Deuterated polycyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a deuterated polycyclic compound as well as a preparation method and application thereof. Specifically, the invention discloses a deuterated compound as shown in a formula (I), and a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the deuterated compound. The compound provided by the invention is a CYP11A1 inhibitor, and can be used for treating and / or preventing CYP11A1-related diseases, especially cancers, such as prostatic cancer and breast cancer. # imgabs0 #

Description

Technical Field

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

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

[0003] Prostate cancer is a common malignancy of the male genitourinary system. Androgen receptor (AR) signaling, driven by androgens (testosterone and dihydrotestosterone), promotes the growth and proliferation of prostate cancer cells, playing a crucial role in disease progression. Therefore, inhibiting testicular androgen synthesis, thereby reducing androgen levels in the body, through medication or surgery, can effectively inhibit prostate cancer cell growth and achieve disease regression. This treatment, known as androgen deprivation therapy (ADT), is the standard of care for prostate cancer. However, because the adrenal glands and prostate cancer cells also produce androgens, prostate cancer can continue to progress after a period of ADT, even though circulating androgen concentrations remain low. This is also known as castration resistance. Currently approved treatments for castration-resistant prostate cancer (CRPC), in addition to AR inhibitors such as enzalutamide, are primarily abiraterone. Abiraterone is a CYP17 enzyme inhibitor that inhibits tumor growth by preventing the adrenal gland from synthesizing androgens such as pregnenolone, further shutting off the production of androgens needed by tumor cells. Although abiraterone is very effective in the early stages, drug resistance inevitably develops. At this time, the available treatment options for these patients with CRPC progression are very limited, so new mechanisms of therapy and drugs are urgently needed. Studies on CRPC progression have shown that activation of the AR signaling pathway still plays an important role in tumor growth at this time, and AR gene amplification and AR mutations lead to increased AR affinity for endogenous hormones other than testosterone and dihydrotestosterone, which is one of the important reasons for AR signaling pathway activation. Therefore, deeply shutting off AR signaling pathway activation in CRPC by inhibiting the synthesis of most or even all steroid hormones is a very promising prostate cancer treatment.

[0004] The synthesis of all steroid hormones in the human body, including glucocorticoids, mineralocorticoids, and sex hormones, is derived from the same precursor, cholesterol. The entire process is a series of complex transformations catalyzed by P450 cytochromes and hydroxysteroid dehydrogenases, ultimately resulting in the various hormones needed by the human body. In the first step of these transformations, the CYP11A1 enzyme catalyzes the side chain cleavage oxidation reaction of cholesterol. Therefore, inhibiting the catalytic activity of CYP11A1 can effectively cut off the body's use of cholesterol to synthesize various hormones, thereby blocking various hormone-mediated physiological functions. CYP11A1 has therefore become a potential target for the treatment of endocrine cancers such as prostate cancer and breast cancer.

[0005] Currently, no drug has been approved for this target, and there is a strong demand for the development of highly active CYP11A1 inhibitors. Summary of the Invention

[0006] The purpose of this application is to provide a deuterated polycyclic compound with a completely new structure.

[0007] The present application also aims to provide a use of the deuterated polycyclic compound as described above as a CYP11A1 inhibitor.

[0008] The present application also aims to provide a pharmaceutical composition comprising the deuterated polycyclic compound as described above and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0009] The present application also aims to provide a use of the deuterated polycyclic compound as described above in a drug for treating CYP11A1-related diseases.

[0010] The present application also aims to provide a method for preventing or treating CYP11A1-related diseases, such as cancer, particularly prostate cancer and breast cancer.

[0011] In the first aspect of the present invention, there is provided a deuterated compound as represented by formula (I), a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof,

[0012]

[0013] Among them, X2, X4, X 3a 、X 3b 、X 3c 、Z1a、Z 1b 、Z 2a 、Z 2b 、Z 3a 、Z 3b 、Z 3c 、Z 3d 、Z 4a 、Z 4b 、Z 4c 、Z 4d 、Z 5a 、Z 5b and Z 5c each independently hydrogen or deuterium;

[0014] X1 is selected from the group consisting of hydrogen, deuterium, and trifluoromethyl;

[0015] Additional conditions are: X1, X2, X 3a 、X 3b 、X 3c , X4, Z 1a 、Z 1b、Z 2a 、Z 2b 、Z 3a 、Z 3b 、Z 3c 、Z 3d 、Z 4a 、Z 4b 、Z 4c 、Z 4d 、Z 5a 、Z 5b 、Z 5c In a preferred embodiment, at least one of Z is deuterium. 1a and Z 1b each independently deuterium.

[0016] In a preferred embodiment, the Z 2a and Z 2b each independently deuterium.

[0017] In a preferred embodiment, the Z 3a 、Z 3b 、Z 3c and Z 3d each independently deuterium.

[0018] In a preferred embodiment, the Z 4a 、Z 4b 、Z 4c and Z 4d each independently deuterium.

[0019] In a preferred embodiment, the Z 5a 、Z 5b and Z 5c each independently deuterium.

[0020] In a preferred embodiment, X1 is selected from the following group: hydrogen, deuterium, and trifluoromethyl.

[0021] In another preferred embodiment, X2 is selected from the following group: hydrogen and deuterium.

[0022] In another preferred embodiment, the X 3a 、X 3b and X 3c are each independently selected from the group consisting of hydrogen and deuterium.

[0023] In another preferred embodiment, X4 is selected from the following group: hydrogen and deuterium.

[0024] In a preferred embodiment, the compound is selected from the following group:

[0025]

[0026]

[0027] The second aspect of the present invention provides a pharmaceutical composition, characterized in that the composition comprises:

[0028] (i) the deuterated compound according to the first aspect of the present invention, its crystal form, pharmaceutically acceptable salt, hydrate or solvate; and

[0029] (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

[0030] The third aspect of the present invention provides a use of the deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to the first aspect of the present invention, or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used to prepare a medicament for treating and / or preventing diseases related to CYP11A1;

[0031] Preferably, the disease associated with CYP11A1 is cancer;

[0032] More preferably, the diseases associated with CYP11A1 are prostate cancer and breast cancer.

[0033] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0034] After long and in-depth research and extensive screening, the inventors discovered for the first time a deuterated polycyclic compound with strong inhibitory activity against CYP11A1 and good metabolic stability. Based on this, the inventors completed the present invention.

[0035] the term

[0036] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0037] As used herein, "deuterated" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or persubstituted. The terms "deuterated one or more" and "deuterated one or more times" are used interchangeably.

[0038] As used herein, the term "polysubstituted" means comprising two or more substitutions.

[0039] As used herein, the term "deuterium" refers to a compound in which one or more hydrogen atoms (H) in the compound are replaced by deuterium atoms (D).

[0040] As used herein, "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0041] The term "plurality" herein refers to a positive integer of 2, 3, 4, 5 or more.

[0042] Active ingredient

[0043] As used herein, "the compound of the present invention" refers to the compound represented by formula (I), and also includes pharmaceutically acceptable salts, crystal forms, solvates or hydrates thereof.

[0044] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0045] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0046] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0047] As used herein, the term "solvate" refers to a complex in which the compound represented by formula (I) is coordinated with solvent molecules to form a specific ratio.

[0048] As used herein, the term "hydrate" refers to a complex formed by the compound represented by formula (I) coordinated with water molecules to form a specific ratio.

[0049] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" refers to the replacement of a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted with multiple substituents of a specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible organic group substitutions. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. Herein, for example, heteroatoms such as nitrogen may be substituted with hydrogen or any of the permissible organic groups described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible organic groups in any way. The present invention recognizes that combinations of substituents and variable groups are advantageous for the treatment of diseases by forming stable compounds. The term "stable" herein refers to compounds that are stable and maintain the structural integrity of the compound over a sufficient period of time for testing, preferably for a sufficient period of time for efficacy, and is used herein for such purposes.

[0050] Pharmaceutical compositions and methods of administration

[0051] Because the compounds of the present invention can inhibit cytochrome P450 monooxygenase 11A1 (CYP11A1) and are useful for treating diseases such as prostate cancer, the compounds of the present invention, their pharmaceutically acceptable salts, crystalline forms, solvates, or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate, or cure) CYP11A1-related diseases (such as prostate cancer and breast cancer).

[0052] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0053] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0054] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0055] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0056] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0057] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0058] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0059] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0060] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0061] Dosage forms of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0062] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0063] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat diseases associated with CYP11A1.

[0064] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0065] The main advantages of the present invention are:

[0066] Compared with existing technologies, the present invention offers the advantage of potent inhibitory activity against CYP11A1, effectively inhibiting its oxidation of cholesterol side chains in vitro, thereby blocking the production of precursors necessary for testosterone synthesis in vivo and achieving a potent anti-tumor effect. Furthermore, deuteration at appropriate positions enhances the compound's metabolic stability, thereby improving the drug's pharmacokinetic properties and reducing its dosage.

[0067] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

[0068] In the following examples, the characterization methods used are as follows.

[0069] H NMR spectroscopy ( 1 H NMR):

[0070] The NMR spectra of the reaction products and intermediates ( 1 H NMR spectra were obtained on a Bruker AVANCE III HD400 / 500 in Germany. Sample preparation is as follows: In a clean, dry glass NMR tube, completely dissolve an appropriate amount of sample in approximately 0.5 mL of a deuterated solvent. Most compounds have good solubility in DMSO-d6, making it the preferred deuterated solvent. DMSO-d6 readily solidifies at relatively low room temperatures and requires a hair dryer to dissolve it before loading. Other suitable deuterated reagents, such as CDCl3 and CD3OD, can also be used depending on testing needs. Tetramethylsilane (TMS) was used as the internal standard for testing at room temperature, with a chemical shift of 0 ppm.

[0071] Preparation of Examples

[0072] Example 1: Preparation of 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy-d2)-4H-pyran-4-one OST-1101002

[0073]

[0074] Step 1: Dissolve 5-hydroxy-2-(hydroxymethyl)pyran-4-one (2.04 g, 14.07 mmol) in thionyl chloride (15.3 mL) and stir at 50°C for 2 hours. Filter the reaction mixture, wash the filter cake with petroleum ether, and vacuum dry to obtain 6-chloromethyl-3-hydroxy-pyran-4(1H)-one (1.65 g, 73.02%) as a yellow solid.

[0075] Step 2: Dissolve 6-chloromethyl-3-hydroxy-pyran-4(1H)-one (500 mg, 3.11 mmol) in acetonitrile (8 mL) and add N,N-diisopropylethylamine (813.11 mg, 6.23 mmol) and isoindoline hydrochloride (1.02 g, 6.23 mmol) sequentially. The reaction mixture is stirred at 50°C for 16 hours. After cooling to room temperature, the mixture is filtered. The filter cake is washed with ethyl acetate and dried under vacuum to yield 2-[(2,3-dihydro-1H-isoindol-2-yl)methyl]-5-hydroxy-4H-pyran-4-one (920 mg, crude).

[0076] Step 3: Add lithium aluminum hydride deuteride (296.73 mg, 6.93 mmol) and tetrahydrofuran (6 mL) to a reaction flask. The atmosphere in the flask was purged with nitrogen three times. Dissolve ethyl 4-piperidinylcarboxylate (500 mg, 3.15 mmol) in tetrahydrofuran (3 mL) and slowly add it dropwise to the solution at 0°C. The reaction system was allowed to react at 25°C for 2 hours. Water, 15% aqueous NaOH solution, and water were then added dropwise to the stirred reaction flask at 0°C. The mixture was stirred for 15 minutes, anhydrous sodium sulfate was added, and the mixture was stirred for an additional 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield piperidin-4-ylmethane-d2-ol (280 mg, yield: 75.88%) as a white solid.

[0077] Step 4: Dissolve piperidin-4-ylmethane-d2-ol (100 mg, 853.32 μmol) in dichloromethane (2 mL). Add triethylamine (218.05 mg, 2.13 mmol) and methanesulfonyl chloride (219.41 mg, 1.88 mmol) sequentially at 0°C. The reaction system is allowed to react at 25°C for 2 hours. The reaction solution is quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase is concentrated to yield (1-(methylsulfonyl)piperidin-4-yl)methyl-d2-methanesulfonate (160 mg, yield: 68.59%) as a white solid.

[0078] Step 5: To the reaction flask were added 2-[(2,3-dihydro-1H-isoindol-2-yl)methyl]-5-hydroxy-4H-pyran-4-one (80 mg, 328.87 μmol), (1-(methylsulfonyl)piperidin-4-yl)methyl-d2 methanesulfonate (89.90 mg, 328.87 μmol), cesium carbonate (218.68 mg, 657.73 μmol), and dimethyl sulfoxide (2 mL). The reaction system was allowed to react at 70°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by reverse phase high pressure separation to obtain 2-(isoindolin-2-ylmethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy-d2)-4H-pyran-4-one (10 mg, yield: 7.23%, purity: 95.09%). ESI-MS found:357.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.15(d,J=1.6Hz,1H),7.28-7.15(m,4H),6.39(s,1H),3.95(s,4H),3.78(s,2H),3.60- 3.55(m,2H),2.85(s,3H),2.72(td,J=12.1,2.5Hz,2H),1.87-1.81(m,3H),1.28(ddd,J=25.9,12.0,4.0Hz,2H).

[0079] Example 2: Preparation of 2-(isoindolin-2-ylmethyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one OST-1101014

[0080]

[0081] Step 1: To a solution of piperidin-4-ylmethanol (10 g, 84.22 mmol) in dichloromethane (150 mL) was added triethylamine (29.56 mL, 210.56 mmol). The mixture was cooled to 0°C and methylsulfonyl chloride (12.72 g, 111.05 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with dilute hydrochloric acid (2 M), saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, respectively. The mixture was then dried over anhydrous sodium sulfate. Filtered, and the filtrate was concentrated to yield crude (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (16.30 g).

[0082] Step 2: Dissolve (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (10.29 g, 37.93 mmol) in N,N-dimethylformamide (300 mL), add 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (5 g, 34.48 mmol) and potassium carbonate (9.63 g, 68.96 mmol), and heat to 80°C with stirring for 36 hours. After cooling to room temperature, the reaction system was diluted with water and extracted with dichloromethane / isopropanol (3:1), washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and purify the crude product by normal phase column chromatography to yield 2-(hydroxymethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (4.40 g, yield: 40.21%). ESI-MS found: 318.2 [M+H] + .

[0083] Step 3: Dissolve 2-(hydroxymethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (1 g, 3.15 mmol) in acetone (18 mL). Add Jones reagent (748.94 mg, 3.78 mmol) at 0°C and stir at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain crude 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-carboxylic acid (650 mg, yield: 62.26%). ESI-MS: 332.1 [M+1] + .

[0084] Step 4: Dissolve 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-carboxylic acid (500 mg, 1.51 mmol) in methanol (10 mL), add concentrated sulfuric acid (0.085 mL, 0.15 mmol), and heat to 65°C with stirring for 4 hours. After the reaction, the system was cooled to room temperature, the reaction solution was concentrated, and the crude product was purified by normal phase column chromatography to obtain methyl 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-carboxylate (370 mg, yield: 59.16%). ESI-MS found: 346.1 [M+1] + .

[0085] Step 5: Methyl 5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-carboxylate (350 mg, 1.01 mmol) was dissolved in methanol (8 mL). Sodium deuterated borohydride (89.31 mg, 2.03 mmol) was added at 0°C and stirred at room temperature for 1 hour. The reaction was quenched with 1M hydrochloric acid (1.5 mL). The system was directly concentrated, and the crude product was purified by normal phase column chromatography to obtain 2-(hydroxymethyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (230 mg, yield: 71.06%). ESI-MS found: 320.1 [M+1]. + .

[0086] Step 6: Dissolve 2-(hydroxymethyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (80 mg, 0.25 mmol) in dichloromethane (2 mL), then add N,N-diisopropylethylamine (0.25 mL, 1.50 mmol) and methylsulfonic anhydride (133.57 mg, 0.75 mmol) in sequence, and heat to 30°C with stirring for 4 hours. The reaction solution is concentrated to give crude (5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-yl)methyl-d2 methanesulfonate (110 mg) ESI-MS: 398.1 [M+1] +

[0087] Step 7: Dissolve (5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-yl)methyl-d2 methanesulfonate (110 mg, 0.28 mmol) in acetonitrile (2.5 mL), add N,N-diisopropylethylamine (0.18 mL, 1.11 mmol) and isoindoline hydrochloride (44.40 mg, 0.28 mmol), and heat to 50°C with stirring for 1 hour. The reaction system was cooled to room temperature, diluted with water, extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate, and the crude product was purified by reverse phase chromatography to obtain 2-(isoindoline-2-ylmethyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (56.64 mg, yield: 35.40%). ESI-MS found:421.2[M+1] + . 1 H NMR: (400MHz, DMSO-d6)δ8.15(s,1H),7.28-7.16(m,4H),6.39(s,1H),3.95(s,4H),3.77-3.70(m, 2H),3.61-3.53(m,2H),2.85(s,3H),2.75-2.68(m,2H),1.84(d,J=12.0Hz,3H),1.33-1.22(m,2H).

[0088] Example 3: Preparation of 2-((isoindolin-2-yl-1,1,3,3-d4)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one OST-1101021

[0089]

[0090] Step 1: Dissolve 2-benzylisoindoline-1,3-dione (7 g, 29.50 mmol) in ultra-dry tetrahydrofuran (50 mL). Evacuate the system and replace with nitrogen three times. Add lithium aluminum tetrahydride-d (4.96 g, 118.01 mmol) at 0°C. Stir and react at room temperature for 2 hours. After completion of the reaction, add the reaction mixture dropwise to saturated ammonium chloride solution at 0°C. The filtrate is diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The crude product is purified by normal phase column chromatography to afford 2-benzylisoindoline-1,1,3,3-d4 (3.2 g, yield: 50.85%).

[0091] Step 2: Dissolve 2-benzylisoindoline-1,1,3,3-d4 (3 g, 14.06 mmol) in ultra-dry dichloromethane (20 mL). Evacuate the system and replace with nitrogen three times. Add 1-chloroethyl chloroformate (10.06 g, 70.23 mmol) at 0°C. Stir and react at room temperature for 24 hours. Then, raise the temperature to reflux and react for 4 hours. Cool the reaction mixture to room temperature and concentrate to obtain the crude product. The crude product was slurried with dichloromethane to obtain isoindoline-1,1,3,3-d4 (3.2 g, yield: 100%).

[0092] Step 3: Dissolve 2-(hydroxymethyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (570 mg, 1.80 mmol) in dichloromethane (10 mL). Add triethylamine (0.62 mL, 4.49 mmol). Add methylsulfonyl chloride (470.01 mg, 4.10 mmol) dropwise at 0°C. React at room temperature for 2 hours. The reaction solution is concentrated, diluted with ethyl acetate, and washed with 2M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, respectively. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is purified by normal phase column chromatography to yield (5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-yl)methyl methanesulfonate (830 mg, yield: 89.89%). ESI-MS found: 396.1 [M+1]. + .

[0093] Step 4: Dissolve (5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4-carbonyl-4H-pyran-2-yl)methyl methanesulfonate (30 mg, 95.86 μmol) in acetonitrile (2 mL). Add N,N-diisopropylethylamine (132.46 mg, 1.01 mmol) and isoindoline-1,1,3,3-d4 (25 mg, 202.94 μmol) sequentially. Heat to 50°C for 16 hours. Cool the reaction system to room temperature, dilute with water, extract with dichloromethane, wash with saturated brine, and dry over anhydrous sodium sulfate. The filtrate was filtered, and the filtrate was concentrated. The crude product was purified by reverse phase chromatography to give 2-((isoindolin-2-yl-1,1,3,3-d4)methyl)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one (29 mg, yield: 34.15%, purity: 98.95%). ESI-MS found: 423.3 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.42-7.06(m,4H),6.39(s,1H),3.78(s,2H),3.72(d,J=6.0Hz,2 H),3.58(d,J=11.6Hz,2H),2.85(s,3H),2.79-2.65(m,2H),1.84(d,J=12.4Hz,3H),1.37-1.22(m,2H).

[0094] Example 4: Preparation of 2-((isoindolin-2-yl-1,1,3,3-d4)methyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one OST-1101025

[0095]

[0096] The preparation of 2-((isoindolin-2-yl-1,1,3,3-d4)methyl-d2)-5-((1-(methylsulfonyl)piperidin-4-yl)methoxy)-4H-pyran-4-one can be performed by referring to the seventh step of the preparation in Example 2, using isoindoline-1,1,3,3-d4 as the starting material. ESI-MS found: 425.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.42-7.03(m,4H),6.38(s,1H),3.71(d,J=6.0Hz,2H) ,3.60-3.53(m,2H),2.85(s,3H),2.77-2.65(m,2H),1.91-1.76(m,3H),1.34-1.19(m,2H).

[0097] Examples 5-40 can be prepared by selecting appropriate raw materials according to the synthesis method of Examples 1-4, and their structures are shown in Table 1.

[0098] Table 1. Structural formula, chemical name and mass spectrometry data of Examples 5-40

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] The NMR data of some of the compounds in the examples are as follows:

[0106]

[0107] Biological test evaluation

[0108] The present invention is further described and explained below in conjunction with biological test experiments, but these experiments are not intended to limit the scope of the present invention.

[0109] 1. Pregnenolone and Testosterone Biosynthesis Inhibition Experiment

[0110] Pregnenolone and testosterone biosynthesis inhibition experiments were conducted using the NCI-H295R cell line. NCI-H295R cells were revived and cultured in complete DMEM medium. Once cells were in good condition, they were added to a 96-well plate at a concentration of 95 μL per well (60,000 cells / well) and incubated overnight in a 37°C, 5% CO2 incubator. After the cells adhered, the diluted test compound was added to the 96-well plate in duplicate according to a concentration gradient, with 5 μL added to each well. Positive and blank controls were treated with equal volumes of complete DMEM medium containing the same DMSO content, mixed by vortexing, and incubated in a 37°C, 5% CO2 incubator for 48 hours. After incubation, 50 μL of the supernatant from the centrifuged culture medium sample was collected and quenched with 50 μL of ice-pure methanol. Subsequently, 150 μL of 100 mM hydroxylamine hydrochloride in 50% methanol (containing 2 ng / mL verapamil) was added. The sample was vortexed for 5 minutes and reacted in a 60°C water bath for 1 hour. After centrifugation, the secretion of pregnenolone and testosterone was analyzed by LC-MS / MS. Data were analyzed using GraphPad Prism 9 software and IC was calculated. 50 IC values ​​of some compounds against CYP11A1 obtained by inhibition of pregnenolone and testosterone biosynthesis 50 See Table 2. "Preg" is the abbreviation for Pregnenolone, "Test" is the abbreviation for Testosterone, and "NT" is the abbreviation for "Not Tested," meaning it has not yet been tested. The positive compound is Example 185 in patent WO2018115591, and its structure is as follows:

[0111]

[0112] Table 2. CYP11A1 inhibitory activity test results of some example compounds

[0113] Compound number <![CDATA[Preg IC 50 ]]> <![CDATA[Test IC 50 ]]> 1 NT 3.8 2 4.3 3.8 3 3.5 3.4 4 2.8 1.8 Positive compounds 4.1 4.2

[0114] From the above test results, it can be seen that the deuterated polycyclic compounds of the present invention exhibit strong inhibitory activity against CYP11A1 in in vitro tests, and some compounds are even stronger than the positive compounds.

[0115] 2. Pharmacokinetic testing in mice

[0116] This experiment tests the metabolic stability of the example compounds after oral administration in mice. Male ICR mice, 20-25g, 3 mice / compound, purchased from Weitonglihua Experimental Animal Co., Ltd. were used in the experiment. On the day of the test, the mice were randomly divided into groups according to body weight. The mice were fasted but not watered for 12 hours one day before administration, and were fed 4 hours after administration. Oral gavage solvent: 0.5% CMCNa. Dose: 5mg / kg. Before and after administration, 30uL of blood was collected from the mandibular vein under isoflurane anesthesia and placed in an EDTA-K2 test tube. After whole blood collection, it was temporarily stored in an ice water bath and centrifuged at 11000rpm for 5 minutes within 30 minutes to separate the plasma. The blood collection points for gavage administration were 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h. The samples were quantitatively analyzed by HPLC-MS / MS. The relevant pharmacokinetic parameters Tmax, Cmax, AUC were calculated using WinNonlin software. 0-t , t 1 / 2 The test results of some example compounds are shown in Table 3. The positive compound is Example 185 in patent WO2018115591.

[0117] Table 3. Results of pharmacokinetic test (oral administration) of some compounds in mice

[0118] Example No. <![CDATA[AUC 0-t (mg / mL)]]> <![CDATA[C max (ng / mL)]]> 1 4293 5380 4 2272 4693 Positive compounds 1523 3350

[0119] From the above test results, it can be seen that the polycyclic compound of the present invention has good metabolic stability in the oral pharmacokinetic test in mice.

[0120] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A deuterated compound represented by formula (I), a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, in, X2, X4, X 3a 、X 3b 、X 3c 、Z 1a 、Z 1b 、Z 2a 、Z 2b 、Z 3a 、Z 3b 、Z 3c 、Z 3d 、Z 4a 、Z 4b 、Z 4c 、Z 4d 、Z 5a 、Z 5b and Z 5c each independently hydrogen or deuterium; X1 is selected from the group consisting of hydrogen, deuterium, and trifluoromethyl; Additional conditions are: X1, X2, X 3a 、X 3b 、X 3c , X4, Z 1a 、Z 1b 、Z 2a 、Z 2b 、Z 3a 、Z 3b 、Z 3c 、Z 3d 、Z 4a 、Z 4b 、Z 4c 、Z 4d 、Z 5a 、Z 5b 、Z 5c At least one of them is deuterium.

2. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The Z 1a and Z 1b each independently deuterium.

3. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The Z 2a and Z 2b each independently deuterium.

4. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The Z 3a 、Z 3b 、Z 3c and Z 3d each independently deuterium.

5. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The Z 4a 、Z 4b 、Z 4c and Z 4d each independently deuterium.

6. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The Z 5a 、Z 5b and Z 5c each independently deuterium.

7. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The X1 is selected from the following group: hydrogen, deuterium, and trifluoromethyl.

8. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The X2 and X4 are each independently deuterium.

9. The deuterated compound, its crystal form, pharmaceutically acceptable salt, hydrate or solvate according to claim 1, wherein: The X 3a 、X 3b and X 3c each independently deuterium.

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

11. A pharmaceutical composition, characterized in that The composition comprises: (i) the deuterated compound according to any one of claims 1 to 10, its crystalline form, pharmaceutically acceptable salt, hydrate or solvate; and (ii) pharmaceutically acceptable carriers, adjuvants or vehicles.

12. Use of the deuterated compound according to any one of claims 1 to 10, its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 11, characterized in that: For preparing a drug for treating and / or preventing diseases associated with CYP11A1; Preferably, the disease associated with CYP11A1 is cancer; More preferably, the diseases associated with CYP11A1 are prostate cancer and breast cancer.

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