Cyp11a1 inhibitors and uses thereof

Abstract

This invention relates to compounds of Formula I and their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs. The compounds of Formula I can be used as inhibitors of cytochrome P450 monooxygenase 11A1 (CYP11A1), effectively inhibiting the synthesis of testosterone and pregnenolone, and have good application prospects in the preparation of drugs for diseases such as prostate cancer and breast cancer.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a compound that can inhibit cytochrome P450 monooxygenase 11A1, its preparation method, composition, and use in the preparation of pharmaceuticals. Background Technology

[0002] Prostate cancer is a common malignant tumor of the male genitourinary system, and its mortality rate is high, making it a leading cause of cancer death in men. Currently, radiotherapy and prostatectomy are the standard treatments for patients with stage I-III prostate cancer, while patients with stage IV and high-risk stage III prostate cancer are treated with surgical or chemical castration androgen deprivation therapy. Studies have shown that prostate cancer is usually caused by androgens, and blocking androgens is beneficial for the treatment of prostate cancer. Chemical castration androgen deprivation therapy (ADT) is based on the mechanism of blocking the production of testosterone and other androgens and is used to treat advanced and / or metastatic prostate cancer (Mamello Sekhoacha, Keamogetswe Riet, PaballoMotloung, Lemohang Gumenku, Ayodeji Adegoke, Samson Mashele. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches[J]. Molecules, 2022, 27(17):5730).

[0003] First-generation ADT treatments include flutamide and bicalutamide, which competitively and reversibly inhibit the binding of testosterone and DHT to the androgen receptor ligand-binding domain. Second-generation ADT treatments mainly include abiraterone and enzalutamide, primarily used to treat metastatic castration-resistant prostate (mCRPC). Abiraterone inhibits the steroid-producing enzyme CYP17A1, which mainly acts on the adrenal glands, catalyzing the conversion of prosteroids into testosterone, DHT, and DHEA. Enzalutamide is a second-generation AR inhibitor that competitively and reversibly inhibits the binding of testosterone and DHT to the androgen receptor ligand-binding domain, and inhibits the translocation of AR from the cytoplasm to the nucleus, recruiting coactivators and binding to DNA in downstream signaling pathways (KunalDesai, Jeffrey M McManus, Nima Sharifi. Hormonal Therapy for Prostate Cancer[J]. Endocrine Reviews, June 2021, 42(3):354–373).

[0004] Clinical treatment has revealed that approximately 50% of CRPC patients are sensitive to abiraterone or enzalutamide, but resistance develops after one to two years of treatment. Furthermore, most abiraterone and enzalutamide-resistant tumors still exhibit high androgen receptor (AR) expression and persistent AR activity. Related research suggests that prostate cancer progression may be due to increased AR gene copy number leading to heightened sensitivity to steroid ligands, or due to AR mutations enhancing steroid ligand binding to maintain tumor growth. In humans, adrenal and prostate cancers can synthesize steroids such as pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone, and their derivatives, converting them into androgens that bind to and activate AR. Therefore, inhibiting the synthesis of most or even all of the relevant steroid hormones in the body may benefit prostate cancer patients (Mari Karimaa, Reetta Riikonen, Henna Kettunen. First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis[J]. MolCancer Ther,2022,21,(12):1765–1776).

[0005] CYP11A1 (cytochrome P450 family 11 subtype A1), located on human chromosome 15q24.1, encodes P450SCC, a member of the cytochrome P450 enzyme superfamily. P450SCC is a monooxygenase that catalyzes many reactions in the human body involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. This protein is located in the inner mitochondrial membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in steroid hormone synthesis; inhibiting this step inhibits steroid hormone synthesis in the body.

[0006] Clinical studies have found that CYP11A1 small molecule inhibitors can rapidly reduce the concentration of steroid hormones in the blood, and the administration of physiological doses of corticosteroid replacement therapy can reduce the corresponding side effects and improve the quality of life of patients. At the same time, clinical studies on CYP11A1 small molecule inhibitors in gynecological tumors such as breast cancer are also underway (Mari Karimaa, Reetta Riikonen, Henna Kettunen. First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis[J]. Mol Cancer Ther, 2022, 21, (12): 1765–1776).

[0007] In conclusion, CYP11A1 is a promising therapeutic target in steroid hormone-related tumors, and CYP11A1 inhibitors have great potential in treating steroid hormone-dependent cancers such as prostate cancer and breast cancer. Summary of the Invention

[0008] The purpose of this invention is to provide a novel small molecule compound with CYP11A1 inhibitory activity, which can be used in the preparation of drugs for treating prostate cancer, breast cancer and other diseases mediated by CYP11A1 activity.

[0009] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0010] The first aspect of this invention provides compounds of Formula I or their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs thereof.

[0011]

[0012] in,

[0013] Ring A is selected from aryl, aromatic rings containing 1-3 heteroatoms, and C rings containing 1-3 heteroatoms. 4-12 Fused heterocycles, C containing 1-3 heteroatoms 4-12 Spiroherocyclic compounds, C atoms containing 1-3 heteroatoms 4-12 One type of bridged heterocyclic structure, wherein the heteroatom includes at least one of N, O, and S;

[0014] Ring B is selected from one of the following structures:

[0015]

[0016] Ring C is selected from one of the following structures:

[0017]

[0018] X is either -O- or -CH2-;

[0019] W represents C, N, O, or S;

[0020] L 1 L 2 Selected from substituted or unsubstituted C 1-4 Alkylene, the substituted C 1-4 The substituents of the alkylene group are selected from one or more of D, CH3, and CF3;

[0021] R 1 For H, C 1-7 Alkyl, C 1-7Hydroxy-substituted alkyl, C 1-7 Haloalkyl, C 1-7 Deuterated alkyl, C 2-7 alkenyl, C 1-7 Haloalkenyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 1-7 Alkoxy carbonyl, -SO2-C 1-7 Alkyl group, -SO2-C 1-7 Deuterated alkyl groups, -SO2-C 1-7 Halogenated alkyl groups, -SO2-C 3-7 Ring, -SO2-C 3-7 Heterocyclic rings, -SO2-NR 9 R 10 -CO-C 1-7 Alkyl, -CO-C 1-7 Deuterated alkyl groups, -CO-C 1-7 Halogenated alkyl or -PO-R 11 R 12 ;

[0022] R 2 R 3 Selected from H, halogen, hydroxyl, and C respectively 1-7 Alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 Alkoxy or C 1-7 Haloalkenyl;

[0023] R 4 R 5 R 6 R 7 Selected from H, halogen, deuterium, cyano, and C respectively 1-7 Alkyl, C 1-7 Haloalkyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 2-7 alkenyl, C 1-7 Haloalkenyl, C 2-7 alkynyl or C 1-7 alkoxycarbonyl;

[0024] R 8 Selected from H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-7 Deuterated alkyl, C 3-7 cycloalkyl, C 3-7 Propylene, C 3-7 Halogenated propenyl, C 1-7 Alkoxyethyl or C 1-7 Alkyl carbonyl;

[0025] R 9 R 10 Selected from H and C respectively 1-7 Alkyl or cycloalkyl;

[0026] R 11 R 12 Selected from C respectively 1-7 alkyl.

[0027] Furthermore, ring A is selected from one of the following structures:

[0028]

[0029] Furthermore, X is -O-.

[0030] Furthermore, W can be C or N.

[0031] Furthermore, L 1 L 2 They are selected from -CH2- or -CH(CH3)-, respectively.

[0032] Furthermore, the compound is preferably a compound with the structure shown in formulas Ia to If:

[0033]

[0034] Among them, rings C and R 1 R 2 R 3 R 4 R 5 R 6 R 7 As defined above for Equation I.

[0035] Furthermore, in the structures shown in Equation I or Equations Ia to If above, ring C is preferably one of the following structures:

[0036]

[0037] Furthermore, in the structures shown in Equation I or Equations Ia to If above, R 1 For H, C 1-7 Hydroxyl-substituted alkyl, -SO2-C 1-7 Alkyl group, -SO2-C 1-7 Deuterated alkyl groups, -SO2-C 1-7 Halogenated alkyl groups, -SO2-C 3-7 cycloalkyl, -SO2-C 3-7 Heterocyclic group, -SO2-NR 9 R 10 -CO-C 1-7 Alkyl, -CO-C 1-7Deuterated alkyl groups, -CO-C 1-7 Halogenated alkyl or -PO-R 11 R 12 , where R 9 R 10 Preferably H or methyl, R 11 R 12 Preferably, H or methyl; in some preferred embodiments, R 1 Selected from H, -C(CH3)2OH, -SO2-CH3, -SO2-CD3, -SO2-CF3, -SO2-NH2, -SO2-cyclopropyl, -SO2-N(CH3)2, -CO-CD3, -CO-CF3 or -PO(CH3)2.

[0038] Furthermore, in the structures shown in Equation I or Equations Ia to If above, R 2 R 3 The preferred components are H, F, or hydroxyl groups, respectively.

[0039] Furthermore, in the structures shown in Equation I or Equations Ia to If above, R 4 R 5 R 6 R 7 The preferred elements are H, deuterium, halogen, cyano, and C, respectively. 1-7 Alkyl, C 1-7 Haloalkyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 2-7 alkenyl or C 2-7 Alkyne group; in some preferred embodiments, R 4 R 5 R 6 R 7 Selected from H, deuterium, F, Cl, Br, cyano, methyl, trifluoromethyl, difluoromethyl, cyclopropyl, methoxy, vinyl, or ethynyl.

[0040] Furthermore, in the structures shown in Equation I or Equations Ia to If above, R 9 R 10 All are H or methyl.

[0041] Furthermore, in the structures shown in Equation I or Equations Ia to If above, R 11 R 12 All are methyl groups.

[0042] Furthermore, the compound represented by Formula I is a compound represented by the following structural formulas I-1 to I-86:

[0043]

[0044]

[0045]

[0046]

[0047]

[0048] A second aspect of the present invention provides a pharmaceutical composition comprising one or more of the following: a compound of Formula I as described in the first aspect, its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph.

[0049] Furthermore, in the pharmaceutical composition, any of the compounds represented by Formula I above, or their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, are used in combination with other drugs.

[0050] The third aspect of the present invention provides the use of the compound of Formula I as described in the first aspect or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, or the pharmaceutical composition described in the second aspect, in the preparation of a medicament for treating CYP11A1-mediated diseases.

[0051] Furthermore, the drug is used to inhibit the synthesis of steroid hormones, including but not limited to pregnenolone, testosterone, etc.

[0052] Furthermore, the conditions mediated by the CYP11A1 activity include, but are not limited to, prostate cancer and breast cancer.

[0053] Furthermore, the drug can be administered orally, parenterally, intravenously, or transdermally.

[0054] Furthermore, in the drug, any of the compounds represented by Formula I above, or their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs, are used in combination with other drugs.

[0055] As used herein, unless otherwise stated, the following definitions and terms shall apply.

[0056] "R" and "S" are terms used to describe isomers and are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. Naming an asymmetrically substituted carbon atom "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rule, which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.

[0057] In this article, the term C i-j This means that this part has ij carbon atoms. For example, "C 1-7 "Alkyl" refers to an alkyl unit having any number of carbon atoms between 1 and 7.

[0058] In this document, the term "fused carbon ring" refers to a fused ring containing one or more heteroatoms. A fused ring is a polycyclic group that shares two adjacent carbon atoms between rings. It may contain 0 or more double or triple bonds, and the heteroatoms include, but are not limited to, O, S, N, etc.

[0059] In this document, the term "bridged heterocycle" refers to a bridged ring containing one or more heteroatoms. A bridged ring is a polycyclic group that shares three or more carbon atoms between rings. It may contain 0 or more double or triple bonds, and the heteroatoms include, but are not limited to, O, S, N, etc.

[0060] In this article, the term "alkyl" refers to a fully saturated straight-chain or branched alkane group, C 1-7 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, and n-heptyl. The term "alkylene" refers to a divalent alkyl group, C10-2000. 1-4 Alkyl groups include, but are not limited to, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)CH2-, etc.

[0061] In this article, the term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0062] In this article, the term "hydroxylated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group, as described above. 1-7 Hydroxyl-substituted alkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, etc.

[0063] In this article, the term "halogenated alkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom, and the above C 1-7 Halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, etc.

[0064] In this article, the term "deuterated alkyl" refers to an alkyl group in which at least one hydrogen atom is substituted by deuterium, as described above. 1-7Deuterated alkyl groups include, but are not limited to, -CD3, -CD2H, and -CH3CD3.

[0065] In this article, the term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which can be straight-chain or branched, or a combination thereof. 2-7 Alkenyl groups include, but are not limited to, vinyl, propenyl, and 2-methyl-1-propenyl. The term "haloalkenyl" refers to an alkenyl group in which at least one hydrogen atom is replaced by a hydroxyl group.

[0066] In this article, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each ring having 3 to 10 carbon atoms. 3-7 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl.

[0067] In this document, the term "alkoxy" refers to a straight-chain or branched alkoxy group having the indicated number of carbon atoms. For example, C 1-7 Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0068] Optical isomers, diastereomers, geometric isomers, and tautomers: Some Formula I compounds may contain one or more ring systems, and therefore may have cis and trans isomers. This invention is intended to cover all such cis and trans isomers. The inclusion of an olefinic double bond, unless otherwise specified, means the inclusion of E and Z geometric isomers.

[0069] Any enantiomer of a compound of general formula I can be obtained by stereo-oriented synthesis using optically pure starting materials or reagents with known configurations.

[0070] Furthermore, compounds of formula I may also include a series of stable isotope-labeled analogs. For example, one or more protons in a compound of formula I may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.

[0071] "Pharmaceutically acceptable salt" refers to the acid salt or base salt of the compounds of this invention, which has the desired pharmacological activity and is neither biologically desirable nor otherwise desirable. The salt can form with acids, including but not limited to acetic acid, adipic acid, benzoate, citric acid, camphoric acid, camphor sulfonate, dicarboxylate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-heptate, glycerol phosphate, hemisulfate, heptanate, hexanoate, hydrobromide hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, and oxalate.

[0072] The term “CYP11A1 activity-mediated” refers to any disease or other harmful condition in which CYP11A1 or its mutants are known to play a role.

[0073] By employing the above technical solution, the present invention has at least the following advantages:

[0074] This invention provides a class of small molecule compounds with CYP11A1 inhibitory activity. These compounds can effectively inhibit the activity of cytochrome P450 monooxygenase 11A1, thereby inhibiting the synthesis of steroid hormones (such as testosterone and pregnenolone) in the body. They can be used to treat diseases mediated by CYP11A1 activity, including prostate cancer and breast cancer. Detailed Implementation

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0076] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0077] The intermediate compounds 2a to 2h were synthesized according to the synthetic method shown in reaction route 1 below:

[0078]

[0079] The preparation process of intermediate compound 2a is as follows:

[0080] Under nitrogen protection, pyridine (26 mL) and methanesulfonic anhydride (7.6 g, 43.4 mmol) were added to a 20 mL acetonitrile solution of compound 1a (2.0 g, 17.4 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and evaporated to dryness. The crude product was slurried with EA, filtered, and the solid was collected and dried under vacuum to obtain the desired product compound 2a (1.8 g, yield: 38.3%). 1 H NMR (400MHz, CDCl3) δ4.10(d,2H),3.87-3.84(m,2H),3.02(s,3H),2.78(s,3H),2.70-2.64(dt,2H),1.90-1.87(m,3H),1.48-1.37(m,2H).

[0081] Intermediate compounds 2b to 2h were prepared by replacing compound 1a with compounds 1b to 1h using the synthetic method shown in reaction route 1.

[0082] Intermediate compounds 4 and 5 were synthesized according to the synthetic method shown in reaction route 2 below:

[0083]

[0084] The preparation process of intermediate compound 4 is as follows:

[0085] Under nitrogen protection, LiAlH4 (1.6 g, 42.2 mmol) was added in portions to a THF (100 mL) solution of compound 3 (4.8 g, 21.1 mmol) at 0 °C. The mixture was then slowly heated to room temperature and reacted for 3 h until TLC showed that compound 3 had reacted completely. Under ice bath conditions, 1.6 mL of H2O was added to the reaction solution, and the mixture was stirred for 10 min. Then, 1.6 mL of 15% NaOH aqueous solution was added, followed by another 1.6 mL of H2O. The reaction solution was filtered through diatomaceous earth, washed with EA, and the organic phase was collected. After drying with anhydrous Na2SO4, the crude compound was concentrated and purified by column chromatography to obtain the desired compound 4 (2.2 g, yield: 48.8%). 1 H NMR (400MHz, CDCl3) δ3.53-3.36(m,4H),3.28-3.25(m,2H),2.91(br,1H),1.36-1.35(m,11H),0.86-0.81(m,1H).

[0086] The preparation process of intermediate compound 5 is as follows:

[0087] Et3N (4.2 g, 41.3 mmol) was added to a DCM (20 mL) solution of compound 4 (2.2 g, 10.3 mmol), followed by TsCl (3.9 g, 20.6 mmol). The reaction mixture was stirred at room temperature for 12 h until TLC showed that compound 4 had reacted completely. The mixture was washed with water, extracted with DCM (20 mL x 3), and the organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography to obtain the desired compound 5 (1.5 g, yield: 39.6%). 1 H NMR (400MHz, CDCl3) δ7.77(d,2H),7.33(d,2H),4.02-3.97(m,1H),3.89-3.84(m,1H),3. 54-3.43(m,2H),3.29-3.26(m,2H),2.44(s,3H),1.43-1.40(m,11H),0.96-0.92(m,1H).

[0088] The intermediate compounds 9a-9h were synthesized according to the synthetic method shown in reaction route 3 below:

[0089]

[0091] The preparation process of intermediate compound 9a is as follows:

[0092] Under nitrogen protection, SOCl2 (5.4 g, 45.7 mmol) was added to a 50 mL solution of acetonitrile containing compound 6 (5.0 g, 35.2 mmol). The reaction mixture was stirred at 50 °C for 1.5 h until TLC showed that compound 6 had reacted completely. A large amount of solvent was removed, and water (20 mL) was slowly added to the reaction mixture and stirred for 30 min. The mixture was filtered, and the solid was washed with water and acetonitrile. The product was collected and dried under vacuum to give compound 7 (5.3 g, yield: 94.6%). 1 H NMR (400MHz, DMSO) δ8.14(s,1H),6.57(s,1H),4.66(s,2H).

[0093] Under nitrogen protection, compound 8a (6.2 g, 39.6 mmol) was added to a 48% KOH (50 mL) aqueous solution at 0 °C, followed by compound 7 (5.3 g, 33.0 mmol). The reaction mixture was stirred at room temperature for 1 h until TLC showed complete reaction of compound 7. AcOH was slowly added dropwise until pH = 7, and the mixture was extracted with EA (30 mL x 3). After washing with water, the organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography to obtain the desired compound 9a (1.5 g, yield: 39.6%). 1 H NMR (400MHz, CDCl3) δ7.87(s,1H),7.24-7.20(m,4H),6.58(s,1H),4.06(s,4H),3.82(s,2H). LCMS(ESI):244.2[M+H] + .

[0094] Intermediate compounds 9b to 9h were prepared by replacing compound 8a with compounds 8b to 8h using the synthetic method shown in reaction route 3.

[0095] Intermediate compound 9b: 1 H NMR (400MHz, CDCl3) δ7.86(s,1H),7.14-7.11(m,1H),6.92-6.88(m,2H),6.56(s,1H),4.02(s,2H),4.00(s,2H),3.80(s,2H). LCMS(ESI):262.3[M+H] + .

[0096] Intermediate compound 9c: 1H NMR(400MHz, CDCl3)δ7.86(s,1H),7.22-7.17(m,1H),6.98(d,1H),6.92-6. 88(t,1H),6.56(s,1H),5.30(s,1H),4.11(s,2H),4.07(s,2H),3.81(s,2H). LCMS(ESI):262.3[M+H]+.

[0097] Intermediate compound 9d: 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.34(m,2H),7.07(d,1H),6.55(s,1H),4.02(s,2H),3.98(s,2H),3.79(s,2H). LCMS(ESI):323.2[M+H] + .

[0098] Intermediate compound 9e: 1 H NMR (400MHz, CDCl3) δ7.86(s,1H),7.54(d,1H),7.49(s,1H),7.31(d,1H),6.56(s,1H),4.09(s,4H),3.82(s,2H). LCMS(ESI):269.3[M+H] + .

[0099] Intermediate compound 9f: LCMS (ESI): 284.3 [M+H] + .

[0100] Intermediate compound 9g: LCMS (ESI): 312.3 [M+H] + .

[0101] Intermediate compound 9h: LCMS (ESI): 294.3 [M+H] + .

[0102] Example 1

[0103]

[0105] Under nitrogen protection, compound 5 (1.6 g, 4.4 mmol) and Cs₂CO₃ (1.4 g, 4.4 mmol) were added to a DMSO (8 mL) solution of compound 9a (0.9 g, 3.7 mmol). The reaction mixture was reacted at 70 °C for 2 h until TLC showed that compound 9a had reacted completely. The mixture was extracted with EA (10 mL x 3), washed with water, and the organic phase was dried over anhydrous Na₂SO₄ and concentrated. The crude compound was purified by column chromatography to obtain the desired compound 10a (550 mg, yield: 34%).

[0106] The HCl / dioxane solution (3 mL) of compound 10a (550 mg, 1.3 mmol) was stirred at room temperature for 30 min until TLC showed that compound 10a was completely reacted. The solution was concentrated under reduced pressure to obtain crude compound 11a (424 mg, yield: 100%), which was used directly in the next step.

[0107] Under nitrogen protection, pyridine (6.5 mL) and methanesulfonic anhydride (0.5 g, 3.0 mmol) were added to a 5 mL solution of compound 11a (0.4 g, 1.2 mmol) in acetonitrile (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and evaporated to dryness. The crude product was purified by column chromatography to obtain the desired product compound I-1 (0.1 g, yield: 20%). 1 HNMR(400MHz, CDCl3)δ7.65(s,1H),7.23-7.21(m,4H),6.48(s,1H),4.04(s,4H),3.88(d,2H),3.77(s ,2H),3.59(d,2H),3.34(d,2H),2.82(s,3H),1.67(s,2H),1.41-1.38(m,1H)LCMS(ESI):417.95[M+H] + .

[0108] Example 2

[0109]

[0110] This compound was prepared by replacing compound 9a with intermediate compound 9b using the synthetic method shown in reaction route 4. 1H NMR(400MHz, CDCl3)δ7.63(s,1H),7.14-7.10(m,1H),6.91-6.87(m,2H),6.47(s,1H),4.01(s,2H),3.98-3.95(m,3H),3.84-3.81(m, 1H),3.75-3.71(m,3H),3.64-3.58(m,2H),3.41-3.37(m,1H),1.98(s,3H),1.72-1.68(m,1H),1.62-1.58(m,1H),1.12-1.07(m,1H). LCMS(ESI):435.2[M+H] + .

[0111] Example 3

[0112]

[0113] This compound was prepared by replacing compound 9a with intermediate compound 9c using the synthetic method shown in reaction route 4. 1 H NMR (400MHz, CDCl3) δ7.64(s,1H),7.21-7.15(m,1H),6.97(d,1H),6.90-6.86(t,1H),6.48(s,1H),4.09(s, 2H),4.05(s,2H),3.87(d,2H),3.77(s,2H),3.58(d,2H),2.81(s,3H),1.67-1.65(m,2H),1.41-1.38(m,1H). LCMS(ESI):435.95[M+H] + .

[0114] Example 4

[0115]

[0116] This compound was prepared by replacing compound 9a with intermediate compound 9d using the synthetic method shown in reaction route 4. LCMS (ESI): 496.4 [M+H] + .

[0117] Example 5

[0118]

[0119] Compound 11d was prepared by replacing compound 9a with intermediate compound 9d using the synthetic method shown in reaction route 4, which prepares compound 11a from compound 9a.

[0120] Compound I-5 was obtained by reacting compound 11d with compound bis(trifluoromethanesulfonic anhydride). LCMS (ESI): 550.4 [M+H] + .

[0121] Example 6

[0122]

[0123] Compound I-6 was obtained by reacting compound 11a with compound aminosulfonyl chloride. LCMS (ESI): 418.5 [M+H] + .

[0124] Examples 7-22

[0125] According to reaction routes 4, 5, or 6, compounds I-7 to I-22 were prepared by replacing reactants. The structures and characterization data of the compounds are shown in the table below:

[0126]

[0127]

[0128] Examples 23 and 24

[0129]

[0130] According to reaction route 3, compound 13 reacts with compounds 8a and 8d respectively to generate corresponding intermediate compounds, and then reacts according to reaction route 4 to obtain compounds I-23 and I-24.

[0131]

[0132] Example 25

[0133]

[0134] According to reaction routes 1 and 4, compound I-25 was prepared by replacing the reactants. 1 HNMR(400MHz, CDCl3)δ7.59(s,1H),7.35-7.33(m,2H),7.06(d,1H),6.47(s,1H),4.02(s,2H),3.98(s,2H), 3.86-3.83(m,2H),3.75-3.73(m,4H),2.78(s,3H),2.72-2.66(m,2H),2.01-1.98(m,3H),1.47-1.41(m,2H). LCMS(ESI):498.7[M+H] + .

[0135] Example 26

[0136]

[0137] Compound I-26 was synthesized according to reaction route 7. 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),7.29-7.27(m,2H),7.01(d,1H),6.41(s,1H),3.96(s,2H),3.92(s ,2H),3.80-3.77(m,2H),3.70-3.67(m,4H),2.70-2.60(m,3H),1.98-1.92(m,2H),1.38-1.31(m,2H). LCMS(ESI):500.1[M+H] + .

[0138] Example 27

[0139]

[0140] Under nitrogen protection, compound I-25 (0.4 g, 0.81 mmol) and compounds sodium deuterate (0.11 g, 1.6 mmol), Pd2dba3 (15 mg, 0.016 mmol), and tBu3P (9.8 mg, 0.048 mmol) were reacted in DMSO (3 mL) solution at 100 °C for 2 h until TLC showed that compound I-25 had reacted completely. The mixture was extracted with EA (5 mL x 3), washed with water, and the organic phase was dried with anhydrous Na2SO4 and concentrated. The crude compound was purified by TLC to obtain the desired compound I-27 (110 mg, yield: 33%). 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),7.14(s,3H),6.42(s,1H),3.97(s,4H),3.78(d,2H),3.71 (s,2H),3.68(d,2H),2.72(s,3H),2.65-2.59(m,2H),1.95-1.92(m,3H),1.41-1.35(m,2H). LCMS(ESI):420.8[M+H] + .

[0141] Examples 28-45

[0142]

[0143] According to reaction routes 1, 4, and 7-9, compounds I-28 to I-45 were synthesized by substitution of reactants. The structures and characterization data of the compounds are shown in the table below:

[0144]

[0145]

[0146]

[0147] Example 46

[0148]

[0149] Compound I-46 was synthesized according to reaction route 10. 1 HNMR(400MHz, CDCl3)δ9.07(s,1H),8.57(s,1H),7.60(s,1H),6.49(s,1H),4.14(s,2H),4.11(s,2H),3.87-3.8 3(m,2H),3.82(s,2H),3.75-3.73(m,2H),2.79(s,3H),2.74-2.66(m,2H),2.01-1.99(m,3H),1.48-1.41(m,2H). LCMS(ESI):421.5[M+H] + .

[0150] Examples 47-60

[0151]

[0152] According to reaction routes 1, 4, and 7-11, compounds I-47 to I-60 were synthesized by substitution of reactants. The structures and characterization data of the compounds are shown in the table below:

[0153]

[0154]

[0155] Example 61

[0156]

[0157] Compound I-61 was synthesized according to reaction route 12. 1 HNMR (400MHz, CDCl3) δ7.95(d,2H),7.63-7.62(m,3H),7.22-7.18(m,4H),6.52(s,1H),5.17(s,2H),4.03(s,4H),3.77(s,2H),3.05(s,3H). LCMS(ESI):412.5[M+H] + .

[0158] Examples 62-69

[0159] According to reaction routes 4 and 12, compounds I-62 to I-69 were synthesized by substitution of reactants. The structures and characterization data of the compounds are shown in the table below:

[0160]

[0161]

[0162] Example 70

[0163]

[0164] At room temperature, K₂CO₃ (17.0 g, 123.8 mmol) and CH₃I (17.6 g, 123.8 mmol) were added to a MeOH (100 mL) solution of compound 6 (8.0 g, 56.3 mmol). The reaction was carried out at 80 °C for 8 h until TLC showed that compound 6 had reacted completely. The reaction solution was extracted with EA (50 mL x 3), the organic phase was washed with water, dried over anhydrous Na₂SO₄, and concentrated. The crude compound was purified by column chromatography to obtain the desired compound 12 (5.1 g, yield: 58%). 1 HNMR (400MHz, DMSO) δ8.08(s,1H),6.30(s,1H),5.71-5.68(m,1H),4.30(d,2H),3.65(s,6H).

[0165] Compound 12 (1.4 g, 8.97 mmol) and methylamine (27 mL, 26.9 mmol, 1 mmol / L) in an ethanol solution were reacted at 100 °C for 4 h until TLC showed that compound 12 had reacted completely. The reaction solution was directly concentrated, and the crude compound obtained was purified by column chromatography to give the desired compound 13a (1.2 g, yield: 79%). 1 HNMR (400MHz, CDCl3) δ7.45(s,1H),6.19(s,1H),4.38(s,2H),3.64(s,3H),3.62(s,3H).

[0166] Under nitrogen protection, SOCl2 (1.5 g, 12.3 mmol) was added to a solution of compound 13a (1.6 g, 9.5 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at 50 °C for 2 h until TLC showed that compound 13a had reacted completely. A large amount of solvent was removed, and water (20 mL) was slowly added to the reaction mixture and stirred for 30 min. The mixture was filtered, and the solid was washed with water and acetonitrile. The product was collected and dried under vacuum to give compound 14a (1.61 g, yield: 91%).

[0167] Under nitrogen protection, compound 8a (1.6 g, 10.2 mmol) was added to a 48% KOH (20 mL) aqueous solution at 0 °C, followed by compound 14a (1.6 g, 8.5 mmol). The reaction mixture was stirred at room temperature for 2 h until TLC showed complete reaction of compound 14a. AcOH was slowly added dropwise until pH = 7, and the mixture was extracted with EA (30 mL x 3). After washing with water, the organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was then purified by column chromatography to obtain the desired compound 15a (2.2 g, yield: 96%). 1 H NMR (400MHz, CDCl3) δ7.20-7.15(m,4H),6.93(s,1H),6.44(s,2H),3.91(s,4H),3.79(s,3H),3.78(s,3H),3.73(s.2H).

[0168] At 0 °C, BBr3 (1.1 mL, 11.1 mmol) was added dropwise to a DCM (5 mL) solution of compound 15a (1.0 g, 3.7 mmol). The reaction mixture was stirred at room temperature for 5 h until TLC showed complete reaction of compound 15a. The solvent was removed, and the residue was dissolved in MeOH, concentrated, and dried again. The solid was washed with DCM:MeOH = 10:1, and the organic phase was washed with a saturated NaHCO3 aqueous solution, dried, and concentrated to give compound 16a (0.8 g, yield: 84%). 1 H NMR (400MHz, DMSO) δ8.38(s,1H),7.69(s,1H),7.40-7.34(m,4H),4.88(s,2H),4.65(s,4H),4.22(s,3H).

[0169] Under nitrogen protection, compound 2a (0.3g, 0.9mmol) and Cs₂CO₃ (0.3g, 0.9mmol) were added to a DMSO (3mL) solution of compound 16a (0.2g, 0.8mmol). The reaction mixture was reacted at 70°C for 2 hours until TLC showed complete reaction of compound 16a. The mixture was extracted with EA (5mL x 3), washed with water, and the organic phase was dried over anhydrous Na₂SO₄ and concentrated. The crude compound was purified by TLC to obtain the desired compound I-70 (51mg, yield: 15%). 1H NMR (400MHz, CDCl3) δ7.23-7.17(m,4H),7.07(s,1H),6.52(s,1H),3.93(s,4H),3.85-3.83(m,4H) ,3.82(s,3H),3.76(s,2H),2.79(s,3H),2.73-2.67(m,2H),2.03-2.00(m,3H),1.47-1.41(m,2H). LCMS(ESI):433.05[M+H] + .

[0170] Example 71

[0171]

[0172] Compound I-71 was synthesized according to reaction route 14. LCMS (ESI): 500.4 [M+H] + .

[0173] Examples 72-75

[0174] According to reaction routes 13 and 14, compounds I-72 to I-75 were synthesized by substitution of reactants. The structures and characterization data of the compounds are shown in the table below:

[0175]

[0176] Example 76

[0177]

[0178] Compound I-76 was synthesized according to reaction route 15. LCMS (ESI): 447.6 [M+H] + .

[0179] Examples 77-86

[0180] Based on the above reaction route, compounds I-77 to I-86 were synthesized by substitution of reactants. The structures and characterization data of the compounds are shown in the table below:

[0181]

[0182]

[0183] Test case

[0184] The bioactivity of some of the target compounds synthesized in Examples 1-86 above was tested, using MK-5684 as a control sample. The inhibitory effect on testosterone and pregnenolone synthesis in NCI-H295R cells was tested, and the specific operation is as follows:

[0185] (1) Testosterone test

[0186] Take 95 μL of an appropriate concentration of NCI-H295R cell suspension and incubate overnight in a 96-well plate at 37°C and 5% CO2. Then, add 5 μL of the test compound to each well and incubate for 72 hours at 37°C and 5% CO2. The final concentrations of the test compound are 1000, 200, 40, 8, 1.6, 0.32, 0.064, and 0 nM. After incubation, centrifuge and transfer 80 μL of the supernatant to the 96-well plate. Determine the testosterone concentration using ELISA. Prepare the testosterone-HRP working solution and elution buffer. First, pipette 25 μL of the sample and add it to the corresponding tube. Then, add 200 μL of the conjugate working solution to each well, shake, and incubate at room temperature for 1 hour. Then, wash each well three times with 300 μL of diluted wash buffer and gently tap the plate on absorbent paper to ensure it is dry. Then, add 200 μL of TMB substrate to each well and incubate at room temperature for 10-15 minutes. Finally, add 100 μL of stop solution to each well. Measure the absorbance at 450 nm using a microplate reader (PerkinElmer, 2105) within 20 minutes. Calculate the IC50 using GraphPad Prism software. 50 value.

[0187] Inhibition rate (%) = 100% - (reading value of compound - average reading value of positive control) / (average reading value of blank control - average reading value of positive control) × 100%.

[0188] (2) Pregnenolone test

[0189] Take 95 μL of an appropriate concentration of NCI-H295R cell suspension and incubate overnight in a 96-well plate at 37°C and 5% CO2. Then, add 5 μL of the test compound to each well and incubate for 72 hours at 37°C and 5% CO2. The final concentrations of the test compound are 1000, 200, 40, 8, 1.6, 0.32, 0.064, and 0 nM. After incubation, centrifuge and transfer 80 μL of the supernatant to the 96-well plate. Dilute the supernatant 8-fold with the special culture medium and determine the concentration of pregnenolone by ELISA. Prepare pregnenolone-HRP working solution and elution buffer. First, pipette 50 μL of the sample and add it to the corresponding tube. Then, add 100 μL of the conjugated working solution to each well, shake, and incubate at room temperature for 1 hour. Then, wash each well three times with 300 μL of diluted wash buffer and gently tap the plate on absorbent paper to ensure it is dry. Then, add 150 μL of TMB substrate to each well and incubate at room temperature for 10–15 minutes. Finally, add 50 μL of stop solution to each well. Measure the absorbance at 450 nm using a microplate reader (PerkinElmer, 2105) within 20 minutes. Calculate the IC50 value using GraphPadPrism software.

[0190] Inhibition rate (%) = 100% - (reading value of compound - average reading value of positive control) / (average reading value of blank control - average reading value of positive control) × 100%.

[0191] Table 1. The ability of different compounds to inhibit testosterone and pregnenolone synthesis in NCI-H295R cells.

[0192] compound <![CDATA[IC for inhibiting testosterone synthesis 50 (nM)]]> <![CDATA[Inhibiting pregnenolone synthesis IC 50 (nM)]]> I-1 53.36 49.84 I-2 62.89 52.91 I-3 158.00 129.7 I-25 4.35 11.88 I-26 2.61 9.49 I-27 3.82 2.91 I-29 17.31 7.02 I-61 23.18 7.39 MK-5684 9.23 14.71

[0193] As shown in Table 1, the small molecule compounds provided in the embodiments of the present invention have good inhibitory effects on the synthesis of intracellular testosterone and pregnenolone. Among them, compounds I-25, I-26, I-27, I-29, and I-61 have better inhibitory effects on the synthesis of testosterone and pregnenolone than MK-5684.

[0194] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. The compound represented by Formula I or its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs thereof. in, Ring A is selected from aryl, aromatic rings containing 1-3 heteroatoms, and C rings containing 1-3 heteroatoms. 4-12 Fused heterocycles, C containing 1-3 heteroatoms 4-12 Spiroherocyclic compounds, C atoms containing 1-3 heteroatoms 4-12 One type of bridged heterocyclic structure, wherein the heteroatom includes at least one of N, O, and S; Ring B is selected from one of the following structures: Ring C is selected from one of the following structures: X is either -O- or -CH2-; W represents C, N, O, or S; L 1 L 2 Selected from substituted or unsubstituted C 1-4 Alkylene, the substituted C 1-4 The substituents of the alkylene group are selected from one or more of D, CH3, and CF3; R 1 For H, C 1-7 Alkyl, C 1-7 Hydroxy-substituted alkyl, C 1-7 Haloalkyl, C 1-7 Deuterated alkyl, C 2-7 alkenyl, C 1-7 Haloalkenyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 1-7 alkoxy carbonyl, -SO2-C 1-7 Alkyl group, -SO2-C 1-7 Deuterated alkyl groups, -SO2-C 1-7 Halogenated alkyl groups, -SO2-C 3-7 Cycloalkyl groups, -SO2- containing heteroatoms in C 3-7 cycloalkyl, -SO2-NR 9 R 10 -CO-C 1-7 Alkyl, -CO-C 1-7 Deuterated alkyl groups, -CO-C 1-7 Halogenated alkyl or -PO-R 11 R 12 ; R 2 R 3 Selected from H, halogen, hydroxyl, and C respectively 1-7 Alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 1-7 Alkoxy or C 1-7 Haloalkenyl; R 4 R 5 R 6 R 7 Selected from H, halogen, deuterium, cyano, and C respectively 1-7 Alkyl, C 1-7 Haloalkyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 2-7 alkenyl, C 1-7 Haloalkenyl, C 2-7 alkynyl or C 1-7 alkoxycarbonyl; R 8 Selected from H, C 1-7 Alkyl, C 1-7 Haloalkyl, C 1-7 Deuterated alkyl, C 3-7 cycloalkyl, C 3-7 Propylene, C 3-7 Halogenated propenyl, C 1-7 Alkoxyethyl or C 1-7 Alkyl carbonyl; R 9 R 10 Selected from H and C respectively 1-7 Alkyl or C 1-7 cycloalkyl; R 11 R 12 Selected from C respectively 1-7 alkyl.

2. The compound of Formula I according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, Ring A is selected from one of the following structures:

3. The compound of Formula I according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, X is -O-; W is C or N.

4. The compound of Formula I according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, The compound is a compound with the structure shown in formulas Ia to If: Among them, rings C and R 1 R 2 R 3 R 4 R 5 R 6 R 7 As defined in claim 1.

5. The compound of Formula I according to any one of claims 1-3, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, Ring C is selected from one of the following structures: R 1 For H, C 1-7 Hydroxyl-substituted alkyl, -SO2-C 1-7 Alkyl group, -SO2-C 1-7 Deuterated alkyl groups, -SO2-C 1-7 Halogenated alkyl groups, -SO2-C 3-7 Cycloalkyl groups, -SO2- containing heteroatoms in C 3-7 cycloalkyl, -SO2-NR 9 R 10 -CO-C 1-7 Alkyl, -CO-C 1-7 Deuterated alkyl groups, -CO-C 1-7 Halogenated alkyl or -PO-R 11 R 12 ; R 2 R 3 Selected from H, F, or hydroxyl groups respectively; R 4 R 5 R 6 R 7 Selected from H, deuterium, halogen, cyano, and C respectively 1-7 Alkyl, C 1-7 Haloalkyl, C 3-7 cycloalkyl, C 1-7 Alkoxy, C 2-7 alkenyl or C 2-7 alkynyl group; R 9 R 10 It is H or methyl; R 11 R 12 It is H or methyl.

6. The compound of Formula I according to claim 1, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph, characterized in that, The compound represented by Formula I is the compound represented by the following structural formulas I-1 to I-86:

7. A pharmaceutical composition, characterized in that, It comprises one or more of the following: the compound of Formula I as described in any one of claims 1-6, its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, and polymorph.

8. The use of a compound of Formula I according to any one of claims 1-6, or its isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug, or polymorph, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating CYP11A1-mediated diseases.

9. The application according to claim 8, characterized in that, The drug is used to inhibit the synthesis of steroid hormones; the conditions mediated by the CYP11A1 activity include prostate cancer and breast cancer.

10. The application according to claim 8, characterized in that, The drug can be administered orally, parenterally, intravenously, or transdermally.

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