12 hours before administration. During the fasting and experiment, drinking water was saline.

[0180] 2.3 Pharmaceutical Preparations A fixed amount of the test compound was collected and adjusted to a final concentration of 2 mg / mL for oral administration. The preparation solvent was 0.5% Tween 80 in 0.5% methylcellulose aqueous solution. After preparation was complete, 1N hydrochloric acid was added to adjust the solution to a clear pH (4-5).

[0181] 2.4 Administration The dose was 20.0 mg / kg and the administration volume was 10.0 ml / kg.

[0182] 3. Procedure At least 0.2 mL of blood was collected intravenously (three animals per time point) at 15, 30, 1, 2, 4, 6, 8, 10, and 24 hours after administration and placed in EDTA-K2 anticoagulation test tubes. The collected blood samples were then placed in labeled ice-water bath centrifuge tubes, and the plasma was quickly separated by centrifugation. The centrifugation conditions were 4000 rpm, 10 minutes, and 4°C. The plasma was stored at -40°C or below for later testing. Food feeding was resumed 4 hours after administration.

[0183] Determination of the content of the target compound in ICR mouse plasma. After thawing the plasma sample at room temperature, 50 μL was taken and added to 300 μL of internal standard (200 ng / mL, acetonitrile, terfenadine). The mixture was vortexed and mixed uniformly for 1 minute, then centrifuged at 15,400 g for 10 minutes at 4°C. The supernatant was collected and injected for LC / MS / MS analysis.

[0184] 4. Data Collection and Statistical Analysis Analyst 1.6.3 software output data such as the original chromatogram, concentration and precision. The mean, standard deviation, coefficient of variation, etc. were calculated using Microsoft Excel 2007 software. AUC, C were calculated by non-compartmental analysis (NCA) using WinNonlin software. max and t 1 / 2 The main pharmacokinetic parameters were calculated.

[0185] 5. Pharmacokinetic parameter results [Table 3]

[0186] The above description is only for specific embodiments of the present disclosure, and the protection scope of the present disclosure is not limited thereto. Any modifications or replacements that can be easily thought of by anyone familiar with the technical field within the technical scope disclosed by the present disclosure should be embraced by the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure should be based on the protection scope of the claims.

Claims

1. A compound represented by general formula (I), or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof: 【Chemistry 1】 (R １ is a hydrogen atom, C １－６ Alkyl, C ３－６ Cycloalkyl, C ６－１４ aryl, a 4- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, １－６ alkyl, the C ３－６ cycloalkyl, the C ６－１４ aryl, said 4- to 8-membered heterocyclyl and said 5- to 8-membered heteroaryl are each independently selected from the group consisting of one or more R ａ optionally substituted by substituents, Each R ａ are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C １－６ Alkoxy, C １－６ Alkyl, C ３－６ cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; １－６ Alkoxy, the above C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, the C ３－６ cycloalkyl, the 4- to 8-membered heterocycloalkyl is C １－６ Alkyl, haloC １－６ Alkyl, halogen, amino, hydroxyl, cyano or C １－６ optionally substituted by 1 to 3 substituents selected from alkoxy; R ２ is a hydrogen atom, a halogen atom, or 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 4- to 8-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ Alkoxy, the above C ３－６ cycloalkyl, the C ６－１４ aryl, said 4- to 8-membered heterocyclyl and said 5- to 8-membered heteroaryl are each independently selected from the group consisting of one or more R ｂ optionally substituted by substituents, Each R ｂ are the same or different and are 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, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; １－６ Alkoxy, the above C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ３－６ cycloalkyl, the 4- to 8-membered heterocycloalkyl is C １－６ Alkyl, haloC １－６ Alkyl, halogen, amino, hydroxyl, cyano or C １－６ optionally substituted by 1 to 3 substituents selected from alkoxy; R ３ But C １－７ Alkylcarbonyl, C ２－７ Alkenylcarbonyl, C ２－７ Alkynylcarbonyl, C １－７ Alkoxycarbonyl, C ３－７ cycloalkylcarbonyl, 3-8 membered heterocycloalkylcarbonyl containing 1-3 heteroatoms selected from N, O and S, NR ｃ R ｄ Carbonyl, sulfonic acid group, aminosulfonyl C １－７ AlkylS(O) ２ -, C ２－７ Alkenyl S(O) ２ -, C ２－７ AlkynylS(O) ２ -, C １－７ Alkoxy S(O) ２ -, C ３－７ CycloalkylS(O) ２ 3-8 membered heterocycloalkylS(O) containing 1-3 heteroatoms selected from -, N, O and S ２ -, NR ｃ R ｄ S (O) ２ -, wherein C １－７ Alkylcarbonyl, the C ２－７ Alkenylcarbonyl, the C ２－７ Alkynylcarbonyl, the C １－７ Alkoxycarbonyl, the C ３－７ cycloalkylcarbonyl, the 3- to 8-membered heterocycloalkylcarbonyl, the C １－７ AlkylS(O) ２ -, the above C ２－７ Alkenyl S(O) ２ -, the above C ２－７ AlkynylS(O) ２ -, the above C １－７ Alkoxy S(O) ２ -, the above C ３－７ CycloalkylS(O) ２ -, the 3- to 8-membered heterocycloalkylS(O) ２ - is one or more R ｅ optionally substituted by substituents, R ｃ and R ｄ But hydrogen, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl and aminosulfonyl, or R ｃ and R ｄ together with the N atom to which it is attached form a 3- to 6-membered heterocycle, Each R ｅ are the same or different and are 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, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; １－６ Alkoxy, the above C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ３－６ cycloalkyl, the 4- to 8-membered heterocycloalkyl is C １－６ Alkyl, haloC １－６ Alkyl, halogen, amino, hydroxyl, cyano or C １－６ optionally substituted by 1 to 3 substituents selected from alkoxy; n1 is an integer of 0, 1, 2, 3, or 4; and n2 is an integer of 1, 2, 3, or 4.

2. R １ is a hydrogen atom, C １－４ Alkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, １－４ alkyl, the C ３－６ cycloalkyl, the C ６－１０ aryl, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are each independently selected from the group consisting of 1 to 3 R ａ optionally substituted by substituents, Each R ａ are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C １－４ Alkoxy, C １－４ Alkyl, C ３－６ cycloalkyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Preferably, R ２ is a hydrogen atom, a halogen atom, or C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Alkoxy, C ３－６ Cycloalkyl, C ６－１０ aryl, 4- to 6-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S; １－４ alkyl, the C ２－４ alkenyl, the C ２－４ Alkynyl, the C １－４ Alkoxy, the above C ３－６ cycloalkyl, the C ６－１０ aryl, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are each independently selected from the group consisting of one or more R ｂ optionally substituted by substituents, Each R ｂ are the same or different and are 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, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S; Preferably, R ３ But C １－４ Alkylcarbonyl, C ２－４ Alkenylcarbonyl, C ２－４ Alkynylcarbonyl, C １－４ Alkoxycarbonyl, C ３－６ cycloalkylcarbonyl, sulfonic acid group, aminosulfonyl, 3- to 6-membered heterocycloalkylcarbonyl containing 1 to 3 heteroatoms selected from N, O and S, NR ｃ R ｄ Carbonyl, C １－４ AlkylS(O) ２ -, C ２－４ Alkenyl S(O) ２ -, C ２－４ AlkynylS(O) ２ -, C １－４ Alkoxy S(O) ２ -, C ３－６ CycloalkylS(O) ２ 3-6 membered heterocycloalkylS(O) containing 1-3 heteroatoms selected from -, N, O and S ２ -, NR ｃ R ｄ S (O) ２ -, wherein C １－４ Alkylcarbonyl, the C ２－４ Alkenylcarbonyl, the C ２－４ Alkynylcarbonyl, the C １－４ Alkoxycarbonyl, the C ３－６ cycloalkylcarbonyl, the 3- to 6-membered heterocycloalkylcarbonyl, the C １－４ AlkylS(O) ２ -, the above C ２－４ Alkenyl S(O) ２ -, the above C ２－４ AlkynylS(O) ２ -, the above C １－４ Alkoxy S(O) ２ -, the above C ３－６ CycloalkylS(O) ２ -, the 3- to 6-membered heterocycloalkylS(O) ２ - is 1 to 3 R ｅ optionally substituted by substituents, R ｃ and R ｄ But hydrogen, C １－４ Alkoxy, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, C ３－６ cycloalkyl and aminosulfonyl, or R ｃ and R ｄ together with the N atom to which it is attached form a 3- to 6-membered heterocycle, Each R ｅ are the same or different and are 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 2. The compound of claim 1, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein each of the 4 to 6 membered heterocycloalkyls containing 1 to 3 heteroatoms selected from cycloalkyl, N, O and S is independently selected from the group consisting of cycloalkyl, 4 to 6 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S.

3. R １ is a hydrogen atom, C １－３ Alkyl, C ３－６ cycloalkyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, １－３ alkyl, the C ３－６ cycloalkyl, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are each independently one or two R ａ optionally substituted by substituents, Each R ａ are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C １－３ Alkoxy, C １－３ Alkyl, C ３－６ cycloalkyl; Preferably, R ２ is a hydrogen atom, a halogen atom, or 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 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O and S, a 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, １－３ alkyl, the C ２－３ alkenyl, the C ２－３ Alkynyl, the C １－３ Alkoxy, the above C ３－６ cycloalkyl, the C ６－１０ aryl, the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are each independently selected from the group consisting of one or more R ｂ optionally substituted by substituents, Each R ｂ are the same or different and are 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, R ３ But C １－３ Alkylcarbonyl, C ２－３ Alkenylcarbonyl, C ２－３ Alkynylcarbonyl, C １－３ Alkoxycarbonyl, C ３－６ cycloalkylcarbonyl, sulfonic acid group, aminosulfonyl, 3- to 6-membered heterocycloalkylcarbonyl containing 1 or 2 heteroatoms selected from N, O and S, NR ｃ R ｄ Carbonyl, C １－３ AlkylS(O) ２ -, C ２－３ Alkenyl S(O) ２ -, C ２－３ AlkynylS(O) ２ -, C １－３ Alkoxy S(O) ２ -, C ３－６ CycloalkylS(O) ２ 3-6 membered heterocycloalkylS(O) containing 1 or 2 heteroatoms selected from -, N, O and S ２ -, NR ｃ R ｄ S (O) ２ -, wherein C １－３ Alkylcarbonyl, the C ２－３ Alkenylcarbonyl, the C ２－３ Alkynylcarbonyl, the C １－３ Alkoxycarbonyl, the C ３－６ cycloalkylcarbonyl, the 3- to 6-membered heterocycloalkylcarbonyl, the C １－３ AlkylS(O) ２ -, the above C ２－３ Alkenyl S(O) ２ -, the above C ２－３ AlkynylS(O) ２ -, the above C １－３ Alkoxy S(O) ２ -, the above C ３－６ CycloalkylS(O) ２ -, the 3- to 6-membered heterocycloalkylS(O) ２ - is one or two R ｅ optionally substituted by substituents, R ｃ and R ｄ But hydrogen, C １－４ Alkoxy, C １－４ Alkyl, C ３－６ cycloalkyl, aminosulfonyl, or R ｃ and R ｄ together with the N atom to which it is attached form a 3- to 6-membered heterocycle, Each R ｅ are the same or different and are hydrogen, deuterium, tritium, halogen, amino, hydroxyl, cyano, C １－３ Alkoxy, C １－３ Alkyl, C ３－６ 2. A compound represented by general formula (I) according to claim 1, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, characterized in that: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,

4. R １ is selected from a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, and deuterated cyclopropyl; Preferably, R ２ 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 and perchloropropyl; Preferably, R ３ is a hydrogen atom, methyl-S(O) ２ -, ethyl-S(O) ２ -, n-propyl-S(O) ２ -, isopropyl-S(O) ２ -, cyclopropyl-S(O) ２ -, oxiranyl-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 -, cyclopropoxy-S(O) ２ -, oxiranyloxy-S(O) ２ -, cyclobutoxy-S(O) ２ -, oxetanyloxy-S(O) ２ -, N,N-dimethylamino-S(O) ２ -, trifluoromethyl-S(O) ２ -, amino-S(O) ２ -, SO ３ H-, pyrroline-1-S(O) ２ -, piperidine-1-S(O) ２ -, morpholine-1-S(O) ２ -, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, oxiranylcarbonyl, cyclobutylcarbonyl, oxetanylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, oxiranyloxycarbonyl, cyclobutoxycarbonyl, oxetanyloxycarbonyl, N,N-dimethylaminocarbonyl, trifluoromethylcarbonyl, and 【Chemistry 2】 is selected from Preferably, n1 is 1, Preferably, a compound represented by general formula (I) according to claim 1, characterized in that n2 is 1, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof.

5. 2. The compound represented by general formula (I) according to claim 1, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, characterized in that the compound represented by general formula (I) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof is one of the following compounds: 【Transformation 3】 【change】 【change】

6. 10. Use of a compound represented by general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, as a CYP11A1 inhibitor.

7. 10. Use of a compound represented by general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a steroid hormone dependent disease.

8. 10. Use of a compound represented by general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a steroid receptor dependent disease such as prostate cancer or breast cancer.

9. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

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

12. A compound represented by general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which can 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, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which may be administered together with one or more other anticancer drugs, wherein the anticancer drugs are selected from at least one of a nonsteroidal androgen receptor antagonist, a steroid synthesis inhibitor, a chemotherapeutic agent, and an estrogen receptor antagonist.

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