A compound having anti-androgen receptor activity and uses thereof

Abstract

The present application relates to a kind of compound with anti-androgen receptor activity and its use, the present application provides the compound shown in formula I, its racemate, stereoisomer, tautomer, solvate, polymorph or their pharmaceutically acceptable salt.The compound has good prostate tumor cell proliferation inhibitory activity and anti-AR activity.The compound has good in vivo metabolic properties, AUC and C max Both are higher, and the drug has good property, can be used for preventing and / or treating male hormone related disorder disease.The compound of the present application also has good hair production promoting effect, can effectively increase the number of hair follicle and the length of hair growth.

Description

[0001] This application claims priority to the following earlier application: Patent application No. 202210476508.3, filed with the China National Intellectual Property Administration on April 29, 2022, entitled "A compound with anti-androgen receptor activity and its use thereof". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to a compound with anti-androgen receptor activity and its uses. Background Technology

[0003] The androgen receptor (AR) is a member of the large family of ligand-associated transcription factors, which are collectively known as the steroid receptor superfamily. The androgen receptor is a steroid hormone receptor possessing a ligand-binding domain, a DNA-binding domain, and multiple phosphorylation sites. In vivo, after binding to its ligand, the AR forms an AR dimer, which is then phosphorylated and translocated from the cytoplasm to the nucleus, where it mediates various transcriptional and activation pathways.

[0004] Androgen-related diseases (ARs) are widely distributed in many parts and organs of the human body and play a crucial role in the development of many androgen-related diseases such as cancer, hair loss, and acne.

[0005] Literature reports that androgens and androgen receptors (ARs) play important roles in the growth of both normal prostate and prostate cancer, and anti-androgen drugs are widely used in the treatment of prostate cancer. Furthermore, high serum androgen levels are associated with acne and androgenic alopecia, suggesting that anti-androgen therapy has potential effects on these conditions. However, androgens participate in numerous biological processes. Blocking or inhibiting the binding of androgens to their corresponding receptors leads to increased levels of effective androgens in the surrounding environment. This increased level of androgens in the environment can affect other androgen-related biological processes and cause undesirable side effects. Currently, inhibiting androgen receptor production has become a research hotspot, and compounds with anti-androgen receptor activity are considered potential therapies for androgen receptor-related disorders.

[0006] Chinese patent application CN03808650.6 discloses a class of curcumin analogs that have anti-androgen receptor activity and can effectively inhibit the production of androgen receptors in cells. However, most of these curcumin analogs are oily or have unsatisfactory activity.

[0007] Mental illnesses such as low self-esteem or depression often plague patients with hair loss, skin conditions, and other ailments, causing them a severe psychological burden. Therefore, there is an urgent need for new compounds that possess good drug-like properties, biological activity, and other desirable characteristics. Summary of the Invention

[0008] This invention provides a curcumin derivative with high bioavailability, good bioactivity, rapid onset of action, and long-term maintenance of stable physiological concentrations in vivo.

[0009] The present invention also aims to provide compositions comprising the above-mentioned curcumin derivatives and the use of the above-mentioned curcumin derivatives in the preparation of medicaments for treating, preventing or improving symptoms or diseases arising from androgen-related disorders.

[0010] The objective of this invention is achieved through the following technical solutions:

[0011] In a first aspect, the present invention provides compounds of formula I, their racemates, stereoisomers, tautomers, solvates, polymorphs, or pharmaceutically acceptable salts thereof.

[0012]

[0013] Wherein, R1, R2, R3, and R4 may be the same or different, and are independently selected from the following groups that are unsubstituted or optionally substituted by one, two, or more Ra: C 1-12 Alkyl or deuterated C 1-12 alkyl;

[0014] The following ring systems represent unsubstituted or optionally substituted rings with one, two, or more Rb: C 3-20 cycloalkyl, C 4-20 Cycloalkenyl, 3-20 membered heterocyclic groups, C 3-20 cycloalkyl and C 3-20 Spirocyclic rings formed by cycloalkyl groups linked together, C 3-20 Spirocyclic rings formed by linking cycloalkyl groups with 3-20 membered heterocyclic groups, and spirocyclic rings formed by linking 3-20 membered heterocyclic groups together;

[0015] Ra may be the same or different, and can be independently selected from halogens, =O, hydroxyl, amino, and C. 1-12 Alkyl, C 1-12 Alkoxy;

[0016] Rb may be the same or different, and may be independently selected from deuterated, halogenated, =O, hydroxyl, amino, unsubstituted, or optionally substituted by one, two, or more Rc groups, including: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, -NHC 1-12 Alkyl, -N(C) 1-12 Alkyl)2、-NHCOC 1-12 Alkyl, -CONHC 1-12 Alkyl, -NHC3-20 cycloalkyl, -NHCOC 3-20 cycloalkyl, -CONHC 3-20 Cycloalkyl, -S(O)2C 1-12 Alkyl, -COOC 1-12 Alkyl; or two Rb atoms attached to the same carbon atom together with the attached carbon atom to form an unsubstituted or optionally substituted ring system as follows: C 3-20 Cycloalkyl groups, 3-20 membered heterocyclic groups;

[0017] The Rc is selected from halogens, hydroxyl groups, amino groups, and C. 1-12 Alkyl, C 1-12 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic, 5-20 membered heteroaryl.

[0018] According to an embodiment of the present invention, R1, R2, R3, and R4 may be the same or different, and are independently selected from C. 1-6 Alkyl or deuterated C 1-6 alkyl;

[0019] According to an embodiment of the present invention, The following ring systems represent unsubstituted or optionally substituted rings with one, two, or more (e.g., 1, 2, 3, 4, or 5) Rb: C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 3-12 membered heterocyclic groups, C 3-12 cycloalkyl and C 3-12 Spirocyclic rings formed by cycloalkyl groups linked together, C 3-12 Spirocyclic rings formed by linking cycloalkyl groups with 3-12-membered heterocyclic groups, and spirocyclic rings formed by linking 3-12-membered heterocyclic groups with 3-12-membered heterocyclic groups;

[0020] According to embodiments of the invention, Rb may be the same or different, and independently selected from deuterated, halogenated, =O, hydroxyl, amino, unsubstituted, or optionally substituted by one, two, or more (e.g., 1, 2, 3, 4, or 5) Rc groups, including: C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-NHCOC 1-6 Alkyl, -NHC 3-12 cycloalkyl, -S(O)2C 1-6 Alkyl, -COOC 1-6 alkyl;

[0021] In some embodiments of the present invention, the Rc is selected from halogens, hydroxyl groups, and C. 3-12 Cycloalkyl, 3-12 membered heterocyclic, 5-12 membered heteroaryl.

[0022] In some embodiments of the present invention, the 3-20 membered heterocyclic group can be a nitrogen-containing heterocyclic group, an oxygen-containing heterocyclic group, etc., such as piperidinyl, piperazine, morpholinyl, dioxane, etc.

[0023] In some embodiments of the present invention The following ring systems can be unsubstituted or optionally substituted by one, two or more Rb: C 3-10 Monocycloalkyl, C 3-10 Monocyclic alkenyl, oxaC 2-10 Monocyclic alkyl, aza-C 2-10 Monocyclic alkyl, spirocyclic C 6-16 Alkyl, oxaspirocyclic C 6-16 Alkyl groups; for example, spirocyclohexyl, spirocycloheptyl, spirocyclooctyl, spirocyclononyl, spirocyclodecyl, azircyclopentane, azircyclohexane, azircycloheptane, oxaspirocyclohexyl, oxaspirocycloheptyl, oxaspirocyclooctyl, oxaspirocyclononyl, and oxaspirocyclodecyl.

[0024] In some embodiments of the present invention The following cyclic systems can be unsubstituted or optionally substituted with one, two or more Rb: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[2,3]hexyl, 1,3-dioxanecyclohexyl, azirane, 1,4-dioxanespiro[4,5]decyl;

[0025] In some embodiments of the present invention, Rb is selected from deuterated, F, Cl, Br, I, =O, hydroxyl, amino, tert-butoxycarbonyl, -S(O)2CH3, -COOC(CH3)3, etc. -N(C2H5)2、-N(CH3)2、

[0026] In some embodiments of the present invention, R1, R2, R3, and R4 may be the same or different, and are independently selected from C. 1-3 Alkyl or deuterated C 1-3 Alkyl groups, such as methyl or deuterated methyl groups;

[0027] In some embodiments of the present invention, the compound represented by Formula I has the following structure:

[0028]

[0029] Among them, R1, R2, R3, and R4 have the definitions described above;

[0030] R5 is a halogen; R6 is a hydroxyl, amino, unsubstituted, or optionally substituted with one, two, or more Rc groups, such as: C 1-12 Alkyl, C1-12 Alkoxy, C 3-20 Cycloalkyl, 3-20 membered heterocyclic groups, -NHC 1-12 Alkyl, -N(C) 1-12 Alkyl)2、-NHCOC 1-12 Alkyl, -CONHC 1-12 Alkyl, -NHC 3-20 cycloalkyl, -S(O)2C 1-12 Alkyl, -COOC 1-12 alkyl;

[0031] In some embodiments of the present invention Represents = O, halogen, Cyclohexyl groups substituted with -N(C2H5)2.

[0032] In one embodiment of the present invention, Represents a cyclohexyl group substituted with =O or a halogen, for example

[0033] In some preferred embodiments of the present invention, the compound represented by Formula I is selected from the following:

[0034]

[0035] In some specific embodiments of the present invention, the compound represented by Formula I is selected from the following:

[0036]

[0037] In some preferred embodiments of the present invention, the compound represented by Formula I is selected from the following:

[0038]

[0039] If the compounds of the present invention can exist in tautomer form, then the present invention includes all tautomer forms.

[0040] The compounds of the present invention can exist in stereoisomeric forms (enantiomers, diastereomers). Therefore, the present invention includes enantiomers or diastereomers and mixtures thereof. From such mixtures of enantiomers and / or diastereomers, the homogeneous stereoisomeric components can be separated in a known manner.

[0041] In some embodiments of the present invention, the pharmaceutically acceptable salt of the compound represented by Formula I is its hydrochloride salt, for example, the hydrochloride salts of compounds 12, 14, 16, 18, 19 and 23.

[0042] The present invention also provides a method for preparing the compound of Formula I above, comprising the following steps:

[0043]

[0044] Wherein, R1-R4 and Rb have the definitions described above, n is an integer from 0 to 17, m is an integer greater than or equal to 0, and X is a halogen, such as bromine; the compound of formula SM-A is reacted with the compound of formula SM-B to obtain the compound of formula I. Furthermore, the compound of formula I can be synthesized by introducing different substituents onto the A ring of the compound of formula I using conventional chemical synthesis methods. For example, some compounds of formula I can be prepared by the following methods, including:

[0045] The compound of formula (I-1) was reacted with R5-L to give the compound of formula (I-2).

[0046]

[0047] Among them, R1, R2, R3, R4, and R5 have the definitions described above; L is a leaving group.

[0048] Alternatively, reacting compound (I-1) with R6-L yields compound (I-3).

[0049]

[0050] Among them, R1, R2, R3, R4, and R6 have the definitions described above; L is a leaving group.

[0051] In some implementations, n is an integer from 0 to 9, such as 0, 1, 2, 3, 4, 5.

[0052] In some implementations, m is an integer from 0 to 10, such as an integer from 0 to 5, like 0, 1, 2, 3, 4.

[0053] The present invention also provides a pharmaceutical composition comprising at least one of a compound of formula I, a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, or a pharmaceutically acceptable salt thereof.

[0054] According to the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0055] Suitable routes of administration for the pharmaceutical compositions of the present invention include, but are not limited to, oral, rectal, topical, oral, parenteral, intramuscular, intradermal, intravenous, and transdermal administration.

[0056] According to the present invention, the pharmaceutical composition is for oral administration, and the pharmaceutical composition may be a tablet, pill, lozenge, sugar-coated tablet, capsule, etc.

[0057] According to the present invention, the pharmaceutical composition is used for topical administration, and the pharmaceutical composition may be an ointment, cream, paste, tincture, plaster, gel, film, coating, aerosol, spray, foam, microsponge, etc.

[0058] The pharmaceutical compositions of the present invention can be prepared using methods well-known in the art, such as conventional mixing, granulation, sugar-coated pill making, grinding, melting, emulsification, and dissolution. For example, solid oral compositions can be prepared by conventional mixing, filling, or tableting methods; topical formulations can be prepared by conventional dissolution, mixing, and stirring. For example, the active compound can be mixed with solid excipients, optionally milled, and other suitable excipients can be added if necessary. The mixture can then be granulated to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, sweeteners, or flavoring agents. For example, an ointment can be prepared by emulsification, which can be obtained by heating and melting oily and oil-soluble components to obtain an oil phase, dissolving water-soluble components in water and heating to obtain an aqueous phase, adding the aqueous phase to the oil phase while stirring until condensation, to obtain an ointment. Suitable excipients include, but are not limited to, bases, pH adjusters, and transdermal absorption enhancers.

[0059] The present invention provides the use of the compounds represented by Formula I above, their racemates, stereoisomers, tautomers, solvates, polymorphs or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention in the preparation of medicaments for treating, preventing or improving symptoms or diseases of androgen-related disorders.

[0060] According to the present invention, non-limiting examples of symptoms or diseases of androgen-related disorders include: androgen-related inflammation, including trauma (the compounds of the present invention can help wound healing), acne, atopic dermatitis, rheumatoid arthritis, psoriasis, and rosacea; Kennedy's disease (spinal and bulbar muscular atrophy or SBMA), polyglutamine-mediated motor neuron degeneration; androgen-related cancers, such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer, and pancreatic cancer; hair loss, including androgenetic alopecia; acne; and hirsutism.

[0061] The present invention also provides a method for treating, preventing, or improving symptoms or diseases of androgen-related disorders, comprising administering to an individual in need a preventive or therapeutically effective amount of a compound of formula I of the present invention, its racemic, stereoisomer, tautomer, solvate, polymorph or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0062] According to the present invention, non-limiting examples of symptoms or diseases of androgen-related disorders include: androgen-related inflammation, including trauma (the compounds of the present invention can help wound healing), acne, atopic dermatitis, rheumatoid arthritis, psoriasis, and rosacea; polyglutamine-mediated motor neuron degeneration, Kennedy's disease (spinal cord and bulbar muscular atrophy or SBMA); androgen-related cancers, such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer, and pancreatic cancer; hair loss, including androgenetic alopecia; acne; and hirsutism.

[0063] In all methods of administration of the compounds represented by Formula I described herein, the daily dose is from 0.01 to 200 mg / kg body weight.

[0064] According to the present invention, the dosing regimen can be adjusted to provide the optimal desired response. For example, it can be administered as a single oral dose, as several fractions administered over time, or as the urgency of the treatment condition indicates, the dose can be reduced or increased proportionally. It should be noted that the dosage value can vary depending on the type and severity of the condition to be alleviated, and can include single or multiple doses. It should be further understood that, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0065] Definitions and Explanations

[0066] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0067] Unless otherwise stated, the following definitions shall apply as used herein. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0068] As used herein, the terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0069] In this document, the term "optional" means either the presence or absence of the stated feature, implying that the event subsequently described may but is not necessarily to occur, and thus includes both cases where the event occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but is not necessarily present, and thus includes cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted.

[0070] In this document, the term "halogen" refers to fluorine, chlorine, bromine, and / or iodine. Accordingly, the term "halogenated" refers to fluorination, chlorination, bromination, and / or iodination. Within the scope of this document, when an atom, residue, group, or part is halogenated, the atom at the halogenated position can be monosubstituted, disubstituted, or polysubstituted up to fully substituted by the halogen atom.

[0071] In this application, "*" indicates a connection site.

[0072] Term "C" 1-12 "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C12. 1-6 Alkyl group. "C" 1-6 "alkyl" should be understood to preferably represent a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C..."). 1-3 Alkyl), such as methyl, ethyl, n-propyl or isopropyl.

[0073] Term "C" 3-20 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C". 3-12 cycloalkyl. The term "C" 3-12 "Cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0074] Term "C" 4-20 "Cycloalkenyl" should be understood as representing an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 4 to 20 carbon atoms and containing at least one unsaturated double bond, such as 1, 2, or 3 unsaturated double bonds. Preferably, "C" is used. 4-12 "Cycloalkenyl". The term "C" 4-12"Cycloalkenyl" should be understood as representing an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and 1, 2, or 3 unsaturated double bonds. The C... 4-12 Cycloalkyl groups are, for example, cyclohexenyl groups.

[0075] The term "3-20 membered heterocyclic group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O, and S, preferably a "3-12 membered heterocyclic group". The term "3-12 membered heterocyclic group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O, and S. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic.

[0076] Term "C" 3-20 cycloalkyl and C 3-20 C in "spirocyclic compound composed of cycloalkyl groups" 3-20 The definition of cycloalkyl is the same as above; it refers to a compound with two carbon atoms. 3-20 Cycloalkyl groups are spirocycles formed by sharing a single carbon atom.

[0077] Term "C" 3-20 "Spirorings composed of cycloalkyl groups and 3-20 membered heterocyclic groups" 3-20 The definitions of cycloalkyl and 3-20 membered heterocyclic groups are the same as above; they refer to groups with one carbon atom. 3-20 A spirocycle consisting of a cycloalkyl group and a 3-20 membered heterocyclic group sharing a single carbon atom.

[0078] The definition of 3-20 membered heterocyclic group in the term "spirocyclic group composed of 3-20 membered heterocyclic group and spirocyclic group composed of 3-20 membered heterocyclic group" is the same as above. It refers to a spirocyclic group composed of two 3-20 membered heterocyclic groups sharing one carbon atom.

[0079] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as "5-12-membered heteroaryl". The term "5-12-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0080] The term "prevention or treatment" means administering the compounds or preparations described in this invention to prevent, improve, or eliminate a disease or one or more symptoms related to said disease, and includes:

[0081] (i) To prevent the occurrence of disease or disease state in mammals, especially when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state;

[0082] (ii) Suppress the disease or disease state, that is, curb its development;

[0083] (iii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0084] The term "therapeutic effective amount" means the amount of the compound of the present invention used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the content of this disclosure.

[0085] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0086] Pharmaceutically acceptable salts of the compounds of the present invention include salts formed with pharmaceutically acceptable acids and salts formed with pharmaceutically acceptable bases.

[0087] As used herein, the term "pharmaceutically acceptable acid" refers to pharmaceutically usable acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, aminosulfonic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pyric acid, nicotinic acid, orotic acid, methylsulfuric acid, dodecyl sulfate, glutamic acid, aspartic acid, gluconic acid, glucuronic acid, or any combination thereof.

[0088] As used herein, the term "pharmaceutically acceptable base" refers to a base that is pharmaceutically usable, such as inorganic bases (alkali metal hydroxides or alkaline earth metal hydroxides, etc.) or organic bases (e.g., amines (primary, secondary, or tertiary amines, etc.)). Examples of suitable salts include, but are not limited to, organic salts derived from amino acids, ammonia, primary, secondary, and tertiary amines, as well as cyclic amines (e.g., diethylamine salts, piperidine salts, morpholine salts, piperazine salts, choline salts, meglumine salts, tromethamine salts, etc.), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0089] The term "solvent" refers to a compound of the present invention that forms a complex with solvent molecules in a solid or liquid state through coordination. A hydrate is a specific form of solvate in which the coordination occurs with water.

[0090] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present invention to an organism.

[0091] The compounds of the present invention are formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, etc., for oral administration to patients. The compounds of the present invention can also be formulated into ointments, creams, pastes, tinctures, plasters, gels, films, ointments, aerosols, sprays, foams, microsponges, etc., for topical administration to patients.

[0092] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0093] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0094] Typical routes of administration of the compounds of this application or their pharmaceutically acceptable salts 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. Oral administration has better patient compliance than intravenous administration.

[0095] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0096] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients. Solid oral compositions can be prepared by conventional mixing, filling, or compression methods. For example, it can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated tablet. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0097] The pharmaceutical compositions of this invention are also suitable for topical administration, such as suitable unit dosage forms of creams, gels, foams, or tinctures. Topical formulations can be prepared using conventional methods of dissolving, mixing, and stirring. For example, creams can be prepared using an emulsification method, obtained by heating and melting oily and oil-soluble components to obtain an oil phase, dissolving water-soluble components in water and heating to obtain an aqueous phase, adding the aqueous phase to the oil phase while stirring until condensation, to obtain an ointment. Suitable excipients include, but are not limited to, bases, pH adjusters, and transdermal absorption enhancers.

[0098] The term "androgen" refers to male hormones such as testosterone and dihydrotestosterone (DHT). DHT is a product of testosterone converted by 5-α-reductase. Androgens stimulate or control the development and maintenance of male characteristics and other physiological functions in vertebrates and activate or regulate genes by binding to androgen receptors, which in turn bind to androgen / AR-controlled genes (DNA).

[0099] The term "androgen receptor" or "AR" refers to the intracellular receptor that specifically binds to androgens, including testosterone and dihydrotestosterone (DHT). ARs include androgen receptor isoforms, binding variants, and polymorphs in all mammals.

[0100] The medical term "androgenetic alopecia" refers to hair loss symptoms and conditions associated with androgen levels in the body. Androgenetic alopecia is generally believed to be caused by sensitivity of hair follicles or surrounding tissues to androgens, a sensitivity that is genetically determined and often passed down through families. In men, androgenetic alopecia is associated with several other medical conditions, including coronary heart disease and enlarged prostate, prostate cancer, insulin resistance conditions (such as diabetes and obesity), and hypertension. In women, hair loss can be associated with an increased risk of polycystic ovary syndrome (PCOS). PCOS is characterized by hormonal imbalances that can lead to menstrual irregularities, acne, excessive hair growth (hirsutism), and weight gain. Hair loss in women is often associated with androgen buildup or increased androgen levels. Androgenetic alopecia is the most common form of hair loss in men, and this condition is also commonly referred to as male pattern baldness. Hair loss occurs in a clearly identifiable manner, starting at the temples. Over time, the hairline recedes to form a typical "M" shape. The hair also thins at the top of the head, often progressing to partial or complete baldness. In women, this manifests as thinning hair across the entire head, without a receding hairline. Androgenetic alopecia rarely leads to complete baldness in women.

[0101] The term "anti-AR activity" refers to the ability of the compounds of this invention to reduce AR expression in human prostate cancer cells LNCaP. In this invention, the percentage reduction in AR expression is used to represent the ability of the compounds to reduce AR expression. The greater the reduction in AR expression, the stronger the anti-AR activity of the compound; that is, the larger the percentage reduction in AR, the stronger the anti-AR activity. The formula for calculating the percentage reduction in AR is: AR reduction percentage (%) = (AR / GAPDH value of DHT group - AR / GAPDH value of test compound group) / AR / GAPDH value of DHT group × 100%.

[0102] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0103] Beneficial effects

[0104] This invention provides a curcumin derivative of Formula I, which exhibits good inhibitory activity against prostate tumor cell proliferation and anti-AR activity. Furthermore, the curcumin derivative of this invention possesses favorable in vivo metabolic properties, with low AUC and C10 values. maxBoth have high efficacy and good pharmaceutical properties, making them suitable for the prevention and / or treatment of androgen-related disorders. Furthermore, the curcumin derivative of this invention also exhibits excellent hair growth promoting effects, effectively increasing the number of hair follicles and the length of hair growth. Attached Figure Description

[0105] Figure 1 Western blot images showing the reduction of AR protein expression in LNCaP cells by different concentrations of the compounds of this invention;

[0106] Figure 2 Pharmacokinetic curves of each compound in the plasma of male rats after oral administration of the compounds of the present invention;

[0107] Figure 3 On day 18 of the experiment, photographs of hair growth and representative HE-stained pathological images of skin tissues of mice in each group of the hair growth promotion experiment in test case 4 were taken. Detailed Implementation

[0108] The following detailed description, in conjunction with specific embodiments, illustrates the general formula compounds of the present invention, their preparation methods, and applications in further detail. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0109] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0110] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0111] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0112] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are by weight, and the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0113] This invention uses the following abbreviations: DHT represents dihydrotestosterone; clacoateone (purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.) is a marketed chemical drug with target indications including androgenetic alopecia and acne, and its mechanism of action is to competitively inhibit the binding of DHT to AR, thereby achieving an anti-androgenic effect; dimethylcurcumin (purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.); the structural formula of raw material A is... (Purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.); The structural formula of raw material B is: The structural formula of raw material C is The structural formula of raw material D is (Raw materials B to D were all purchased from Nanjing Jiming Biomedical Co., Ltd.)

[0114] Example 1: Synthesis of Compound 1

[0115]

[0116] Add starting material A (408 mg, 1.00 mmol, 1.0 eq), 1,2-dibromoethane (225 mg, 1.20 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the phases, and extract the aqueous phase with ethyl acetate (20 mL). Combine the organic phases and wash away DMF with saturated brine. Dry over anhydrous sodium sulfate and concentrate. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) gives 39 mg of a pale yellow solid.

[0117] 1 H NMR (400MHz, DMSO-d6) δ7.53(d,J=15.8Hz,2H),7.30(d,J=2.0Hz,2H),7.24(dd,J=8.4,2.1 Hz,2H),6.97(d,J=8.3Hz,2H),6.94(d,J=15.7Hz,2H),1.54(brs,4H).MSm / z:435.14[M+H] + .

[0118] Example 2: Synthesis of Compound 2

[0119]

[0120] Add starting material A (408 mg, 1.00 mmol, 1.0 eq), 1,3-dibromopropane (242 mg, 1.20 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the phases, and extract the aqueous phase with ethyl acetate (20 mL). Combine the organic phases and wash away DMF with saturated brine. Dry over anhydrous sodium sulfate and concentrate. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) gives 90 mg of a pale yellow solid.

[0121] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=15.6Hz,1H),7.33(d,J=15.8Hz,1H),7.20–6.91(m,6H),6.84(d, J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),4.36–4.06(m,2H),2.76–2.46(m,2H),2.12–1.83(m,2H).MS m / z:449.22[M+H] + .

[0122] Example 3: Synthesis of Compound 3

[0123]

[0124] Add starting material A (408 mg, 1.00 mmol, 1.0 eq), 1,4-dibromobutane (260 mg, 1.20 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the phases, and extract the aqueous phase with ethyl acetate (20 mL). Combine the organic phases and wash away DMF with saturated brine. Dry over anhydrous sodium sulfate and concentrate. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) gives 87 mg of a pale yellow solid.

[0125] 1 H NMR(400MHz,DMSO-d6)δ7.55(d,J=15.6Hz,2H),7.32–7.18(m,4H),6.96(d,J =8.3Hz,2H),6.81(d,J=15.7Hz,2H),2.31–2.15(m,4H),1.67–1.50(m,4H).MS m / z:463.20

[0126] [M+H] + .

[0127] Example 4: Synthesis of Compound 4

[0128]

[0129] Add starting material A (408 mg, 1.00 mmol, 1.0 eq), 1,4-dibromopentane (277 mg, 1.20 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the phases, and extract the aqueous phase with ethyl acetate (20 mL). Combine the organic phases and wash away DMF with saturated brine. Dry over anhydrous sodium sulfate and concentrate. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) gives 92 mg of a pale yellow solid.

[0130] 1 H NMR(400MHz,DMSO-d6)δ7.56(d,J=15.5Hz,2H),7.37–7.18(m,4H),7.03(d,J =15.5Hz,2H),6.96(d,J=8.3Hz,2H),2.21–1.96(m,4H),1.60–1.28(m,6H).MS m / z:477.23

[0131] [M+H] + .

[0132] Example 5: Synthesis of Compound 5

[0133]

[0134] Dimethylcurcumin (500 mg, 1.26 mmol, 1.0 eq), 1,1-bis-bromomethylcyclopropane (340 mg, 1.50 mmol), Cs₂CO₃ (1.00 g, 3.11 mmol), and DMF (15 mL) were added to a reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine to remove DMF. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 20 mg of a pale yellow solid.

[0135] 1H NMR (400MHz, CDCl3) δ8.20(d,J=15.8Hz,1H),7.56(d,J=15.6Hz,1H),7.33(d,J=16.1Hz,1H) ,7.24–6.79(m,6H),6.72(d,J=15.5Hz,1H),3.92(s,12H),1.63(brs,4H),0.70(brs,4H).MS m / z:463.16[M+H] + .

[0136] Example 6: Synthesis of Compound 6

[0137]

[0138] Add starting material A (408 mg, 1.00 mmol, 1.0 eq), deuterated dibromoethane (230 mg, 1.20 mmol), Cs₂CO₃ (814 mg, 2.5 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the phases, and extract the aqueous phase with ethyl acetate (20 mL). Combine the organic phases and wash away DMF with saturated brine. Dry over anhydrous sodium sulfate and concentrate. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) gives 30 mg of a pale yellow solid.

[0139] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=15.8Hz,2H),7.12(dd,J=8.3,2.1Hz,2H),7.00(d,J=2.0Hz,2H),6.83(d,J=8.3Hz,2H),6.79(d,J=15.7Hz,2H).MS m / z:439.18[M+H] + .

[0140] Example 7 Synthesis of Compound 7

[0141]

[0142] Dimethylcurcumin (10.0 g, 25.22 mmol, 1.0 eq), 1,5-dichloropentanone (3.91 g, 25.22 mmol), KBr (12.01 g, 100.9 mmol), K₂CO₃ (10.46 g, 75.67 mmol), and DMF (300 mL) were added to a reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (700 mL) and ethyl acetate (400 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (400 mL). The organic phases were combined and washed with saturated brine to remove DMF. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 3.6 g of a yellow, foamy solid.

[0143] 1 H NMR(400MHz, CDCl3)7.75(d,J=15.5Hz,2H),7.15(dd,J=8.4,2.0Hz,2H),7.02(d,J=2.0H z,2H),6.85(d,J=8.4Hz,2H),6.74(d,J=15.4Hz,2H),3.91(s,12H),2.56–2.40(m,8H).MS m / z:479.29[M+H] + .

[0144] Example 8: Synthesis of Compound 8

[0145]

[0146] Under nitrogen protection, compound 7 (2.0 g, 4.18 mmol), dichloromethane (20 mL), and 1 drop of pyridine hydrofluoric acid were added to the reaction flask. The mixture was stirred and cooled to 0 °C, and then 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (2.1 g, 8.36 mmol) was added in a single batch. The reaction mixture was reacted at 10–15 °C for 6 h. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and subjected to column chromatography (petroleum ether / ethyl acetate 10:1–2:1) to obtain the crude product. HPLC preparation (acetonitrile / water 10:90–80:20) yielded 150 mg of a pale yellow solid.

[0147] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=15.4Hz,2H),7.14(d,J=8.3Hz,2H),7.09–6.96(m,2H),6.85( d,J=8.4Hz,2H),6.72(d,J=15.4Hz,2H),3.91(s,12H),2.45–2.18(m,4H),2.12–1.91(m,4H). 19F NMR(376MHz,CDCl3)δ-97.28.MS m / z:501.27[M+H] + .

[0148] Example 9: Synthesis of Compound 9

[0149]

[0150] Step (1) Synthesis of intermediate 9-1

[0151] Dimethylcurcumin (2.00 g, 5.0 mmol) and tetrahydrofuran (16 mL) were added sequentially to the reaction flask and stirred until dissolved. The reaction temperature was controlled between -1 and 0 °C, and formaldehyde aqueous solution (37–40%, 860 mg, 10.6 mmol) and catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (93 mg) were added sequentially. The reaction was then carried out at 0–10 °C for 1–2 hours, followed by rotary evaporation at room temperature to concentrate the solution. Column chromatography (MeOH / CH2Cl2 1:100–1:50) yielded 900 mg of a yellow solid.

[0152] 1 H NMR(400MHz, CDCl3) δ7.73(d,J=15.4Hz,2H),7.15(dd,J=8.3,2.1Hz,2H),7.01(d,J=2.1Hz,2H),6.84 (d,J=8.4Hz,2H),6.73(d,J=15.4Hz,2H),4.34(d,J=8.0Hz,4H),3.90(s,12H),2.97(t,J=8.0Hz,2H).

[0153] Step (2) Synthesis of Compound 9

[0154] Under nitrogen protection, intermediate 9-1 (300 mg, 0.65 mmol), dichloromethane (7 mL), and pyridine (156 mg, 1.97 mmol) were added to a reaction flask, and the mixture was stirred and cooled to -70 °C. A solution of di(trichloromethyl) carbonate (97 mg, 0.33 mmol) in dichloromethane (1 mL) was added dropwise, and the reaction was carried out at -70 °C for 2 h. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and then subjected to column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 210 mg of a pale yellow solid. MS m / z: 483.35 [M+H] + .

[0155] Example 10: Synthesis of Compound 10

[0156]

[0157] Dimethylcurcumin (500 mg, 1.26 mmol, 1.0 eq), 1,5-dibromopentane (435 mg, 1.89 mmol), K₂CO₃ (523 mg, 3.78 mmol), and DMF (15 mL) were added to the reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine to remove DMF. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 150 mg of a yellow, foamy solid.

[0158] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=15.5Hz,2H),7.12(dd,J=8.3,1.9Hz,2H),7.01(d,J=2.0Hz,2H),6.83(d,J=8 .3Hz,2H),6.75(d,J=15.4Hz,2H),3.90(s,12H),2.17–2.02(m,4H),1.66–1.53(m,4H),1.50–1.37(m,2H).MS m / z:465.31[M+H] + .

[0159] Example 11 Synthesis of Compound 11

[0160]

[0161] Compound 7 (500 mg, 1.04 mmol), ethylene glycol (324 mg, 5.22 mmol), acetonitrile (5 mL), and oxalic acid (94 mg, 1.04 mmol) were added to a reaction flask, and the mixture was stirred at 25 °C for 20 h. After the reaction was complete, the reaction solution was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 420 mg of a pale yellow solid.

[0162] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=15.5Hz,2H),7.12(dd,J=8.3,2.0Hz,2H),7.00(d,J=1.9Hz,2H),6.82(d, J=8.4Hz,2H),6.75(d,J=15.4Hz,2H),3.93(s,4H),3.89(s,12H),2.36–2.22(m,4H),1.82–1.68(m,4H).MS m / z:523.33[M+H] + .

[0163] Example 12 Synthesis of Compound 12 and its hydrochloride

[0164]

[0165] Compound 7 (200 mg, 0.4 mmol), acetic acid (25 mg, 0.4 mmol), 1,2-dichloroethane (1.5 mL), and morpholine (36 g, 0.4 mmol) were added to a reaction flask. Sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added all at once, and the mixture was stirred at 25 °C for 7 h. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The solution was dried over sodium sulfate and concentrated. TLC (petroleum ether / ethyl acetate 1:1) yielded 30 mg of a pale yellow solid.

[0166] 1 H NMR(400MHz, CDCl3)7.68(d,J=15.5Hz,1H),7.66(d,J=15.5Hz,1H),7.16–7.09(m,2H),7.03–6.98(m,2H),6.83(dd,J=8.4,3.1H z,2H),6.75(d,J=15.5Hz,1H),6.69(d,J=15.5Hz,1H),3.90(s,12H),3.88–3.72(m,4H),2.87–2.40(m,7H),2.10–1.45(m,6H).MS m / z:550.48[M+H] + .

[0167] Synthesis of compound 12 hydrochloride:

[0168] Compound 12 (200 mg), methanol (0.5 mL), and ethyl acetate (5 mL) were added to a reaction flask and stirred to dissolve. Ethyl hydrochloride (1 mol / L, 0.5 mL) was added, filtered, and dried under vacuum to obtain 120 mg of a pale yellow solid.

[0169] 1H NMR (400MHz, CDCl3) δ12.96(brs,1H),7.72(d,J=15.2Hz,1H),7.69(d,J=15.3Hz,1 H),7.17–7.10(m,2H),7.03–6.96(m,2H),6.84(dd,J=8.4,3.5Hz,2H),6.71(d,J=15 .4Hz,1H),6.62(d,J=15.4Hz,1H),4.56–4.29(m,2H),4.05–3.80(m,2H),3.91(s,1 2H),3.34–2.88(m,5H),2.83–2.68(m,2H),2.43–2.27(m,2H),1.91–1.69(m,4H).MS m / z:550.48[M+H] + .

[0170] Example 13 Synthesis of Compound 13

[0171]

[0172] Compound 7 (200 mg, 0.4 mmol), acetic acid (25 mg, 0.4 mmol), and 1,2-dichloroethane (5 mL) were added to a reaction flask. Sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added all at once, and the mixture was stirred at 25 °C for 5 h. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The solution was dried over sodium sulfate and concentrated. TLC (petroleum ether / ethyl acetate 2:1) yielded 20 mg of a pale yellow solid.

[0173] 1 H NMR (400MHz, CDCl3) δ7.68(d,J=15.5Hz,1H),7.66(d,J=15.5Hz,1H),7.17–7.10(m,2H),7.03–6.99(m,2H),6.83(dd,J=8.3,2.6H z,2H),6.76(d,J=15.4Hz,1H),6.73(d,J=15.5Hz,1H),3.90(s,12H),3.79–3.69(m,1H),2.00–1.86(m,4H),1.72–1.50(m,4H).MS m / z:481.24[M+H] + .

[0174] Example 14 Synthesis of Compound 14 and its hydrochloride

[0175]

[0176] Under nitrogen protection, compound 7 (300 mg, 0.63 mmol), ammonium trifluoroacetate (160 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol). The reaction was allowed to proceed at room temperature for 5 hours, after which ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added. The mixture was separated, and the organic phase was washed with purified water. The solution was dried over sodium sulfate and concentrated to obtain a yellow oily substance. HPLC preparation (acetonitrile / water 10:90–80:20) yielded a yellow solid compound 14 (MS m / z: 480.26 [M+H]). + Add ethyl acetate (7 mL) and methanol (0.1 mL), stir to dissolve at room temperature, and add ethyl hydrochloride (0.5 N / 1.2 mL) dropwise. Filter and dry under vacuum at 40 °C to give 20 mg of yellow solid compound 14 hydrochloride.

[0177] 1 H NMR (400MHz, CDCl3) δ8.39(brs,3H),7.68(d,J=15.4Hz,1H),7.66(d,J=15.4Hz,1H),7 .18–7.06(m,2H),7.05–6.95(m,2H),6.83(d,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),6.73 (d,J=15.5Hz,1H),6.68(d,J=15.5Hz,1H),3.89(s,6H),3.88(s,3H),3.87(s,3H),3.32 –3.10(m,1H),2.77–2.52(m,2H),2.31–2.06(m,2H),1.99–1.53(m,4H).MSm / z:480.26.

[0178] [M+H] + .

[0179] Example 15 Synthesis of Compound 16 and its hydrochloride

[0180]

[0181] Under nitrogen protection, compound 7 (300 mg, 0.63 mmol), diethylamine (9 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol). The reaction was allowed to proceed at room temperature for 5 hours, after which ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added. The mixture was separated, and the organic phase was washed with purified water. The solution was dried over sodium sulfate and concentrated to give a yellow oily compound, which was then prepared by TLC (petroleum ether / ethyl acetate 1:1) to give a pale yellow solid compound 16 (MS m / z: 536.44 [M+H]). + Add ethyl acetate (12 mL) and methanol (0.2 mL), stir to dissolve at room temperature, and add ethyl hydrochloride (0.5 N / 1.2 mL) dropwise. Filter and dry under vacuum at 40 °C to give 160 mg of a yellow solid, which is the hydrochloride salt of compound 16.

[0182] 1 H NMR (400MHz, CDCl3) δ11.95(brs,1H),7.72(d,J=15.1Hz,1H),7.69(d,J=14.8Hz,1H), 7.14(dd,J=8.3,1.9Hz,2H),7.04–6.96(m,2H),6.85(dd,J=8.4,2.7Hz,2H),6.71(d,J =15.4Hz,1H),6.63(d,J=15.4Hz,1H),3.91(s,12H),3.42–3.22(m,1H),3.18–2.96(m, 4H),2.82–2.66(m,2H),2.37–2.22(m,2H),1.92–1.67(m,4H),1.51(t,J=7.2Hz,6H).MS m / z:536.44[M+H] + .

[0183] Example 16 Synthesis of Compound 18

[0184]

[0185] Under nitrogen protection, compound 7 (300 mg, 0.63 mmol), 3,3-difluorocyclobutylamine hydrochloride (200 mg, 1.25 mmol), triethylamine (130 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was stirred at 25 °C for 30 min, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol). The reaction was allowed to proceed for 2 h at room temperature, then ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added. The mixture was separated, and the organic phase was washed with purified water. The solution was dried over anhydrous sodium sulfate and concentrated. TLC (petroleum ether / ethyl acetate 1:1) yielded 6 mg of compound 18 as a pale yellow solid. MS m / z: 584.50 [M+H] + .

[0186] 1 H NMR (400MHz, CDCl3) δ7.68(d,J=15.5Hz,1H),7.65(d,J=15.5Hz,1H),7.17–7.06(m,2H),7.01(d,J=2.0Hz,1H),7.00(d,J=2.0Hz,1H),6.83(dd,J=8.4, 3.4Hz,2H),6.76(d,J=15.5Hz,1H),6.70(d,J=15.5Hz,1H),3.90(s,12H),2 .72–2.56(m,2H),2.50–2.36(m,1H),2.06–1.88(m,4H),1.80–1.41(m,10H).

[0187] 19 F NMR (376MHz, CDCl3) δ -97.80.

[0188] Example 17 Synthesis of Compound 19 and its hydrochloride

[0189]

[0190] Under nitrogen protection, compound 7 (300 mg, 0.63 mmol), piperidine (110 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol). The reaction was allowed to proceed at room temperature for 3 hours, after which ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added. The mixture was separated, and the organic phase was washed with purified water. The solution was dried over sodium sulfate and concentrated to give a yellow oily compound. TLC (petroleum ether / ethyl acetate 1:1) yielded a pale yellow solid compound 19 (MS m / z: 548.45 [M+H]). +Add ethyl acetate (12 mL) and methanol (0.2 mL), stir to dissolve at room temperature, and add ethyl hydrochloride (0.5 N / 1.2 mL) dropwise. Filter and dry under vacuum at 40 °C to give 120 mg of yellow solid compound 19 hydrochloride.

[0191] 1 H NMR (400MHz, CDCl3) δ11.95(brs,1H),7.71(d,J=15.4Hz,1H),7.68(d,J=15.4Hz ,1H),7.14(dd,J=8.4,2.0Hz,2H),7.05–6.96(m,2H),6.84(dd,J=8.4,3.3Hz,2H) ,6.71(d,J=15.4Hz,1H),6.63(d,J=15.4Hz,1H),3.91(s,12H),3.45–3.28(m,2H ),3.17–3.03(m,1H),2.86–2.62(m,4H),2.56–2.29(m,4H),2.00–1.52(m,8H).MS m / z: 548.45 [M+H] + .

[0192] Example 18 Synthesis of Compound 22

[0193]

[0194] Under nitrogen protection, compound 7 (1.00 g, 2.09 mmol) and dichloromethane (20 mL) were added to a reaction flask. The mixture was stirred at 0 °C for 10 minutes, and diethylaminotrifluoride (0.40 g, 2.51 mmol) was added dropwise. The reaction was then allowed to proceed overnight at room temperature, followed by the addition of a saturated aqueous sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane. After concentration, column chromatography (petroleum ether / ethyl acetate 10:1–2:1) yielded 320 mg of crude product. HPLC preparation (acetonitrile / water 10:90–80:20) gave 0.10 g of a pale yellow solid.

[0195] 1 H NMR (400MHz, CDCl3) δ7.704(d,J=15.4Hz,2H),7.138(dd,J=8.3,1.9Hz,2H),7.013(d,J=1.9Hz,2H),6.842(d,J=8.3Hz,2H),6.727( d,J=15.4Hz,2H),5.326–5.169(m,1H),3.910(s,6H),3.904(s,6H),2.822–2.606(m,2H),2.469–2.352(m,2H),2.317–2.198(m,2H). 19F NMR(377MHz,CDCl3)δ-102.82.MS m / z:481.99[M+H] + .

[0196] Example 19 Synthesis of Compound 23 and its hydrochloride

[0197]

[0198] Under nitrogen protection, compound 7 (300 mg, 0.63 mmol), 3,3-difluorocyclobutylamine hydrochloride (180 mg, 1.25 mmol), triethylamine (130 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a 50 mL reaction flask. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol), and the reaction was carried out at room temperature for 2 hours. Ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added, the mixture was separated, the organic phase was washed with purified water, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily compound 23 (MS m / z: 570.43 [M+H)). + Add ethyl acetate (15 mL) and methanol (0.3 mL), stir to dissolve at room temperature, and add ethyl hydrochloride (0.5 N / 1.2 mL) dropwise. Filter and dry under vacuum at 40 °C to give 120 mg of yellow solid compound 23 hydrochloride.

[0199] 1 H NMR (400MHz, CDCl3) δ10.26(brs,2H),7.71(d,J=15.4Hz,1H),7.67(d,J=15.4Hz,1H),7 .18–7.06(m,2H),7.03–6.97(m,2H),6.82(d,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),6.74 (d,J=15.4Hz,1H),6.69(d,J=15.5Hz,1H),3.88(s,12H),3.66–3.50(m,1H),3.41–3.22 (m,2H),3.13–2.88(m,3H),2.81–2.60(m,2H),2.28–2.13(m,2H),1.94–1.73(m,4H).MS m / z:570.43[M+H] + .

[0200] Example 20 Synthesis of Compound 24

[0201]

[0202] Dimethylcurcumin (500 mg, 1.26 mmol), dibromoethylmethanesulfonamide (460 mg, 1.50 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) were added to the reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine to remove DMF, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 20 mg of a pale yellow solid. MS m / z: 544.42 [M+H] + .

[0203] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=15.4Hz,2H),7.15(dd,J=8.4,2.0Hz,2H),7.01(d,J=2.0Hz,2H),6.85(d ,J=8.3Hz,2H),6.69(d,J=15.4Hz,2H),3.91(s,12H),3.36–3.27(m,4H),2.76(s,3H),2.42–2.28(m,4H).

[0204] Example 21 Synthesis of Compound 25

[0205]

[0206] Dimethylcurcumin (500 mg, 1.26 mmol), tert-butyl bis(2-bromoethyl)carbamate (500 mg, 1.50 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) were added to a reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine to remove DMF, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 90 mg of a pale yellow solid.

[0207] MS m / z: 566.47 [M+H] + .

[0208] 1H NMR (400MHz, CDCl3) δ7.69(d,J=15.4Hz,2H),7.13(dd,J=8.4,2.0Hz,2H),7.00(d,J=2.0Hz,2H),6.83(d ,J=8.4Hz,2H),6.70(d,J=15.5Hz,2H),3.90(s,12H),3.54–3.26(m,4H),2.30–2.10(m,4H),1.44(s,9H).

[0209] Example 22 Synthesis of Compound 26

[0210]

[0211] Dimethylcurcumin (500 mg, 1.26 mmol), dibromoethylcyclopropane (390 mg, 1.52 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) were added to a reaction flask, and the mixture was stirred at 50 °C for 20 hours. After the reaction was complete, water (50 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine to remove DMF, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 50 mg of a pale yellow solid.

[0212] 1 H NMR (400MHz, CDCl3) δ7.69(s,2H),7.13(dd,J=8.3,1.9Hz,2H),7.01(d,J=2.0Hz,2H),6.83(d,J=8.3 Hz,2H),6.77(d,J=15.5Hz,2H),3.90(s,12H),2.26–2.13(m,4H),1.45–1.37(m,4H),0.25(s,4H).MS m / z:491.42[M+H] + .

[0213] Example 23 Synthesis of Compound 27

[0214]

[0215] Add starting material B (500 mg, 1.25 mmol), 1,5-dibromo-3,3-difluoropentane (317 mg, 1.2 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the layers, and extract the aqueous phase with ethyl acetate (20 mL). Wash the organic phase with saturated brine to remove DMF, dry to anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 30 mg of a pale yellow solid.

[0216] 1 H NMR (400MHz, CDCl3) δ7.707(d,J=15.5Hz,2H),7.139(dd,J=8.3,2.0Hz,2H),7.009(d,J=2.0Hz,2H),6.840(dd,J =8.4,2.4Hz,2H),6.722(d,J=15.4Hz,2H),3.907(s,6H),3.903(s,3H),2.38–2.27(m,4H),2.12–1.85(m,4H).MS m / z:504.44[M+H] + .

[0217] Example 24 Synthesis of Compound 28

[0218]

[0219] Add starting material C (500 mg, 1.24 mmol), 1,5-dibromo-3,3-difluoropentane (317 mg, 1.2 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the layers, and extract the aqueous phase with ethyl acetate (20 mL). Wash the organic phase with saturated brine to remove DMF, dry to anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 35 mg of a pale yellow solid.

[0220] 1H NMR (400MHz, CDCl3) δ7.709 (d, J=15.4Hz, 2H), 7.140 (dd, J=8.3, 2.0Hz, 2H), 7.027–6.982 (m, 2H), 6.843 (dd, J=8. 4,2.5Hz,2H),6.722(d,J=15.4Hz,2H),3.910(s,3H),3.907(s,3H),2.372–2.227(m,4H),2.116–1.949(m,4H).MS m / z:507.46[M+H] + .

[0221] Example 25 Synthesis of Compound 29

[0222]

[0223] Add starting material D (500 mg, 1.24 mmol), 1,5-dibromo-3,3-difluoropentane (317 mg, 1.2 mmol), K₂CO₃ (520 mg, 3.76 mmol), and DMF (15 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (50 mL) and ethyl acetate (20 mL), separate the layers, and extract the aqueous phase with ethyl acetate (20 mL). Wash the organic phase with saturated brine to remove DMF, dry to anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 25 mg of a pale yellow solid.

[0224] 1 H NMR(400MHz, CDCl3) δ7.704(d,J=15.4Hz,2H),7.136(dd,J=8.4,2.0Hz,2H),7.007(d,J=2.0Hz,2H),6.8 34(d,J=8.3Hz,2H),6.720(d,J=15.4Hz,2H),3.904(s,6H),2.366–2.227(m,4H),2.117–1.939(m,4H).MS m / z:507.51[M+H] + .

[0225] Example 26 Synthesis of Compound 30 and its hydrochloride

[0226]

[0227] Synthesis of intermediate 30-1 in step 1

[0228] Add starting material D (1.0 g, 2.50 mmol, 1.0 eq), 1,5-dichloropentanone (0.391 g, 2.52 mmol), KBr (1.20 g, 10.1 mmol), K₂CO₃ (1.05 g, 7.57 mmol), and DMF (30 mL) to a reaction flask, and stir at 50 °C for 20 hours. After the reaction is complete, add water (70 mL) and ethyl acetate (40 mL), separate the layers, and extract the aqueous phase with ethyl acetate (400 mL). Wash the organic phase with saturated brine to remove DMF, dry to anhydrous sodium sulfate, concentrate, and perform column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to give 600 mg of a yellow solid.

[0229] Step 2: Synthesis of compound 30 and its hydrochloride

[0230] Under nitrogen protection, intermediate 30-1 (300 mg, 0.62 mmol), diethylamine (9 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to a reaction flask. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (270 mg, 1.25 mmol), and the reaction was carried out at room temperature for 5 hours. Ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added, and the mixture was separated. The organic phase was washed with purified water, dried over sodium sulfate, and concentrated to obtain a yellow oily compound. TLC (petroleum ether / ethyl acetate 1:1) yielded a pale yellow solid compound 30 (MS m / z: 542.57 [M+H]). + Add ethyl acetate (12 mL) and methanol (0.2 mL), stir to dissolve at room temperature, and add ethyl hydrochloride (0.5 N / 1.2 mL) dropwise. Filter and dry under vacuum at 40 °C to give 60 mg of the hydrochloride salt of yellow solid compound 30.

[0231] 1 H NMR(400MHz, CDCl3)δ11.83(brs,1H),7.77–7.60(m,2H),7.14(d,J=8.2Hz,2H) ,7.01(dd,J=4.2,1.8Hz,2H),6.84(dd,J=8.3,2.7Hz,2H),6.72(d,J=15.4Hz,1 H),6.63(d,J=15.4Hz,1H),3.91(s,6H),3.37–3.20(m,1H),3.17–2.88(m,4H), 2.82–2.63(m,2H),2.37–2.19(m,2H),1.91–1.63(m,4H),1.56–1.37(m,6H).MS m / z: 542.57 [M+H] + .

[0232] Test Example 1: Cell viability inhibition test of the compound of the present invention on human prostate cancer cells.

[0233] Human prostate cancer cells LNCaP and 22Rvl exist in prostate cancer patients. The androgen DHT can promote the growth of human prostate cancer cells LNCaP. The purpose of using the above cell model is to study the inhibitory effect of the compound of the present invention on the growth of human prostate cancer cells (human prostate cancer cells LNCaP and human prostate cancer cells 22Rvl) in the presence or absence of DHT.

[0234] Experimental materials: test compounds (prepared by the method of this invention), human prostate cancer cells LNCaP (American Type Culture Collection (ATCC), Cat No: CRL-1740), human prostate cancer cells 22Rvl (American Type Culture Collection (ATCC), Cat No: CRL-2505), RPMI 1640 medium (Invitrogen; Cat. No. 11875119), fetal bovine serum (Certified FBS Charcoal Stripped, Biohivsl Industries, Cat. No. 04-204-1A), penicillin-streptomycin mixture (Solepro; Cat No: P1400), CellTiter-Glo (CTG) reagent (Promega, Cat#G7573).

[0235] Experimental Methods: Human prostate cancer cells LNCaP and 22Rvl, both in the exponential growth phase, were observed under a microscope to ensure good cell growth. The culture medium in the culture dish was discarded, and 5 mL of trypsin was added for digestion for approximately 3 minutes. 10 mL of fresh culture medium was added to stop the digestion. The cells were thoroughly dispersed and transferred to a 15 mL centrifuge tube, centrifuged at 1000 rpm for 5 minutes to collect the cells. The collected cells were resuspended in 11 mL of fresh culture medium, and 1 mL was used for cell counting and viability assessment. An appropriate amount of culture medium was added to adjust the cell density to 1 × 10⁻⁶ cells / mL. 4 Cells / mL were seeded at 200 μL / well in 96-well plates and incubated overnight in a cell incubator.

[0236] After cell adhesion, the human prostate cancer cell group (LNCaP) was incubated in 96-well plates with the test compound (0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM) and DHT (1 nM, to induce AR expression) for 5 days; the human prostate cancer cell group (22Rvl) was incubated in 96-well plates with the test compound (0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM) for 5 days. After 5 days, the 96-well plates were removed from the incubator, and the cell state was observed under a microscope, showing no abnormalities. The 96-well plates were then equilibrated at room temperature for 30 min.

[0237] Cell viability was assessed using the CTG method. Before the assay, CellTiter was thawed. The buffer and its substrate (collectively referred to as CTG reagent) were prepared and equilibrated to room temperature. Then, 100 mL of buffer and substrate were gently mixed to form a homogeneous solution. 100 μL / well was added to a 96-well plate and incubated on a shaker for 15 min. The fluorescence values ​​of each well were then measured. The fluorescence values ​​of each well were detected using a multi-mode plate reader (M200Pro, TECAN, Switzerland) according to the supplier's manual after adding the CTG reagent (integration time: 500 ms) to quantify the effect of the inhibitor on cell viability. For data analysis, the experimental background value, measured in wells containing culture medium but without cells, was subtracted from all data points. Data processing and IC50 calculations for each test compound were performed using XLfit software (XLfit 5.2, IDBS, UK). 50 Values, IC50 values ​​of typical compounds of the present invention against human prostate cancer cells LNCaP and human prostate cancer cells 22Rvl. 50 The values ​​are shown in Table 1 below.

[0238] Table 1. Inhibitory activity of the compounds of the present invention against human prostate cancer cells LNCaP and 22Rvl.

[0239]

[0240] "-" indicates that the relevant experiment was not conducted.

[0241] As can be seen from the experimental data in the table above, the compound of the present invention has good inhibitory activity against the growth of prostate cancer cells and can effectively inhibit the growth of prostate cancer cells.

[0242] Test Example 2: Test on the effect of the compound of the present invention on the expression of AR protein in human prostate cancer cells LNCaP

[0243] Androgen receptors (ARs) are key factors regulating the androgen response of prostate cancer cells, and also key factors in the androgen response of hair follicles or surrounding tissues. Decreased AR levels not only downregulate the growth of prostate cancer cells but also inhibit androgenic alopecia. This test case examines the effect of the compound of this invention on the reduction of AR protein expression in human prostate cancer cells (LNCaP) in the presence of DHT. Western blotting was used to analyze the anti-AR activity of the compound of this invention in human prostate cancer cells (LNCaP) by measuring the reduction in AR protein.

[0244] Experimental materials: test compounds (prepared using the method of this invention), human prostate cancer cells LNCaP (American Type Culture Collection (ATCC), Cat No: CRL-1740), RPMI 1640 medium (Invitrogen; Cat. No. 11875119), fetal bovine serum (Certified FBS Charcoal Stripped, Biohivsl Industries, Cat. No. 04-204-1A), BCA protein quantification kit (Thermo; Cat. No. 23225), color prestained protein marker (Beyotime; Cat. No. P0069), GAPDH antibody (Millipore; Cat. No. MAB374), AR antibody (CST; Cat. No. 5153).

[0245] Experimental method: Human prostate cancer cells LNCaP were injected at 4×10 5 Cells were seeded at a density of 2 mL / mL in 6-well plates and incubated overnight in a cell incubator. DMSO and dihydrotestosterone (DHT, 1 nM) were used as control groups. The experiment was conducted in the presence of DHT (1 nM). After culturing cells with the test compounds for a specified time, they were collected and dissolved using known Western blotting techniques in the biochemical field. The experiment included DMSO, DHT (1 nM), and test compound groups (containing 1 nM DHT). DMSO and DHT (1 nM DHT) were added to the corresponding 6-well plates for the DMSO and DHT groups, respectively. DHT (1 nM) and test compounds (0.6 μM, 1.2 μM, 2.5 μM, 5 μM, 10 μM) were added to the corresponding 6-well plates for the test compound groups. After incubation for 48 h in the control and test compound groups, cells were collected and lysed. Protein concentration was quantified using a BCA kit, and samples were stored for later use.

[0246] The content of AR protein in each group was determined by Western blotting, with a sample loading of 30 μg for each group. The Western blotting method is already disclosed in the prior art. Specifically, cells were collected in 2x sodium dodecyl sulfate / polyacrylamide gel electrophoresis loading buffer or in radioimmunoprecipitation assay (RIPA) buffer enhanced with 10 μg / mL benzalkonium chloride, 10 μg / mL trypsin inhibitor, and 1 mM benzyl sulfonyl fluoride. A sample of total protein (approximately 40 μg) from each cell lysate was separated by electrophoresis on an SDS / PAGE gel. After electrophoretic separation, the protein was transferred from the gel to a nitrocellulose membrane following standard procedures. The membrane was then incubated for 1 hour in phosphate-buffered saline supplemented with 0.1% Tween 20 (PBST) with 10% nonfat milk, followed by overnight incubation at 4°C with a primary human AR-specific antibody (purchased from BD-Harlingen). After incubation, the membrane was washed three times with PBST buffer for 10 minutes each time; then, alkaline phosphatase conjugate secondary antibody was added, and the membrane was incubated at room temperature for 1 hour. After the second incubation, the membrane was washed again with PBST, and the AR protein signal in the membrane was visualized by adding alkaline phosphatase medium, bromochloroindolyl phosphate, and nitrotetrazole. To ensure an equal amount of protein in each sample, a portion of the membrane was kept with a specific antibody for managing the protein GAPDH (SantaCruz Biotechnology), and the GAPDH signal was visualized using the aforementioned secondary antibody. Protein signal intensity (as shown by the color bands on the membrane) was measured using a hydrometer and analyzed using NIH Imaging J software (NIH 1.33). The AR protein signal (relative to GAPDH) in each sample was normalized and expressed as the ratio of AR gray value to GAPDH gray value, as detailed in the appendix. Figure 1 .

[0247] The above experiments tested the ability of some compounds of the present invention to reduce AR expression in human prostate cancer cells LNCaP (i.e., anti-AR activity), and compared the anti-AR activity of each compound with the DHT group and DMSO group control at multiple concentrations. The relative efficacy of the anti-AR activity of the compounds of the present invention is expressed as the percentage reduction in AR after incubation at 2.5 μM, 5 μM, and 10 μM concentrations for 48 hours (containing 1 nM DHT). The evaluation indicators are shown in Table 2 below:

[0248] Table 2 Relative Efficacy Evaluation Table

[0249] + 12.5＜*≤25 ++ 25＜*≤37.5 +++ 37.5＜*≤50 ++++ 50＜*≤62.5 +++++ 62.5＜*≤75 ++++++ 75＜*≤100

[0250] The formula for calculating the percentage reduction in AR is: Percentage reduction in AR (%) = (AR / GAPDH value of DHT group - AR / GAPDH value of test compound group) / AR / GAPDH value of DHT group × 100%.

[0251] The ability of the compounds of the present invention to reduce AR expression (i.e., anti-AR activity) in human prostate cancer cell line LNCaP is shown in Table 3. The values in Table 3 refer to the percentage reduction of AR (%), the concentration in Table 3 refers to the concentration of the test compound, and the more the number of "+" in the relative potency column in Table 3, the better the anti-AR activity of the compound.

[0252] Table 3 Ability of the compounds of the present invention to reduce AR expression in human prostate cancer cell line LNCaP

[0253]

[0254] "-" indicates not performed. Since the hydrochlorides of compounds 12, 16 and 19 have shown excellent relative potency at a concentration of 2.5 μmol / L, the relevant tests were not performed at higher concentrations.

[0255] Conclusion: DHT can up-regulate the expression of AR protein in human prostate cancer cell line LNCaP, and the compounds of the present invention can dose-dependently inhibit the expression of AR protein in human prostate cancer cell line LNCaP, that is, the compounds of the present invention have anti-AR activity. Considering the relative potency comprehensively, the compounds of the present invention, especially compound 7, compound 8, the hydrochloride of compound 12, the hydrochloride of compound 16 and the hydrochloride of compound 19, have significant anti-AR activity.

[0256] [[ID=1现17]]Test Example 3 Study on Pharmacokinetic Properties

[0257] This test example aims to study the single oral administration of the solutions of the compounds of the present invention to SD rats, detect the concentration of the active ingredient in plasma, and evaluate the pharmacokinetic (PK) characteristics of the compounds in SD rats.

[0258] Experimental materials: Male SD rats (weighing 180 - 220 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016 - 0006), experimental compounds (prepared according to the methods of the examples of the present invention), purified water (self-made).

[0259] Experimental method: Male SD rats were randomly divided into groups (3 rats in each group). They were allowed to drink water freely during the experiment, fasted for more than 12 hours before dosing, and fed 4 hours after dosing. Oral gavage was used for administration. Each group of SD rats was given a 0.5% suspension aqueous solution of the experimental compound (prescription includes: 0.5% test compound, 1% CMCNa, 0.5% Tween 80, 98% purified water) at a dose of 50 mg / kg (calculated based on the amount of the experimental compound).

[0260] Blood samples were collected into K2EDTA anticoagulant tubes at 0 min before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 h after administration, and stored on ice until centrifugation.

[0261] Blood plasma should be centrifuged within 60 minutes after collection (8000 rpm for 5 minutes at 2-8℃). After centrifugation, the plasma should be transferred to a 96-well plate or centrifuge tube, transported on ice, and stored at ≤-15℃ for LC-MS / MS analysis. The drug concentration in SD rat plasma was detected using LC-MS / MS bioanalytical methods. A non-compartmental model was used, and WinNonlin™ (Version 8.3, Certara, USA) was used to analyze the blood drug concentration-time data to evaluate its pharmacokinetic (PK) characteristics in SD rats. Data are shown in Table 4, and pharmacokinetic curves are shown in [Table 4]. Figure 2 .

[0262] Table 4. Pharmacokinetic parameters of the compound of the present invention in the plasma of male rats after oral administration.

[0263]

[0264] Figure 2 The drug-time curves showed that compound 10 had a C10 value in rats. max Lowest, AUC last Minimum; C of compounds 7 and 8 max Similar, but the AUC of compound 8 last It is higher than compound 7. These results indicate that, when administered orally to SD rats at the same dose, compound 10 may have the worst efficacy due to the lowest exposure in rats, followed by compound 7, and compound 8 due to its higher C content. max and AUC last All of these levels increased significantly, and the drug's efficacy may be at its best.

[0265] The above results demonstrate that the compounds of the present invention possess significantly improved pharmacokinetic properties. Specifically, after administration of the compounds of the present invention, the AUC and C0.05... max All showed extremely significant improvements. Therefore, the compounds of this invention have good drug-like properties and can achieve better efficacy at lower dosages.

[0266] Test Example 4: Hair growth promotion test of the compound of the present invention in alopecia mice.

[0267] Experimental objective: To test the hair growth-promoting effect of the compounds of this invention on a mouse model of hair loss.

[0268] Test materials: C57BL / 6 mice (purchased from Spf (Beijing) Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2019-0010), test compounds (obtained by the method of the present invention), rosin (Shanghai Yuanye Bio-Technology Co., Ltd., batch number: Y18M10C83144), liquid paraffin (Shanghai Yuanye Bio-Technology Co., Ltd., batch number: Z22S11Y125555), chloral hydrate (Sinopharm Chemical Reagent Co., Ltd., batch number: 20190823, prepared into a 2% chloral hydrate solution with 0.9% sodium chloride solution when in use), testosterone propionate (Shanghai Aladdin Reagent Co., Ltd., batch number: T101368, prepared into a 0.5% testosterone propionate solution with soybean oil for injection when in use), soybean oil for injection (Tieling Beiya Medicinal Oil Co., Ltd., batch number:国药准字H21024303), paraformaldehyde (Xilong Scientific Co., Ltd., batch number: 1705022), 0.9% sodium chloride solution (Jiangsu Shuanghe Pharmaceutical Co., Ltd., batch number: 210322-3C), electronic balance (Sartorius Instrument Systems Co., Ltd., Beijing, model: BS224 S; GZX-9140MBE), digital display electrothermal constant temperature forced air drying oven (Shanghai Boxun Industry Co., Ltd.).

[0269] Test method: Select 8-week-old male C57BL / 6 mice, anesthetize them by intraperitoneal injection of 2% chloral hydrate (400 mg / kg), weigh equal amounts of rosin and paraffin, heat and mix them evenly, apply them to the back of the mice, in an area of about 2 cm × 2.5 cm. After the mixture cools and hardens, gently tear off the solidified hair with tweezers. Exclude animals with dark skin color found after hair tearing from this study, where the dark skin color indicates that these animals are in the hair growth phase of active hair follicle growth.

[0270] Qualified C57BL / 6 mice (n=3 per group) were randomly assigned to the blank control group, the model group, the positive control drug group (7.5% clacoate ketone group), and the experimental group (including 0.3% compound 8 group and 0.3% compound 7 group). The control group mice received 0.1 mL of physiological saline solution applied to the hair-removed area every morning for 17 consecutive days. The model group received 0.1 mL of 0.5% testosterone propionate solution applied to the hair-removed area every morning for 17 consecutive days, and 0.5 mL of control solution applied to the hair-removed area every afternoon for 16 consecutive days. The positive control group received 0.1 mL of 0.5% testosterone propionate solution applied to the hair-removed area every morning for 17 consecutive days, and 0.5 mL of 7.5% clacotone solution applied to the hair-removed area every afternoon for 16 consecutive days. The experimental group received 0.1 mL of 0.5% testosterone propionate solution applied to the hair-removed area every morning for 17 consecutive days, and 0.5 mL of control solution applied to the hair-removed area every afternoon. A 0.3% test compound solution was administered once daily for 16 consecutive days starting from day 2. The test compound solution consisted of 0.3% test compound, 40% DMSO, 30% ethanol, and the remainder water; the control solution consisted of 40% DMSO, 30% ethanol, and the remainder water; the positive control group consisted of 7.5% clacotone, 40% DMSO, 30% ethanol, and the remainder water. Hair regrowth was observed in the bald areas of mice in each group, and photographs were taken 16 days after the start of topical administration of the test compound solution.

[0271] On day 18 of the experiment, five newly grown hairs were plucked from the bald area on the back of each mouse in each group, and the hair length was measured using calipers. The hair length of each group was counted. Skin samples from the bald area of ​​each mouse were excised and stained with hematoxylin and eosin (HE staining). The morphology of hair follicles was observed under a microscope. Six fields of view (×100) were randomly selected for observation of each sample, and the average number of hair follicles per field of view was calculated. The software used for data analysis was Graph Pad 8.0. All data are expressed as mean ± standard deviation (X±SD), as shown in Table 5 below. Photographs of hair growth and representative HE-stained sections of skin tissue from representative mice in each group on day 18 are shown in Table 5. Figure 3 .

[0272] Table 5. Hair length and number of hair follicles in different groups (expressed as X±SD)

[0273] Blank group 0 6.035±0.038 110.00±41.867 Model group 0 0.948±0.090 18.20±2.615 Positive control group 37.5mg clacotone 5.649±0.059 53.533±24.929 Group 7 of compounds 1.5mg compound 7 3.850±0.009 95.600±26.091 Group 8 of compounds 1.5mg compound 8 4.493±0.024 116.733±35.809

[0274] Figure 3The results showed that, compared with the blank group, the model group mice had poor hair growth and significantly fewer hair follicles, indicating that applying 0.5% testosterone propionate solution could induce a hair loss mouse model. Compared with the model group, the positive control group mice showed significant hair growth and a significant increase in the number of hair follicles, indicating that the hair loss mouse model was reliable. Compounds 7 and 8 of the present invention, at a daily dose of 1.5 mg, showed better hair and hair follicle growth than the positive control group, indicating that low doses of the compounds of the present invention have better efficacy in treating hair loss than high doses of the positive control.

[0275] The experimental data above show that the compound of the present invention can significantly increase the hair length and number of hair follicles in the experimental group mice at a small dose, and can promote the generation of hair follicles and hair growth in alopecia mice, thus having a good hair growth promoting effect.

[0276] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Compounds represented by Formula I or their pharmaceutically acceptable salts, in, R1, R2, R3, and R4 may be the same or different, and are independently selected from C. 1-6 Alkyl or deuterated C 1-6 alkyl; The following cyclic systems are substituted with one or two Rb: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[2,3]hexyl; or, 1,3-dioxane-hexyl substituted with one =O, or unsubstituted 1,4-dioxane-spiro[4,5]decyl; Rb is selected from F, =O, hydroxyl, amino, -S(O)2CH3, -COOC(CH3)3. -N(C2H5)2, -N(CH3)2 or 2. The compounds of claim 1 or their pharmaceutically acceptable salts, wherein, R1, R2, R3, and R4 may be the same or different, and are independently selected from C. 1-3 Alkyl or deuterated C 1-3 alkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, The compounds shown in Formula I are selected from the following:

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, The compounds shown in Formula I are selected from the following:

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein, The pharmaceutically acceptable salt of the compound represented by Formula I is its hydrochloride salt.

6. A pharmaceutical composition comprising at least one of the compounds of Formula I as described in any one of claims 1-4 or pharmaceutically acceptable salts thereof.

7. The pharmaceutical composition according to claim 6, wherein, The pharmaceutical composition also includes one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 6 or 7, wherein, Suitable routes of administration for the pharmaceutical composition include: oral, rectal, local, oral, parenteral, intramuscular, intradermal, intravenous, and transdermal administration.

9. The pharmaceutical composition according to claim 6 or 7, wherein, The pharmaceutical composition is for topical administration and is an ointment, cream, paste, tincture, plaster, gel, film, coating, aerosol, spray, foam, or microsponge.

10. Use of the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 6-9, in the preparation of a medicament for treating, preventing, or improving symptoms or diseases of androgen-related disorders.

11. The use according to claim 10, wherein, The symptoms or diseases of androgen-related disorders mentioned above are selected from: androgen-related inflammation; polyglutamine-mediated motor neuron degeneration, Kennedy's disease; androgen-related cancers; hair loss; acne and hirsutism.

12. The use according to claim 11, wherein, The symptoms or diseases of androgen-related disorders mentioned above are selected from: trauma, acne, atopic dermatitis, rheumatoid arthritis, psoriasis, rosacea, spinal and bulbar muscular atrophy, prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, pancreatic cancer, and androgenic alopecia.

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