Dioxoimidazolidine local effect androgen receptor antagonist

Abstract

The invention discloses a dioxoimidazolidine locally acting androgen receptor antagonist. The androgen receptor antagonist is a compound as shown in a formula I, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of the compound. The compound provided by the invention is relatively good in skin stability and slow in metabolism, plays a role in resisting androgen alopecia, but is extremely poor in stability in plasma, so that systemic androgen antagonism side effects caused by systemic distribution are avoided. Meanwhile, the compound provided by the invention has relatively high skin retention volume in a rat in-vitro skin transdermal test. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of chemistry, and in particular to a novel substituted thioimidazolidinone compound as a locally acting androgen receptor antagonist, as well as a pharmaceutical composition comprising such a compound, and for treating androgen receptor-related diseases or conditions, such as androgenic alopecia and acne. Background Art

[0002] Androgenic alopecia (AGA), also known as seborrheic alopecia or premature balding, is divided into male and female pattern hair loss and is the most common clinically diagnosed non-scarring hair loss. AGA primarily occurs in late adolescence and is characterized by progressive atrophy of the hair follicles. In males, the disease primarily manifests as a receding hairline or thinning and loss of hair on the top of the head; in females, it primarily manifests as thinning and loss of hair on the top of the head. A minority of patients experience diffuse hair thinning without affecting the hairline. A 2010 epidemiological survey showed that the prevalence of AGA in my country was 21.3% among men and 6.0% among women. A family history of AGA was reported in 29.7% of men and 19.2% of women, respectively. The incidence of hair loss in Chinese men is increasing, with the onset occurring at younger ages. Young and middle-aged men are now the primary group affected. Sixty percent of men experience hair loss before the age of 25, and nearly 84% before the age of 30. Qi J, Ho CH et al. reported that 50% of men and women suffer from varying degrees of AGA. Androgenic alopecia commonly occurs in men between the ages of 17 and 20, with a peak incidence around age 30. While the incidence decreases with age, symptoms worsen, eventually leading to total alopecia. While AGA does not affect a patient's physical health, it can impact their mental health and quality of life. In severe cases, it can lead to depression, anxiety, strained interpersonal relationships, and sensitivity.

[0003] Androgenic alopecia is an androgen-dependent, polygenic, inherited disease. Since Hamilton Norwood first proposed in 1942 that androgens were involved in the development of AGA, research on AGA has focused primarily on androgens and their metabolic enzymes in the scalp. However, the exact etiology and pathogenesis of this disease remain unclear. Some researchers have found that the incidence of the disease is also associated with factors such as race, ethnicity, age, gender, living environment, lifestyle, psychological factors, and bacterial infections (such as Pityrosporum fumigatus and Corynebacterium acnes). In recent years, the incidence of AGA has been increasing, with a younger age group. Therefore, treatment is urgently needed.

[0004] Male androgens are primarily synthesized in the testes, including testosterone, dihydrotestosterone (DHT), androstenedione (DHEA), and dehydroepiandrosterone (ASD). Female androgens are primarily derived from the adrenal cortex. Testosterone and androstenedione can be reduced to DHT by 5α-reductase, which has a fivefold greater affinity for the androgen receptor (AR) than testosterone. The human body has two 5α-reductase isoenzymes: 5α-reductase I and 5α-reductase II. 5α-reductase I is primarily distributed in the sebaceous glands and liver, while 5α-reductase II is primarily distributed in the scalp hair follicles, epididymis, vas deferens, seminal vesicles, prostate, and fetal genital skin. Studies have shown that scalp hair follicles are a target organ for androgens. Hair biopsies from male patients with AGA reveal significantly higher 5α-reductase activity in the balding area of the scalp compared to the non-balding area of the occipital region. Other studies have shown that AR expression is elevated in follicles in the balding area of the scalp, accelerating hair loss in this region. DHT has a strong affinity for AR. After binding to AR, it enters the cell nucleus, inhibiting adenylate cyclase in the hair follicles, reducing the synthesis of cyclic glycosides and related proteins, and causing hair to enter the resting phase prematurely. It also inhibits the growth of hair follicles, causing them to shrink, stimulating the proliferation of sebaceous glands and oil secretion, further reducing the size of hair follicles and gradually disappearing, thereby promoting hair loss.

[0005] AGA patients are numerous, but there are few medications specifically for the condition. Currently, only finasteride and minoxidil are approved for the treatment of AGA, while most other drugs are used off-label. While existing AGA therapies are effective, they also carry numerous side effects, such as male sexual dysfunction with finasteride and propylene glycol allergy and orthostatic hypotension with minoxidil. These side effects limit their clinical use. Therefore, there is an urgent need for AGA medications that are locally effective, avoid systemic distribution, have low side effects, and are easy to use. Summary of the Invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to provide a compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in view of the deficiencies in the prior art.

[0007] Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] A further technical problem to be solved by the present invention is to provide the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or the use of the above-mentioned pharmaceutical composition.

[0009] A further technical problem to be solved by the present invention is to provide a method for preventing and / or treating diseases or conditions mediated by androgen or androgen receptor activity in mammals, and reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity in mammals.

[0010] In order to solve the above-mentioned first technical problem, the present invention discloses a compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0011]

[0012] in:

[0013] R1 is selected from substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted three-membered to six-membered cycloalkyl, substituted or unsubstituted four-membered to six-membered heterocycloalkyl; wherein the substituted C1-C5 alkyl, substituted three-membered to six-membered cycloalkyl, substituted four-membered to six-membered heterocycloalkyl, the substitution is substituted by one or more methyl, hydroxyl, methoxy or NR3(R4);

[0014] R3 and R4 are each independently selected from hydrogen, methyl or ethyl;

[0015] R2 is selected from hydrogen, methyl, methoxy, trifluoromethyl or halogen;

[0016] X is selected from N or CH;

[0017] Y is selected from N or CR5;

[0018] R5 is selected from hydrogen or halogen.

[0019] In some embodiments, R1 is selected from substituted or unsubstituted C1-C5 alkyl, or Wherein, the substitution in the substituted C1-C5 alkyl group is substitution by one or more methyl groups, hydroxyl groups, methoxy groups or NR3(R4);

[0020] R3, R4, and R6 are each independently selected from hydrogen, methyl, or ethyl; Z is selected from O, NCH3, or CH2; p and q are each independently selected from 0-2, and are not 0 at the same time.

[0021] In some embodiments, the Selected from

[0022] In some embodiments, R1 is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted pentyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted piperidinyl; wherein the substituted methyl, substituted ethyl, substituted propyl, substituted butyl, substituted cyclopropyl, substituted pentyl, substituted Replaced Replaced Replaced Replaced In the substituted piperidinyl group, the substitution is by one or more methyl, hydroxy, methoxy or NR3(R4); R3 and R4 are each independently selected from hydrogen, methyl or ethyl.

[0023] In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isobutyl, tert-amyl, cyclopropyl,

[0024] In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isobutyl, tert-amyl, cyclopropyl,

[0025] In some embodiments, R3, R4 are each independently selected from hydrogen, methyl, or ethyl.

[0026] In some embodiments, R2 is selected from hydrogen, methyl, methoxy, trifluoromethyl, chloro, or fluoro.

[0027] In some embodiments, X is selected from N or CH.

[0028] In some embodiments, Y is selected from N or CR5.

[0029] In some embodiments, R5 is selected from hydrogen, fluoro, or chloro.

[0030] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0031]

[0032]

[0033] In order to solve the above-mentioned second technical problem, the present invention discloses a pharmaceutical composition comprising (i) the compound of formula I or its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in the above-mentioned first technical problem, and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0034] In order to solve the third technical problem mentioned above, the present invention discloses the use of the compound of formula I or its stereoisomer, or a pharmaceutically acceptable salt thereof, described in the first technical problem mentioned above, or the pharmaceutical composition described in the second technical problem mentioned above in the preparation of a drug for preventing and / or treating diseases or conditions mediated by androgen or androgen receptor activity, or reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity.

[0035] In some embodiments, the disease or condition mediated by androgen or androgen receptor activity is selected from prostate cancer, acne, or alopecia.

[0036] At the same time, the present invention also discloses the use of the compound of formula I or its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition described in the second technical problem as an androgen receptor antagonist.

[0037] In order to solve the fourth technical problem mentioned above, the present invention discloses a method for preventing and / or treating diseases or conditions mediated by androgen or androgen receptor activity in mammals, and reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity in mammals, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I or its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in the first technical problem above, or the pharmaceutical composition as described in the second technical problem above.

[0038] In some embodiments, the mammal is a human.

[0039] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0040] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence of the particular atom is normal and the compound after the substitution is stable.

[0041] The term "optionally" or "optionally" means that the event or circumstance described subsequently may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0042] In this article, C n ~C m , means that the moiety has an integer number of carbon atoms in the given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C1-C3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0043] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. Thus, for example, if a group is substituted with two R's, each R has an independent alternative.

[0044] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0045] The term "hydroxy" refers to an -OH group.

[0046] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1- "C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1- "C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0047] The term "alkoxy" refers to an alkyl group as described above with the specified number of carbon atoms attached through an oxygen bridge. C1-C6 alkoxy groups include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S-pentoxy.

[0048] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C3-C4 cycloalkyl includes cyclopropyl and cyclobutyl.

[0049] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen, or a 4 to 6-membered ring. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, and oxetanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, and tetrahydrofuranyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0050] The term "treating" means administering the compounds or preparations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: i. inhibiting a disease or disease state, i.e. curbing its development; ii. alleviating a disease or disease state, i.e., causing the disease or disease state to regress.

[0051] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0052] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0053] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0054] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds discovered herein with specific substituents with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a suitable base. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a suitable acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0055] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0056] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0057] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0058] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0059] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0060] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0061] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0062] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0063] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, heavy hydrogen may be substituted for hydrogen to form a deuterated drug, such as d3-methyl, which means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. "Optional" or "optionally" means that the event or situation described subsequently may but is not required to occur, and the description includes situations in which the event or situation occurs as well as situations in which the event or situation does not occur.

[0064] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, respectively.

[0065] Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H and 14C) can be used in compound and / or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15O, 13N, 11C, and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the schemes and / or examples below, by replacing an isotopically labeled reagent with an isotopically labeled reagent.

[0066] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of this application.

[0067] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0068] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0069] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0070] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0071] The therapeutic dose of the compounds of the present invention may depend, for example, on the specific therapeutic application, the manner in which the compound is administered, the patient's health and condition, and the discretion of the prescribing physician. The proportion or concentration of the compounds of the present invention in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In certain embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.

[0072] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0073] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0074] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0075] The compounds, stereoisomers and pharmaceutically acceptable salts thereof provided by the present invention are locally acting androgen antagonists. Such compounds have a large skin retention amount and can be rapidly metabolized and eliminated in the blood after percutaneous administration, thereby improving safety. DETAILED DESCRIPTION

[0076] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in this application are commercially available and can be used without further purification.

[0077] Example 1: Preparation of tert-amyl 4-(3-(4-cyano-3-fluorophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 1)

[0078]

[0079] Synthesis route:

[0080]

[0081]

[0082] Synthesis method

[0083] Step 1: Synthesis of compound 1-1

[0084] To a 250 mL three-necked flask, add 100 mL of dichloromethane, followed by 10.00 g (45.66 mmol) of 4-bromo-2-fluorobenzoic acid, 4.00 g (45.66 mmol) of tert-amyl alcohol, 14.10 g (68.34 mmol) of N,N'-dicyclohexylcarbodiimide, and 0.59 g (4.57 mmol) of 4-dimethylaminopyridine. Stir and react at room temperature. After completion of the reaction, filter and collect the filtrate, wash three times with saturated brine, and dry the organic phase over anhydrous sodium sulfate and concentrate. The resulting crude product is purified by column chromatography to yield 4.82 g of compound 1-1.

[0085] Step 2: Synthesis of compound 1-2

[0086] To a 25 mL eggplant-shaped flask, add 10 mL of N,N-dimethylformamide, followed by 1.00 g (5.00 mmol) of 4-bromo-2-fluorobenzonitrile, 0.83 g (6.50 mmol) of 5,5-dimethylhydantoin, and 0.71 g (5.00 mmol) of cuprous oxide. Heat under reflux under nitrogen for 6 h. After the reaction is complete, allow to cool and filter. Add the filtrate to 160 mL of water, stir for 20 min, add 20 mL of aqueous ammonia, and continue stirring for 30 min. Filter, collect, and dry the filter cake to yield 0.4 g of compound 1-2.

[0087] MS (ESI, [M+H] + )m / z:248.4

[0088] Step 3: Synthesis of compound 1

[0089] A 25 mL round-bottom flask was added with 10 mL of toluene, followed by 0.3 g (1.21 mmol) of compound 1-2 prepared in step 2 above, 0.35 g (1.21 mmol) of compound 1-1 prepared in step 1 above, 70.2 mg (0.12 mmol) of tris(dibenzylideneacetone)dipalladium, 69.4 mg (0.12 mmol) of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, and 791.7 mg (2.43 mmol) of cesium carbonate. The mixture was heated under reflux under nitrogen for 26 h. After the reaction was completed, the mixture was allowed to cool, 20 mL of ethyl acetate was added, and the organic phase was washed three times with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain 36 mg of compound 1 as a white solid.

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.13(t,J=8.4,7.4Hz,1H),7.94(t,J=8.4Hz,1H),7.78(dd,J=10.8,1.8Hz,1H),7.66(dd,J=8.5,1.8H z,1H),7.53(dd,J=11.9,2.0Hz,1H),7.43(dd,J=8.5,2.0Hz,1H),1.87(q,J=7.5Hz,2H),1.55(d,12H),0.93(t,J=7.5Hz,3H).

[0091] MS (ESI, [M+H] + )m / z:456.2

[0092] Example 2: Preparation of methyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 2)

[0093]

[0094] Synthesis route:

[0095]

[0096]

[0097] Synthesis method:

[0098] Compound 2 was obtained by referring to the synthetic method of Example 1.

[0099] 1 H NMR(400MHz,Chloroform-d)δ8.08(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J= 8.5Hz,1H),7.72(dd,J=8.5,2.0Hz,1H),7.28–7.21(m,2H),3.99(s,3H),1.66(s,6H).

[0100] MS (ESI, [M+Cl] - )m / z:450.2.

[0101] Example 3: Preparation of ethyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 3)

[0102]

[0103] Synthesis route:

[0104]

[0105] Synthesis method:

[0106] Compound 3 was obtained by referring to the synthetic method of Example 1.

[0107] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.4Hz,1H),8.01(dd,2H),7.77(dd,J=8.5,1.9Hz,1H),7.56(dd ,J=12.1,2.0Hz,1H),7.46(dd,J=8.4,2.0Hz,1H),4.35(q,J=7.1Hz,2H),1.56(s,6H),1.33(t,3H).

[0108] MS (ESI, [M+Cl] -)m / z:464.2.

[0109] Example 4: Preparation of propyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 4)

[0110]

[0111] Synthesis route:

[0112]

[0113] Synthesis method:

[0114] Compound 4 was obtained by referring to the synthetic method of Example 1.

[0115] 1 H NMR(400MHz,Chloroform-d)δ8.08(s,1H),7.90(d,J=2.0Hz,1H),7.80(d,J=8.4Hz,1H),7.72(dd,J=8.5,2 .0Hz,1H),7.27–7.22(m,2H),4.35(t,J=6.6Hz,2H),1.88–1.78(m,2H),1.65(s,6H),1.06(t,J=7.4Hz,3H).

[0116] MS (ESI, [M+Cl] - )m / z:478.2.

[0117] Example 5: Preparation of (S)-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid sec-butyl ester (Compound 5)

[0118]

[0119] Synthesis route:

[0120]

[0121] Synthesis method:

[0122] Compound 5 was obtained by referring to the synthetic method of Example 1.

[0123] 1H NMR(400MHz,Chloroform-d)δ8.06(t,J=8.3Hz,1H),7.90(d,J=1.9Hz,1H),7.80(d,J=8.4Hz,1H),7.72(dd,J=8.5,2.0Hz ,1H),7.28–7.18(m,2H),5.22–5.10(m,1H),1.86–1.67(m,2H),1.65(s,6H),1.38(d,J=6.3Hz,3H),1.01(t,J=7.4Hz,3H).

[0124] MS (ESI, [M+Cl] - )m / z:492.2.

[0125] Example 6: Preparation of (R)-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid sec-butyl ester (Compound 6)

[0126]

[0127] Synthesis route:

[0128]

[0129] Synthesis method:

[0130] Compound 6 was obtained by referring to the synthetic method of Example 1.

[0131] 1 H NMR(400MHz,Chloroform-d)δ8.06(t,J=8.3Hz,1H),7.90(d,J=1.9Hz,1H),7.80(d,J=8.4Hz,1H),7.72(dd,J=8.5,2.0Hz ,1H),7.28–7.18(m,2H),5.22–5.10(m,1H),1.86–1.67(m,2H),1.65(s,6H),1.38(d,J=6.3Hz,3H),1.01(t,J=7.4Hz,3H).

[0132] MS (ESI, [M+Cl] - )m / z:492.2.

[0133] Example 7: Preparation of cyclopropyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 7)

[0134]

[0135] Synthesis route:

[0136]

[0137] Synthesis method:

[0138] Compound 7 was obtained by referring to the synthetic method of Example 1.

[0139] 1 H NMR(400MHz,Chloroform-d)δ8.04(t,J=8.7,7.9Hz,1H),7.90(d,J=1.9Hz,1H),7.80(d,J=8.5Hz,1H ),7.71(dd,J=8.5,2.0Hz,1H),7.27–7.19(m,2H),4.48–4.39(m,1H),1.65(s,6H),0.91–0.82(m,4H).

[0140] MS (ESI, [M+H] + )m / z:442.4.

[0141] Example 8: Preparation of 1-methylcyclopropyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 8)

[0142]

[0143] Synthesis route:

[0144]

[0145] Synthesis method:

[0146] Compound 8 was obtained by referring to the synthetic method of Example 1.

[0147] 1 H NMR(400MHz,Chloroform-d)δ8.03(t,1H),7.90(d,J=2.0Hz,1H),7.80(d,J=8.5Hz,1H),7.71(dd,J =8.4,2.0Hz,1H),7.27–7.18(m,2H),1.62(d,J=16.8Hz,9H),1.08–0.98(m,2H),0.83–0.73(m,2H).

[0148] MS (ESI, [M+H] + )m / z:456.3.

[0149] Example 9: Preparation of oxetane-3-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 9)

[0150]

[0151] Synthesis route:

[0152]

[0153] Synthesis method:

[0154] Compound 9 was obtained by referring to the synthetic method of Example 1.

[0155] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=8.4Hz,1H),8.09(t,J=8.4Hz,1H),7.99(d,J=1.9Hz,1H),7.77(dd,J=8.4,1.9Hz,1H),7.60(dd,J =12.1,2.0Hz,1H),7.50(dd,J=8.5,2.0Hz,1H),5.65(tt,J=6.3,5.1Hz,1H),4.91(t,J=7.4Hz,2H),4.69–4.62(m,2H),1.58(s,6H).

[0156] MS (ESI, [M+H] + )m / z:458.3.

[0157] Example 10: Preparation of 3-methyloxetan-3-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 10)

[0158]

[0159] Synthesis route:

[0160]

[0161] Synthesis method:

[0162] Compound 10 was obtained by referring to the synthetic method of Example 1.

[0163] 1H NMR (400MHz, Chloroform-d) δ8.07(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.72( dd,J=8.5,2.0Hz,1H),7.30–7.27(m,2H),4.94(d,J=7.3Hz,2H),4.65(d,2H),1.89(s,3H),1.67(s,6H).

[0164] MS (ESI, [M+H] + )m / z:472.3.

[0165] Example 11: Preparation of (R)-tetrahydrofuran-3-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 11)

[0166]

[0167] Synthesis route:

[0168]

[0169] Synthesis method:

[0170] Compound 11 was obtained by referring to the synthetic method of Example 1.

[0171] 1 H NMR(400MHz,Chloroform-d)δ8.07(t,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.71(dd,J=8.5,2.0Hz, 1H),7.28–7.21(m,2H),5.64–5.56(m,1H),4.10–3.90(m,4H),2.39–2.25(m,1H),2.25–2.15(m,1H),1.66(s,6H).

[0172] MS (ESI, [M+H] + )m / z:472.1.

[0173] Example 12: Preparation of Tetrahydro-2H-pyran-4-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 12)

[0174]

[0175] Synthesis route:

[0176]

[0177] Synthesis method:

[0178] Compound 12 was obtained by referring to the synthetic method of Example 1.

[0179] 1 H NMR (400MHz, DMSO-d6) δ8.18(d,J=8.5Hz,1H),8.04(t,J=8.3Hz,1H),7.99(d,J=1.9Hz,1H),7.77(dd,J=8.4,1.9Hz,1H),7.57(dd,J=12.0,2.0H z,1H),7.47(dd,J=8.5,2.0Hz,1H),5.24–5.12(m,1H),3.90–3.78(m,2H ),3.61–3.50(m,2H),2.04–1.93(m,2H),1.76–1.63(m,2H),1.57(s,6H).

[0180] MS (ESI, [M+H] + )m / z:486.7.

[0181] Example 13: Preparation of 4-methyltetrahydro-2H-pyran-4-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 13)

[0182]

[0183] Synthesis route:

[0184]

[0185] Synthesis method:

[0186] Compound 13 was obtained by referring to the synthetic method of Example 1.

[0187] 1 H NMR(400MHz,Chloroform-d)δ8.05(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.72(dd,J=8.5, 2.0Hz,1H),7.27–7.20(m,2H),3.83–3.76(m,4H),2.38–2.28(m,2H),1.91–1.79(m,2H),1.72(s,3H),1.66(s,6H).

[0188] MS (ESI, [M+H] + )m / z:500.1.

[0189] Example 14: Preparation of 1-methylpiperidin-4-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 14)

[0190]

[0191] Synthesis route:

[0192]

[0193] Synthesis method:

[0194] Compound 14 was obtained by referring to the synthetic method of Example 1.

[0195] 1 H NMR(400MHz,Chloroform-d)δ8.07(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.4Hz,1H),7.72(dd,J=8.4,2.0Hz,1H),7.28–7 .21(m,2H),5.18–5.11(m,1H),2.76–2.65(m,2H),2.47–2.37(m,2H),2.35(s,3H),2.11–2.04(m,2H),1.96–1.88(m,2H),1.65(s,6H).

[0196] MS (ESI, [M+H] + )m / z:499.3.

[0197] Example 15: Preparation of (S)-1-methoxypropan-2-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 15)

[0198]

[0199] Synthesis route:

[0200]

[0201] Synthesis method:

[0202] Compound 15 was obtained by referring to the synthetic method of Example 1.

[0203] 1H NMR(400MHz,Chloroform-d)δ8.07(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.80(d,J=8.4Hz,1H),7.71(dd,J=8.5,2.0Hz,1H),7.31–7.1 9(m,2H),5.45–5.33(m,1H),3.62(dd,J=10.7,6.4Hz,1H),3.55(dd,J=10.7,4.0Hz,1H),3.43(s,3H),1.64(s,6H),1.40(d,J=6.4Hz,3H).

[0204] MS (ESI, [M+H] + )m / z:474.2.

[0205] Example 16: Preparation of (R)-1-methoxypropan-2-yl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 16)

[0206]

[0207] Synthesis route:

[0208]

[0209] Synthesis method:

[0210] Compound 16 was obtained by referring to the synthetic method of Example 1.

[0211] 1 H NMR(400MHz,Chloroform-d)δ8.07(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.80(d,J=8.5Hz,1H),7.71(dd,J=8.5,2.0Hz,1H),7.26–7.1 9(m,2H),5.43–5.34(m,1H),3.62(dd,J=10.7,6.4Hz,1H),3.55(dd,J=10.7,3.9Hz,1H),3.43(s,3H),1.64(s,6H),1.40(d,J=6.5Hz,3H).

[0212] MS (ESI, [M+H] + )m / z:474.2.

[0213] Example 17: Preparation of (R)-2,3-dihydroxypropyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 17)

[0214]

[0215] Synthesis route:

[0216]

[0217] Synthesis method:

[0218] Step 1:

[0219] Compound 17-1 was obtained by referring to the method of step 2 of Example 2.

[0220] Step 2: Referring to the method of step 3 of Example 2, compound 17-2 was prepared by reacting compound 2-1 obtained in step 1 of Example 2 with compound 17-1.

[0221] 1 H NMR(400MHz,Chloroform-d)δ8.10(t,J=8.5Hz,1H),7.89(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.71(dd,J=8.5,2.0Hz,1 H),7.28–7.23(m,2H),4.48–4.43(m,3H),4.17(q,J=6.2Hz,1H),3.89-3.93(m,1H),1.65(s,6H),1.48(s,3H),1.41(s,3H).

[0222] Step 3:

[0223] In a 25 mL eggplant-shaped flask, 5 mL of methanolic hydrochloric acid solution (10% w / w) was added, followed by 100 mg of compound 17-2, and the mixture was stirred at room temperature for reaction. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and 56 mg of compound 17 was obtained by column chromatography.

[0224] 1H NMR(400MHz,Chloroform-d)δ8.10(t,J=8.3Hz,1H),7.89(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.71(dd,J=8.5,2.0Hz,1H),7.32–7.27 (m,2H),4.56–4.41(m,2H),4.11(q,J=4.8Hz,1H),3.88–3.79(m,1H),3.75(m,1H),2.63(d,J=5.2Hz,1H),2.18–2.10(m,1H),1.67(s,6H).

[0225] MS (ESI, [M+H]+) m / z: 476.2.

[0226] Example 18: Preparation of (S)-2,3-dihydroxypropyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 18)

[0227]

[0228] Synthesis route:

[0229]

[0230] Synthesis method:

[0231] Compound 18 was obtained by referring to the synthetic method of Example 17.

[0232] 1 H NMR(400MHz,Chloroform-d)δ8.10(t,J=8.3Hz,1H),7.89(d,J=2.0Hz,1H),7.81(d, J=8.5Hz,1H),7.71(dd,J=8.5,2.0Hz,1H),7.29(dd,J=6.0,3.8Hz,2H),4.52(dd,J=1 1.5,4.6Hz,1H),4.45(dd,J=11.5,6.0Hz,1H),4.11(t,J=5.1Hz,1H),3.83(dd,J=11 .4,4.0Hz,1H),3.75(dd,J=11.3,5.7Hz,1H),2.62(s,1H),2.13(s,1H),1.67(s,6H).

[0233] MS (ESI, [M+H] + )m / z:476.2.

[0234] Example 19: Preparation of 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Compound 19)

[0235]

[0236] Synthesis route:

[0237]

[0238] Synthesis method:

[0239] Step 1: Synthesis of compound 19

[0240] To a 25 mL eggplant-shaped flask, add 3 mL of a 1:1 mixture of tetrahydrofuran and water, 150 mg (0.36 mmol) of compound 2, monohydrate, and 45.5 mg (1.08 mmol) of lithium hydroxide. Stir the mixture at 40°C. After completion of the reaction, adjust the pH to acidic. Extract three times with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and concentrated. The resulting crude solid is purified by column chromatography to yield 40 mg of compound 19.

[0241] 1 H NMR(400MHz,Chloroform-d)δ8.17(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.82(d,J=8.5H z,1H),7.72(dd,J=8.5,2.0Hz,1H),7.32(d,J=2.2Hz,1H),7.31–7.29(m,1H),1.70(s,6H).

[0242] MS (ESI, [MH] - )m / z:400.1.

[0243] Example 20: Preparation of 2-hydroxyethyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 20)

[0244]

[0245] Synthesis route:

[0246]

[0247] Synthesis method:

[0248] Step 1: Synthesis of compound 20

[0249] To a 25-mL eggplant-shaped flask, add 3 mL of ethylene glycol and 100 mg of compound 19, then dropwise add 1 mL of thionyl chloride. Stir the reaction at 60°C. After completion of the reaction, add 5 mL of toluene and concentrate under reduced pressure. Redissolve the mixture in 20 mL of ethyl acetate, wash the organic phase three times with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate. The resulting crude solid was purified by column chromatography to yield 36 mg of compound 20.

[0250] 1 H NMR(400MHz,Chloroform-d)δ8.11(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.72(dd,J=8 .5,2.0Hz,1H),7.29(dd,1H),7.26(d,1H),4.64(t,J=6.3,5.0Hz,2H),3.85(t,J=6.3,5.0Hz,2H),1.67(s,6H).

[0251] MS (ESI, [M+H] + )m / z:446.1.

[0252] Example 21: Preparation of 2-(dimethylamino)ethyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 21)

[0253]

[0254] Synthesis route:

[0255]

[0256] Synthesis method:

[0257] Step 1: Synthesis of compound 21

[0258] To a 25 mL eggplant-shaped flask, 100 mg (0.5 mmol) of compound 19, 2 mL of isopropyl acetate, and 1 mL of thionyl chloride were added sequentially. The mixture was stirred at 95°C under nitrogen for 1 h. 5 mL of toluene was added and the mixture was concentrated under reduced pressure. The residue was redissolved in 3 mL of anhydrous tetrahydrofuran and, under an ice bath, added dropwise to 5 mL of a tetrahydrofuran solution containing 130 mg (1.5 mmol) of N,N-dimethylethanolamine and 30 mg of 4-dimethylaminopyridine. The reaction was allowed to react at room temperature overnight. The mixture was diluted with 30 mL of ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting crude solid was purified by column chromatography to yield 36 mg of compound 21.

[0259] 1H NMR(400MHz,Chloroform-d)δ8.09(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.4Hz,1H),7.72(dd,J=8.5,2.0 Hz,1H),7.27–7.25(m,1H),7.24–7.21(m,1H),4.50(t,J=5.7Hz,2H),2.77(t,J=5.7Hz,2H),2.38(s,6H),1.65(s,6H).

[0260] MS (ESI, [M+H] + )m / z:473.2.

[0261] Example 22: Preparation of 2-(diethylamino)ethyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 22)

[0262]

[0263] Synthesis route:

[0264]

[0265] Synthesis method:

[0266] Compound 22 was obtained by referring to the synthetic method of Example 21.

[0267] 1 H NMR(400MHz,Chloroform-d)δ8.08(t,J=8.3Hz,1H),7.90(d,J=2.0Hz,1H),7.81(d,J=8.5Hz,1H),7.72(dd,J=8.5,2.0Hz,1H),7.29–7 .26(m,1H),7.25–7.21(m,1H),4.45(t,J=6.2Hz,2H),2.87(t,J=6.2Hz,2H),2.65(q,J=7.1Hz,4H),1.65(s,6H),1.09(t,J=7.1Hz,6H).

[0268] MS (ESI, [M+H] + )m / z:501.1.

[0269] Example 23: Preparation of tert-amyl 4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)benzoate (Compound 23)

[0270]

[0271] Synthesis route:

[0272]

[0273] Synthesis method:

[0274] Compound 23 was obtained by referring to the synthetic method of Example 1.

[0275] 1 H NMR(400MHz,Chloroform-d)δ8.13(d,J=8.2Hz,2H),7.93(d,J=1.9Hz,1H),7.77(dd,2 H),7.40(d,J=8.3Hz,2H),1.96(q,J=7.4Hz,2H),1.61(s,12H),1.00(t,J=7.5Hz,3H).

[0276] MS (ESI, [M+H] + )m / z:454.1.

[0277] Example 24: Preparation of tert-amyl 2-chloro-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)benzoate (Compound 24)

[0278]

[0279] Synthesis route:

[0280]

[0281] Synthesis method:

[0282] Compound 24 was obtained by referring to the synthetic method of Example 1.

[0283] 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=2.0Hz,1H),7.87(d,J=8.3Hz,1H),7.80(d,J=8.4Hz,1H),7.72(dd,J=8.5,2.0 Hz,1H),7.46(d,J=2.1Hz,1H),7.30(dd,J=8.3,2.1Hz,1H),1.97(q,J=7.5Hz,2H),1.62(d,12H),1.01(t,J=7.5Hz,3H).

[0284] MS (ESI, [M+H] + )m / z:488.0.

[0285] Example 25: Preparation of tert-amyl 2-chloro-4-(3-(4-cyanophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)benzoate (Compound 25)

[0286]

[0287] Synthesis route:

[0288]

[0289] Synthesis method:

[0290] Compound 25 was obtained by referring to the synthetic method of Example 1.

[0291] 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J=8.3Hz,1H),7.83–7.72(m,4H),7.47(d,J=2.1Hz,1 H),7.32(dd,J=8.3,2.1Hz,1H),1.97(q,J=7.5Hz,2H),1.63(s,12H),1.01(t,J=7.5Hz,3H).

[0292] MS (ESI, [M+H] + )m / z:454.6.

[0293] Example 26: Preparation of tert-amyl 4-(3-(4-cyano-3-methylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 26)

[0294]

[0295] Synthesis route:

[0296]

[0297] Synthesis method:

[0298] Compound 26 was obtained by referring to the synthetic method of Example 1.

[0299] 1H NMR(400MHz,Chloroform-d)δ8.00(t,J=8.4Hz,1H),7.73(d,J=8.3Hz,1H),7.58(d,J=2.1Hz,1H),7.52(dd,J=8.3, 2.1Hz,1H),7.27–7.17(m,2H),2.63(s,3H),1.93(q,J=7.5Hz,2H),1.64(s,6H),1.60(s,6H),1.00(t,J=7.5Hz,3H).

[0300] MS (ESI, [M+H] + )m / z:452.3.

[0301] Example 27: Preparation of tert-amyl 4-(3-(4-cyano-3-methoxyphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 27)

[0302] Synthesis route:

[0303]

[0304] Synthesis method:

[0305] Compound 26 was obtained by referring to the synthesis method of Example 1

[0306] 1 H NMR(400MHz,Chloroform-d)δ8.00(t,J=8.3Hz,1H),7.67(d,J=8.2Hz,1H),7.30(d,J=11.2Hz,2H),7. 25–7.18(m,2H),3.98(s,3H),1.93(q,J=7.5Hz,2H),1.64(s,6H),1.60(s,6H),1.00(t,J=7.5Hz,3H).

[0307] MS (ESI, [M+H] + )m / z:468.2.

[0308] Example 28: Preparation of tert-amyl 4-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 28)

[0309]

[0310] Synthesis route:

[0311]

[0312] Synthesis method:

[0313] Compound 28 was obtained by referring to the synthetic method of Example 1.

[0314] 1 H NMR (400MHz, Chloroform-d) δ8.19(s,1H),8.08–7.95(m,3H),7.25–7.16(m,2H),1.94(q,J=7.4Hz,2H),1.66(s,6H),1.61(s,6H),1.01(t,J=7.5Hz,3H).

[0315] MS (ESI, [M+H] + )m / z:506.2.

[0316] Example 29: Preparation of tert-amyl 4-(3-(4-cyano-3-chlorophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 29)

[0317]

[0318] Synthesis route:

[0319]

[0320] Synthesis method:

[0321] Compound 29 was obtained by referring to the synthetic method of Example 1.

[0322] 1 H NMR(400MHz,Chloroform-d)δ8.01(t,J=8.2Hz,1H),7.90(d,J=1.8Hz,1H),7.80(d,J=8.5Hz,1H),7.72(dd,J =8.5,1.8Hz,1H),7.25–7.16(m,2H),1.94(q,J=7.5Hz,2H),1.64(s,6H),1.61(s,6H),1.00(t,J=7.5Hz,3H).

[0323] MS (ESI, [M+H] + )m / z:472.4.

[0324] Example 30: Preparation of tert-amyl 5-(3-(4-cyano-3-chlorophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-pyridine-2-carboxylate (Compound 30)

[0325]

[0326] Synthesis route:

[0327]

[0328] Synthesis method:

[0329] Compound 30 was obtained by referring to the synthetic method of Example 1.

[0330] 1 H NMR(400MHz,Chloroform-d)δ8.77(d,J=2.3Hz,1H),8.20(d,J=8.4Hz,1H),7.91(d,J=1.8Hz,1H),7.87(dd,J=8.4,2.4Hz, 1H),7.81(d,J=8.5Hz,1H),7.73(dd,J=8.5,1.8Hz,1H),2.02(q,J=7.4Hz,2H),1.67–1.63(m,12H),1.02(t,J=7.5Hz,3H).

[0331] MS (ESI, [M+H] + )m / z:455.2.

[0332] Example 31: Preparation of tert-amyl 5-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-pyridine-2-carboxylate (Compound 31)

[0333]

[0334] Synthesis route:

[0335]

[0336] Synthesis method:

[0337] Compound 31 was obtained by referring to the synthetic method of Example 1.

[0338] 1 H NMR(400MHz,Chloroform-d)δ8.77(d,J=2.5Hz,1H),8.24–8.14(m,2H),8.05(dd,J=8.4,2.1Hz,1H),7.99(d,J =8.4Hz,1H),7.88(dd,J=8.4,2.5Hz,1H),2.02(q,J=7.5Hz,2H),1.65(d,J=5.4Hz,12H),1.02(t,J=7.5Hz,3H).

[0339] MS (ESI, [M+H] + )m / z:489.1.

[0340] Example 32: Preparation of tert-amyl 4-(3-(2-cyano-3-trifluoromethylpyridin-5-yl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 32)

[0341]

[0342] Synthesis route:

[0343]

[0344] Synthesis method:

[0345] Compound 32 was obtained by referring to the synthetic method of Example 1.

[0346] 1 H NMR(400MHz,Chloroform-d)δ9.35(d,J=2.3Hz,1H),8.59(d,J=2.3Hz,1H),8.03(t,J=8.2Hz,1 H),7.25–7.15(m,2H),1.94(q,J=7.5Hz,2H),1.67(s,6H),1.61(s,6H),1.01(t,J=7.5Hz,3H).

[0347] MS (ESI, [M+H] + )m / z:507.6.

[0348] Example 33: Preparation of tert-pentyl 5-(3-(2-cyano-3-trifluoromethylpyridin-5-yl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-pyridine-2-carboxylate (Compound 33)

[0349]

[0350] Synthesis route:

[0351]

[0352] Synthesis method:

[0353] Compound 33 was obtained by referring to the synthetic method of Example 1.

[0354] 1H NMR(400MHz,Chloroform-d)δ9.35(d,J=2.3Hz,1H),8.77(d,J=2.5Hz,1H),8.58(d,J=2.4Hz,1H),8.22(d,J=8 .4Hz,1H),7.87(dd,J=8.4,2.5Hz,1H),2.02(q,J=7.5Hz,2H),1.68(s,6H),1.65(s,6H),1.02(t,J=7.5Hz,3H).

[0355] MS (ESI, [M+H] + )m / z:490.2.

[0356] Example 34: Preparation of tert-amyl 4-(3-(2-cyano-3-chloropyridin-5-yl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 34)

[0357]

[0358] Synthesis route:

[0359]

[0360] Synthesis method:

[0361] Compound 33 was obtained by referring to the synthetic method of Example 1.

[0362] 1 H NMR(400MHz,Chloroform-d)δ9.05(d,J=2.1Hz,1H),8.34(d,J=2.1Hz,1H),8.03(t,J=8.1Hz,1 H),7.25–7.13(m,2H),1.94(q,J=7.5Hz,2H),1.66(s,6H),1.61(s,6H),1.01(t,J=7.5Hz,3H).

[0363] MS (ESI, [M+H] + )m / z:473.2.

[0364] Application Experimental Example 1: Antagonistic activity of compounds on androgen receptor

[0365] 1) All test compounds were dissolved in DMSO to prepare 5 mM, 1 mM, and 0.25 mM solutions.

[0366] 2) HEK293T cells (ATCC, CRL-3216) were cultured according to ATCC recommendations (https: / / www.atcc.org / ). Cells were assayed during the exponential growth phase.

[0367] 3) Remove the culture medium from the dish, rinse the cells with phosphate buffered saline, add trypsin solution to the dish to detach the cells, and wash the cells once with complete culture medium.

[0368] 4) Wash the cells twice with phosphate buffered saline to remove phenol red and resuspend them in culture medium to an appropriate concentration.

[0369] 5) 6*10 6 HEK293T cells were seeded into 100 mm culture dishes (only cells with a viability greater than 90% were used for analysis) and cultured at 37°C and 5% CO2 for 16 h.

[0370] 6) Plasmids (pGL4.36[luc2P / MMTV / Hygro], Promega, E1360; pBIND-AR Vector, Pharmaron; LTX&Plus Reagent, Invitrogen, 15338-100) was transfected into HEK293T cells and cultured at 37°C and 5% CO2 for 5-6 h.

[0371] 7) 50 nl of compound dilutions were transferred to a 384-well assay plate using a non-contact nanoliter acoustic pipetting system (Labcyte, Echo550).

[0372] 8) The transfected HEK293T cells were plated at 15,000 cells / well and 1 nM DHT (MCE, HY-A0120)

[0373] The final concentration was inoculated into a 384-well assay plate (25 μl).

[0374] 9) The cells were cultured at 37°C and 5% CO2 for 18-20 hours.

[0375] 10) Add 25 μl of luciferase assay reagent (britelite plus, PerkinElmer, 6066769) to each well of a 384-well assay plate.

[0376] 11) Luminescence values were recorded using a microplate reader (Envision 2105, PerkinElmer) and the inhibition rate was calculated.

[0377] Table 1. Antagonistic activity of compounds on androgen receptor

[0378]

[0379]

[0380] Application Experiment 2: Stability of Compounds on Human Skin S9 Enzyme System

[0381] Phosphate buffer solution: Dissolve 8.709 g of potassium hydrogen phosphate in 950 mL of water, adjust the pH to 7.4 with hydrochloric acid, add water to make up to 1 L, filter through a 0.22 μm filter, and store at 4°C until use.

[0382] Preparation of reaction stop solution: Dissolve terfenadine and tolbutamide in DMSO to prepare stock solutions of 1 mg / mL each. Dilute the terfenadine and tolbutamide stock solutions with acetonitrile and mix them to prepare a mixed stop solution containing 5 ng / mL terfenadine and 10 ng / mL tolbutamide.

[0383] Compound solution preparation: The test compound was prepared into a 200 μM solution using DMSO;

[0384] Preparation of human skin S9 working solution: Thaw human skin S9 (1.89 mg / mL) in a 37°C ice-water bath and dilute to 0.629 mg / mL with phosphate-buffered saline.

[0385] NADPH working solution preparation: NADPH was prepared into a 5 mM solution using phosphate buffered saline;

[0386] Add 238.5 μL of human skin S9 working solution to a 1.1 mL mini centrifuge tube and incubate at 37°C for 5 minutes. Add 60 μL of NADPH working solution and 1.5 μL of the test compound solution, mix well, and continue incubation at 37°C. At 0 min, 5 min, 15 min, 30 min, 60 min, and 120 min, aspirate 30 μL of the reaction solution and add it to 300 μL of the reaction stop solution and mix well. Vortex for 1 minute and centrifuge at 4000 rpm for 15 minutes at 4°C. Aspirate 100 μL of the supernatant and dilute with 100 μL of water. Detect the compound concentration by LC-MS, calculate the residual rate, and fit the curve to calculate T. 1 / 2 .

[0387] Table 2. Human skin S9 stability of some compounds

[0388]

[0389]

[0390] The compounds of the present invention have good skin stability.

[0391] Application Experiment 3: Rat Plasma Stability of Compounds

[0392] The test compound was prepared into a 10mM stock solution with DMSO. The test compound was diluted to a 2mM working solution with DMSO. 10μL of 2mM working solution was added to 990μL rat plasma, vortexed for 5s, and configured to a reaction system with an initial concentration of 20μM. The reaction was incubated at 37°C, and 80μL plasma samples were taken at 0min, 10min, 20min, 30min, 1h, 2h, 4h and 6h. 240μL of methanol was added to the plasma sample, vortexed for 3min, and centrifuged at 14400rpm for 3min. 200μL of supernatant was aspirated, and the HPLC test was performed to calculate the concentration. The concentration was calculated according to the formula T 1 / 2 =-0.693 / k to calculate the half-life. The results are shown in Table 3.

[0393] Table 3. Rat plasma half-life

[0394] Example <![CDATA[T 1 / 2 (min)]]> 13 <5 16 <5 17 <5 24 <5 27 <5 28 <5 29 <5 31 <5 34 <5

[0395] The results show that the compounds provided by the present invention are extremely unstable in plasma and can be almost completely degraded after 5 minutes of plasma incubation. That is, the compounds of the present invention are rapidly inactivated after entering the blood and cannot be distributed throughout the body, thereby unable to cause systemic androgen antagonism. Therefore, they will not cause side effects such as decreased libido, decreased sperm production, and ED. This can effectively solve the problem that existing drugs such as finasteride are systemically distributed, resulting in systemic androgen inhibition and causing side effects such as decreased libido, decreased sperm production, and ED.

[0396] Application Experiment 4: Skin Permeability and Skin Retention of Compounds

[0397] Preparation of test drug solution: Accurately weigh 24 mg of the test compound into a 2 mL centrifuge tube, add 1.5 mL of a mixed solvent of ethanol: glycerol: triethylhexanoin = 75:15:10, sonicate to dissolve, and store at 4°C until use.

[0398] Transdermal test:

[0399] (1) Thaw the frozen rat back skin and cut it into appropriate sizes. Store the excess skin pieces at -20°C.

[0400] (2) The mouse skin was washed with 0.01 M PBS (pH 7.4) solution and cut into appropriate sizes with scissors. The front and back sides were dried with absorbent paper and then sandwiched between the supply and receiving cells of a Franz diffusion cell (with the stratum corneum facing upward and the transdermal area of 2.2 cm). 2 , receiving pool volume 8mL);

[0401] (3) Add 8 mL of a 1:1 mixture of water and ethanol to the receiving cell, taking care to remove any bubbles.

[0402] (4) Equilibrate at 36°C and 300 rpm for 30 min;

[0403] (5) Add 200 μL of the test drug solution to the supply cell;

[0404] (6) Take 1 mL of the receiving solution at 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h, transfer it to a 1.5 mL centrifuge tube, and re-inject 1 mL of a 1:1 water:ethanol mixture into the receiving pool after sampling;

[0405] (7) The receiving solution sample was centrifuged at 14,400 rpm for 3 min. 200 μL of the supernatant was transferred to an HPLC injection vial using a pipette and analyzed by HPLC. The cumulative permeation per unit area was calculated.

[0406] (8) After sampling at 24 hours, the mouse skin between the receiving tank and the supply tank was removed, and a cotton swab was dipped in a 1:1 mixed solvent of fresh water and ethanol to scrub the front and back of the mouse skin for 6 groups (6 scrubbings per group). A skin piece with a diameter of 1 cm was removed from the center of the mouse skin with a perforator and rinsed with a 1:1 mixed solvent of fresh water and ethanol (shake 20 times);

[0407] (9) Wipe the surface moisture with absorbent paper and weigh on a balance;

[0408] (10) Cut the skin into small pieces with scissors, add 1.5 mL of a 3:1 ethanol:water mixture, and homogenize with a homogenizer;

[0409] (11) Transfer 1 mL of the homogenate to a 1.5 mL centrifuge tube and centrifuge at 14,400 rpm for 3 min. Transfer 200 μL of the supernatant to an HPLC injection vial for HPLC analysis. Calculate the skin retention amount.

[0410] Table 4. Cumulative permeation and skin retention of some compounds per unit area in isolated rat skin over 24 hours

[0411]

[0412] The compound of the present invention has low skin permeability but high skin retention, which is beneficial for interacting with androgen receptors in hair follicles.

[0413] In summary, the compounds provided by the present invention have good skin stability and slow metabolism, effectively exerting anti-androgenic alopecia effects. However, their stability in plasma is extremely poor, avoiding systemic androgen antagonism side effects caused by systemic distribution. Furthermore, the compounds provided have high skin retention in rat ex vivo skin permeation tests.

[0414] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: R1 is selected from substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted three-membered to six-membered cycloalkyl, substituted or unsubstituted four-membered to six-membered heterocycloalkyl; wherein the substituted C1-C5 alkyl, substituted three-membered to six-membered cycloalkyl, substituted four-membered to six-membered heterocycloalkyl, the substitution is substituted by one or more methyl, hydroxyl, methoxy or NR3(R4); R3 and R4 are each independently selected from hydrogen, methyl or ethyl; R2 is selected from hydrogen, methyl, methoxy, trifluoromethyl or halogen; X is selected from N or CH; Y is selected from N or CR5; R5 is selected from hydrogen or halogen.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: R1 is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted pentyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted piperidinyl; wherein the substituted methyl, substituted ethyl, substituted propyl, substituted butyl, substituted pentyl, substituted cyclopropyl, substituted Replaced Replaced Replaced Replaced In the substituted piperidinyl group, the substitution is by one or more methyl, hydroxy, methoxy or NR3(R4); R3 and R4 are each independently selected from hydrogen, methyl or ethyl.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from methyl, ethyl, n-propyl, isobutyl, tert-pentyl, cyclopropyl, 4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from methyl, ethyl, n-propyl, isobutyl, tert-pentyl, cyclopropyl, 5. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R3 and R4 are each independently selected from hydrogen, methyl or ethyl; R2 is selected from hydrogen, methyl, methoxy, trifluoromethyl, chlorine or fluorine; X is selected from N or CH; Y is selected from N or CR5; R5 is selected from hydrogen, chlorine or fluorine.

6. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that The compound is any one of the following structural formulas; 7. A pharmaceutical composition, characterized in that The invention comprises (i) the compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

8. Use of the compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating a disease or condition mediated by androgen or androgen receptor activity, or reducing the progression of a disease or condition mediated by androgen or androgen receptor activity.

9. The use according to claim 8, characterized in that The disease or condition mediated by androgen or androgen receptor activity is selected from prostate cancer, acne or alopecia.

10. Use of the compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 as an androgen receptor antagonist.

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